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Background: Emerging evidence identified sex as a variable regulating immune system functions and modulating response to immunotherapy in cancer patients., Objective: This retrospective study analysed sex-related differences in immunotherapy outcomes in a real-world population of non-small cell lung cancer (NSCLC) patients treated with immune checkpoint inhibitors (ICIs)., Methods: We retrospectively investigated clinical data of 99 patients with advanced NSCLC and treated with single-agent nivolumab and pembrolizumab at Medical Oncology Unit, Careggi University Hospital, Florence (Italy), between April 2014 to August 2019. Main clinical characteristics and clinical outcomes were analysed., Results: Our study showed that the efficacy of ICI treatment differed according to gender. A trend for better median progression-free survival (mPFS) was reported in males (mPFS 5.0 months, 95% Confidence Interval [CI] 4.0-11.0) than females (mPFS 4.5 months, 95% CI 2.0-9.0) (p=0.133), while no significant difference for overall survival (OS) between the two sex groups was observed (p=0.622). In the nivolumab cohort, we showed a statistically significant difference for a longer PFS in men compared to women (log-rank p=0.054), HR for PFS in females versus males was 1.81 (95% CI 0.97- 3.37, p=0.062). Disease control rate (DCR) was achieved in 55.7% and 45.7% of men and women, respectively, while disease progression was registered in 44.3% of males and 54.3% of females (p=0.386)., Conclusion: Gender is a variable that should be taken into account in the choice of immunotherapy. Future prospective randomized trials testing tailored sex-based immunotherapy strategies are required to validate our findings before integrating into clinical practice., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Globally, more than 1 million new cases of gastric cancer were estimated in 2020, ranking fourth in cancer mortality. Currently although in resectable gastric cancer and esophagogastric junction (EGJ) adenocarcinoma a perioperative triplet chemotherapy regimen including a fluoropyrimidine, a platinum compound and docetaxel (FLOT) demonstrated a better overall survival, the survival rate is still very low, and a massive effort is still required to improve clinical prognosis. High microsatellite instability (MSI-H) status in gastric cancer is a favorable prognostic factor but poor data are available on its predictive role for perioperative FLOT chemotherapy in resectable gastric cancer. Here, we presented the case of two patients with advanced MSI-H gastric cancer/EGJ adenocarcinoma who had no residual tumor following neoadjuvant FLOT chemotherapy maintaining a complete response for more than 30 months, suggesting MSI-H status to be a positive prognostic marker also in patients treated with a taxane-containing triplet in this setting. We also discuss the future perspectives including the opportunity to achieve excellent clinical outcomes with immune checkpoint inhibitor (ICI)-based regimens., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Platinum chemotherapy (CT) remains the backbone of systemic therapy for patients with small-cell lung cancer (SCLC). The nucleotide excision repair (NER) pathway plays a central role in the repair of the DNA damage exerted by platinum agents. Alteration in this repair mechanism may affect patients' survival., Materials and Methods: We conducted a retrospective analysis of data from 38 patients with extensive disease (ED)-SCLC who underwent platinum-CT at the Clinical Oncology Unit, Careggi University Hospital, Florence (Italy), from 2015 to 2020. mRNA expression analysis and single nucleotide polymorphism (SNP) characterization of three NER pathway genes-namely ERCC1 , ERCC2 , and ERCC5 -were performed on patient tumor samples., Results: Overall, elevated expression of ERCC genes was observed in SCLC patients compared to healthy controls. Patients with low ERCC1 and ERCC5 expression levels exhibited a better median progression-free survival (mPFS = 7.1 vs . 4.9 months, p = 0.39 for ERCC1 and mPFS = 6.9 vs . 4.8 months, p = 0.093 for ERCC5 ) and overall survival (mOS = 8.7 vs . 6.0 months, p = 0.4 for ERCC1 and mOS = 7.2 vs . 6.2 months, p = 0.13 for ERCC5 ). Genotyping analysis of five SNPs of ERCC genes showed a longer survival in patients harboring the wild-type genotype or the heterozygous variant of the ERCC1 rs11615 SNP ( p = 0.24 for PFS and p = 0.14 for OS) and of the rs13181 and rs1799793 ERCC2 SNPs ( p = 0.43 and p = 0.26 for PFS and p = 0.21 and p = 0.16 for OS, respectively) compared to patients with homozygous mutant genotypes., Conclusions: The comprehensive analysis of ERCC gene expression and SNP variants appears to identify patients who derive greater survival benefits from platinum-CT., Competing Interests: The authors declare no conflicts of interest to report regarding the present study., (© 2025 The Authors.)

Hyponatremia has been established as a prognostic indicator of survival in metastatic non-small cell lung cancer (mNSCLC). Conversely, the influence of normal sodium levels remains unexplored. This study aims to investigate the impact of natremia in mNSCLC patients undergoing treatment with immune checkpoint inhibitors (ICIs). Clinical and biochemical data of patients treated with ICIs for mNSCLC were obtained. Availability of baseline sodium values was a study inclusion criterion. Patients were categorized into two groups based on the cut off sodium value, determined using the receiver operating characteristic curve. Subsequently, the influence of sodium levels on response rate (RR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS) was analyzed. PFS and OS were assessed via the Kaplan-Meier method. Univariate and multivariate Cox regression analyses were conducted to evaluate prognostic factors for PFS and OS. The analysis included 88 patients, of whom 73.1% were men, with a median age of 71 years (range, 47-91). A comparison between patients with baseline natremia ≥ 140 mEq/L (n = 43) and those with < 140 mEq/L (n = 45) revealed PFS durations of 7.0 vs. 2.1 months (p < .01) and OS durations of 15.6 vs. 6.8 months, respectively (p = .02). In the univariate survival analysis, pre-ICI serum sodium ≥ 140 mEq/L (p = .01) was associated with improved PFS, while factors associated with OS included brain metastasis (p = .05) and pre-ICI serum sodium ≥ 140 mEq/L (p = .02). In the multivariate analysis, pre-ICI serum sodium ≥ 140 mEq/L maintained a statistically significant association with OS (p = .04)..This study represents the first investigation into the impact of normonatremia in mNSCLC. Our findings suggest that serum sodium levels < 140 mEq/L at baseline and initial assessment are independently associated with poorer PFS and OS in mNSCLC patients undergoing first-line treatment with ICIs., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

