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Introduction: Fluorescence imaging of sentinel node biopsy in melanoma is a novel method. Both indocyanine green (ICG) and methylene blue (MB) have fluorescent properties. The aim of this study was to present, for the first time in a clinical series of patients, the possible usage of MB as a fluorescent dye for sentinel node biopsy during surgery for melanoma., Material and Methods: Twenty patients with skin melanoma, who were candidates for sentinel node biopsy were enrolled in our study. All patients underwent simultaneous use of standard nanocolloid and blue dye. Transcutaneous visualization of the sentinel node, visualization of lymphatic channels as well as sentinel node fluorescent visualization were all measured. We also performed calculations of Signal to Background ratios (SBR)., Results: In 15% (3/20) of patients, the fluorescent sentinel node was visible through the skin. The median SBR for the sentinel node visualization by fluorescence was 3.15 (range, 2.7-3.5). Lymphatic channels were visible in lymphatic tissue via fluorescence before visualization by the naked eye in 4 patients (20%). The median SBR ratio was 3.69 (range, 2.7-4.2). Sentinel nodes were visible by fluorescence in 13 cases (65%). The median SBR ratio was 2.49 (range, 1.5-5.7). No factors were found to be associated with fluorescent MB visualization of a sentinel node during biopsy., Conclusion: This is the first clinical study presenting the usefulness of fluorescent sentinel node biopsy in melanoma patients using MB as a fluorophore. Further studies are necessary to provide methods for its' clinical implementation.

Urothelial carcinoma of the bladder is one of the most prevalent cancers worldwide, diagnosed as muscle invasive in 25% of cases. Although several studies have demonstrated an overall 5% absolute survival benefit at 5 years with cisplatin-based combination neoadjuvant treatment, administration of chemotherapy prior to radical cystectomy (RC) in muscle-invasive bladder cancer (MIBC) patients is still a matter of debate. This may be due to the perceived modest survival benefit, cisplatin-based chemotherapy ineligibility, or fear of delaying potentially curative surgery in non-responders. However, immunotherapy and novel targeted therapies have shown to prolong survival in advanced disease and are under investigation in the neoadjuvant and adjuvant settings to reduce systemic relapse and improve cure rates. Genomic characterization of MIBC could help select the most effective chemotherapeutic regimen for the individual patient. Large cohort studies on neoadjuvant treatments with immune checkpoint inhibitors (ICIs) and molecular therapies, alone or combined with chemotherapy, are ongoing. In this review, we trace the development of neoadjuvant therapy in MIBC and explore recent advances that may soon change clinical practice., Competing Interests: UG received honoraria for advisory boards or invited speaker fees from Pfizer, BMS, MSD, PharmaMar, Astellas, Bayer, Ipsen, Novartis, Roche, Clovis, AstraZeneca, institutional research grants from AstraZeneca, Sanofi and Roche. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be constructed as a potential conflict of interest., (Copyright © 2022 Roviello, Catalano, Santi, Santoni, Galli, Amorosi, Polom, De Giorgi and Nesi.)

