Primary Mucosal Melanoma: Clinical Experience from a Single Italian Center.

(1) Background: Mucosal melanoma (MM) is a rare tumor, accounting for about 1% of all diagnosed melanomas. The etiology and pathogenesis of this tumor are unknown. It is characterized by an aggressive phenotype with poor prognosis and a low response rate to approved treatments. (2) Methods: We retrospectively analyzed the clinical features, treatments and outcomes of patients diagnosed with MM from different sub-sites (head and neck, gynecological and gastro-intestinal region) between 2013 and 2023 at our Institute. Survival times were estimated with the Kaplan-Meier method. Multivariate Cox regression was used to test the independence of significant factors in univariate analysis. (3) Results: Twenty-five patients were included in this study; the disease was equally distributed among females and males. The median age at diagnosis was 74 years old. The majority had MM originating from the head and neck (56%), particularly from the nasal cavity. BRAF V600 mutations were detected in 16% of the study population, limited to gastro-intestinal and gynecological MM. At diagnosis, at least half the patients (52%) had the disease located also at distant sites. The median overall survival (OS) in the whole study population was 22 months, with a longer OS for patients diagnosed at an early stage (38 months, p < 0.001). Longer OSs were reported for head and neck MM compared to other anatomic regions (0.06). Surgery of the primary tumor and radiotherapy were performed in 64% and 36% of the study population, respectively. Radiotherapy was performed only in head and neck MM. At multivariate analysis, the single factor that showed a reduced hazard ratio for death was radiotherapy. (4) Conclusions: The overall survival of MM from different sub-sites treated at our Italian Institution was 22 months, with better outcomes for early-stage disease and head and neck MM. Performing radiotherapy may have a protective effect on OS for head and neck MM. New treatment strategies are urgently needed to improve the outcome in this disease.

Clinical and mutational profile of AT-rich interaction domain 1A-mutated cancers.

Aim: AT-rich interaction domain 1A (ARID1A) encodes a key component of the SWItch/Sucrose Non-Fermentable (SWI/SNF) chromatin remodeling complex that participates in gene expression. ARID1A alterations are quite common among cancer patients, although their role remains debated. The aim of this article was to study ARID1A-mutated cancer patients. Methods: Molecular and clinical data of cancer patients evaluated at Phase 1 Unit of Fondazione Policlinico Universitario A. Gemelli IRCCS were collected. Molecular analyses were performed using FoundationOne® CDx (Foundation Medicine Inc., Cambridge, MA, United States). Cancer patients with at least one molecular alteration in ARID1A gene were identified as ARID1A+. Results: Among the 270 patients undergoing molecular analysis, we found 25 (9%) with at least one pathogenic alteration in ARID1A. The vast majority of these patients were female (84%). The median age at diagnosis was 59; most of the cancers (15, 60%) were gynecological (especially endometrioid endometrial cancers and clear cell ovarian cancers), diagnosed at an early stage. Frameshift alterations in ARID1A were the most common (19/31, 61%) alterations. The median number of mutations in ARID1A+ population was higher compared to ARID1A- population (6 vs. 4), as well as tumor mutational burden (TMB) [20 mutations/megabase (mut/Mb) vs. 1.26 mut/Mb]. Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), phosphatase and tensin homolog (PTEN), catenin beta 1 (CTNNB1), and lysine methyltransferase 2D (MLL2) mutations were enriched in ARID1A+ population. In this cohort, ARID1A did not display any relation with response to platinum chemotherapy. Cancers with double alterations in ARID1A (ARID1A2+) were all gynecological cancers (83% endometrioid endometrial cancers). Conclusions: This analysis provides clinical and molecular details about the phenotypes of ARID1A+ cancers, in particular the subgroup of gynecologic cancers. The high frequency of concurrent mutations in the phosphoinositide 3-kinase (PI3K) pathway among endometrioid endometrial cancers may support the proposal of a new treatment strategy based on the combination of ataxia telangiectasia and Rad3-related (ATR) inhibitor and PIK3CA inhibitor.

Overview of Trop-2 in Cancer: From Pre-Clinical Studies to Future Directions in Clinical Settings.

