Scientific letter
Long-term effect of combined therapy with somatostatin analogs and dopamine agonists as a primary treatment in a non-functioning invasive pituitary macroadenoma
Efecto terapéutico a largo plazo de los analógos de somatostatina y agonistas dopaminérgicos como tratamiento médico primario en un macroadenoma hipofisario no funcionante invasivo
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C: RMN de control al mes del diagnóstico: desaparición del absceso hipotalámico. Persistencia de una lesión infiltrativa en la gándula hipófisis y en el tallo hipofisiario. D: RMN de control a los 6 meses. Resolución del absceso hipotálamo-hipofisiario.</p>" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Luz María Reyes Céspedes, Rebeca Barahona San Millán, Eva Gómez Roselló, Joel Chara Cervantes, Mónica Recasens Sala" "autores" => array:5 [ 0 => array:2 [ "nombre" => "Luz María" "apellidos" => "Reyes Céspedes" ] 1 => array:2 [ "nombre" => "Rebeca" "apellidos" => "Barahona San Millán" ] 2 => array:2 [ "nombre" => "Eva" "apellidos" => "Gómez Roselló" ] 3 => array:2 [ "nombre" => "Joel" "apellidos" => "Chara Cervantes" ] 4 => array:2 [ "nombre" => "Mónica" "apellidos" => "Recasens Sala" ] ] ] ] ] "idiomaDefecto" => "es" "Traduccion" => array:1 [ "en" => array:9 [ "pii" => "S253001802100086X" "doi" => "10.1016/j.endien.2021.10.005" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S253001802100086X?idApp=UINPBA00004N" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2530016420302044?idApp=UINPBA00004N" "url" => "/25300164/0000006800000006/v1_202106060537/S2530016420302044/v1_202106060537/es/main.assets" ] "itemAnterior" => array:19 [ "pii" => "S2530016420302494" "issn" => "25300164" "doi" => "10.1016/j.endinu.2020.09.004" "estado" => "S300" "fechaPublicacion" => "2021-06-01" "aid" => "1106" "copyright" => "SEEN y SED" "documento" => "article" "crossmark" => 1 "subdocumento" => "rev" "cita" => "Endocrinol Diabetes Nutr. 2021;68:428-38" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "es" => array:12 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">REVISIÓN</span>" "titulo" => "Manejo nutricional del paciente con cáncer gástrico" "tienePdf" => "es" "tieneTextoCompleto" => "es" "tieneResumen" => array:2 [ 0 => "es" 1 => "en" ] "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "428" "paginaFinal" => "438" ] ] "titulosAlternativos" => array:1 [ "en" => array:1 [ "titulo" => "Nutritional management of gastric cancer" ] ] "contieneResumen" => array:2 [ "es" => true "en" => true ] "contieneTextoCompleto" => array:1 [ "es" => true ] "contienePdf" => array:1 [ "es" => true ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Elena Carrillo Lozano, Virginia Osés Zárate, Rocío Campos del Portillo" "autores" => array:3 [ 0 => array:2 [ "nombre" => "Elena" "apellidos" => "Carrillo Lozano" ] 1 => array:2 [ "nombre" => "Virginia" "apellidos" => "Osés Zárate" ] 2 => array:2 [ "nombre" => "Rocío" "apellidos" => "Campos del Portillo" ] ] ] ] ] "idiomaDefecto" => "es" "Traduccion" => array:1 [ "en" => array:9 [ "pii" => "S2530018021000822" "doi" => "10.1016/j.endien.2020.09.005" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2530018021000822?idApp=UINPBA00004N" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2530016420302494?idApp=UINPBA00004N" "url" => "/25300164/0000006800000006/v1_202106060537/S2530016420302494/v1_202106060537/es/main.assets" ] "en" => array:14 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Scientific letter</span>" "titulo" => "Long-term effect of combined therapy with somatostatin analogs and dopamine agonists as a primary treatment in a non-functioning invasive pituitary macroadenoma" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "439" "paginaFinal" => "441" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "Pedro Iglesias, Jorge Cardona, Juan J. Díez" "autores" => array:3 [ 0 => array:4 [ "nombre" => "Pedro" "apellidos" => "Iglesias" "email" => array:1 [ 0 => "piglo65@gmail.com" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "cor0005" ] ] ] 1 => array:3 [ "nombre" => "Jorge" "apellidos" => "Cardona" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] ] ] 2 => array:3 [ "nombre" => "Juan J." "apellidos" => "Díez" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] ] "afiliaciones" => array:2 [ 0 => array:3 [ "entidad" => "Department of Endocrinology, Hospital Universitario Puerta de Hierro Majadahonda, Madrid, Spain" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Department of Nuclear Medicine, Hospital Universitario Puerta de Hierro Majadahonda, Madrid, Spain" "etiqueta" => "b" "identificador" => "aff0010" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Efecto terapéutico a largo plazo de los analógos de somatostatina y agonistas dopaminérgicos como tratamiento médico primario en un macroadenoma hipofisario no funcionante invasivo" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1559 "Ancho" => 2507 "Tamanyo" => 255822 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Axial (left above), sagittal (center above), and sagittal (right above) images of the SPECT-TC with <span class="elsevierStyleSup">99m</span>Tc-EDDA/HYNIC-Tyr3-Octreotide (tektrotyd) scintigraphy at diagnosis showing a hypercaptant lesion at the level of the pituitary tumor. Pituitary MRI at diagnosis showing an invasive pituitary tumor of 2.0<span class="elsevierStyleHsp" style=""></span>×<span class="elsevierStyleHsp" style=""></span>1.7<span class="elsevierStyleHsp" style=""></span>×<span class="elsevierStyleHsp" style=""></span>3.0<span class="elsevierStyleHsp" style=""></span>cm with suprasellar extension with greater involvement of the right side, extending to both cavernous sinuses and encompassing the right and partially left carotid (left down). Pituitary MRI 3 months (center down) and 6 months (right down) after starting combined therapy with lanreotide and cabergoline.</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">Pituitary adenoma (PA) constitutes 15% of intracranial tumors. Non-functioning PA (NFPA) is the second most common type of PA after prolactinoma, with a prevalence of 22.2 cases/100,000 inhabitants.<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">1</span></a> In most cases, NFPA is a macroadenoma (≥1<span class="elsevierStyleHsp" style=""></span>cm) whose clinical presentation is variable; from an incidental oligosymptomatic finding to a true giant PA with great local involvement of neighboring structures and different degrees of hypopituitarism.<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">2</span></a> Its clinical management varies depending on the size of the tumor, its growth over time and neuro-ophthalmic involvement. Surgical treatment followed by radiotherapy of the remnant or tumor recurrence is the usual treatment. The clinical experience with medical treatment with somatostatin analogs (SSA) and dopamine agonists (DA) as a primary treatment in these tumors is poorly defined.</p><p id="par0010" class="elsevierStylePara elsevierViewall">A 46-year-old man was referred to us for assessment of pituitary tumor discovered in a cranial CT during the study of headache in the last 5–6 months. Clinically, the patient did not show symptoms of adenohypophyseal hypo-hyperfunction or diabetes insipidus. No galactorrhea or erectile dysfunction, and libido was preserved. Hormonal evaluation showed central hypogonadism [FSH 2.3<span class="elsevierStyleHsp" style=""></span>mIU/ml (NR, 1.4–18), LH 1.5<span class="elsevierStyleHsp" style=""></span>mUI/ml (1.5–9.3), testosterone 93.9<span class="elsevierStyleHsp" style=""></span>ng/dl (241 – 827)], and mild hyperprolactinemia [PRL 49.1<span class="elsevierStyleHsp" style=""></span>ng/ml (2.2–17.7), PRL after dilution 47.8<span class="elsevierStyleHsp" style=""></span>ng/ml]. The rest of the pituitary function was normal [TSH 2.05<span class="elsevierStyleHsp" style=""></span>μIU/ml (0.35–5.0), free T4 1.09<span class="elsevierStyleHsp" style=""></span>ng/dl (0.7–1.98), ACTH 56.3<span class="elsevierStyleHsp" style=""></span>pg/ml (9.0–55.0), cortisol 13.6<span class="elsevierStyleHsp" style=""></span>μg/dl (4.3–22.4), urinary free cortisol 16<span class="elsevierStyleHsp" style=""></span>μg/24<span class="elsevierStyleHsp" style=""></span>h (11.0–71.0), Nugent test: cortisol 0.8<span class="elsevierStyleHsp" style=""></span>μg/dl, GH 0.8<span class="elsevierStyleHsp" style=""></span>ng/ml (4.3–6.3), and IGF-I 134<span class="elsevierStyleHsp" style=""></span>ng/ml (55.0–420.0)]. Pituitary MRI confirmed the presence of an invasive pituitary tumor of 2.0<span class="elsevierStyleHsp" style=""></span>×<span class="elsevierStyleHsp" style=""></span>1.7<span class="elsevierStyleHsp" style=""></span>×<span class="elsevierStyleHsp" style=""></span>3.0<span class="elsevierStyleHsp" style=""></span>cm with suprasellar extension with greater involvement of the right side, extending to both cavernous sinuses and encompassing the right and partially left carotid (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>). The campimetric study of the visual fields was normal. A <span class="elsevierStyleSup">99m</span>Tc-EDDA/HYNIC-Tyr3-Octreotide (tektrotyd) scintigraphy revealed a hypercaptant lesion at pituitary level (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>). With the clinical diagnosis of invasive non-functioning pituitary macroadenoma associated with mild hyperprolactinemia, due to probable compression of the pituitary stalk, and central hypogonadism, he started therapy with lanreotide autogel 120<span class="elsevierStyleHsp" style=""></span>mg/month sc and oral cabergoline 0.5<span class="elsevierStyleHsp" style=""></span>mg/week, and was referred to the Neurosurgery Department for surgical treatment of the PA. Shortly after starting medical treatment, the patient showed a marked clinical improvement of headaches, without visual disturbances. A new pituitary MRI performed 3 months after starting medical treatment showed a marked reduction in pituitary adenoma size (1.2<span class="elsevierStyleHsp" style=""></span>×<span class="elsevierStyleHsp" style=""></span>1.5<span class="elsevierStyleHsp" style=""></span>×<span class="elsevierStyleHsp" style=""></span>2.5<span class="elsevierStyleHsp" style=""></span>cm) (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>). Due to the excellent clinical and radiological evolution, it was decided to postpone surgery. At 6 months after starting medical treatment, the patient referred notable clinical improvement of headaches without visual disturbances, the adenohypophyseal function was controlled (testosterone 496.10<span class="elsevierStyleHsp" style=""></span>ng/dl and PRL 0.5<span class="elsevierStyleHsp" style=""></span>ng/ml) and pituitary MRI showed marked reduction of the macroadenoma size with respect to the previous MRI (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>). From that moment the patient was treated with lanreotide autogel 120<span class="elsevierStyleHsp" style=""></span>mg/month sc and oral cabergoline 0.25<span class="elsevierStyleHsp" style=""></span>mg/week. A year and a half after starting treatment, pituitary function remained controlled (testosterone 418<span class="elsevierStyleHsp" style=""></span>ng/dl and PRL 0.5<span class="elsevierStyleHsp" style=""></span>ng/ml) and tumor size remained stable with respect to the last pituitary MRI performed at sixth month.</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0015" class="elsevierStylePara elsevierViewall">NFPA is around 25–35% of pituitary tumors, being most of them gonadotropinomas, which account for as many as 40–50% of all pituitary macroadenomas.<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">3</span></a> At diagnosis, most NFPAs are macroadenomas and, on many occasions, they are incidentally diagnosed.