The RAS gene family comprises genes that regulate cell growth and differentiation. KRAS, a member of this family, is often mutated in different cancers, resulting in uncontrolled cell growth and tumor development. Recent clinical trial results on KRAS inhibition in NSCLC have defined the presence of a significant proportion of patients resistant to direct G12C inhibition. The presence of co-mutations and the occurrence of secondary resistance phenomena observed in preclinical and clinical settings partly justify these poor results. In addition, all other non-G12C mutations currently remain without specific strategies. Evidence of interactions between KRAS signaling and the TME suggests potential in vitro efficacy of immune checkpoint inhibitors. In this short paper, we have reviewed the most relevant data from recent conferences, with a focus on KRAS inhibitors resistance mechanisms and interactions with the peri-tumor immune system. Commentary., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Background: Real-life spectrum and survival implications of immune-related adverse events (irAEs) in patients treated with extended interval dosing (ED) immune checkpoint inhibitors (ICIs) are unknown., Methods: Characteristics of 812 consecutive solid cancer patients who received at least 1 cycle of ED monotherapy (pembrolizumab 400 mg Q6W or nivolumab 480 mg Q4W) after switching from canonical interval dosing (CD; pembrolizumab 200 mg Q3W or nivolumab 240 mg Q2W) or treated upfront with ED were retrieved. The primary objective was to compare irAEs patterns within the same population (before and after switch to ED). irAEs spectrum in patients treated upfront with ED and association between irAEs and overall survival were also described., Results: A total of 550 (68%) patients started ICIs with CD and switched to ED. During CD, 225 (41%) patients developed any grade and 17 (3%) G3 or G4 irAEs; after switching to ED, any grade and G3 or G4 irAEs were experienced by 155 (36%) and 20 (5%) patients. Switching to ED was associated with a lower probability of any grade irAEs (adjusted odds ratio [aOR] = 0.83, 95% confidence interval [CI] = 0.64 to 0.99; P = .047), whereas no difference for G3 or G4 events was noted (aOR = 1.55, 95% CI = 0.81 to 2.94; P = .18). Among patients who started upfront with ED (n = 232, 32%), 107 (41%) developed any grade and 14 (5%) G3 or G4 irAEs during ED. Patients with irAEs during ED had improved overall survival (adjusted hazard ratio [aHR] = 0.53, 95% CI = 0.34 to 0.82; P = .004 after switching; aHR = 0.57, 95% CI = 0.35 to 0.93; P = .025 upfront)., Conclusions: Switching ICI treatment from CD and ED did not increase the incidence of irAEs and represents a safe option also outside clinical trials., (© The Author(s) 2023. Published by Oxford University Press.)

Resectable gastric or gastroesophageal (G/GEJ) cancer is a heterogeneous disease with no defined molecularly based treatment strategy. Unfortunately, nearly half of patients experience disease recurrence despite standard treatments (neoadjuvant and/or adjuvant chemotherapy/chemoradiotherapy and surgery). In this review, we summarize the evidence of potential tailored approaches in perioperative treatment of G/GEJ cancer, with a special focus on patients with human epidermal growth factor receptor-2(HER2)-positive and microsatellite instability-high (MSI-H) tumors. In patients with resectable MSI-H G/GEJ adenocarcinoma, the ongoing INFINITY trial introduces the concept of non-operative management for patients with complete clinical-pathological-molecular response, and this could be a novel and potential practice changing strategy. Other pathways involving vascular endothelial growth factor receptor (VEGFR), fibroblast growth factor receptor (FGFR), claudin18 isoform 2 (CLDN18.2), and DNA damage repair proteins are also described, with limited evidence until now. Although tailored therapy appears to be a promising strategy for resectable G/GEJ cancer, there are several methodological issues to address: inadequate sample size for pivotal trials, underestimation of subgroup effects, and choice of primary endpoint (tumor-centered vs. patient-centered endpoints). A better optimization of G/GEJ cancer treatment allows maximizing patient outcomes. In the perioperative phase, although caution is mandatory, times are changing and tailored strategies could introduce new treatment concepts. Overall, MSI-H G/GEJ cancer patients possess the characteristics to be the subgroup that could receive the most benefit from a tailored approach., Competing Interests: The authors declare no conflict of interest.