Trophoblast cell surface antigen-2 (Trop-2) is a glycoprotein that was first described as a membrane marker of trophoblast cells and was associated with regenerative abilities. Trop-2 overexpression was also described in several tumour types. Nevertheless, the therapeutic potential of Trop-2 was widely recognized and clinical studies with drug-antibody conjugates have been initiated in various cancer types. Recently, these efforts have been rewarded with the approval of sacituzumab govitecan from both the Food and Drug Administration (FDA) and European Medicines Agency (EMA), for metastatic triple-negative breast cancer patients. In our work, we briefly summarize the various characteristics of cancer cells overexpressing Trop-2, the pre-clinical activities of specific inhibitors, and the role of anti-Trop-2 therapy in current clinical practice. We also review the ongoing clinical trials to provide a snapshot of the future developments of these therapies.

Efficacy and safety of antiemetic regimens for highly emetogenic chemotherapy-induced nausea and vomiting: A systematic review and network meta-analysis.

BACKGROUND: Several regimens have been introduced in clinical practice in the last twenty years to treat chemotherapy-induced nausea and vomiting (CINV). However, direct comparative data remain insufficient, as many new regimes lack head-to-head comparisons. In this study, through an indirect comparison, we overcome this limit by providing the most up-to-date estimate of the efficacy and safety of all combinations used for HEC-induced nausea and vomiting. PATIENTS AND METHODS: We retrieved randomized controlled trials (RCTs) published in Pubmed, Embase, and Cochrane Library until June, 30th 2022. We included phase II-III RCTs, including adults with any cancer receiving HEC, and compared different antiemetic regimes to prevent CINV. The primary outcome was the overall complete response (defined as the absence of vomiting and of the use of rescue drugs from 0 to 120 hrs since chemotherapy); secondary outcomes were acute (absence of vomiting and use of rescue medicine 0-24 hrs after chemotherapy) and delayed (24-120 hrs) response and adverse events. RESULTS: A total of 53 RCTs enrolling 22 228 patients were included. We classified the different antiemetic regimes into 21 different groups. Overall, 3- or 4-drug regimens containing a combination of dexamethasone, 5HT3 antagonists, mirtazapine or olanzapine with or without NK antagonists, yielded the highest probability to be the most effective regimen in terms of complete response. Regimens containing a combination of dexamethasone and 5-HT3 antagonist have the lowest probability of being the most effective regimen in terms of complete, acute, and delayed response. CONCLUSION: In our network meta-analysis, 4-drug regimens with olanzapine displayed the highest probability of efficacy in terms of complete response. A 3-drug regimen with olanzapine represents a valid option in a limited resource context.

Molecular Profile and Matched Targeted Therapy for Advanced Breast Cancer Patients.

(1) Background: Precision oncology is opening new treatment opportunities for patients suffering from solid tumors. In the last two decades, the advent of CDK4/6 inhibitors, immunotherapy, and antibody-drug conjugates (ADC) improved survival outcomes for advanced or metastatic breast cancers (BC). Nevertheless, some patients progress to approved therapies and still maintain good clinical conditions. (2) Methods: With the aim to estimate the accrual rate to experimental precision oncology treatments, we collected molecular and clinical characteristics of BC patients evaluated at Phase 1 Unit of Fondazione Policlinico Gemelli. Clinical data were retrieved from hospital records. Molecular analysis was performed using Next-Generation Sequencing (NGS) FoundationOne CDx on tissue or blood. (3) Results: Among the 38 BC patients referred to our unit, 35 completed the genomic analysis. All patients were female with advanced (mean number of metastatic sites: 3, range 1-6) BC. Median age at our evaluation was 52 (IQR, 48-59). ECOG PS was good in 97% of the study population, although heavily pre-treated (median number of systemic treatments: 5, IQR 3-7). Half of referred patients were HR+/HER2- BC, with 39% triple negative breast cancer (TNBC). NGS testing was performed on relapsed disease among most (71%) participants, in particular lymph nodes and soft tissue. Liquid biopsy was requested in 23% of cases. The median time from sample collection to NGS testing was 1 month and from diagnosis 54 months. The median value of mutations, VUS, and TMB were 6, 11, and 5, respectively. TP53, PIK3CA, BRCA2, ESR1, and RAD21 were the genes with the highest number of molecular alterations. In 5 patients (14%), the molecular analysis was helpful to assign targeted therapy in the context of clinical trials with a median progression-free survival of 5 months. (4) Conclusions: HR+/HER2- and TNBC were the most frequent subtypes referred for NGS testing. Tissue biopsy of relapsed disease was feasible in 71% of cases. The molecular analysis offered a new treatment opportunity in 14% of patients. The real benefit of these treatments remains to be evaluated in larger cohorts.

