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Abstract Following administration of the SARS-CoV-2 vaccine, many women worldwide reported short-term menstrual irregularities. Although menstrual bleeding, “the fifth vital sign”, is experienced by more than 300 million people on any given day worldwide, these changes were only partially studied. Irregular periods are important well beyond fertility and the discomfort they impose; they are associated with the risk of cardiovascular morbidity, chronic diseases, and premature mortality. Pre-clinical examination of the vaccine polymeric envelope indicates its accumulation in the ovaries. The somatic endocrine cells of the ovarian follicle - the granulosa cells (GCs)—participate in the strict hypothalamic-pituitary-ovarian (HPO) feedback loop that governs the menstrual cycle via endocrine and paracrine regulators, as AMH and Inhibins. We aimed to unravel the direct effect of the COVID-19 vaccine on GCs and link their post-vaccine activity to changes in menstrual patterns. Human primary GCs exposed in-vitro to the Pfizer COVID-19 vaccine BNT162b2, demonstrated no change in their viability but altered mRNA transcripts, specifically of the regulatory key factors: InhibinB was upregulated, whereas AMH was downregulated. We further examined pre- and post-vaccination blood samples from individual women and found a 2–3 folds change in the post-vaccination FSH/InhibinB protein level ratio, compared to their pre-vaccination values. This altered expression of InhibinB could significantly impact the HPO axis in vaccinated women and may ultimately influence the endometrium cyclicity, manifested clinically by the commonly reported changes in menstrual bleeding patterns.

PURPOSE: This study aimed to identify baseline clinical features associated with the outcomes of patients enrolled in the COMBI-MB phase II study of dabrafenib and trametinib treatment in patients with V600 BRAF-mutant metastatic melanoma with melanoma brain metastases (MBM). Exploratory biomarker analysis was also conducted as part of the synergistic COMBI-BRV trial (BRV116521), to identify molecular and immunologic changes associated with dabrafenib in MBMs and extracranial metastases (ECM). PATIENTS AND METHODS: Post hoc analysis was performed for baseline features of patients (n = 125) enrolled in COMBI-MB. Analyses were performed to identify baseline clinical features associated with intracranial response rate (ICRR), progression-free survival (PFS), and overall survival (OS). UNLABELLED: Exploratory biomarker analysis was performed on biospecimen collected in the COMBI-BRV trial in which patients with BRAF-mutant, resectable MBM were treated with dabrafenib for 10 to 14 days prior to craniotomy. Accessible ECM were resected or biopsied at the time of craniotomy. Biospecimens underwent molecular and immunologic profiling for comparative analyses. RESULTS: In COMBI-MB baseline treatment with corticosteroids was independently associated with lower ICRR [39% vs. 63%; OR, 0.323; 95 % confidence interval (CI), 0.105-0.996; P = 0.049] and shorter PFS (HR, 1.93; 95% CI, 1.06-3.51; P = 0.031). Additional significant associations identified in the multivariate analysis were improved PFS in patients with a BRAFV600E genotype (HR, 0.565; 95% CI, 0.321-0.996; P = 0.048) and improved OS in patients with Eastern Cooperative Oncology Group 0 (HR, 0.44; 95% CI, 0.25-0.78; P = 0.005). CONCLUSIONS: Corticosteroid treatment was associated with reduced ICRR and PFS in COMBI-MB, similar to results with immunotherapy for MBMs. Baseline corticosteroid treatment is a key factor to consider in MBM patient management and clinical trial design/interpretation.

Summary: Background: Sézary syndrome is an extremely rare and fatal cutaneous T-cell lymphoma (CTCL). Mogamulizumab, an anti-CCR4 monoclonal antibody, has recently been associated with increased progression-free survival in a randomized clinical trial in CTCL. We aimed to evaluate OS and prognostic factors in Sézary syndrome, including treatment with mogamulizumab, in a real-life setting. Methods: Data from patients with Sézary (ISCL/EORTC stage IV) and pre-Sézary (stage IIIB) syndrome diagnosed from 2000 to 2020 were obtained from 24 centers in Europe. Age, disease stage, plasma lactate dehydrogenases levels, blood eosinophilia at diagnosis, large-cell transformation and treatment received were analyzed in a multivariable Cox proportional hazard ratio model. This study has been registered in ClinicalTrials (SURPASSe01 study: NCT05206045). Findings: Three hundred and thirty-nine patients were included (58% men, median age at diagnosis of 70 years, Q1-Q3, 61–79): 33 pre-Sézary (9.7% of 339), 296 Sézary syndrome (87.3%), of whom 10 (2.9%) had large-cell transformation. One hundred and ten patients received mogamulizumab. Median follow-up was 58 months (95% confidence interval [CI], 53–68). OS was 46.5% (95% CI, 40.6%–53.3%) at 5 years. Multivariable analysis showed that age ≥ 80 versus

