Intrahepatic, Perihilar and Distal Cholangiocarcinoma: Management and Outcomes

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"documento" => "article" "crossmark" => 0 "licencia" => "http://creativecommons.org/licenses/by-nc-nd/4.0/" "subdocumento" => "fla" "cita" => "Ann Hepatol. 2017;16:140-8" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:2 [ "total" => 112 "formatos" => array:3 [ "EPUB" => 6 "HTML" => 69 "PDF" => 37 ] ] "en" => array:11 [ "idiomaDefecto" => true "titulo" => "Observational Cohort Study of Hepatic Encephalopathy After Transjugular Intrahepatic Portosystemic Shunt (TIPS)" "tienePdf" => "en" "tieneTextoCompleto" => "en" "tieneResumen" => "en" "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "140" "paginaFinal" => "148" ] ] "contieneResumen" => array:1 [ "en" => true ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "f0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 919 "Ancho" => 2074 "Tamanyo" => 133056 ] ] "descripcion" => array:1 [ "en" => "Etiology of portal hypertension." ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Michaela Routhu, Vaclav Safka, Sunil Kumar Routhu, Tomas Fejfar, Vaclav Jirkovsky, Antonin Krajina, Eva Cermakova, Petr Hulek, Ladislav Hosak" "autores" => array:9 [ 0 => array:2 [ "nombre" => "Michaela" "apellidos" => "Routhu" ] 1 => array:2 [ "nombre" => "Vaclav" "apellidos" => "Safka" ] 2 => array:2 [ "nombre" => "Sunil Kumar" "apellidos" => "Routhu" ] 3 => array:2 [ "nombre" => "Tomas" "apellidos" => "Fejfar" ] 4 => array:2 [ "nombre" => "Vaclav" "apellidos" => "Jirkovsky" ] 5 => array:2 [ "nombre" => "Antonin" "apellidos" => "Krajina" ] 6 => array:2 [ "nombre" => "Eva" "apellidos" => "Cermakova" ] 7 => array:2 [ "nombre" => "Petr" "apellidos" => "Hulek" ] 8 => array:2 [ "nombre" => "Ladislav" "apellidos" => "Hosak" ] ] ] ] ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S1665268119303710?idApp=UINPBA00004N" "url" => "/16652681/0000001600000001/v1_201905311015/S1665268119303710/v1_201905311015/en/main.assets" ] "itemAnterior" => array:19 [ "pii" => "S1665268119303692" "issn" => "16652681" "doi" => "10.5604/16652681.1226823" "estado" => "S300" "fechaPublicacion" => "2017-01-01" "aid" => "70191" "copyright" => "Fundación Clínica Médica Sur, A.C." "documento" => "article" "crossmark" => 0 "licencia" => "http://creativecommons.org/licenses/by-nc-nd/4.0/" "subdocumento" => "fla" "cita" => "Ann Hepatol. 2017;16:123-32" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:2 [ "total" => 105 "formatos" => array:3 [ "EPUB" => 11 "HTML" => 50 "PDF" => 44 ] ] "en" => array:11 [ "idiomaDefecto" => true "titulo" => "Utility and Safety of Tolvaptan in Cirrhotic Patients with Hyponatremia: a Prospective Cohort Study" "tienePdf" => "en" "tieneTextoCompleto" => "en" "tieneResumen" => "en" "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "123" "paginaFinal" => "132" ] ] "contieneResumen" => array:1 [ "en" => true ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "f0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 2222 "Ancho" => 2074 "Tamanyo" => 261319 ] ] "descripcion" => array:1 [ "en" => "Kaplan-Meier curve of 30-day survival in (A) the tolvaptan and control groups (p = 0.36), (B) patients with and without normalization of serum sodium level (135-145 mmol/L) on day 7 (p = 0.0019), and (C) patients with and without improvement of serum sodium level on day 7 (p = 0.013). Footnote: Improved serum sodium was defined as an increase of serum sodium from < 125 mmol/L to ≥ 125 mmol/L in patients with baseline serum sodium < 125 mmol/L, or from < 135 mmol/L to ≥ 135 mmol/L in patients with baseline serum sodium 125-134 mmol/L." ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Ji-Dong Jia, Wen Xie, Hui-Guo Ding, Hua Mao, Hui Guo, Yonggang Li, Xiaojin Wang, Jie-Fei Wang, Wei Lu, Cheng-Zhong Li, Yimin Mao, Gui-Qiang Wang, Yue-qiu Gao, Bangmao Wang, Qin Zhang, Yan Ge, Vincent Wai-Sun Wong" "autores" => array:17 [ 0 => array:2 [ "nombre" => "Ji-Dong" "apellidos" => "Jia" ] 1 => array:2 [ "nombre" => "Wen" "apellidos" => "Xie" ] 2 => array:2 [ "nombre" => "Hui-Guo" "apellidos" => "Ding" ] 3 => array:2 [ "nombre" => "Hua" "apellidos" => "Mao" ] 4 => array:2 [ "nombre" => "Hui" "apellidos" => "Guo" ] 5 => array:2 [ "nombre" => "Yonggang" "apellidos" => "Li" ] 6 => array:2 [ "nombre" => "Xiaojin" "apellidos" => "Wang" ] 7 => array:2 [ "nombre" => "Jie-Fei" "apellidos" => "Wang" ] 8 => array:2 [ "nombre" => "Wei" "apellidos" => "Lu" ] 9 => array:2 [ "nombre" => "Cheng-Zhong" "apellidos" => "Li" ] 10 => array:2 [ "nombre" => "Yimin" "apellidos" => "Mao" ] 11 => array:2 [ "nombre" => "Gui-Qiang" "apellidos" => "Wang" ] 12 => array:2 [ "nombre" => "Yue-qiu" "apellidos" => "Gao" ] 13 => array:2 [ "nombre" => "Bangmao" "apellidos" => "Wang" ] 14 => array:2 [ "nombre" => "Qin" "apellidos" => "Zhang" ] 15 => array:2 [ "nombre" => "Yan" "apellidos" => "Ge" ] 16 => array:2 [ "nombre" => "Vincent" "apellidos" => "Wai-Sun Wong" ] ] ] ] ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S1665268119303692?idApp=UINPBA00004N" "url" => "/16652681/0000001600000001/v1_201905311015/S1665268119303692/v1_201905311015/en/main.assets" ] "en" => array:17 [ "idiomaDefecto" => true "titulo" => "Intrahepatic, Perihilar and Distal Cholangiocarcinoma: Management and Outcomes" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "133" "paginaFinal" => "139" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "David Waseem, Patel Tushar" "autores" => array:2 [ 0 => array:2 [ "nombre" => "David" "apellidos" => "Waseem" ] 1 => array:4 [ "nombre" => "Patel" "apellidos" => "Tushar" "email" => array:1 [ 0 => "patel.tushar@mayo.edu" ] "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "*" "identificador" => "cor1" ] ] ] ] "afiliaciones" => array:1 [ 0 => array:3 [ "entidad" => "Department of Transplantation, Mayo Clinic Florida, USA" "etiqueta" => "*" "identificador" => "aff1" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor1" "etiqueta" => "*" "correspondencia" => "Correspondence and reprint request:" ] ] ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "f0015" "etiqueta" => "Figure 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 774 "Ancho" => 2074 "Tamanyo" => 123552 ] ] "descripcion" => array:1 [ "en" => "Management and outcomes. The median survival in months of patients undergoing either single modality (surgery, chemotherapy or radiation), or multimodality treatment (two or more modalities). Median survival for patients who did not undergo any treatment is shown outside the Venn diagram." ] ] ] "textoCompleto" => "Introduction and AimCholangiocarcinomas (CCAs) are a heterogeneous group of tumors that arise from the biliary tract epithelia, and account for ~3% of all gastrointestinal tumors.<a class="elsevierStyleCrossRef" href="#bib0005">1</a> The epidemiology of these cancers has been poorly understood. The management of these uncommon cancers has been challenging, in part because of the lack of effective treatments. The absence of a consistent nomenclature and the propensity to consider different tumor types together in many published reports have contributed to a lack of clarity regarding the natural history, epidemiology and optimal approaches to the management of these cancers.Recent studies have focused on the recognition of three types of cholangiocarcinoma that can be described on the basis of their anatomic location, clinical presentation, and molecular features; intrahepatic CCA (iCCA), perihilar CCA (pCCA), or distal CCA (dCCA).<a class="elsevierStyleCrossRef" href="#bib0010">2</a> These three types of CCA are distinct in their presentation and natural history, as well as the approach to diagnosis and management. However, the characteristics of the different types of tumors are not accurately reflected in the literature. For example, studies suggest that iCCA comprise of only 5-10% of all CCA, but these are not borne out by observations in clinical practice.<a class="elsevierStyleCrossRefs" href="#bib0015">3,4</a> Data from epidemiological studies such as from the National Cancer Institute’s Surveillance, Epidemiology and End Results (SEER) database have increased recognition of the incidence of these cancers.<a class="elsevierStyleCrossRef" href="#bib0025">5</a> However, these data have been compromised by inconsistencies in coding as intrahepatic and extrahepatic cholangiocarcinoma.