Comparing efficacy and safety of upfront treatment strategies for anaplastic lymphoma kinase-positive non-small cell lung cancer: a network meta-analysis.

Aim: This article is based on our previous research, which was presented as a post at the Congress Aiom 2022 Congress and published in Tumori Journal as Conference Abstract (Tumori J. 2022;108:1-194. doi: 10.1177/03008916221114500). In this paper, a comprehensive presentation of all the achieved results is provided. Several tyrosine kinase inhibitors (TKIs) have been investigated to treat patients with anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC). However, direct comparisons between these TKIs are lacking, with many only being compared to crizotinib. To address this gap, a network meta-analysis was conducted to compare the efficacy and safety of various first-line systemic therapies for ALK-positive NSCLC. Methods: A thorough search of PubMed, Embase, and Cochrane Library was performed to identify randomized controlled trials (RCTs) published between January 01, 2000 and April 01, 2022, and included trials that investigated upfront treatments for this molecular subgroup and reported overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and adverse events (AEs) of grade 3 or higher (grade ≥ 3 AEs). Results: The analysis included 9 RCTs with 2,443 patients receiving eight different treatments: alectinib (at two different dosages), brigatinib, ceritinib, crizotinib, ensartinib, lorlatinib, and chemotherapy. Second and third-generation TKIs significantly prolonged PFS compared to crizotinib, with lorlatinib having the highest probability of yielding the most favorable PFS, followed by alectinib (300 mg or 600 mg). However, only alectinib has been shown to significantly prolong OS compared to crizotinib to date. Lorlatinib appears superior in reducing the risk of central nervous system (CNS) progression, followed by alectinib 600 mg. Ceritinib had the highest rate of AEs, followed by lorlatinib and brigatinib. Conclusions: Based on the network meta-analysis, alectinib and lorlatinib emerged as the most promising upfront treatment options. These treatments provide prolonged disease control while maintaining an acceptable safety profile.

Debates Feministas en Revistas Argentinas de la Primera Mitad del Siglo XX / Debates Feministas em Revistas Argentinas da Primeira Metade do Século XX / Feminists Debates in Argentine Magazines of the First Half of the 20th Century

En el ámbito de la investigación histórica sobre las particularidades de los "feminismos" en la Argentina, el objetivo del presente artículo es abordar esta problemática, con base en las revistas feministas (Nuestra causa, Vida Femenina, Criterio), publicadas en el transcurso de la mitad del siglo XX. En continuidad con líneas de investigación anteriores, proponemos profundizar en los debates producidos entre las mujeres feministas, que, con el fin de la defensa de derechos, exponen diversos grupos ideológicos alojados en instituciones que a menudo están en conflicto. Las discusiones reflejadas por la lectura de fuentes de primera mano nos han dado la posibilidad de llegar a algunas conclusiones preliminares sobre la pertenencia ideológica-política de los grupos de mujeres, que sustenta la edición de las revistas, y las razones de los debates. Dada las posibilidades de espacio, recortamos, tres corrientes que se desprenden del análisis de las fuentes: la vertiente feminista de tradición socialista, las agrupaciones que representan ideologías liberales y por último las mujeres católicas. Con respecto a éste último grupo interesará a los fines de la discusión incorporar, la Revista Sur, dirigida por Victoria Ocampo (1890-1986), que permitirá examinar los debates y discrepancias ideológicas entre las mujeres católicas y las liberales.