Nine drugs have been marketed for 10 years for the treatment of advanced melanoma (AM). With half of patients reaching a second line, the optimal sequence of treatments remains unclear. To inform policy-makers about their efficiency, we performed a cost-effectiveness analysis of sequential strategies in clinical practice in France, for BRAF-mutated and wild-type patients. A multistate model was developed to describe treatment sequences, associated costs, and health outcomes over 10 years. Sequences, clinical outcomes, utility scores, and economic data were extracted from the prospective Melbase cohort, collecting individual data in 1518 patients since 2013, from their AM diagnosis until their death. To adjust the differences in patients’ characteristics among sequences, weighting by inverse probability was used. In the BRAF-mutated population, the MONO-targeted therapies (TT)-anti-PD1 sequence was the less expensive, whereas the anti-PD1-BI-TT sequence had an incremental cost-effectiveness ratio (ICER) of 180,441 EUR/QALY. Regarding the BRAF wild-type population, the three sequences constituted the cost-effective frontier, with ICERs ranging from 116 to 806,000 EUR/QALY. For BRAF-mutated patients, the sequence anti-PD1-BI-TT appeared to be the most efficient one in BRAF-mutated AM patients until 2018. Regarding the BRAF wild-type population until 2018, the sequence starting with IPI+NIVO appeared inefficient compared to anti-PD1, considering the extra cost for the QALY gained.

Tyrosine kinase inhibitors (TKIs) are used as targeted cancer therapies in adults and have an off-label pediatric application for the treatment of Langerhans cell histiocytosis. A multitarget LC-MS/MS method was developed and validated for the determination of alectinib, alectinib-M4, binimetinib, cobimetinib, crizotinib, dabrafenib, encorafenib, imatinib, lorlatinib, osimertinib, AZ5104, and trametinib. A total of 150 µL of internal standard methanolic solution was added to 50 µL of plasma sample to precipitate proteins. After centrifugation, 10 µL of the supernatant was injected into the chromatographic system. The chromatographic separation was conducted on a Kinetex C18 Polar column with a gradient of 2 mM ammonium formate in 0.1% formic acid and acetonitrile over 5 min. Limits of detection and quantification, linearity, accuracy, precision, selectivity, carryover, matrix effect, recovery, and stability were evaluated and satisfied EMA guidelines on bioanalytical methods. This method has been successfully applied to the therapeutic drug monitoring (TDM) of adults with melanoma and lung cancer, as well as children with histiocytosis, to improve the pharmacokinetic data for these drugs, with the aim of enhancing the therapeutic management and follow-up of patients. Blood concentrations of trametinib and binimetinib were different in the two groups, highlighting the age-related inter-individual variability of these molecules and the need for TDM.

The aim of this multi-centre French retrospective study was to identify severe, i.e. crusted and profuse, scabies patients. Records were retrieved from 22 Dermatology or Infectious Diseases departments in the Ile-de-France from January 2009 to January 2015 to characterize epidemiology, demography, diagnosis, contributing factors, treatment features, and outcomes in severe scabies. A total of 95 inpatients (57 crusted and 38 profuse) were included. A higher number of cases was observed among elderly patients (>75 years), mostly living in institutions. Thirteen patients (13.6%) reported a history of previously treated scabies. Sixty-three patients (66.3%) had been seen by a previous practitioner for the current episode (up to 8 previous visits). Initial misdiagnosis (e.g. eczema, prurigo, drug-related eruptions, psoriasis) was documented in 41 patients (43.1%). Fifty-eight patients (61%) had already received 1 or more previous treatments for their current episode. Forty percent received corticosteroids or acitretin for an initial diagnosis of eczema or psoriasis. Median time from the onset of symptoms to the diagnosis of severe scabies was 3 months (range 0.3–22). Itch was present in all patients at diagnosis. Most patients (n=84, 88.4%) had comorbidities. Diagnostic and therapeutic approaches varied. Complications occurred in 11.5% of cases. To date, there is no consensus for diagnosis and treatment, and future standardization of is required for optimal management.