<a class="elsevierStyleCrossRefs" href="#bib0030">6-8</a> In particular, pCCA have been variably and inconsistently coded as either intrahepatic or ex-trahepatic. An emerging appreciation of the differences between these different types of tumors is reflected in the recent TNM 7 staging system from the AJCC now includes separate staging systems for all three types of cholangiocarcinoma. Most therapeutic trials of patients with these cancers have grouped together all types of biliary tract cancers, and several have also included gallbladder cancer. Tumors classified as intrahepatic or extra-hepatic differ in response to combination therapy with gemcitabine-cisplatin in the ABC-01 and ABC-02 stud-ies,<a class="elsevierStyleCrossRefs" href="#bib0045">9,10</a> although the responsiveness of perihilar cancers has not been specifically established. Given the implications of inaccurate classification in determining optimal therapeutic strategies, we sought to systematically define the different types within a cohort of cholangiocarcinomas, and to analyze their management and outcomes.Material and MethodsIdentification of patientsPatients seen at the Mayo Clinic in Florida from 1992 to 2010 and enrolled in the Mayo Clinic Cancer registry with a relevant diagnosis were identified. We included all patients with ICD-O-3 codes of C22.1, C 24.0, 24.8, 24.9, and 23.9. All patients enrolled in the Registry were followed on an annual basis. The following definitions were used. For intrahepatic cholangiocarcinoma, a topography code of c22.1 (intrahepatic bile duct) and histology codes 8140, 8160, 8161, 8020 and 8010 were used. For extrahepat-ic cholangiocarcinoma, a topography code of C24.0 was used along with histology codes 8010, 8020, 8041, 8070, 8140, 8144, 8160, 8161, 8260, 8310, 8480, 8490 and 8560. Patients with gall-bladder cancer were identified using a topography code of c23.9 but were not analyzed further as these have generally been characterized separately from the other types of cholangiocarcinoma. The study was reviewed by the Institutional IRB and noted to be exempt from IRB review.Classification and stagingChart review was performed and all patients were classified into intrahepatic, perihilar or distal cholangiocarci-noma based on conventional classifications.<a class="elsevierStyleCrossRefs" href="#bib0010">2,11,12</a> Re-classification was verified by an independent observer to ensure validity and accuracy. Staging was performed based on the TNM 7 staging system on either clinical or pathological criteria and where all necessary information to assign a stage was available.<a class="elsevierStyleCrossRefs" href="#bib0065">13-15</a> The vital status at the most recent follow-up was verified.Data collectionPatient demographics, pathology, and the nature of any treatments received were documented. Treatments were categorized as surgery (which included surgical resection or transplantation), systemic chemotherapy, or radiation therapy (which also included intrabiliary brachytherapy). Locoregional therapies were not considered as a separate category because these were inconsistently used during the study period. Data on patient survival and disease recurrence were obtained annually by cancer registry staff from the time of enrollment to the time of last follow-up. Patients were grouped into three multi-year eras in order to examine temporal trends in management and their outcomes. Survival curves for each of the three types of cholangiocarcinoma were generated and temporal trends and outcomes of single or multimodality treatment were determined.Statistical analysisFor analysis of trends for categorical data, the Mantel-Haenszel χ<a class="elsevierStyleCrossRef" href="#bib0010">2</a> test was used. For continuous data, one-way analysis of variance was used to test the null hypothesis that multiple population mean values are all equal. Kaplan Meier plots were used to assess patients’ survival. To test median values across multiple groups, p values were computed using the nonparametric t test. All statistical analyses were performed using SAS 6.12, SAS Institute, Cary, North Carolina.ResultsA total of 242 patients with a diagnosis of cholangiocar-cinoma encountered at a single institution between 1992 and 2010 were identified using a cancer registry. 123 patients had been classified as intrahepatic, 110 as extrahepat-ic, and 9 as non-specified bile duct cancer. Follow-up was available for all patients for a median of 11.6 months (range 3.1-24.3 months). All cases were re-classified into iCCA, pCCA or dCCA by two independent observers with 100% concordance. Overall, there were 90 iCCA, 104 pCCA and 48 dCCA. The mean age at diagnosis was 63 years (range 22 - 91) with only 18 patients (7.4%) less than forty years of age at the time of diagnosis. Some demographic differences were noted. Compared to either pCCA or iCCA, dCCA presented at an older median age. There were gender differences noted with 49% of iCCA, 67% of pCCA and 71% of dCCA being male.Amongst those patients originally classified as intrahe-patic, 37 patients (30%) were reclassified as pCCA, and 3 patients (2.4%) as dCCA (<a class="elsevierStyleCrossRef" href="#t0005">Table 1</a>). Similarly, differences were also noted between the registry coded diagnoses of extrahepatic cholangiocarcinoma, six of which were re-classified as iCCA (5.4%). The remainder of the patients coded as extrahepatic were reclassified into pCCA (63 patients) or dCCA (41 patients). Moreover, nine patients who were coded as biliary cancer with no specified location could be reclassified into four pCCA, four dCCA and one iCCA. These data indicate the high potential for mis-classification of these cancers even in carefully annotated datasets from trained cancer registrars. They highlight and emphasize a major limitation in epidemiological studies that are based on inconsistent classifications.<elsevierMultimedia ident="t0005"></elsevierMultimedia>The clinical and pathological TNM staging at presentation for each of the three types of CCA is shown in <a class="elsevierStyleCrossRef" href="#f0005">Figure 1</a>. Tumor staging could not be described for all patients because of inadequate data. Overall, 13.8% of patients presented with stage I, 5.8% with stage II, 9.6% with stage III, 28% with stage IV, and 41.8% were unknown. The overall median survival (MS) of all patients was 15.8 months. As expected, patients with early stage disease had a higher median survival compared to those presenting at later stages with median survivals of 23, 25, 14, and 4.5 months for stages I, II, III, and IV respectively. More patients with iCCA presented with advanced disease at stage IV (51%) as compared to either pCCA (12%), or dCCA (18%). In contrast, patients with pCCA presented more frequently with stage I disease. The median survival for unstaged pCCA, iCCa and dCCA was 17, 21.5 and 28 months respectively, as shown in <a class="elsevierStyleCrossRef" href="#t0010">table 2</a>.<elsevierMultimedia ident="f0005"></elsevierMultimedia><elsevierMultimedia ident="t0010"></elsevierMultimedia>The median survival for iCCA (13.5 months) was similar to that for pCCA (13.9 months), but was lower than dCCA (22 months). However, overall survival was not significantly different between the three types (<a class="elsevierStyleCrossRef" href="#f0010">Figure 2</a>). Median survival was significantly higher for patients with pCCA or dCCA who received treatment compared to those who did not receive any treatment. However, this was not observed for patients with iCCA and could reflect more advanced stage at time of presentation. 156 patients [62 iCCA, 63 pCCA, and 31 dCCA] underwent surgery, chemotherapy, radiotherapy, or a combination of these. Surgery with or without chemoradiation provided an overall survival benefit (25 vs. 7.5 months, p < 0.0001). The median survival of patients with each of the three types of CCA who underwent different treatment modalities is illustrated in <a class="elsevierStyleCrossRef" href="#f0015">Figure 3</a>.<elsevierMultimedia ident="f0010"></elsevierMultimedia><elsevierMultimedia ident="f0015"></elsevierMultimedia>To examine the temporal trends in management, patients were grouped into one of three eras based on their date of diagnosis, namely pre 2001, 2001-2005, and 2005-2010. In the most recent era (2005-2010), median survival ranged from 20-54 months for patients who had surgery compared to 3-7 months for those who did not have surgery, Similar results were observed for other eras examined. These findings could potentially arise from more advanced disease in non-surgical patients.For patients with iCCA, the presence of underlying diabetes mellitus, liver cirrhosis, primary sclerosing cholan-gitis or a history of smoking, alcohol use, or inflammatory bowel disease did not significantly alter median survival. Surgical resection was performed in 39% of the patients either as a single modality intervention (22%) or combined with chemotherapy (10%), radiation therapy (1.1%), or chemo-radiation therapy (5.5%). Twenty one percent of patients with iCCA received only chemotherapy, 2.2% received only radiation therapy, and 6.6% received chemo-radiation in combination. The highest median survival with any single modality was noted with surgery, whereas multimodality therapy of surgery combined with chemotherapy achieved the highest median survival.For patients with pCCA, 62% underwent surgical resection either as a single intervention (15.3%) or combined with chemotherapy (1.9%), radiation therapy (1%), and chemo-radiation therapy (20.1%). 3.8% received only chemotherapy, 1.9% received only radiation therapy, and 16.3% received combination chemo-radiation therapy. The median survival of patients who underwent any multimodali-ty treatment was significantly higher than with any single treatment modality. As with iCCA, the highest median survival was observed for patients who underwent a combination of surgery and chemoradiation when compared to other single or multimodality treatments. A multi-modality approach of chemoradiation followed by liver transplantation has been used to treat patients in this group, and the improved survival of this intervention has been reported.<a class="elsevierStyleCrossRefs" href="#bib0080">16-18</a>For patients with dCCA, 87% underwent surgical resection either as single modality (52%) or combined with chemotherapy (3%) or chemo-radiation therapy (32%). 