No âmbito da pesquisa histórica sobre as particularidades dos "feminismos" na Argentina, o objetivo deste artigo é abordar esta questão com base em levantamento das revistas feministas (Nuestra causa, Vida Femenina, Criterio), publicadas ao longo da primeira metade do século XX. Em continuidade com linhas de pesquisa anteriores, propomos aprofundar nos debates produzidos entre as mulheres feministas que, com o objetivo de defender direitos, revelam diversos grupos ideológicos abrigados em instituições frequentemente em confronto. As discussões decorrentes da leitura de fontes primárias nos deram a possibilidade de chegar a algumas conclusões preliminares sobre a pertença ideológico-política dos grupos de mulheres que sustentam a edição das revistas, e as razões para os debates. Dadas as possibilidades de espaço, apresentaremos três correntes que emergem da análise das fontes: o lado feminista da tradição socialista, os grupos que representam as ideologias liberais e, finalmente, as mulheres católicas. Com respeito a este último grupo, incorporamos a revista Sur, dirigida por Victoria Ocampo (1890-1986), que nos permitirá examinar os debates e as discrepâncias ideológicas entre as mulheres católicas e liberais.

Within the framework of historical inquiries into the specific features of "feminisms" in Argentina, this article aims to address this issue on the basis of a new study of feminist journals (Nuestra causa, Vida Femenina, Criterio), published in the mid-20th century. In keeping with previous lines of research, we intend to delve into the debates between feminist women, which, with the purpose of defending rights, reveal diverse ideological groups supported by institutions that were often at odds with each other. The discussions reflected by the reading of first-hand sources will give us the possibility of reaching some preliminary conclusions about the ideological-political affiliation of the women's groups that underpins the publication of the magazines and the reasons for the debates. Given the possibilities of space, we will limit ourselves to three currents that emerge from the analysis of the sources: the feminist trend in the socialist tradition, the groups representing liberal ideologies and, finally, the Catholic women. With regard to the latter group, for the purposes of the discussion, we will be concerned here with the Revista Sur, directed by Victoria Ocampo (1890-1986), which will allow us to examine the debates and ideological discrepancies between Catholic and liberal women.

New first-line immunotherapy-based combinations for metastatic renal cell carcinoma: A systematic review and network meta-analysis.

Several first-line immune-checkpoints inhibitors (ICI) based combinations have been studied in metastatic renal cell carcinoma (mRCC) without any direct comparison between the regimens. The objective of this systematic review and network meta-analysis was to provide the most updated evidence about the preferred first line ICI-based regimen for mRCC. We searched various databases, including PubMed, Web of Science and Scopus and the major conference proceedings (ASCO, ESMO). Eligible studies were randomized trial, published before June 2021 that evaluated first-line, ICI-based combinations compared with the standard of care in mRCC. Screening was performed independently by two investigators. A Cochrane risk-of-bias tool was used to assess trial quality. Relative effects of competing treatments were assessed by Bayesian network meta-analysis. The Preferred Reporting Items for Systematic Reviews and Meta-analyses guideline was used. Outcomes included overall survival (OS), progression-free survival (PFS), overall response rate, complete response and adverse events. Six trials with 5478 patients comparing 7 treatments were identified. Network meta-analysis showed that lenvatinib plus pembrolizumab had the highest probability to be the best treatment in terms of OS (surface under the cumulative ranking (SUCRA) 80.7%) and PFS (SUCRA 99.6%), while in sarcomatoid patients, nivolumab plus cabozantinib had the highest rank in terms of survival outcomes (SUCRA 85.8% and SUCRA 77.3%, respectively). Although we established a ranking among new first-line mRCC treatment combinations, the absence of direct comparisons between the multiple treatment options represents a major hurdle in establishing optimal therapeutic sequences. Our results could represent a starting point for head-to-head trials between the most promising combinations.

Oncologic Drugs Approval in Europe for Solid Tumors: Overview of the Last 6 Years.