Colorectal cancer (CRC) is the third most common cancer worldwide, with approximately 1.9 million new diagnoses and 935 000 deaths annually. Overall, there is accumulating evidence that receiving all available treatments leads to a survival advantage and, although tailored treatments might be appropriate for selected patients, the one-size-fits-all approach is still widely used in chemo-refractory patients. Currently, different antiangiogenics and multitarget agents are indicated in treatment of metastatic CRC (mCRC) whereas the identification of useful predictive factors for the treatment response is lacking. Analysis of potential predictive biomarkers of efficacy of regorafenib is still ongoing but may prove to be difficult because of its nonspecific activity across a wide range of angiogenic, oncogenic, stromal, and intracellular signaling kinases. We present a case of a 57-year-old Caucasian woman diagnosed with recurrence after curative surgery for rectal adenocarcinoma stage III (ypT3N2). Despite undergoing multiple lines of standard chemotherapy, disease control could not be maintained. Consequently, regorafenib, a multikinase inhibitor with antiangiogenic proprieties, was started as a late-line treatment and a dose reduction strategy allowed a long-term response of more than 9 years with good tolerability., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

For many years the standard of care for small cell lung cancer (SCLC) has remained unchanged. Despite decades of active research, current treatment options are limited and the prognosis of patients with extended disease (ED) SCLC remains poor. The introduction of immune checkpoint inhibitors (ICIs) represents an exception and the only recent approval for ED-SCLC. However, the magnitude of benefit obtained with immunotherapy in SCLC is much more modest than that observed in other malignancies. Different pro-immunogenic or immunosuppressive features within the tumor microenvironment of SCLC may either modulate the sensitivity to immunotherapy or conversely dampen the efficacy of ICIs. Beside immunotherapy, a deeper understanding of the molecular biology of SCLC has led to the identification of new therapeutic targets for this lethal malignancy. Recent epigenetic and gene expression studies have resulted into a new molecular classification of four distinct subtypes of SCLC, defined by the relative expression of key transcription regulators and each characterized by specific therapeutic vulnerabilities. This review discusses the rationale for immunotherapy in SCLC and summarizes the main ICIs-trials in this tumor. We provide also an overview of new potential therapeutic opportunities and their integration with the new molecular classification of SCLC., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: About half of metastatic colorectal cancers (CRCs) harbor Rat Sarcoma (RAS) activating mutations as oncogenic driver, but the prognostic role of RAS mutations is not fully elucidated. Interestingly, specific hotspot mutations have been identified as potential candidates for novel targeted therapies in several malignancies as per G12C. This study aims at evaluating the association between KRAS hotspot mutations and patient characteristics, prognosis and response to antiangiogenic drugs., Methods: Data from RAS-mutated CRC patients referred to Careggi University Hospital, between January 2017 and April 2022 were retrospectively and prospectively collected. Tumor samples were assessed for RAS mutation status using MALDI-TOF Mass Spectrometry, Myriapod NGS-56G Onco Panel, or Myriapod NGS Cancer Panel DNA., Results: Among 1047 patients with available RAS mutational status, 183 KRAS-mutated patients with advanced CRC had adequate data for clinicopathological and survival analysis. KRAS mutations occurred at codon 12 in 67.2% of cases, codon 13 in 23.5%, codon 61 in 2.2%, and other codons in 8.2%. G12C mutation was identified in 7.1% of patients and exon 4 mutations in 7.1%. KRAS G12D mutation, as compared to other mutations, was significantly associated with liver metastases (1-sided p=0.005) and male sex (1-sided p=0.039), KRAS G12C mutation with peritoneal metastases (1-sided p=0.035), KRAS G12V mutation with female sex (1-sided p=0.025) and no surgery for primary tumor (1-sided p=0.005). No associations were observed between specific KRAS variants and age, ECOG PS, site of primary tumor, pattern of recurrence for resected patients, and lung, distant lymph node, bone, or brain metastases.Overall survival (OS) was significantly longer in patients with KRAS exon 4 mutations than in those with other KRAS mutations (mOS 43.6 months vs 20.6 months; HR 0.45 [0.21-0.99], p=0.04). No difference in survival was observed for mutations at codon 12/13/61 (p=0.1). Treatment with bevacizumab (BV) increased significatively mPFS (p=0.036) and mOS (p=0.019) of the entire population with a substantial benefit in mOS for G12V mutation (p=0.031)., Conclusions: Patterns of presentation and prognosis among patients with specific RAS hotspot mutations deserve to be extensively studied in large datasets, with a specific attention to the uncommon isoforms and the role of anti-angiogenic drugs., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Lavacchi, Fancelli, Roviello, Castiglione, Caliman, Rossi, Venturini, Pellegrini, Brugia, Vannini, Bartoli, Cianchi, Pillozzi and Antonuzzo.)

Background: KRAS is commonly mutated in non-small cell lung cancer (NSCLC); however, the prognostic and predictive impact of each G12 substitution has not been fully elucidated. The approval of specific G12C inhibitors has modified the idea of KRAS "undruggability", and although the first-line standard consists of immune checkpoint inhibitors (ICIs) with or without chemotherapy, as suggested at ASCO 2022, the outcome in KRAS-mutated population is still controversial., Methods: We retrospectively described the clinical and pathological characteristics of a homogeneous G12 mutated cohort of 219 patients treated in four Italian oncologic units. We evaluated the outcome (PFS at 18 months and OS at 30 months) of those who underwent standard first-line treatment according to PD-L1 status, focusing on differences across single mutations., Results: In the study population, 47.9% of patients harbor the KRAS G12C mutation; 20.5%, G12V; 17.4%, G12D; and 8.2%, G12A. Smoking was a common behavior of patients harboring transversions and transition mutations. PD-L1 expression does not show particular distribution in the case series, although we recorded a prevalence of PD-L1 <1% in G12V (51.4%) compared to G12A (26.7%). ICIs alone was the clinician's choice in 32.7% of patients, and the chemo-immune combination in 17.3% of patients. We described the independent prognostic role of young age ( p = 0.007), female gender ( p = 0.016), and an ICI-based regimen ( p = 0.034) regardless of mutations. Overall, our data confirm the worst prognostic value of G12V mutation apart from treatment choice unlike the other major mutations (C, D, and A) that showed a favorable trend in PFS., Conclusions: KRAS G12 mutations are confirmed to have different characteristics, and the outcome is influenced by ICI first-line regimen. This study provides valuable information for further analysis in the future., Competing Interests: The authors declare that the research was conducted in the absence of commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Fancelli, Caliman, Mazzoni, Paglialunga, Gatta Michelet, Lavacchi, Berardi, Mentrasti, Metro, Birocchi, Delmonte, Priano, Comin, Castiglione, Bartoli, Voltolini, Pillozzi and Antonuzzo.)