7% received only chemotherapy, 3% received only radiation therapy, and 3% received combined chemo-radiation therapy. Patients who underwent multimodality treatment had higher median survival compared with those who underwent surgery alone or with any other single modality treatment (P = 0.0009). Likewise, surgery and chemoradi-ation therapy resulted in a higher median survival compared to other single modality treatments, although not statistically significant, likely due to the small number of patients in the dCCA cohort.DiscussionA recognition of the distinctive nature of different types of cholangiocarcinoma is now emerging. In this study, patients with cholangiocarcinoma were reviewed, reclassified and systematically analyzed to derive a detailed and accurate description of the frequency, management and outcomes of the three different types of cholangiocarcinoma. This study thus provides a relevant snapshot of contemporary management and outcomes of patients with these cancers by eliminating the confounding effects of inconsistencies that arise from inaccurate coding.The optimal choice of individual or multimodality therapeutic strategies for cholangiocarcinoma remains obscure, and the management of these cancers continues to evolve. Median survival was increased for all patients who underwent surgery, regardless of resection margin. Since CCA usually presents in late stages, R1 resections are frequent even when surgery is performed with curative in-tent.<a class="elsevierStyleCrossRef" href="#bib0095">19</a> Adjuvant therapy is not routinely used, although chemotherapy and/or radiotherapy can improve survival following R1 resections compared to those patients who do not undergo surgery.<a class="elsevierStyleCrossRefs" href="#bib0100">20-23</a> Irrespective of the type of cholangiocarcinoma, surgical resection along with chemo-radiation therapy may have the greatest impact on survival for patients with resectable disease.<a class="elsevierStyleCrossRef" href="#bib0110">22</a>Many patients are not eligible for curative surgical resection due to advanced disease at diagnosis. The median survival for patients who did not undergo any surgery ranged from 5-12 months for all three types of cholangi-ocarcinoma. For unresectable lesions, a multimodality treatment approach could be considered.<a class="elsevierStyleCrossRef" href="#bib0120">24</a> Higher survival rates were observed with the use of multimodality treatment compared to the use of single modality treatment with surgery, chemotherapy, or radiation therapy at all disease stages.<a class="elsevierStyleCrossRefs" href="#bib0125">25,26</a> This was particularly true for pCCA, where multi-modality strategies have been most extensively used. These cancers present at an earlier stage but have a poor survival, justifying an aggressive approach. In contrast to pCCA, median survival was greater for iCCA where surgery alone or with chemotherapy was performed. A potential reason is that smaller lesions that are amenable to complete resection may have a greater chance of curative resection, or have a lower risk for invasion or recurrence. These cancers often present at a later stage and effective strategies for earlier detection are needed.Compared to other types of cholangiocarcinoma, patients with dCCA had the highest median survival, although the number of patients in this group was small. For this group, surgical approaches offer the best outcomes when combined with chemotherapy or radiation. Our observations regarding improved prognosis of dCCA are consistent with reports in extrahepatic CCA. The median survival reported by DeOliveira, et al.<a class="elsevierStyleCrossRef" href="#bib0060">12</a> for iCCA were greater (28 vs. 13.5 months), whereas the median survival for dCCA were lower (18 vs. 22 months) than those in our cohort. We speculate that these differences could reflect regional variations in management or in risk factors for these cancers.There are limitations to this study, as with any other retrospective analyses. In particular, data regarding variables that can influence choice of therapy or outcomes including performance status and underlying organ function were not available and thus could not be incorporated in the analysis. Other factors such as patient desire, access to therapies and physician and institutional expertise in managing these conditions are mitigated in part by restricting this analysis to a single institution that offers all conventional therapeutic options for the management of these cancers, including liver transplantation for pCCA. These studies thereby provide a more accurate practice-based and temporal representation of trends in the management and outcomes of each of the three different types of cholangi-ocarcinoma.Abbreviations<ul class="elsevierStyleList" id="l0010"><li class="elsevierStyleListItem" id="u0005">•CI: confidence intervals.</li><li class="elsevierStyleListItem" id="u0010">•dCCA: distal cholangiocarcinoma.</li><li class="elsevierStyleListItem" id="u0015">•HBV: hepatitis B virus.</li><li class="elsevierStyleListItem" id="u0020">•HCC: hepatocellular carcinoma.</li><li class="elsevierStyleListItem" id="u0025">•HCV: hepatitis C virus.</li><li class="elsevierStyleListItem" id="u0030">•iCCA: intrahepatic cholangiocarcinoma.</li><li class="elsevierStyleListItem" id="u0035">•ICD: international classification of disease.</li><li class="elsevierStyleListItem" id="u0040">•OR: odds ratio.</li><li class="elsevierStyleListItem" id="u0045">•pCCA: perihilar cholnagiocarcinoma.</li></ul>Conflict of InterestThere are no conflicts of interest to disclose.AcknowledgementsWe acknowledge, with gratitude, the assistance provided by Nicholas Figura and Abigail Trotter in data collection.Financial SupportSupported in part by NIH grant DK 069370 (TP)." "textoCompletoSecciones" => array:1 [ "secciones" => array:11 [ 0 => array:3 [ "identificador" => "xres1198039" "titulo" => "Abstract" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abs0010" "titulo" => "Introduction and aims" ] 1 => array:2 [ "identificador" => "abs0015" "titulo" => "Materials and methods" ] 2 => array:2 [ "identificador" => "abs0020" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abs0025" "titulo" => "Conclusion" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1116683" "titulo" => "Key words" ] 2 => array:2 [ "identificador" => "s0005" "titulo" => "Introduction and Aim" ] 3 => array:3 [ "identificador" => "s0010" "titulo" => "Material and Methods" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "s0015" "titulo" => "Identification of patients" ] 1 => array:2 [ "identificador" => "s0020" "titulo" => "Classification and staging" ] 2 => array:2 [ "identificador" => "s0025" "titulo" => "Data collection" ] 3 => array:2 [ "identificador" => "s0030" "titulo" => "Statistical analysis" ] ] ] 4 => array:2 [ "identificador" => "s0035" "titulo" => "Results" ] 5 => array:2 [ "identificador" => "s0040" "titulo" => "Discussion" ] 6 => array:2 [ "identificador" => "s0045" "titulo" => "Abbreviations" ] 7 => array:2 [ "identificador" => "s0050" "titulo" => "Conflict of Interest" ] 8 => array:2 [ "identificador" => "s0055" "titulo" => "Acknowledgements" ] 9 => array:2 [ "identificador" => "s0060" "titulo" => "Financial Support" ] 10 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2016-04-06" "fechaAceptado" => "2016-05-08" "PalabrasClave" => array:1 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Key words" "identificador" => "xpalclavsec1116683" "palabras" => array:4 [ 0 => "Biliary cancers" 1 => "Natural history" 2 => "Management" 3 => "Survival" ] ] ] ] "tieneResumen" => true "resumen" => array:1 [ "en" => array:3 [ "titulo" => "Abstract" "resumen" => "Introduction and aimsCholangiocarcinomas are a heterogeneous group of tumors that can be classified into three clinically distinct types of cancers, intrahepatic, perihilar and distal cholangiocarcinoma. The inconsistent use of nomenclature for these cancers has obscured a true knowledge of the epidemiology, natural history and response to therapy of these cancers. Our aims were to define demographic characteristics, management and outcomes of these three distinct cancer types. Materials and methodsA retrospective study of patients enrolled in an institutional cancer registry from 1992 to 2010. Median survival was compared between different treatment modalities over three time periods for the three types of cholangiocarcinoma at different stages of the disease using Kaplan Meyer analysis. Results242 patients were identified. All cases were reviewed and classified into intrahepatic (90 patients), distal (48 patients) or perihilar (104 patients) cholangiocarcinomas. These cancers differed in median age of onset, gender distribution, median survival and stage. 