(1) Background: Drug development in oncology is changing rapidly. The aim of the present study was to provide an insight into the features of anti-tumor drugs approved in Europe; (2) Methods: We included all the indications for solid tumors issued by the European Medicines Agency (EMA) between 2015 and 2020. We extracted data from European Public Assessments Reports (EPAR), including drug name, mechanism of action, setting, features of pivotal clinical trials, primary end-points, quality of life (QoL); (3) Results: In the explored period, EMA issued 132 new indications (81 indications' extensions) for 62 oncology drugs. In about half of indications (47%), the approval was biomarker-based. Immune check point inhibitors (ICIs) and signal transduction inhibitors were the two most representative drug categories (62%). Most of the indications were for the advanced setting (91%) and front-line therapy (66%). The most common tumor types were non-small cell lung cancer (24%), breast (16%), and melanoma (10%). Two thirds of the indications (73%) were approved based on phase III trials. Overall survival (OS) represented the primary end-point only in 39% of indications, mainly limited to advanced setting (98%) and ICI trials (80%). Almost all (94%) cell cycle and DNA repair mechanism inhibitors were approved based on progression free survival (PFS) data. In pivotal trials with signal transduction inhibitors, objective response rate (ORR) was the prevalent (45%) primary end-point. QoL was never considered as primary end-point; (4) Conclusions: In this analysis, we intended to offer an updated picture of the recent drug development in oncology. Most of the efforts led to broadening indications of pre-existing molecules, with signal transduction inhibitor and ICIs contending the leadership. Twenty-seven percent of the indication were approved without a phase III trial. The majority of drugs entered the market without evidence of OS or QoL benefit but based on surrogate outcomes.

Toll-Like Receptors in Stem/Progenitor Cells.

One of the bridges that control the cross-talk between the innate and adaptive immune systems is toll-like receptors (TLRs). TLRs interact with molecules shared and maintained by the source pathogens, but also with endogenous molecules derived from injured tissues (damage/danger-associated molecular patterns - DAMPs). This is likely why some kinds of stem/progenitor cells (SCs) have been found to express TLRs. The role of TLRs in regulating basal motility, proliferation, processes of differentiation, self-renewal, and immunomodulation has been demonstrated in these cells. In this book chapter, we will discuss the many different functions assumed by the TLRs in SCs, pointing out that, depending on the context and the type of ligands they perceive, they may have different effects. In addition, the role of TLR in SC's response to specific tissue damage and in reparative processes will be addressed, as well as how the discovery of molecules mediating TLR signaling's differential function may be decisive for the development of new therapeutic strategies. Given the available studies on TLRs in SCs, the significance of TLRs in sensing an injury to stem/progenitor cells and evaluating their action and reparative activity, which depends on the circumstances, will be discussed here. It could also be possible that SCs used in therapy could theoretically be exposed to TLR ligands, which could modulate their in vivo therapeutic potential. In this context, we need to better understand the mechanisms of action of TLRs on SCs and learn how to regulate these receptors and their downstream pathways in a precise way in order to modulate SC proliferation, survival, migration, and differentiation in the pathological environment. In this way, cell therapy may be strengthened and made safer in the future.

Breast Cancer Drug Approvals Issued by EMA: A Review of Clinical Trials.

Breast cancer represents the first cause of cancer worldwide and the leading cause of cancer mortality for women. Therefore, new therapies are needed to improve the prognosis of women diagnosed with this disease. In this review, we summarize the new drug indications for the treatment of breast cancer approved by European Medicines Agency between January 2015 and June 2021. In particular, we analyzed the clinical trials results leading to approvals and their update (when available), according to setting (localized and locally advanced or metastatic) and clinical features (hormone receptor positive, HER2 positive, triple negative, BRCA 1/2 mutation). The aim of this paper is to describe the clinical benefit obtained with the new indications.

In silico drug repurposing in COVID-19: A network-based analysis.

The SARS-CoV-2 pandemic is a worldwide public health emergency. Despite the beginning of a vaccination campaign, the search for new drugs to appropriately treat COVID-19 patients remains a priority. Drug repurposing represents a faster and cheaper method than de novo drug discovery. In this study, we examined three different network-based approaches to identify potentially repurposable drugs to treat COVID-19. We analyzed transcriptomic data from whole blood cells of patients with COVID-19 and 21 other related conditions, as compared with those of healthy subjects. In addition to conventionally used drugs (e.g., anticoagulants, antihistaminics, anti-TNFα antibodies, corticosteroids), unconventional candidate compounds, such as SCN5A inhibitors and drugs active in the central nervous system, were identified. Clinical judgment and validation through clinical trials are always mandatory before use of the identified drugs in a clinical setting.