<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">2</span></a> Surgery is the treatment of choice for symptomatic (headache, visual disturbances and neurological involvement) NFPAs, those associated with pituitary apoplexy and those that show growth during the surveillance. However, complete surgical resection, especially in invasive adenomas (Knosp grades 3–4) is exceptionally achieved. For this reason and, as a complementary treatment to a debulking surgery, radiotherapy is usually used to control the tumor remnant or its recurrence.<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">4</span></a> Radiotherapy achieves an excellent long-term local tumor control but at the expense of a high rate of hypopituitarism.</p><p id="par0020" class="elsevierStylePara elsevierViewall">As occurs with prolactinomas, where DAs constitute the first-line therapy, NFPAs also express dopamine D2 receptors (D2R). D2R expression has been reported in about 35–40% of NFPAs and DAs (bromocriptine and cabergoline) have been shown to decrease gonadotropin and alpha-subunit secretion in gonadotroph adenomas.<a class="elsevierStyleCrossRefs" href="#bib0085"><span class="elsevierStyleSup">5–7</span></a> Therefore, DAs could have a therapeutic role in the medical management of NFPAs. In fact, in these patients, pooled results have shown a reduction of tumor size and stabilization of disease in 30% and 58% of patients, respectively.<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">8</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">On the other hand, NFPAs can also express somatostatin receptors (SSTRs),<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">9</span></a> although its clinical relevance has not been fully defined. The finding of significant expression of SSTR type 2 (SSTR2) and type 5 (SSTR5) has suggested a possible therapeutic role regarding the use of SST analogs in preventing tumor recurrence in NFPAs.<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">10</span></a> SSA as primary medical therapy for NFPAs has shown low tumor response rates (12–40%),<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">11</span></a> however the combination therapy with DA and SSA can increase tumor response rate [mean reduction in tumor volume of 30<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>4% (18–46%) after 6 months of combination therapy with octreotide and cabergoline] in 60% of NFPA patients.<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">12</span></a> SSTRs and D2R may have additive effects on cell proliferation in pituitary adenomas thought interaction by heterodimerization as shown for SSTR1-SSTR5, SSTR5-D2R, SSTR2-SSTR3, and SSTR2-D2R.<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">8</span></a> In fact, SSA and cabergoline are usually used after surgery in invasive NFPA.</p><p id="par0030" class="elsevierStylePara elsevierViewall">In our patient, the long-term clinical management with combined medical treatment with SSA and DA was encouraged for several facts: (1) the positive tumor uptake in scintigraphy with 99mTc-tektrotyd that was compatible with high SSTR expression by the tumor; (2) the spectacular and rapid clinical response of headache to medical treatment associated with good tolerance; (3) the adequate control of hyperprolactinemia and hypogonadism with cabergoline; (4) the low probability of complete surgical resection due to the high degree of invasiveness of the tumor (Knosp grades 3–4); and (5) the rapid (3 months) and striking response in terms of tumor size reduction (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>).</p><p id="par0035" class="elsevierStylePara elsevierViewall">In summary, our clinical case suggests that those patients with large and invasive NFPAs without neuro-ophthalmological involvement and little likelihood of complete surgical resection, that are associated with mild hyperprolactinemia and positive tumor uptake in SSTR scintigraphy, combined treatment with DA and SSA could be considered as an initial therapeutic alternative to surgical treatment.