13.8% of patients presented with stage I, 5.8% with stage II, 9.6% with stage III, 28% with stage IV, with 41.8% having unknown stage. The overall median survival was 15.8 months, and was 23, 25, 14, and 4.5 months for stages I, II, III, and IV respectively. Surgery improved survival in both early and advanced stages. Multimodality therapies further improved outcomes, particularly for perihilar cholangiocarcinoma. ConclusionPerihilar, distal and intrahepatic cholangiocarcinoma vary in their presentation, natural history and therapeutic approach to management. A consistently applied classification is essential for meaningful interpretation of studies of these cancers." "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abs0010" "titulo" => "Introduction and aims" ] 1 => array:2 [ "identificador" => "abs0015" "titulo" => "Materials and methods" ] 2 => array:2 [ "identificador" => "abs0020" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abs0025" "titulo" => "Conclusion" ] ] ] ] "multimedia" => array:5 [ 0 => array:7 [ "identificador" => "f0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 2036 "Ancho" => 2068 "Tamanyo" => 360631 ] ] "descripcion" => array:1 [ "en" => "TNM staging and survival. The overall survival is depicted for clinical TNM stages, and for pathological TNM stages for each type of CCA. The p values indicate the statistical differences in survival fraction between the four stages for each type of cancer." ] ] 1 => array:7 [ "identificador" => "f0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 755 "Ancho" => 1001 "Tamanyo" => 76252 ] ] "descripcion" => array:1 [ "en" => "Overall survival of patients with cholangiocarcinoma. Kaplan Meier plot of overall survival for 104 patients with pCCA, 90 patients with iCCA and 48 patients with dCCA. iCCA vs. dCCA (p = 0.05), pCCA vs. dCCA (p = 0.13), and iCCA vs. pCCA (p = 0.61)." ] ] 2 => array:7 [ "identificador" => "f0015" "etiqueta" => "Figure 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 774 "Ancho" => 2074 "Tamanyo" => 123552 ] ] "descripcion" => array:1 [ "en" => "Management and outcomes. The median survival in months of patients undergoing either single modality (surgery, chemotherapy or radiation), or multimodality treatment (two or more modalities). Median survival for patients who did not undergo any treatment is shown outside the Venn diagram." ] ] 3 => array:7 [ "identificador" => "t0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">pCCA \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">dCCA \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">iCCA \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Total \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Demographics \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Number \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">104 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">48 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">90 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">242 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Median age (range) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">64 (53-75) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">70 (65-78) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">63 (52-71) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Male % \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">67% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">71% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">49% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Registry code \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Intrahepatic C221 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">37 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">83 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">123 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Extrahepatic C240 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">63 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">41 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">110 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Biliary tract NOS C249 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">9 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab2046035.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Re-classification of cancer registry coded cholangiocarcinomas." ] ] 4 => array:7 [ "identificador" => "t0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">iCCA = 90 n, median survival in months (m) \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">pCCA = 104 n, median survival in n, months (m) \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">dCCA = 48 median survival in months (m) \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="4" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Clinical TNM stage</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">8, 22 m \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">18, 23 m \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">7, 16 m \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">5, 25 m \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">5, 21 m \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">4, 21 m \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">9, 17 m \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">14, 12 m \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">None \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">46, 6 m \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">13, 7 m \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">9, 6 m \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Unknown \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">22, 21.5 m \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">51, 17 m \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">28, 28 m \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">P value (Log-Rank) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.003 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.015 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.09 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Pathologic TNM stage \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">7, 61 m \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">11, 49 m \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">4, 132 m \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">4, 13 m \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">10, 45 m \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">13, 39 m \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">17, 25 m \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">9, 18.6 m \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">4, 14 m \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">17, 8.6 m \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">8, 4.3 m \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">6, 9.6 m \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Unknown \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">45, 10 m \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">64, 10 m \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">21, 13 m \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">P value (Log-Rank) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.003 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.02 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.01 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab2046036.png" ] ] ] ] "descripcion" => array:1 [ "en" => "TNM staging and median survival." ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bs0010" "bibliografiaReferencia" => array:26 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1." 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David Waseem, Patel Tushar

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patel.tushar@mayo.edu

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* Department of Transplantation, Mayo Clinic Florida, USA

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    "titulo" => "Intrahepatic&#44; Perihilar and Distal Cholangiocarcinoma&#58; Management and Outcomes"
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          "en" => "<p id="sp0015" class="elsevierStyleSimplePara elsevierViewall">Management and outcomes&#46; The median survival in months of patients undergoing either single modality &#40;surgery&#44; chemotherapy or radiation&#41;&#44; or multimodality treatment &#40;two or more modalities&#41;&#46; Median survival for patients who did not undergo any treatment is shown outside the Venn diagram&#46;</p>"
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="s0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0035">Introduction and Aim</span><p id="p0005" class="elsevierStylePara elsevierViewall">Cholangiocarcinomas &#40;CCAs&#41; are a heterogeneous group of tumors that arise from the biliary tract epithelia&#44; and account for ~3&#37; of all gastrointestinal tumors&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> The epidemiology of these cancers has been poorly understood&#46; The management of these uncommon cancers has been challenging&#44; in part because of the lack of effective treatments&#46; The absence of a consistent nomenclature and the propensity to consider different tumor types together in many published reports have contributed to a lack of clarity regarding the natural history&#44; epidemiology and optimal approaches to the management of these cancers&#46;</p><p id="p0010" class="elsevierStylePara elsevierViewall">Recent studies have focused on the recognition of three types of cholangiocarcinoma that can be described on the basis of their anatomic location&#44; clinical presentation&#44; and molecular features&#59; intrahepatic CCA &#40;iCCA&#41;&#44; perihilar CCA &#40;pCCA&#41;&#44; or distal CCA &#40;dCCA&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> These three types of CCA are distinct in their presentation and natural history&#44; as well as the approach to diagnosis and management&#46; However&#44; the characteristics of the different types of tumors are not accurately reflected in the literature&#46; For example&#44; studies suggest that iCCA comprise of only 5-10&#37; of all CCA&#44; but these are not borne out by observations in clinical