Strategies for Psychiatric Rehabilitation and their Cognitive Outcomes in Schizophrenia: Review of Last Five-year Studies.

BACKGROUND: Cognitive deficits are core features of Schizophrenia, showing poor response to antipsychotic treatment, therefore non-pharmacological rehabilitative approaches to such a symptom domain need to be identified. However, since not all patients with Schizophrenia exhibit the same cognitive impairment profile, individualized rehabilitative approaches should be set up. OBJECTIVES: We explored the last five-year literature addressing the issue of cognitive dysfunction response to rehabilitative methodologies in Schizophrenia to identify possible predictors of response and individualized strategies to treat such a dysfunction. CONCLUSION: A total of 76 studies were reviewed. Possible predictors of cognitive rehabilitation outcome were identified among patient-specific and approach-specific variables and a general overview of rehabilitative strategies used in the last five years has been depicted. Studies suggest the existence of multifaced and multi-domain variables that could significantly predict pro-cognitive effects of cognitive rehabilitation, which could also be useful for identifying individual-specific rehabilitation trajectories over time.An individualized rehabilitative approach to cognitive impairment in Schizophrenia is possible if taking into account both patient and approach specific predictors of outcomes.

Involvement of vascular endothelial growth factor in schizophrenia.

Vascular endothelial growth factor (VEGF), which acts as an angiogenic and neurotrophic factor, is involved the regulation of cerebral blood volume and flow in Schizophrenia (SCZ). Several evidence indicates that modification of brain blood circulation due to alterations in the VEGF system affects cognitive performance and brain function in patients with SCZ. The aim of this study is: 1) To analyze the literature data concerning the role of VEGF in modulating the angiogenic response in SCZ. These data are controversial because some studies found elevated VEGF serum levels of VEGF in patients with SCZ, whereas others demonstrated no significant differences between SCZ patients and controls. 2)To analyze the role of VEGF as a predictive factor on the effects of antipsychotics agents used in the treatment of SCZ. In this context, high VEGF levels, associated to better responses to antipsychotics, might be predictive of the use of first generation antipsycotic drugs, whereas low VEGF levels, expression of resistance to therapy, might be predictive for the use of second generation antipsycotic drugs.

Selective Use of Radioactive Iodine Therapy for Papillary Thyroid Cancers With Low or Lower-Intermediate Recurrence Risk.

CONTEXT: Current guidelines recommend a selective use of radioiodine treatment (RAI) for papillary thyroid cancer (PTC). OBJECTIVE: This work aimed to determine how policy changes affect the use of RAI and the short-term outcomes of patients. METHODS: A retrospective analysis of longitudinal data was conducted in an academic referral center of patients with nonaggressive PTC variants; no extrathyroidal invasion or limited to soft tissues, no distant metastases, and 5 or fewer central-compartment cervical lymph node metastases. In cohort 1, standard treatments were total thyroidectomy and RAI (May 2005-June 2011); in cohort 2 decisions on RAI were deferred for approximately 12 months after surgery (July 2011-December 2018). Propensity score matching was used to adjust for sex, age, tumor size, lymph node status, and extrathyroidal extension. Intervention included immediate RAI or deferred choice. Main outcome measures were responses to initial treatment during 3 or more years of follow-up. RESULTS: In cohort 1, RAI was performed in 50 of 116 patients (51.7%), whereas in cohort 2, it was far less frequent: immediately in 10 of 156 (6.4%), and in 3 more patients after the first follow-up data. The frequencies of structural incomplete response were low (1%-3%), and there were no differences between the 2 cohorts at any follow-up visit. Cohort 2 patients had higher rates of "gray-zone responses" (biochemical incomplete or indeterminate response). CONCLUSION: Selective use of RAI increases the rate of patients with "uncertain" status during early follow-up. The rate of structural incomplete responses remains low regardless of whether RAI is used immediately. Patients should be made aware of the advantages and drawbacks of omitting RAI.

Combination Therapy of High-Dose Rabeprazole Plus Metronomic Capecitabine in Advanced Gastro-Intestinal Cancer: A Randomized Phase II Trial.