Background: To explore the long-term safety and dynamics of the immune response induced by the second and third doses of the BNT162b2 mRNA COVID-19 vaccine in adolescents with juvenile-onset autoimmune inflammatory rheumatic diseases (AIIRDs) compared with healthy controls. Methods: This international prospective study included adolescents with AIIRDs and controls vaccinated with two (AIIRDs n = 124; controls n = 80) or three (AIIRDs n = 64; controls n = 30) doses of the BNT162b2 vaccine, evaluated for vaccine side-effects, disease activity, COVID-19 breakthrough infection rates and severity, and anti-spike S1/S2 IgG antibody titers in a sample from both groups. Results: The vaccination safety profile was favorable, with most patients reporting mild or no side-effects. The rheumatic disease remained stable at 98% and 100% after the second and third doses, respectively. The two-dose vaccine induced comparable seropositivity rates among patients (91%) and controls (100%), (p = 0.55), which declined within 6 months to 87% and 100%, respectively (p = 0.3) and increased to 100% in both groups after the third vaccine dose. The overall post-vaccination COVID-19 infection rate was comparable between patients and controls, 47.6% (n = 59) and 35% (n = 28), respectively; p = 0.5278, with most infections occurring during the Omicron surge. In relation to the last vaccination, time-to-COVID-19 infection was similar between patients and controls, at a median of 5.5 vs. 5.2 months, respectively (log-rank p = 0.1555). Conclusion: The safety profile of three doses of the BNT162b2 mRNA vaccine was excellent, with adequate humoral response and similar efficacy among patients and controls. These results support the recommendation for vaccinating adolescents with juvenile-onset AIIRDs against COVID-19.

Background: Surgery is the primary treatment for basal cell carcinoma (BCC). In locally advanced basal cell carcinoma (laBCC), surgery may cause functional or aesthetic damage. In laBCC, neoadjuvant administration of vismodegib, an inhibitor of the Hedgehog signaling pathway, may reduce tumor size, facilitate resection, and reduce functional and aesthetic consequences of surgery. The VISMONEO study assessed efficacy and safety of vismodegib in neoadjuvant treatment of laBCC. Methods: VISMONEO (NCT02667574) is an open-label, noncomparative, multicenter, phase 2 study. Patients with ≥1 histologically confirmed facial BCC, inoperable or operable with functional or major aesthetic sequelae risk, were included. Oral vismodegib 150 mg was administered once daily for 4 to 10 months before planned surgery, which was performed once the best response under vismodegib was observed. Primary endpoint was percentage of patients with BCC with tumor downstaging following surgical resection after neoadjuvant vismodegib. Downstaging was defined according to a 6-stage surgical classification related to the aesthetic and functional consequences of surgery. Findings: 55 patients (median age: 73 years) with laBCC were included from November 2014 to June 2015. At inclusion, 4 patients were inoperable, 15 were operable with a major functional risk, and 36 were operable with a minor functional risk or a major aesthetic risk. Mean size of target lesion was 47.3 mm (SD: 27.2 mm). 44 patients presented with downstaging after vismodegib treatment (80%; 95% confidence interval [CI], 67 to 90). Of these 44 patients, 27 had a complete response (25 proved by biopsy). Mean treatment duration was 6.0 months. Overall Response Rate according to RECIST 1.1 criteria was 71% (95% CI, 59 to 88). At 3-years of follow-up, 16/44 patients had known recurrence (36%; 95%CI, 22 to 51). Interpretation: Neoadjuvant vismodegib allows for a downstaging of the surgical procedure for laBCCs in functionally sensitive locations. Funding: VISMONEO was funded by F. Hoffmann-La Roche Ltd.

Este artículo analiza las transformaciones de las prácticas financieras de los sectores populares del cordón industrial rosarino durante los gobiernos kirchneristas. En este periodo, los trabajadores de la economía popular accedieron por primera vez al crédito al consumo de forma masiva, como consecuencia de su incorporación al sistema de protección social y de la formalización parcial de trabajos precarios. Los trabajadores percibieron esta transformación de forma ambivalente: por un lado, el acceso a dicho crédito significó una forma de inclusión para quienes no habían tenido acceso a este por falta de ingresos estables; por otro lado, expuso a los trabajadores de la economía popular a una nueva forma de explotación basada en el desfasaje temporal entre las finanzas y el trabajo precario, que agudizó las estratificaciones vigentes dentro de los sectores populares. Para incluir sin explotar, resulta imprescindible vincular finanzas y derechos.