The treatment landscape for metastatic castration-resistant prostate cancer has evolved extremely in recent years and several drug classes are now available. Nonetheless, the lack of validated predictive biomarkers makes therapeutic choice and the best sequential approach difficult. The location of the metastatic site could be a valid criterion for choosing among the treatment options available. Although bone remains the most frequent metastatic site and a possible target for many drugs, recent data suggest a profound shift in the disease spectrum with visceral metastases increasing incidence. This review describes the presently available and ongoing therapies for patients with CRPC and bone metastases, focusing on the role of bone metastases as a possible driver for selecting therapies in these patients., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background and Objectives : The incidence of urothelial cancer in males is higher than in females; however, females have a higher risk of recurrence and progression. The aim of our study was to report the effect of gender on the oncological outcome in advanced urothelial cancer. Materials and Methods : In our retrospective study, all patients had undergone primary surgical treatment for urothelial cancer and were affected by stage IV disease at the time of chemotherapy. Response to therapy and toxicity were evaluated. Subgroups were analyzed for tumour presentation, first- and second-line treatment response, progression-free survival (PFS) and overall survival (OS). Results. Seventy-five patients, 18 (24%) females and 57 (76%) males, were considered. Investigation into the distribution of individual characteristics according to gender revealed a significant difference only for smoking, with a prevalence of smokers in women ( p = 0.029). At the end of follow-up, OS was higher in females (27.5% vs. 17.4%; p = 0.047). Smoking did not significantly influence OS ( p = 0.055), while univariate Cox regression analysis confirmed that males had a higher risk of death (HR = 2.28, 95% CI 0.99-129 5.25), with borderline statistical significance ( p = 0.053). Men showed higher PFS than women both after first-line ( p = 0.051) and second-line chemotherapy ( p = 0.018), with a lower risk of progression (HR = 0.29, 95% CI 0.10-0.86; p = 0.026). No differences were found between genders with regard to toxicity. Conclusions. In our series, PFS rates following first- and second-line therapies for advanced urothelial carcinoma confirmed that females have a greater risk of progression than males.

Aim: The rapid outbreak of the coronavirus disease 2019 (COVID-19) pandemic posed challenges across different medical fields, especially reproductive health, and gave rise to concerns regarding the effects of SARS-CoV-2 on male infertility, owing to the fact that the male reproductive system indicated to be extremely vulnerable to SARS-CoV-2 infection. Only a small number of studies have investigated the effects of SARS-CoV-2 on male reproduction, but the results are not consistent. So, we performed this meta-analysis to draw a clearer picture and evaluate the impacts of COVID-19 on male reproductive system., Method: We searched Embase, Web of Science, PubMed, and Google Scholar databases to identify the potentially relevant studies. Standardized mean difference (SMD) with 95% confidence interval (CI) was applied to assess the relationship. Heterogeneity testing, sensitivity analysis, and publication bias testing were also performed., Results: A total of twelve studies including 7 case control investigations and 5 retrospective cohort studies were found relevant and chosen for our research. Our result showed that different sperm parameters including semen volume [SMD =  - 0.27 (- 0.46, - 1.48) (p = 0.00)], sperm concentration [SMD =  - 0.41 (- 0.67, - 0.15) (p = 0.002)], sperm count [SMD =  - 0.30 (- 0.44, - 0.17) (p = 0.00)], sperm motility [SMD =  - 0.66 (- 0.98, - 0.33) (p = 0.00)], and progressive motility [SMD =  - 0.35 (- 0.61, - 0.08) (p = 0.01)] were negatively influenced by SARS-CoV-2 infection. However, sperm concentration (p = 0.07) and progressive motility (p = 0.61) were not found to be significantly associated with SARS-CoV-2 infection in case control studies. No publication bias was detected., Conclusion: The present study revealed the vulnerability of semen quality to SARS-CoV-2 infection. Our data showed a strong association of different sperm parameters with SARS-CoV-2 infection. The results suggested that SARS-CoV-2 infection in patients may negatively influence their fertility potential in a short-term period, but more studies are needed to decide about the long-term effects., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Few studies have evaluated the impact of risk factors such as performance status (PS) and comorbidities on overall survival (OS) in patients with metastatic pancreatic cancer (mPC). We investigated the influence of comorbidity, PS and age on nab-paclitaxel and gemcitabine (NabGem) effectiveness profile in naive patients with mPC. 153 patients with mPC treated with NabGem upfront was divided in three groups (score 0 to 3) based on the absence or the presence of one or more risk factors among: age ≥ 70 years, PS 1 and comorbidities and the clinical outcomes was compared. Fifty-five patients were elderly (≥ 70 years), 80 patients have PS 1, whereas the other have PS 0. Patients with no risk factors (score 0) had an overall survival higher (20 months) than patients with one or two risk factors (score 1-2) (OS 11 months) and with three risk factors (score 3) (OS 8 months) (p < 0.01). The difference in OS was also statistically significant in patients without comorbidities (OS 15 months) compared to those with ≥ 1 comorbidity (OS 10 months) (p < 0.001). NabGem chemotherapy represent an effective treatment in naive patients. Age, PS, and comorbidities were prognostic factors in patients with metastatic pancreatic cancer., (© 2022. The Author(s).)