BACKGROUND: In recent years, proton pump inhibitors (PPIs) have been investigated at high-dose to modulate tumor microenvironment acidification thus restoring chemotherapeutic sensitivity. This is the first trial to study activity and safety of repurposing high dose rabeprazole combined with metronomic capecitabine (mCAP). METHODS: A phase II study in which patients with gastrointestinal cancer, refractory to standard treatments, who had a life expectancy >3 months, were blind randomized 1:1 to mCAP, 1500 mg/daily, continuously with or without rabeprazole 1.5 mg/kg bid, three days a week. The primary endpoint was 3-months progression-free survival (PFS). The secondary endpoints were clinical benefit (CB) and overall survival (OS). Safety and plasma concentrations of capecitabine and its metabolites (5'-DFUR and 5-FU) were also evaluated. RESULTS: Sixty-seven (median age 69 years; 63% male; 84% colorectal cancer, 76% ECOG-PS ≤ 1; 84% pretreated with two or more lines of chemotherapy) out of 90 patients screened for eligibility, were randomized to receive mCAP+rabeprazole (n = 32) vs. mCAP (n = 35). All patients were evaluable for response. No significant difference between mCAP+rabeprazole vs. mCAP, in terms of 3-months PFS rate (HR = 1.43, 95%CI 0.53-3.85; p = 0.477), median PFS (HR = 1.22, 95%CI 0.75-2.00, p = 0.420), CB (RR = 0.85, 95%CI 0.29-2.44; p = 0.786) and median OS (HR = 0.89, 95%CI 0.54-1.48; p = 0.664) was observed. However, a 3-year OS rate of 10% and 12% was reported in the mCAP-rabeprazole and mCAP groups, respectively. Overall, no grade 3 or 4 toxicity occurred but grade 1 or 2 adverse event of any type were more frequently in the mCAP+rabeprazole group than in the mCAP (OR 2.83, 95%CI 1.03-7.79; p = 0.043). Finally, there was not statistically significant difference in the plasma concentration of capecitabine and its metabolites between the two groups. CONCLUSIONS: Although the adjunct of high dose rabeprazole to mCAP was not shown to affect mCAP activity, as PPI are being investigated worldwide as drugs to be repositioned in cancer treatment and also considering the limited sample size as well as the favorable safety profile of the combination in the present study, further clinical investigations are desirable.

Sonographic Risk Stratification Systems for Thyroid Nodules as Rule-Out Tests in Older Adults.

Ultrasonographic risk-stratification systems (RSS), including various Thyroid Imaging Reporting and Data Systems (TIRADS), were proposed to improve reporting and reduce the number of fine-needle aspiration biopsies. However, age might be a confounder since some suspicious ultrasonographic features lack specificity in elderly patients. We aimed to investigate whether the diagnostic performance of the RSS varied between age groups. All patients consecutively referred for thyroid biopsy between November 1, 2015, and March 10, 2020, were included. The malignancy risk of each nodule was estimated according to five RSS: the American Association of Clinical Endocrinologists/American College of Endocrinology/Associazione Medici Endocrinologi guidelines, the American College of Radiology (ACR) TIRADS, the American Thyroid Association guidelines, the European TIRADS, and the Korean TIRADS. Overall, 818 nodules (57 malignant) were evaluated. The malignancy rate was higher in patients ≤ 65 years (8.1%) than in patients > 65 years (3.8%; p = 0.02). All RSS confirmed a significant discriminative performance in both age groups, with a negative predictive value of 100% in patients > 65 years, although specificity was lower in older patients. The ACR TIRADS was the best performing in both age groups. RSS could avoid a sizable number of biopsies when applied as rule-out tests in elderly patients.

Loss of Function SETD2 Mutations in Poorly Differentiated Metastases from Two Hürthle Cell Carcinomas of the Thyroid.