practice&#46;<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3&#44;4</span></a> Data from epidemiological studies such as from the National Cancer Institute&#8217;s Surveillance&#44; Epidemiology and End Results &#40;SEER&#41; database have increased recognition of the incidence of these cancers&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> However&#44; these data have been compromised by inconsistencies in coding as intrahepatic and extrahepatic cholangiocarcinoma&#46;<a class="elsevierStyleCrossRefs" href="#bib0030"><span class="elsevierStyleSup">6-8</span></a> In particular&#44; pCCA have been variably and inconsistently coded as either intrahepatic or ex-trahepatic&#46; An emerging appreciation of the differences between these different types of tumors is reflected in the recent TNM 7 staging system from the AJCC now includes separate staging systems for all three types of cholangiocarcinoma&#46; Most therapeutic trials of patients with these cancers have grouped together all types of biliary tract cancers&#44; and several have also included gallbladder cancer&#46; Tumors classified as intrahepatic or extra-hepatic differ in response to combination therapy with gemcitabine-cisplatin in the ABC-01 and ABC-02 stud-ies&#44;<a class="elsevierStyleCrossRefs" href="#bib0045"><span class="elsevierStyleSup">9&#44;10</span></a> although the responsiveness of perihilar cancers has not been specifically established&#46; Given the implications of inaccurate classification in determining optimal therapeutic strategies&#44; we sought to systematically define the different types within a cohort of cholangiocarcinomas&#44; and to analyze their management and outcomes&#46;</p></span><span id="s0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0040">Material and Methods</span><span id="s0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0045">Identification of patients</span><p id="p0015" class="elsevierStylePara elsevierViewall">Patients seen at the Mayo Clinic in Florida from 1992 to 2010 and enrolled in the Mayo Clinic Cancer registry with a relevant diagnosis were identified&#46; We included all patients with ICD-O-3 codes of C22&#46;1&#44; C 24&#46;0&#44; 24&#46;8&#44; 24&#46;9&#44; and 23&#46;9&#46; All patients enrolled in the Registry were followed on an annual basis&#46; The following definitions were used&#46; For intrahepatic cholangiocarcinoma&#44; a topography code of c22&#46;1 &#40;intrahepatic bile duct&#41; and histology codes 8140&#44; 8160&#44; 8161&#44; 8020 and 8010 were used&#46; For extrahepat-ic cholangiocarcinoma&#44; a topography code of C24&#46;0 was used along with histology codes 8010&#44; 8020&#44; 8041&#44; 8070&#44; 8140&#44; 8144&#44; 8160&#44; 8161&#44; 8260&#44; 8310&#44; 8480&#44; 8490 and 8560&#46; Patients with gall-bladder cancer were identified using a topography code of c23&#46;9 but were not analyzed further as these have generally been characterized separately from the other types of cholangiocarcinoma&#46; The study was reviewed by the Institutional IRB and noted to be exempt from IRB review&#46;</p></span><span id="s0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0050">Classification and staging</span><p id="p0020" class="elsevierStylePara elsevierViewall">Chart review was performed and all patients were classified into intrahepatic&#44; perihilar or distal cholangiocarci-noma based on conventional classifications&#46;<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#44;11&#44;12</span></a> Re-classification was verified by an independent observer to ensure validity and accuracy&#46; Staging was performed based on the TNM 7 staging system on either clinical or pathological criteria and where all necessary information to assign a stage was available&#46;<a class="elsevierStyleCrossRefs" href="#bib0065"><span class="elsevierStyleSup">13-15</span></a> The vital status at the most recent follow-up was verified&#46;</p></span><span id="s0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0055">Data collection</span><p id="p0025" class="elsevierStylePara elsevierViewall">Patient demographics&#44; pathology&#44; and the nature of any treatments received were documented&#46; Treatments were categorized as surgery &#40;which included surgical resection or transplantation&#41;&#44; systemic chemotherapy&#44; or radiation therapy &#40;which also included intrabiliary brachytherapy&#41;&#46; Locoregional therapies were not considered as a separate category because these were inconsistently used during the study period&#46; Data on patient survival and disease recurrence were obtained annually by cancer registry staff from the time of enrollment to the time of last follow-up&#46; Patients were grouped into three multi-year eras in order to examine temporal trends in management and their outcomes&#46; Survival curves for each of the three types of cholangiocarcinoma were generated and temporal trends and outcomes of single or multimodality treatment were determined&#46;</p></span><span id="s0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0060">Statistical analysis</span><p id="p0030" class="elsevierStylePara elsevierViewall">For analysis of trends for categorical data&#44; the Mantel-Haenszel &#967;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> test was used&#46; For continuous data&#44; one-way analysis of variance was used to test the null hypothesis that multiple population mean values are all equal&#46; Kaplan Meier plots were used to assess patients&#8217; survival&#46; To test median values across multiple groups&#44; p values were computed using the nonparametric t test&#46; All statistical analyses were performed using SAS 6&#46;12&#44; SAS Institute&#44; Cary&#44; North Carolina&#46;</p></span></span><span id="s0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0065">Results</span><p id="p0035" class="elsevierStylePara elsevierViewall">A total of 242 patients with a diagnosis of cholangiocar-cinoma encountered at a single institution between 1992 and 2010 were identified using a cancer registry&#46; 123 patients had been classified as intrahepatic&#44; 110 as extrahepat-ic&#44; and 9 as non-specified bile duct cancer&#46; Follow-up was available for all patients for a median of 11&#46;6 months &#40;range 3&#46;1-24&#46;3 months&#41;&#46; All cases were re-classified into iCCA&#44; pCCA or dCCA by two independent observers with 100&#37; concordance&#46; Overall&#44; there were 90 iCCA&#44; 104 pCCA and 48 dCCA&#46; The mean age at diagnosis was 63 years &#40;range 22 - 91&#41; with only 18 patients &#40;7&#46;4&#37;&#41; less than forty years of age at the time of diagnosis&#46; Some demographic differences were noted&#46; Compared to either pCCA or iCCA&#44; dCCA presented at an older median age&#46; There were gender differences noted with 49&#37; of iCCA&#44; 67&#37; of pCCA and 71&#37; of dCCA being male&#46;</p><p id="p0040" class="elsevierStylePara elsevierViewall">Amongst those patients originally classified as intrahe-patic&#44; 37 patients &#40;30&#37;&#41; were reclassified as pCCA&#44; and 3 patients &#40;2&#46;4&#37;&#41; as dCCA &#40;<a class="elsevierStyleCrossRef" href="#t0005">Table 1</a>&#41;&#46; Similarly&#44; differences were also noted between the registry coded diagnoses of extrahepatic cholangiocarcinoma&#44; six of which were re-classified as iCCA &#40;5&#46;4&#37;&#41;&#46; The remainder of the patients coded as extrahepatic were reclassified into pCCA &#40;63 patients&#41; or dCCA &#40;41 patients&#41;&#46; Moreover&#44; nine patients who were coded as biliary cancer with no specified location could be reclassified into four pCCA&#44; four dCCA and one iCCA&#46; These data indicate the high potential for mis-classification of these cancers even in carefully annotated datasets from trained cancer registrars&#46; They highlight and emphasize a major limitation in epidemiological studies that are based on inconsistent classifications&#46;</p><elsevierMultimedia ident="t0005"></elsevierMultimedia><p id="p0045" class="elsevierStylePara elsevierViewall">The clinical and pathological TNM staging at presentation for each of the three types of CCA is shown in <a class="elsevierStyleCrossRef" href="#f0005">Figure 1</a>&#46; Tumor staging could not be described for all patients because of inadequate data&#46; Overall&#44; 13&#46;8&#37; of patients presented with stage I&#44; 5&#46;8&#37; with stage II&#44; 9&#46;6&#37; with stage III&#44; 28&#37; with stage IV&#44; and 41&#46;8&#37; were unknown&#46; The overall median survival &#40;MS&#41; of all patients was 15&#46;8 months&#46; As expected&#44; patients with early stage disease had a higher median survival compared to those presenting at later stages with median survivals of 23&#44; 25&#44; 14&#44; and 4&#46;5 months for stages I&#44; II&#44; III&#44; and IV respectively&#46; More patients with iCCA presented with advanced disease at stage IV &#40;51&#37;&#41; as compared to either pCCA &#40;12&#37;&#41;&#44; or dCCA &#40;18&#37;&#41;&#46; In contrast&#44; patients with pCCA presented more frequently with stage I disease&#46; The median survival for unstaged pCCA&#44; iCCa and dCCA was 17&#44; 21&#46;5 and 28 months respectively&#44; as shown in <a class="elsevierStyleCrossRef" href="#t0010">table 2</a>&#46;</p><elsevierMultimedia ident="f0005"></elsevierMultimedia><elsevierMultimedia ident="t0010"></elsevierMultimedia><p id="p0050" class="elsevierStylePara elsevierViewall">The median survival for iCCA &#40;13&#46;5 