To date, treatment options for patients with chemorefractory cholangiocarcinoma (CCA) are limited. However, the advancements in molecular techniques have recently increased the opportunity to offer molecularly targeted therapies to patients with several cancer types and some targetable oncogenic alterations have been identified also in CCA. Among these potentially actionable molecular alterations, isocitrate dehydrogenase-1 (IDH1) mutations have been detected in approximately 10-20% of intrahepatic CCA (iCCA). IDH1 is responsible for the accumulation of oncometabolites inducing epigenetic changes that are involved in various signaling pathways. Ivosidenib is the first IDH1 inhibitor which significantly improved progression-free survival (PFS) (2.7 vs 1.4 months) and overall survival (OS) (10.3 vs 5.1 months [adjusted median OS]) compared with placebo in chemorefractory IDH1-mutated CCA. The very low incidence of grade (G) 3-4 adverse events (AEs) and treatment discontinuation due to toxicity, associated with a significantly less marked decline in health-related quality of life for patients in the ivosidenib group than in placebo group, facilitates patient adherence and clinician confidence. Here, we review the development of ivosidenib in CCA patients and evaluate the clinical impact of the results of the phase III ClarIDHy trial which was responsible for the Food and Drug Administration (FDA) approval for patients with IDH1-mutated CCA whose disease progressed after standard chemotherapy (CT). We also discuss the known primary and secondary resistance mechanisms, including concomitant and acquired mutations in other genes (e.g. IDH2 mutations), second-site mutation in IDH1, and enhanced activation of other pathways (e.g. PI3K/AKT/mTOR pathway). Finally we examine the future directions, as the opportunity to combine ivosidenib with other synergistic agents, including standard chemotherapy (CT), immune checkpoint inhibitors (ICIs), and IDH2 inhibitors., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Clinical responses to anticancer therapies in advanced soft tissue sarcoma (STS) are unluckily restricted to a small subgroup of patients. Much of the inter-individual variability in treatment efficacy is as result of polymorphisms in genes encoding proteins involved in drug pharmacokinetics and pharmacodynamics. The nucleotide excision repair (NER) system is the main defense mechanism for repairing DNA damage caused by carcinogens and chemotherapy drugs. Single nucleotide polymorphisms (SNPs) of NER pathway key genes, altering mRNA expression or protein activity, can be significantly associated with response to chemotherapy, toxicities, tumor relapse or risk of developing cancer. In the present study, in a cohort of STS patients, we performed DNA extraction and genotyping by SNP assay, RNA extraction and quantitative real-time reverse transcription PCR (qPCR), a molecular dynamics simulation in order to characterize the NER pathway in STS. We observed a severe deregulation of the NER pathway and we describe for the first time the effect of SNP rs1047768 in the ERCC5 structure, suggesting a role in modulating single-stranded DNA (ssDNA) binding. Our results evidenced, for the first time, the correlation between a specific genotype profile of ERCC genes and proficiency of the NER pathway in STS.