</p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Informed consent</span><p id="par0040" class="elsevierStylePara elsevierViewall">The patient signed the consent for the publication of the clinical case.</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Conflicts of interest</span><p id="par0045" class="elsevierStylePara elsevierViewall">The authors have no conflict of interest and financial support in relation to the present manuscript.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0005" "titulo" => "Informed consent" ] 1 => array:2 [ "identificador" => "sec0010" "titulo" => "Conflicts of interest" ] 2 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "multimedia" => array:1 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1559 "Ancho" => 2507 "Tamanyo" => 255822 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Axial (left above), sagittal (center above), and sagittal (right above) images of the SPECT-TC with <span class="elsevierStyleSup">99m</span>Tc-EDDA/HYNIC-Tyr3-Octreotide (tektrotyd) scintigraphy at diagnosis showing a hypercaptant lesion at the level of the pituitary tumor. Pituitary MRI at diagnosis showing an invasive pituitary tumor of 2.0<span class="elsevierStyleHsp" style=""></span>×<span class="elsevierStyleHsp" style=""></span>1.7<span class="elsevierStyleHsp" style=""></span>×<span class="elsevierStyleHsp" style=""></span>3.0<span class="elsevierStyleHsp" style=""></span>cm with suprasellar extension with greater involvement of the right side, extending to both cavernous sinuses and encompassing the right and partially left carotid (left down). Pituitary MRI 3 months (center down) and 6 months (right down) after starting combined therapy with lanreotide and cabergoline.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0015" "bibliografiaReferencia" => array:12 [ 0 => array:3 [ "identificador" => "bib0065" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Prevalence of pituitary adenomas: a community-based, cross-sectional study in Banbury (Oxfordshire, UK)" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "A. Fernandez" 1 => "N. Karavitaki" 2 => "J.A. Wass" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Clin Endocrinol (Oxf)" "fecha" => "2010" "volumen" => "72" "paginaInicial" => "377" "paginaFinal" => "382" ] ] ] ] ] ] 1 => array:3 [ "identificador" => "bib0070" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Prevalence, clinical features, and natural history of incidental clinically non-functioning pituitary adenomas" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "P. Iglesias" 1 => "K. Arcano" 2 => "V. Trivino" 3 => "P. García-Sancho" 4 => "J.J. Díez" 5 => "C. 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| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 4 | 4 | 8 |
| 2024 October | 27 | 14 | 41 |
| 2024 September | 51 | 9 | 60 |
| 2024 August | 40 | 10 | 50 |
| 2024 July | 32 | 16 | 48 |
| 2024 June | 35 | 11 | 46 |
| 2024 May | 30 | 17 | 47 |
| 2024 April | 27 | 12 | 39 |
| 2024 March | 53 | 15 | 68 |
| 2024 February | 48 | 7 | 55 |
| 2024 January | 50 | 7 | 57 |
| 2023 December | 33 | 1 | 34 |
| 2023 November | 37 | 7 | 44 |
| 2023 October | 72 | 6 | 78 |
| 2023 September | 35 | 1 | 36 |
| 2023 August | 27 | 2 | 29 |
| 2023 July | 58 | 4 | 62 |
| 2023 June | 19 | 8 | 27 |
| 2023 May | 34 | 2 | 36 |
| 2023 April | 32 | 2 | 34 |
| 2023 March | 26 | 6 | 32 |
| 2023 February | 17 | 8 | 25 |
| 2023 January | 22 | 7 | 29 |
| 2022 December | 16 | 8 | 24 |
| 2022 November | 27 | 9 | 36 |
| 2022 October | 19 | 12 | 31 |
| 2022 September | 25 | 15 | 40 |
| 2022 August | 19 | 10 | 29 |
| 2022 July | 13 | 7 | 20 |
| 2022 June | 18 | 7 | 25 |
| 2022 May | 11 | 5 | 16 |
| 2022 April | 19 | 11 | 30 |
| 2022 March | 19 | 11 | 30 |
| 2022 February | 18 | 3 | 21 |
| 2022 January | 23 | 6 | 29 |
| 2021 December | 15 | 6 | 21 |
| 2021 November | 0 | 1 | 1 |
| 2021 October | 1 | 0 | 1 |
| 2021 September | 1 | 2 | 3 |
| 2021 July | 1 | 0 | 1 |
| 2021 June | 16 | 10 | 26 |
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