months&#41; was similar to that for pCCA &#40;13&#46;9 months&#41;&#44; but was lower than dCCA &#40;22 months&#41;&#46; However&#44; overall survival was not significantly different between the three types &#40;<a class="elsevierStyleCrossRef" href="#f0010">Figure 2</a>&#41;&#46; Median survival was significantly higher for patients with pCCA or dCCA who received treatment compared to those who did not receive any treatment&#46; However&#44; this was not observed for patients with iCCA and could reflect more advanced stage at time of presentation&#46; 156 patients &#91;62 iCCA&#44; 63 pCCA&#44; and 31 dCCA&#93; underwent surgery&#44; chemotherapy&#44; radiotherapy&#44; or a combination of these&#46; Surgery with or without chemoradiation provided an overall survival benefit &#40;25 <span class="elsevierStyleItalic">vs&#46;</span> 7&#46;5 months&#44; p &#60; 0&#46;0001&#41;&#46; The median survival of patients with each of the three types of CCA who underwent different treatment modalities is illustrated in <a class="elsevierStyleCrossRef" href="#f0015">Figure 3</a>&#46;</p><elsevierMultimedia ident="f0010"></elsevierMultimedia><elsevierMultimedia ident="f0015"></elsevierMultimedia><p id="p0055" class="elsevierStylePara elsevierViewall">To examine the temporal trends in management&#44; patients were grouped into one of three eras based on their date of diagnosis&#44; namely pre 2001&#44; 2001-2005&#44; and 2005-2010&#46; In the most recent era &#40;2005-2010&#41;&#44; median survival ranged from 20-54 months for patients who had surgery compared to 3-7 months for those who did not have surgery&#44; Similar results were observed for other eras examined&#46; These findings could potentially arise from more advanced disease in non-surgical patients&#46;</p><p id="p0060" class="elsevierStylePara elsevierViewall">For patients with iCCA&#44; the presence of underlying diabetes mellitus&#44; liver cirrhosis&#44; primary sclerosing cholan-gitis or a history of smoking&#44; alcohol use&#44; or inflammatory bowel disease did not significantly alter median survival&#46; Surgical resection was performed in 39&#37; of the patients either as a single modality intervention &#40;22&#37;&#41; or combined with chemotherapy &#40;10&#37;&#41;&#44; radiation therapy &#40;1&#46;1&#37;&#41;&#44; or chemo-radiation therapy &#40;5&#46;5&#37;&#41;&#46; Twenty one percent of patients with iCCA received only chemotherapy&#44; 2&#46;2&#37; received only radiation therapy&#44; and 6&#46;6&#37; received chemo-radiation in combination&#46; The highest median survival with any single modality was noted with surgery&#44; whereas multimodality therapy of surgery combined with chemotherapy achieved the highest median survival&#46;</p><p id="p0065" class="elsevierStylePara elsevierViewall">For patients with pCCA&#44; 62&#37; underwent surgical resection either as a single intervention &#40;15&#46;3&#37;&#41; or combined with chemotherapy &#40;1&#46;9&#37;&#41;&#44; radiation therapy &#40;1&#37;&#41;&#44; and chemo-radiation therapy &#40;20&#46;1&#37;&#41;&#46; 3&#46;8&#37; received only chemotherapy&#44; 1&#46;9&#37; received only radiation therapy&#44; and 16&#46;3&#37; received combination chemo-radiation therapy&#46; The median survival of patients who underwent any multimodali-ty treatment was significantly higher than with any single treatment modality&#46; As with iCCA&#44; the highest median survival was observed for patients who underwent a combination of surgery and chemoradiation when compared to other single or multimodality treatments&#46; A multi-modality approach of chemoradiation followed by liver transplantation has been used to treat patients in this group&#44; and the improved survival of this intervention has been reported&#46;<a class="elsevierStyleCrossRefs" href="#bib0080"><span class="elsevierStyleSup">16-18</span></a></p><p id="p1060" class="elsevierStylePara elsevierViewall">For patients with dCCA&#44; 87&#37; underwent surgical resection either as single modality &#40;52&#37;&#41; or combined with chemotherapy &#40;3&#37;&#41; or chemo-radiation therapy &#40;32&#37;&#41;&#46; 7&#37; received only chemotherapy&#44; 3&#37; received only radiation therapy&#44; and 3&#37; received combined chemo-radiation therapy&#46; Patients who underwent multimodality treatment had higher median survival compared with those who underwent surgery alone or with any other single modality treatment &#40;P &#61; 0&#46;0009&#41;&#46; Likewise&#44; surgery and chemoradi-ation therapy resulted in a higher median survival compared to other single modality treatments&#44; although not statistically significant&#44; likely due to the small number of patients in the dCCA cohort&#46;</p></span><span id="s0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0070">Discussion</span><p id="p0070" class="elsevierStylePara elsevierViewall">A recognition of the distinctive nature of different types of cholangiocarcinoma is now emerging&#46; In this study&#44; patients with cholangiocarcinoma were reviewed&#44; reclassified and systematically analyzed to derive a detailed and accurate description of the frequency&#44; management and outcomes of the three different types of cholangiocarcinoma&#46; This study thus provides a relevant snapshot of contemporary management and outcomes of patients with these cancers by eliminating the confounding effects of inconsistencies that arise from inaccurate coding&#46;</p><p id="p0075" class="elsevierStylePara elsevierViewall">The optimal choice of individual or multimodality therapeutic strategies for cholangiocarcinoma remains obscure&#44; and the management of these cancers continues to evolve&#46; Median survival was increased for all patients who underwent surgery&#44; regardless of resection margin&#46; Since CCA usually presents in late stages&#44; R1 resections are frequent even when surgery is performed with curative in-tent&#46;<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a> Adjuvant therapy is not routinely used&#44; although chemotherapy and&#47;or radiotherapy can improve survival following R1 resections compared to those patients who do not undergo surgery&#46;<a class="elsevierStyleCrossRefs" href="#bib0100"><span class="elsevierStyleSup">20-23</span></a> Irrespective of the type of cholangiocarcinoma&#44; surgical resection along with chemo-radiation therapy may have the greatest impact on survival for patients with resectable disease&#46;<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a></p><p id="p0080" class="elsevierStylePara elsevierViewall">Many patients are not eligible for curative surgical resection due to advanced disease at diagnosis&#46; The median survival for patients who did not undergo any surgery ranged from 5-12 months for all three types of cholangi-ocarcinoma&#46; For unresectable lesions&#44; a multimodality treatment approach could be considered&#46;<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">24</span></a> Higher survival rates were observed with the use of multimodality treatment compared to the use of single modality treatment with surgery&#44; chemotherapy&#44; or radiation therapy at all disease stages&#46;<a class="elsevierStyleCrossRefs" href="#bib0125"><span class="elsevierStyleSup">25&#44;26</span></a> This was particularly true for pCCA&#44; where multi-modality strategies have been most extensively used&#46; These cancers present at an earlier stage but have a poor survival&#44; justifying an aggressive approach&#46; In contrast to pCCA&#44; median survival was greater for iCCA where surgery alone or with chemotherapy was performed&#46; A potential reason is that smaller lesions that are amenable to complete resection may have a greater chance of curative resection&#44; or have a lower risk for invasion or recurrence&#46; These cancers often present at a later stage and effective strategies for earlier detection are needed&#46;</p><p id="p0085" class="elsevierStylePara elsevierViewall">Compared to other types of cholangiocarcinoma&#44; patients with dCCA had the highest median survival&#44; although the number of patients in this group was small&#46; For this group&#44; surgical approaches offer the best outcomes when combined with chemotherapy or radiation&#46; Our observations regarding improved prognosis of dCCA are consistent with reports in extrahepatic CCA&#46; The median survival reported by DeOliveira&#44; <span class="elsevierStyleItalic">et al</span>&#46;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> for iCCA were greater &#40;28 <span class="elsevierStyleItalic">vs&#46;</span> 13&#46;5 months&#41;&#44; whereas the median survival for dCCA were lower &#40;18 <span class="elsevierStyleItalic">vs&#46;</span> 22 months&#41; than those in our cohort&#46; We speculate that these differences could reflect regional variations in management or in risk factors for these cancers&#46;</p><p id="p0090" class="elsevierStylePara elsevierViewall">There are limitations to this study&#44; as with any other retrospective analyses&#46; In particular&#44; data regarding variables that can influence choice of therapy or outcomes including performance status and underlying organ function were not available and thus could not be incorporated in the analysis&#46; Other factors such as patient desire&#44; access to therapies and physician and institutional expertise in managing these conditions are mitigated in part by restricting this analysis to a single institution that offers all