Introduction: COVID-19 has disrupted the global health care system since March 2020. Lung cancer (LC) patients (pts) represent a vulnerable population highly affected by the pandemic. This multicenter Italian study aimed to evaluate whether the COVID-19 outbreak had an impact on access to cancer diagnosis and treatment of LC pts compared with pre-pandemic time., Methods: Consecutive newly diagnosed LC pts referred to 25 Italian Oncology Departments between March and December 2020 were included. Access rate and temporal intervals between date of symptoms onset and diagnostic and therapeutic services were compared with the same period in 2019. Differences between the 2 years were analyzed using the chi-square test for categorical variables and the Mann-Whitney U test for continuous variables., Results: A slight reduction (-6.9%) in newly diagnosed LC cases was observed in 2020 compared with 2019 (1523 versus 1637, P = 0.09). Newly diagnosed LC pts in 2020 were more likely to be diagnosed with stage IV disease (P < 0.01) and to be current smokers (someone who has smoked more than 100 cigarettes, including hand-rolled cigarettes, cigars, cigarillos, in their lifetime and has smoked in the last 28 days) (P < 0.01). The drop in terms of new diagnoses was greater in the lockdown period (percentage drop -12% versus -3.2%) compared with the other months included. More LC pts were referred to a low/medium volume hospital in 2020 compared with 2019 (P = 0.01). No differences emerged in terms of interval between symptoms onset and radiological diagnosis (P = 0.94), symptoms onset and cytohistological diagnosis (P = 0.92), symptoms onset and treatment start (P = 0.40), and treatment start and first radiological revaluation (P = 0.36)., Conclusions: Our study pointed out a reduction of new diagnoses with a shift towards higher stage at diagnosis for LC pts in 2020. Despite this, the measures adopted by Italian Oncology Departments ensured the maintenance of the diagnostic-therapeutic pathways of LC pts., Competing Interests: Disclosure DS received personal fees from AstraZeneca, Merck Sharp & Dohme (MSD), Boehringer Ingelheim and received travel grants from Roche, AstraZeneca, Bristol Myers Squibb (BMS), MSD. AMo received honoraria from Roche, AstraZeneca, Boehringer, Pfizer, MSD, BMS, Novartis, Lilly, Takeda. RC received fees for speaker's bureau and advisory boards participation in BMS, MSD, Roche, Pfizer, AstraZeneca, Takeda, Amgen, Boehringer, Novartis. FM received founding from AstraZeneca, Incyte and served as consultant for MSD. RB is a consultant/advisory board member for AstraZeneca, Boehringer Ingelheim, Novartis, MSD, Otsuka, Eli Lilly, Roche. All other authors have declared no conflicts of interest., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objectives: Immune checkpoint inhibitors (ICIs) have led to a paradigm shift in non-small cell lung cancer (NSCLC) treatment. We investigated absolute eosinophil count (AEC) as a predictor of clinical outcomes and toxicity in NSCLC patients receiving ICIs., Materials and Methods: AEC was retrospectively collected at baseline and during treatment from 158 advanced NSCLC patients treated with single agent anti-PD1/anti-PDL1 monoclonal antibody in first or subsequent line of therapy at Medical Oncology Unit, Careggi University Hospital, Florence (Italy), between January 2016 to October 2020., Results: We found a significant association between high baseline AEC (≥130/μL) and better clinical outcomes. The response rates were 64.4% and 35.6% for patients with high and low AEC, respectively (p = 0.009). The high-AEC group showed a significantly longer PFS and OS than the low-AEC group (mPFS = 7.0 months, 95% CI 5.0-10.0 vs 2.5 months, 95% CI 2.0-4.0, p = 0.007 and mOS = 9.0 months, CI 95% 7.0-15.0 vs 5.5 months, 95% CI 4.0-8.0, p = 0.009, respectively). An increased risk of immune-related adverse events (irAEs) was reported in the high-AEC group (p = 0.133). IrAEs resulted an independent prognostic factor for both better outcomes (mPFS = 8.0 months, 95% CI 7.0-12.0 vs 2.0 months, 95% CI 2.0-3.0, p<0.001; mOS = 13.0 months 95% CI 9.0-19.0 vs 4.0 months 95% CI 3.0-6-0, p<0.001) and response to ICIs (response rate = 33.8% vs 14.9%, disease control rate = 72.0% vs 32.1%, p<0.001)., Conclusion: High baseline AEC value (≥130/μL) is a predictive biomarker of clinical benefit and irAEs occurrence in NSCLC patients treated with ICIs., (Copyright © 2022. Published by Elsevier Ltd.)

Background: Perioperative FLOT (5-fluorouracil, oxaliplatin and docetaxel) has recently become the gold standard treatment for fit patients with operable gastric (GC) or gastroesophageal (GEJ) adenocarcinoma, getting a 5-year overall survival (OS) of 45%, over 23% with surgery alone., Methods: RealFLOT is an Italian, multicentric, observational trial, collecting data from patients with resectable GC or GEJ adenocarcinoma treated with perioperative FLOT. Aim of the study was to describe feasibility and safety of FLOT, pathological complete response rate (pCR), surgical outcomes and overall response rate (ORR) in an unselected real-world population. Additional analyses evaluated the correlation between pCR and survival and the prognostic role of microsatellite instability (MSI) status., Results: Of 206 patients enrolled that received perioperative FLOT at 15 Italian centers, 124 (60.2%) received at least 4 full-dose cycles, 190 (92.2%) underwent surgery, and 142 (68.9%) started the postoperative phase. Among patients who started the postoperative phase, 105 (51.0%) received FLOT, while 37 (18%) received de-intensified regimens, depending on clinical condition or previous toxicities. pCR was achieved in 7.3% of cases. Safety profile was consistent with literature. Neutropenia was the most common G 3-4 adverse event (AE): 19.9% in the preoperative phase and 16.9% in the postoperative phase. No toxic death was observed and 30-day postoperative mortality rate was 1.0%. ORR was 45.6% and disease control rate (DCR) was 94.2%. Disease-free survival (DFS) and OS were significantly longer in case of pCR (p = 0.009 and p = 0.023, respectively). A trend towards better DFS was observed among MSI-H patients., Conclusions: These real-world data confirm the feasibility of FLOT in an unselected population, representative of the clinical practice. pCR rate was lower than expected, nevertheless we confirm pCR as a predictive parameter of survival. In addition, MSI-H status seems to be a positive prognostic marker also in patients treated with taxane-containing triplets., (© 2021. The Author(s).)