Aim: To describe treatment patterns among patients with stage III melanoma who underwent surgical excision in years 2011–2016, and assess outcomes among patients who subsequently received systemic adjuvant therapy versus watch-and-wait. Methods: Chart review of 380 patients from 17 melanoma centers in North America, South America and Europe. Results: Of 129 (34%) patients treated with adjuvant therapy, 85% received interferon α-2b and 56% discontinued treatment (mostly due to adverse events). Relapse-free survival was significantly longer for patients treated with adjuvant therapy versus watch-and-wait (hazard ratio = 0.63; p < 0.05). There was considerable heterogeneity in adjuvant treatment schedules and doses. Similar results were found in patients who received interferon-based adjuvant therapy. Conclusion: Adjuvant therapies with better safety/efficacy profiles will improve clinical outcomes in patients with stage III melanoma.

Information on the role of radiotherapy in anti-PD-1 monoclonal antibody-treated melanoma patients is limited. We report on a prospective cohort of advanced melanoma patients treated simultaneously with radiotherapy and anti-PD-1 therapy between 01/01/15 and 30/06/16. Tumor evaluations (RECIST 1.1) were performed every 3 months on radiated and non-radiated lesions. Twenty-five advanced melanoma patients (64% AJCC stage IV M1c, 64% on second-line treatment or more, 60% with elevated LDH serum levels) were included. Radiotherapy was performed early (median: 24 days) after the first anti-PD-1 dose in 15 patients with rapidly progressing symptomatic lesion(s) or later (median: 5.4 months) in 10 patients with progressive disease (PD) despite PD-1 blockade. Radiotherapy was limited to one organ in 24 patients and consisted mainly of hypo-fractioned radiotherapy (median dose 26 Gy in 3–5 fractions, 17 patients) or brain radiosurgery (5 patients). Median follow-up after first anti-PD-1 dose was 16.9 m (range 2.7-27.4), with 44% of patients alive at last follow-up. For radiated lesions, rates of complete (CR), partial (PR) responses, stable disease (SD) or PD were 24%, 12%, 24%, and 32%, respectively. For non-radiated lesions, rates of CR, PR, SD, and PD were 20%, 19%, 12%, and 40%, respectively. Responses achieved after radiotherapy for radiated and non-radiated areas were correlated (Pearson correlation r: 0.89, P

Merkel cell carcinoma (MCC) is a rare skin cancer caused by Merkel cell polyomavirus (MCPyV) infection and/or ultraviolet radiation–induced somatic mutations. The presence of tumor-infiltrating lymphocytes is evidence that an active immune response to MCPyV and tumor-associated neoantigens occurs in some patients. However, inhibitory immune molecules, including programmed death-1 (PD-1) and programmed death-ligand 1 (PD-L1), within the MCC tumor microenvironment aid in tumor evasion of T-cell–mediated clearance. Unlike chemotherapy, treatment with anti–PD-L1 (avelumab) or anti–PD-1 (pembrolizumab) antibodies leads to durable responses in MCC, in both virus-positive and virus-negative tumors. As many tumors are established through the evasion of infiltrating immune-cell clearance, the lessons learned in MCC may be broadly relevant to many cancers.

Clinical outcomes of advanced melanoma of unknown primary (MUP) in the era of novel therapies have been scarcely studied. To investigate the efficacy and safety of systemic treatments in patients with advanced MUP compared to patients with stage-matched melanoma of known cutaneous primary (cMKP). Based on the nationwide MelBase prospective database, this study included advanced melanoma patients treated from March 2013 to June 2021 with first-line immunotherapies, targeted therapies, or chemotherapy. Co-primary outcomes were progression-free survival and overall survival. Secondary outcome was treatment-related toxicities. Multivariate and propensity score analyses were performed. Of 1882 patients, 265 (14.1%) had advanced MUP. Patients with advanced MUP displayed more often unfavorable initial prognostic factors than those with cMKP. Progression-free and overall survival did not differ significantly between the groups (P =.73 and P =.93, respectively), as well as treatment-related toxicity rate and severity, regardless of treatment type. No record of standard diagnostic criteria of MUP used in the participating centers. Although patients with MUP had less favorable baseline prognostic factors, they benefited from the novel therapies as much as those with cMKP. They should be managed according to similar strategies. [ABSTRACT FROM AUTHOR]