Hürthle cell carcinomas (HCC) are rare differentiated thyroid cancers that display low avidity for radioactive iodine and respond poorly to kinase inhibitors. Here, using next-generation sequencing, we analyzed the mutational status of primary tissue and poorly differentiated metastatic tissue from two HCC patients. In both cases, metastatic tissues harbored a mutation of SETD2, each resulting in loss of the SRI and WW domains of SETD2, a methyltransferase that trimethylates H3K36 (H3K36me3) and also interacts with p53 to promote its stability. Functional studies of the novel p.D1890fs6* mutation (case 1) revealed significantly reduced H3K36me3 levels in SETD2-mutated tissue and primary cell cultures and decreased levels of the active form of p53. Restoration of SETD2-wildtype expression in the SETD2-mutant cells significantly reduced the expression of four well-known stemness markers (OCT-4, SOX2, IPF1, Goosecoid). These findings suggest potential roles for SETD2 loss-of-function mutations in HCC progression, possibly involving p53 destabilization and promotion of stemness. Their prevalence and potential treatment implications in thyroid cancer, especially HCC, require further study.

Cancer Care During COVID-19 Era: The Quality of Life of Patients With Thyroid Malignancies.

Background: The Covid-19 pandemic's potential psychological impact has been widely discussed on the basis of expert opinion and previous experience with emergencies of this type. We conducted a survey of cancer patients to explore more objectively the outbreak's impact on their emotional well-being and quality of life. Methods: Between March 18 and April 4, 2020, at an endocrine cancer center in Rome, Italy, 137 patients were asked to complete an online 6-item questionnaire developed by our staff to explore the emotional effects of the Covid-19 outbreak in Italy (Covid-19 Emotional Impact Survey, C-19EIS). For validation purposes, we also asked participants to complete an online version of the validated Italian translation of the EORTC QLQ-C30 questionnaire. Responses were analyzed in relation to responders' age, sex, and clinical status (advanced/metastatic disease undergoing systemic treatment vs. stable metastatic thyroid cancer in active surveillance vs. low-risk thyroid cancers with no evidence of structural disease during standard follow-up). Results: Response rates were high (51% for the C-19EIS, 44.5% for the EORTC QLQ-C30). Overall C-19EIS scores indicated high concern over the outbreak (median 8/12). Scores were higher in women (8 [IQR 5-9] vs. 6 [IQR 5-8] in men; p = 0.048) and in patients <65 years (8 [IQR 5-9] vs. 6 [IQR 4-8] in older patients; p = 0.013). No differences emerged across clinical status groups. C-19EIS scores were inversely correlated with the EORTC QLQ-C30 Emotional function subscale (rho -0.69; p < 0.001). Conclusions: There is objective evidence that the Covid-19 outbreak is causing substantial emotional distress among cancer patients, regardless of their disease severity or current health-care needs.

Analytical validation of a novel targeted next-generation sequencing assay for mutation detection in thyroid nodule aspirates and tissue.

PURPOSE: The identification of somatic mutations in cancer specimens enables detection of molecular markers for personalized treatment. We recently developed a novel molecular assay and evaluated its clinical performance as an ancillary molecular method for indeterminate thyroid nodule cytology. Herein we describe the analytical validation of the novel targeted next-generation sequencing (NGS) assay in thyroid samples from different sources. METHODS: We present validation data of a novel NGS-based panel on 463 thyroid samples, including 310 fine-needle aspiration (FNA) specimens from different sources (FNA collected in preservative solution, liquid-based, and stained smears), 10 fresh frozen, and 143 formalin-fixed paraffin-embedded (FFPE) thyroid tissue specimens. Sequencing performance in the different samples was evaluated along with reproducibility, repeatability, minimum nucleic acid input to detect variants, and analytical sensitivity of the assay. RESULTS: All thyroid samples achieved high sequencing performance, with a mean base coverage depth ranging from 2228 × (in liquid-based FNA) to 3661 × (in FNA stained smears), and coverage uniformity ranging from 86% (in FFPE) to 95% (in FNA collected in preservative solution), with all target regions covered above the minimum depth required to call a variant (500×). The minimum nucleic acid input was 1 ng. Analytic sensitivity for mutation detection was 2-5% mutant allele frequency. CONCLUSIONS: This validation study of a novel NGS-based assay for thyroid nodules demonstrated that the assay can be reliably used on multiple thyroid sample types, including FNA from different sources and FF and FFPE thyroid samples, thus providing a robust and reliable assay to genotype thyroid nodules, which may improve thyroid cancer diagnosis and care.