Background: Immunotherapy has completely changed the treatment of solid tumors. Although immune checkpoint inhibitors (ICIs) seem to be an appealing alternative to chemotherapy, especially in elderly patients, due to a more tolerable toxicity profile, they can lead to a peculiar variety of immune-related adverse events (irAEs). However, data on tolerability and outcome of ICIs in the elderly are lacking due to poor accrual in clinical trials of these patients., Methods: We performed a retro-prospective analysis on patients treated with single agent anti-PD-L1/PD-1 at the Clinical Oncology Unit, Careggi University Hospital, from March 2016 to March 2020. Data on the treatment responses, type and severity of irAEs, as well as the corticosteroids (CCS) dosage used for irAEs and the discontinuation rate, were described per each patient, according to two different age-based cohorts of patients (< or ≥70 years)., Results: We reported a lower incidence of all-grade toxicity in elderly compared to younger patients (64.9% vs. 44.9%, p = 0.018). The two age-cohorts showed a different profile of irAEs. Endocrine irAEs were significantly higher in younger patients (39.7% vs. 21.7%, p = 0.002), while dermatologic toxicities were more common in the older group (35.0% vs. 11.3%, p = 0.047). Use of CCS and treatment discontinuation rate do not differ significantly between the two age groups., Conclusion: Our findings suggest that treatment with ICIs in elderly populations is safe and feasible. Patients over 70 years are more prone to develop skin irAEs, while younger patients are more subject to experience endocrine toxicities.

The study presented in this article aims at investigating the clinical usefulness of a novel test, called T-PEC, for the diagnosis of Developmental Language Disorder in Italian preschool children. The instrument exploits the production of clitic pronouns, in particular third person direct object clitics (3PDO-CL), as a clinical marker for the disorder. Psychometric properties and normative data were computed on a sample of 70 children ranging in age from 4.6 to 5.8 years: 22 children diagnosed as language-impaired by expert clinicians according to international guidelines, and 48 typically developing peers. The statistical analysis of the collected data revealed good internal consistency (Cronbach's α = 0.86) and confirmed the effectiveness of the T-PEC test in distinguishing typically developing and DLD children, especially when the latter showed morphosyntactic deficits (AUC = 79.9%). Its high accuracy, combined with the rapidity and easiness of its administration, makes the T-PEC test suitable for use in clinical settings.

The potent, RET-selective tyrosine kinase inhibitors (TKIs) pralsetinib and selpercatinib, are effective against the RET V804L/M gatekeeper mutants, however, adaptive mutations that cause resistance at the solvent front RET G810 residue have been found, pointing to the need for the development of the next-generation of RET-specific TKIs. Also, as seen in EGFR- and ALK-driven NSCLC, the rising of the co-occurring amplifications of KRAS and MET could represent other escaping mechanisms from direct inhibition. In this review, we summarize actual knowledge on RET fusions, focusing on those involved in NSCLC, the results of main clinical trials of approved RET-inhibition drugs, with particular attention on recent published results of selective TKIs, and finally, pre-clinical evidence regarding resistance mechanisms and suggestion on hypothetical and feasible drugs combinations and strategies viable in the near future.

Cancer immunotherapy based on the use of antibodies targeting the so-called checkpoint inhibitors, such as programmed cell death-1 receptor, its ligand, or CTLA-4, has shown durable clinical benefit and survival improvement in melanoma and other tumors. However, there are some special situations that could be a challenge for clinical management. Persons with chronic infections, such as HIV-1 or viral hepatitis, latent tuberculosis, or a history of solid organ transplantation, could be candidates for cancer immunotherapy, but their management requires a multidisciplinary approach. The Spanish Melanoma Group (GEM) panel in collaboration with experts in virology and immunology from different centers in Spain reviewed the literature and developed evidence-based guidelines for cancer immunotherapy management in patients with chronic infections and immunosuppression. These are the first clinical guidelines for cancer immunotherapy treatment in special challenging populations. Cancer immunotherapy in chronically infected or immunosuppressed patients is feasible but needs a multidisciplinary approach in order to decrease the risk of complications related to the coexistent comorbidities., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

TAS-102 is a preconstituted drug combination comprising an oral fluoropyrimidine (trifluridine, TFT) and a potent inhibitor of thymidine phosphorylase (tipiracil hydrochloride, TPI). TFT/TPI has recently received Food and Drug Administration (FDA) approval also for the treatment of gastric cancer after at least two lines of chemotherapy. The approval was based on a large phase 3 trial (TAGS), in which TAS-102 showed a 31 % decrease in the risk of death compared with placebo. Here, we review the pharmacological properties, clinical development and potential future directions of TAS-102 in gastric cancer., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflict of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: Second line of treatment of hepatocellular carcinoma (HCC) has notably changed in recent years as three novel drugs with a different mechanism of action have demonstrated to improve survival compared to placebo; thus, there is a need to better define the profile of optimal candidates to second-line treatment with these drugs in order to maximize clinical benefit., Materials and Methods: We performed a pooled analysis from the subgroup analysis of all published phase III trials for approved targeted therapy in the second line of treatment for HCC, with the aim to discover possible clinical-pathological predictive factors., Results: Four studies were included in the analysis for a total of 2137 cases whose results supported the use of these novel agents in male patients with ECOG: 0, extrahepatic metastases, and HBV infection., Conclusions: Future studies are awaited to define best candidates for novel agents approved in the second line of treatment for HCC., Competing Interests: All authors declare that there are no conflicts of interest in this work., (Copyright © 2020 Giandomenico Roviello et al.)