conventional therapeutic options for the management of these cancers&#44; including liver transplantation for pCCA&#46; These studies thereby provide a more accurate practice-based and temporal representation of trends in the management and outcomes of each of the three different types of cholangi-ocarcinoma&#46;</p></span><span id="s0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0075">Abbreviations</span><p id="p0095" class="elsevierStylePara elsevierViewall"><ul class="elsevierStyleList" id="l0010"><li class="elsevierStyleListItem" id="u0005"><span class="elsevierStyleLabel">&#8226;</span><p id="p0100" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">CI&#58;</span> confidence intervals&#46;</p></li><li class="elsevierStyleListItem" id="u0010"><span class="elsevierStyleLabel">&#8226;</span><p id="p0105" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">dCCA&#58;</span> distal cholangiocarcinoma&#46;</p></li><li class="elsevierStyleListItem" id="u0015"><span class="elsevierStyleLabel">&#8226;</span><p id="p0110" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">HBV&#58;</span> hepatitis B virus&#46;</p></li><li class="elsevierStyleListItem" id="u0020"><span class="elsevierStyleLabel">&#8226;</span><p id="p0115" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">HCC&#58;</span> hepatocellular carcinoma&#46;</p></li><li class="elsevierStyleListItem" id="u0025"><span class="elsevierStyleLabel">&#8226;</span><p id="p0120" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">HCV&#58;</span> hepatitis C virus&#46;</p></li><li class="elsevierStyleListItem" id="u0030"><span class="elsevierStyleLabel">&#8226;</span><p id="p0125" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">iCCA&#58;</span> intrahepatic cholangiocarcinoma&#46;</p></li><li class="elsevierStyleListItem" id="u0035"><span class="elsevierStyleLabel">&#8226;</span><p id="p0130" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">ICD&#58;</span> international classification of disease&#46;</p></li><li class="elsevierStyleListItem" id="u0040"><span class="elsevierStyleLabel">&#8226;</span><p id="p0135" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">OR&#58;</span> odds ratio&#46;</p></li><li class="elsevierStyleListItem" id="u0045"><span class="elsevierStyleLabel">&#8226;</span><p id="p0140" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">pCCA&#58;</span> perihilar cholnagiocarcinoma&#46;</p></li></ul></p></span><span id="s0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0080">Conflict of Interest</span><p id="p0145" class="elsevierStylePara elsevierViewall">There are no conflicts of interest to disclose&#46;</p></span><span id="s0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0085">Acknowledgements</span><p id="p0150" class="elsevierStylePara elsevierViewall">We acknowledge&#44; with gratitude&#44; the assistance provided by Nicholas Figura and Abigail Trotter in data collection&#46;</p></span><span id="s0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0090">Financial Support</span><p id="p0155" class="elsevierStylePara elsevierViewall">Supported in part by NIH grant DK 069370 &#40;TP&#41;&#46;</p></span></span>"
    "textoCompletoSecciones" => array:1 [
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        0 => array:3 [
          "identificador" => "xres1198039"
          "titulo" => "Abstract"
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              "titulo" => "Introduction and aims"
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              "titulo" => "Conclusion"
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        1 => array:2 [
          "identificador" => "xpalclavsec1116683"
          "titulo" => "Key words"
        ]
        2 => array:2 [
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          "titulo" => "Introduction and Aim"
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          "titulo" => "Material and Methods"
          "secciones" => array:4 [
            0 => array:2 [
              "identificador" => "s0015"
              "titulo" => "Identification of patients"
            ]
            1 => array:2 [
              "identificador" => "s0020"
              "titulo" => "Classification and staging"
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            2 => array:2 [
              "identificador" => "s0025"
              "titulo" => "Data collection"
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            3 => array:2 [
              "identificador" => "s0030"
              "titulo" => "Statistical analysis"
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          "titulo" => "Results"
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          "titulo" => "Discussion"
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        6 => array:2 [
          "identificador" => "s0045"
          "titulo" => "Abbreviations"
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        7 => array:2 [
          "identificador" => "s0050"
          "titulo" => "Conflict of Interest"
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        8 => array:2 [
          "identificador" => "s0055"
          "titulo" => "Acknowledgements"
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        9 => array:2 [
          "identificador" => "s0060"
          "titulo" => "Financial Support"
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        10 => array:1 [
          "titulo" => "References"
        ]
      ]
    ]
    "pdfFichero" => "main.pdf"
    "tienePdf" => true
    "fechaRecibido" => "2016-04-06"
    "fechaAceptado" => "2016-05-08"
    "PalabrasClave" => array:1 [
      "en" => array:1 [
        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Key words"
          "identificador" => "xpalclavsec1116683"
          "palabras" => array:4 [
            0 => "Biliary cancers"
            1 => "Natural history"
            2 => "Management"
            3 => "Survival"
          ]
        ]
      ]
    ]
    "tieneResumen" => true
    "resumen" => array:1 [
      "en" => array:3 [
        "titulo" => "Abstract"
        "resumen" => "<span id="abs0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0010"><span class="elsevierStyleBold">Introduction and aims</span></span><p id="sp0030" class="elsevierStyleSimplePara elsevierViewall">Cholangiocarcinomas are a heterogeneous group of tumors that can be classified into three clinically distinct types of cancers&#44; intrahepatic&#44; perihilar and distal cholangiocarcinoma&#46; The inconsistent use of nomenclature for these cancers has obscured a true knowledge of the epidemiology&#44; natural history and response to therapy of these cancers&#46; Our aims were to define demographic characteristics&#44; management and outcomes of these three distinct cancer types&#46;</p></span> <span id="abs0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0015"><span class="elsevierStyleBold">Materials and methods</span></span><p id="sp0035" class="elsevierStyleSimplePara elsevierViewall">A retrospective study of patients enrolled in an institutional cancer registry from 1992 to 2010&#46; Median survival was compared between different treatment modalities over three time periods for the three types of cholangiocarcinoma at different stages of the disease using Kaplan Meyer analysis&#46;</p></span> <span id="abs0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0020"><span class="elsevierStyleBold">Results</span></span><p id="sp0040" class="elsevierStyleSimplePara elsevierViewall">242 patients were identified&#46; All cases were reviewed and classified into intrahepatic &#40;90 patients&#41;&#44; distal &#40;48 patients&#41; or perihilar &#40;104 patients&#41; cholangiocarcinomas&#46; These cancers differed in median age of onset&#44; gender distribution&#44; median survival and stage&#46; 13&#46;8&#37; of patients presented with stage I&#44; 5&#46;8&#37; with stage II&#44; 9&#46;6&#37; with stage III&#44; 28&#37; with stage IV&#44; with 41&#46;8&#37; having unknown stage&#46; The overall median survival was 15&#46;8 months&#44; and was 23&#44; 25&#44; 14&#44; and 4&#46;5 months for stages I&#44; II&#44; III&#44; and IV respectively&#46; Surgery improved survival in both early and advanced stages&#46; Multimodality therapies further improved outcomes&#44; particularly for perihilar cholangiocarcinoma&#46;</p></span> <span id="abs0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0025"><span class="elsevierStyleBold">Conclusion</span></span><p id="sp0045" class="elsevierStyleSimplePara elsevierViewall">Perihilar&#44; distal and intrahepatic cholangiocarcinoma vary in their presentation&#44; natural history and therapeutic approach to management&#46; A consistently applied classification is essential for meaningful interpretation of studies of these cancers&#46;</p></span>"
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            "identificador" => "abs0010"
            "titulo" => "Introduction and aims"
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            "titulo" => "Materials and methods"
          ]
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            "identificador" => "abs0020"
            "titulo" => "Results"
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            "identificador" => "abs0025"
            "titulo" => "Conclusion"
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        "etiqueta" => "Figure 1"
        "tipo" => "MULTIMEDIAFIGURA"