Treatment of advanced (metastatic) non-small-cell lung cancer (NSCLC) is currently mainly based on immunotherapy with antibodies against PD-1 or PD-L1, alone, or in combination with chemotherapy. In locally advanced NSCLC and in early resected stages, immunotherapy is also employed. Tumor PD-L1 expression by immunohistochemistry is considered the standard practice. Response rate is low, with median progression free survival very short in the vast majority of studies reported. Herein, numerous biological facets of NSCLC are described involving driver genetic lesions, mutations ad fusions, PD-L1 glycosylation, ferroptosis and metabolic rewiring in NSCLC and lung adenocarcinoma (LUAD). Novel concepts, such as immune-transmitters and the effect of neurotransmitters in immune evasion and tumor growth, the nascent relevance of necroptosis and pyroptosis, possible new biomarkers, such as gasdermin D and gasdermin E, the conundrum of K-Ras mutations in LUADs, with the growing recognition of liver kinase B1 (LKB1) and metabolic pathways, including others, are also commented. The review serves to charter diverse treatment solutions, depending on the main altered signaling pathways, in order to have effectual immunotherapy. Tumor PDCD1 gene (encoding PD-1) has been recently described, in equilibrium with tumor PD-L1 (encoded by PDCD1LG1). Such description explains tumor hyper-progression, which has been reported in several studies, and poises the fundamental criterion that IHC PD-L1 expression as a biomarker should be revisited.

Background: Merkel cell carcinoma (MCC) is a rare neuroendocrine malignancy of the skin characterized by high aggressiveness. Four main factors are implicated in its development: immunosuppression, ultraviolet radiation, age and the Merkel cell polyomavirus (MCPyV). In recent years, immune checkpoint inhibitors have shown clinical activity in MCC treatment., Case Presentation: We report the case of an 82-year-old man with a lung adenocarcinoma diagnosis, who underwent immunotherapy with nivolumab as second-line treatment. Seven months after the diagnosis of lung cancer during the nivolumab treatment, the patient developed an eyelid MCC, initially misdiagnosed as a chalazion. A palliative radiotherapy was performed with clinical benefit. After a total of seven cycles of nivolumab, computed tomography showed a lung and cerebral disease progression. In addition, clinical conditions worsened leading to the patient's death 13 months after the initial lung cancer diagnosis., Conclusions: Cases of co-occurrence of MCC and non-small cell lung cancer (NSCLC) have rarely been reported. Interestingly, common risk factors may be postulated for both cancers. Considering the rarity of this adverse event, its short-term temporal relation with the administration of the drug, which makes a relation improbable, and the coexistence of other risk factors, which may provide plausible explanations, it is possible to conclude according to the WHO Adverse Reaction Terminology that a causal relation between the occurrence of this serious adverse event and the exposure to the drug is unlikely. However, the case deserves to be reported in the literature.

Background: The aim of the study was to compare the patterns of care and clinical outcomes of HER2-positive metastatic breast cancer (MBC) patients with de novo or recurrent disease who underwent first-line trastuzumab-based therapy., Patients and Methods: This was a multicenter retrospective cohort study including consecutive patients with HER2-positive MBC who received first-line trastuzumab-based therapy. Analyses on treatment response and effectiveness were conducted according to type of metastatic presentation (ie, de novo vs. recurrent disease). Exploratory analyses were used to evaluate whether the use of surgery of the primary tumor in the de novo cohort influenced patients' survival., Results: From January 2000 to December 2013, 416 patients were included in the study, 113 (27.2%) presented with de novo MBC and 303 (72.8%) with recurrent disease. Compared with patients in the recurrence cohort, those in the de novo cohort had worse baseline characteristics, received more aggressive first-line treatments, and showed better survival, with an adjusted hazard ratio (HR) for progression-free survival (PFS) of 0.65 (95% confidence interval [CI], 0.43-0.97; P = .035) and for overall survival (OS) of 0.53 (95% CI, 0.30-0.95; P = .034). In the de novo cohort, the 54 patients (47.8%) who underwent surgery of the primary tumor had significantly better PFS (adjusted HR, 0.44; 95% CI, 0.26-0.72; P = .001) and OS (adjusted HR, 0.49; 95% CI, 0.26-0.93; P = .029) than those who did not undergo surgery., Conclusion: Patients with de novo HER2-positive MBC showed significantly better survival outcomes than those with recurrent disease. In this population, surgery of the primary breast tumor was associated with better outcomes., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Species identification plays an important role in food allergy prevention and food substitution detection that can reduce the commercial value of a product. For these reasons, many molecular methods have been developed to determine species origin; among them, polymerase chain reaction (PCR)-based methods were successfully applied to processed or unprocessed foodstuffs. An updated PCR-RFLP (restriction fragment length polymorphism) method of the cytb gene was developed for the identification of the 4 species of main interest in the dairy industry (Bos, Ovis, Capra, Bubalus). The comparative analysis of the 92 cytb sequences available in the database belonging to the 4 species allowed identification of 2 highly conserved regions, which were used to design 2 oligonucleotides for the PCR amplification of a 275 base-pair (bp) cytb fragment. The in silico analysis allowed identification of a set of species-specific restriction endonucleases (HaeIII, TaqI, and MwoI), which generated easily analyzable species-specific restriction profiles of the 275 bp cytb DNA fragment. The system was developed for both purified DNA and DNA extracted from meat or dairy products and finally tested on mixed samples, indicating its applicability to foodstuffs.

We analyzed the genetic diversity of 531 Sinorhizobium meliloti strains isolated from nodules of Medicago sativa cultivars in two different Italian soils during 4 years of plant growth. The isolates were analyzed for DNA polymorphism with the random amplified polymorphic DNA method. The populations showed a high level of genetic polymorphism distributed throughout all the isolates, with 440 different haplotypes. Analysis of molecular variance allowed us to relate the genetic structure of the symbiotic population to various factors, including soil type, alfalfa cultivar, individual plants within a cultivar, and time. Some of these factors significantly affected the genetic structure of the population, and their relative influence changed with time. At the beginning of the experiment, the soil of origin and, even more, the cultivar significantly influenced the distribution of genetic variability of S. meliloti. After 3 years, the rhizobium population was altered; it showed a genetic structure based mainly on differences among plants, while the effects of soil and cultivar were not significant.

In this study the description of a new insertion sequence of Sinorhizobium meliloti, ISRm10, is reported. ISRm10 was found in the intergenic region between nodJ and nodQ of a natural isolated strain. ISRm10 was 1047 bp long and showed the typical features of the ISs belonging to the IS630-Tc1/IS3 superfamily. In particular the ISRm10 nucleotide sequence showed the highest homology (62%) with a Sphingomonas aromaticivorans IS. ISRm10 was present in 32% of the analyzed S. meliloti strains while it was not found in the reference strains of other Rhizobium species.

We analysed the genetic diversity of 270 Sinorhizobium meliloti strains isolated from nodules of three different Medicago sativa varieties, planted in three different Italian soils, combining the Analysis of Molecular Variance (AMOVA) with the Random Amplified Polymorphic DNA (RAPD) technique to estimate variance among RAPD patterns with the aim to draw an objective description of the population genetic structure. Results indicated that a general intraspecific genetic diversity was globally distributed among all the population, however a very high level of diversity was found among strains nodulating different Medicago sativa varieties. Moreover the distribution of the RAPD haplotypes among the plant varieties also showed to be non-random. The overall data indicated that the plant genotype is a major factor in shaping the genetic structure of this natural Rhizobium population.

We investigated the genetic diversity of 96 Rhizobium meliloti strains isolated from nodules of four Medicago sativa varieties from distinct geographic areas and planted in two different northern Italian soils. The 96 isolates, which were phenotypically indistinguishable, were analyzed for DNA polymorphism with the following three methods: (i) a randomly amplified polymorphic DNA (RAPD) method, (ii) a restriction fragment length polymorphism (RFLP) analysis of the 16S-23S ribosomal operon spacer region, and (iii) an RFLP analysis of a 25-kb region of the pSym plasmid containing nod genes. Although the bacteria which were studied constituted a unique genetic population, a considerable level of genetic diversity was found. The new analysis of molecular variance (AMOVA) method was used to estimate the variance among the RAPD patterns. The results indicated that there was significant genetic diversity among strains nodulating different varieties. The AMOVA method was confirmed to be a useful tool for investigating the genetic variation in an intraspecific population. Moreover, the data obtained with the two RFLP methods were consistent with the RAPD results. The genetic diversity of the population was found to reside on the whole bacterial genome, as suggested by the RAPD analysis results, and seemed to be distributed on both the chromosome and plasmid pSym.

Four Burkholderia cepacia strains isolated from the rhizosphere and pathological samples of infected human patients were characterized at the molecular level by different methodologies, including the determination of 16S ribosomal rDNA sequence, restriction endonuclease analysis of total DNA, random amplified polymorphic DNA fingerprinting and Southern hybridization with gene probes for nitrogen fixation and siderophore synthesis. The results indicate that the four strains cluster together within genus Burkholderia, but differ from one another. The DNA from the four strains hybridized to the nifA gene probe from Klebsiella pneumoniae, and an appreciable homology with the nifHDK structural genes of Azospirillum brasilense was demonstrated for one rhizosphere strain. Although the four isolates produced an ornibactin-like siderophore, they did not give hybridization with the pvdA probe for hydroxamate biosynthesis from Pseudomonas aeruginosa.

The 16S rDNA of 17 strains of Azospirillum, 14 assigned to one of the known species A. amazonense, A. brasilense, A. halopraeferens, A. irakense and A. lipoferum, and the other three of uncertain taxonomic position, was sequenced after polymerase chain reaction amplification and analysed in order to investigate the phylogenetic relationships at the intra-generic and super-generic level. The phylogenetic analysis confirms that the genus Azospirillum constitutes a phylogenetically separate entity within the alpha subclass of Proteobacteria and that the five species are well defined. A. brasilense and A. lipoferum are closely related species and form one cluster together with A. halopraeferens; the pair of species A. amazonense and A. irakense forms a second cluster in which Rhodospirillum centenum is also placed.

DNA fingerprints of several Azospirillum strains, belonging to the five known species A. amazonense, A. brasilense, A. halopraeferens, A. irakense and A. lipoferum, were obtained by restriction analysis of the amplified 16S rDNA and by restriction fragment length polymorphism of the histidine biosynthetic genes. Data obtained showed that amplified rDNA restriction analysis is an easy, fast, reproducible and reliable tool for identification of Azospirillum strains, mainly at the species level, whereas restriction fragment length polymorphism could, in some cases, differentiate strains belonging to the same species. Moreover, both analyses gave congruent results in grouping strains and in the assignment of new strains to a given species.

The regulatory sequences of Azospirillum brasilense Sp7 nifH gene were fused with the cam reporter gene and used for studying the factors controlling nifH transcription. A DNA sequence, downstream the ATG codon of nifH, that could be involved in the negative regulation of nifH transcription, was identified. The effect of 1 and 2 mM of ammonium on the transcription of the A. brasilense nifH gene and on the nitrogenase activity, in the presence of the Klebsiella pneumoniae NifA protein, was examined.