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        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr1.jpeg"
            "Alto" => 2036
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          "en" => "<p id="sp0005" class="elsevierStyleSimplePara elsevierViewall">TNM staging and survival&#46; The overall survival is depicted for clinical TNM stages&#44; and for pathological TNM stages for each type of CCA&#46; The p values indicate the statistical differences in survival fraction between the four stages for each type of cancer&#46;</p>"
        ]
      ]
      1 => array:7 [
        "identificador" => "f0010"
        "etiqueta" => "Figure 2"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr2.jpeg"
            "Alto" => 755
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            "Tamanyo" => 76252
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        "descripcion" => array:1 [
          "en" => "<p id="sp0010" class="elsevierStyleSimplePara elsevierViewall">Overall survival of patients with cholangiocarcinoma&#46; Kaplan Meier plot of overall survival for 104 patients with pCCA&#44; 90 patients with iCCA and 48 patients with dCCA&#46; iCCA vs&#46; dCCA &#40;p &#61; 0&#46;05&#41;&#44; pCCA vs&#46; dCCA &#40;p &#61; 0&#46;13&#41;&#44; and iCCA vs&#46; pCCA &#40;p &#61; 0&#46;61&#41;&#46;</p>"
        ]
      ]
      2 => array:7 [
        "identificador" => "f0015"
        "etiqueta" => "Figure 3"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr3.jpeg"
            "Alto" => 774
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        "descripcion" => array:1 [
          "en" => "<p id="sp0015" class="elsevierStyleSimplePara elsevierViewall">Management and outcomes&#46; The median survival in months of patients undergoing either single modality &#40;surgery&#44; chemotherapy or radiation&#41;&#44; or multimodality treatment &#40;two or more modalities&#41;&#46; Median survival for patients who did not undergo any treatment is shown outside the Venn diagram&#46;</p>"
        ]
      ]
      3 => array:7 [
        "identificador" => "t0005"
        "etiqueta" => "Table 1"
        "tipo" => "MULTIMEDIATABLA"
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                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">pCCA&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">dCCA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">iCCA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Total&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
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                  \t\t\t\t">Demographics&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Number&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">104&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">48&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">90&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">242&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Median age &#40;range&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">64 &#40;53-75&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">70 &#40;65-78&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">63 &#40;52-71&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Male &#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">67&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">71&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">49&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Registry code&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Intrahepatic C221&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">37&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">83&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">123&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Extrahepatic C240&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">63&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">41&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">110&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Biliary tract NOS C249&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
              "imagenFichero" => array:1 [
                0 => "xTab2046035.png"
              ]
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="sp0020" class="elsevierStyleSimplePara elsevierViewall">Re-classification of cancer registry coded cholangiocarcinomas&#46;</p>"
        ]
      ]
      4 => array:7 [
        "identificador" => "t0010"
        "etiqueta" => "Table 2"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "tabla" => array:1 [
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">iCCA &#61; 90 n&#44; median survival in months &#40;m&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">pCCA &#61; 104 n&#44; median survival in n&#44; months &#40;m&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">dCCA &#61; 48 median survival in months &#40;m&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="4" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Clinical TNM stage</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">8&#44; 22 m&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">18&#44; 23 m&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">7&#44; 16 m&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">5&#44; 25 m&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">5&#44; 21 m&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">4&#44; 21 m&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">9&#44; 17 m&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">14&#44; 12 m&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">None&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">46&#44; 6 m&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">13&#44; 7 m&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">9&#44; 6 m&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Unknown&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">22&#44; 21&#46;5 m&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">51&#44; 17 m&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">28&#44; 28 m&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">P value &#40;Log-Rank&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;003&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;015&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;09&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Pathologic TNM stage&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">7&#44; 61 m&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">11&#44; 49 m&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">4&#44; 132 m&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">4&#44; 13 m&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">10&#44; 45 m&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">13&#44; 39 m&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">17&#44; 25 m&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">9&#44; 18&#46;6 m&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">4&#44; 14 m&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">17&#44; 8&#46;6 m&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">8&#44; 4&#46;3 m&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">6&#44; 9&#46;6 m&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Unknown&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">45&#44; 10 m&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">64&#44; 10 m&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">21&#44; 13 m&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">P value &#40;Log-Rank&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;003&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;02&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
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                  \t\t\t\t">0&#46;01&nbsp;\t\t\t\t\t\t\n
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Article information

ISSN: 16652681
Original language: English

DOI:10.5604/16652681.1226927

The statistics are updated each day

Year/Month	Html	Pdf	Total

2024 November	1	1	2
2024 October	38	8	46
2024 September	47	21	68
2024 August	35	7	42
2024 July	25	1	26
2024 June	31	4	35
2024 May	35	2	37
2024 April	28	6	34
2024 March	41	3	44
2024 February	34	7	41
2024 January	25	6	31
2023 December	27	5	32
2023 November	36	11	47
2023 October	20	9	29
2023 September	11	3	14
2023 August	30	2	32
2023 July	20	7	27
2023 June	43	13	56
2023 May	110	7	117
2023 April	59	0	59
2023 March	70	4	74
2023 February	34	1	35
2023 January	55	12	67
2022 December	38	11	49
2022 November	35	6	41
2022 October	76	16	92
2022 September	59	12	71
2022 August	37	8	45
2022 July	35	9	44
2022 June	22	7	29
2022 May	30	4	34
2022 April	43	11	54
2022 March	44	9	53
2022 February	30	6	36
2022 January	78	4	82
2021 December	34	10	44
2021 November	39	16	55
2021 October	66	12	78
2021 September	90	25	115
2021 August	93	15	108
2021 July	36	22	58
2021 June	26	10	36
2021 May	34	11	45
2021 April	105	17	122
2021 March	70	23	93
2021 February	44	17	61
2021 January	63	56	119
2020 December	24	5	29
2020 November	34	10	44
2020 October	27	6	33
2020 September	28	9	37
2020 August	32	12	44
2020 July	24	9	33
2020 June	27	14	41
2020 May	35	10	45
2020 April	31	2	33
2020 March	25	6	31
2020 February	38	33	71
2020 January	33	7	40
2019 December	33	10	43
2019 November	22	10	32
2019 October	40	6	46
2019 September	23	6	29
2019 August	14	1	15
2019 July	14	5	19
2019 June	11	9	20
2019 May	2	4	6

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