Immune checkpoint inhibitors (ICIs) are approved for the treatment of head and neck carcinoma. They have significantly improved survival in these patients but may cause immune-related adverse events (irAEs), some of which may be serious. The report presents a rare case of a neurologic adverse event associated with programmed death-1 inhibitor monotherapy. Neurologic irAEs (NirAEs) can occur in various and atypical forms, be potentially disabling and occur at various times during and after treatment. Prompt identification and drug withdrawal are essential to improve outcomes. A high dose of systemic corticosteroid has been recommended for the management of NirAEs, although optimal immunomodulatory treatment is still debated.

The topic of sustainability of reinforced concrete structures is strictly related with their durability in aggressive environments. In particular, at equal environmental impact, the higher the durability of construction materials, the higher the sustainability. The present review deals with the possible strategies aimed at producing sustainable and durable reinforced concrete structures in different environments. It focuses on the design methodologies as well as the use of unconventional corrosion-resistant reinforcements, alternative binders to Portland cement, and innovative or traditional solutions for reinforced concrete protection and prevention against rebars corrosion such as corrosion inhibitors, coatings, self-healing techniques, and waterproofing aggregates. Analysis of the scientific literature highlights that there is no preferential way for the production of "green" concrete but that the sustainability of the building materials can only be achieved by implementing simultaneous multiple strategies aimed at reducing environmental impact and improving both durability and performances.

Background: Considerable numbers of patients with metastatic urothelial carcinoma (mUC) develop bone metastases (BoM). Their impact on the efficacy of immune-checkpoint inhibitors (ICIs) is not yet investigated., Methods: Between July 2014 and August 2020 data on pts treated with single-agent ICIs after failure of at least 1 previous line of chemotherapy for advanced disease, were retrospectively collected across 14 Italian centers. Overall survival (OS) and progression-free survival (PFS) were analyzed using the Kaplan-Meier method. Cox regression analysis was performed evaluating potential prognostic factors for OS and PFS. Each factor was evaluated in univariable (UVA) and multivariable analysis (MVA)., Results: A total of 208 evaluable patients treated with ICIs were identified, including 122 (59%) without BoM (BoM-) and 86 (41%) with bone metastases (BoM+). After a median follow-up of 22.3 months, BoM+ patients showed shorter OS (median 3.9 vs 7.8 months, HR 1.59 [95%CI, 1.15-2.20], P = .005) and shorter PFS (median 2.0 vs 2.6 months, HR 1.76 [95%CI, 1.31-2.37], P < .001). Probability of being alive was 62% vs 40% after 6 months, 38% vs 23% after 1 year and 24% vs 13% after 2 years, in BoM- and BoM+ respectively. Within each Bellmunt score, OS and PFS of BoM+ patients were shorter. Both presence of BoM and higher Bellmunt risk score were significantly associated with shorter OS and PFS in UVA and MVA., Conclusion: Patients treated with single-agent ICIs for BoM+ mUC have a dismal prognosis compared to BoM-. Further research is needed to understand the mechanism behind these outcomes., (Copyright © 2021. Published by Elsevier Inc.)

Cancer treatment has been deeply changed by immunotherapy, achieving unprecedented improvement in overall and progression-free survival in several advanced and metastatic cancers. Currently, immune checkpoint inhibitor (ICI) antibodies against cytotoxic T-lymphocyte antigen (CTLA-4) and programmed death/ligand 1 (PD-1/PD-L1) are being tested and approved for different tumors, ranging from melanoma to lung carcinoma. However, only a subgroup of patients can reach treatment benefits and long-term responses, and reliable biomarkers that can accurately predict clinical responses to immunotherapy are still unidentified. In the last decade, accumulating evidence seems to suggest the gut microbiota as one of the modulators that can alter the efficacy and toxicity of immunotherapy drugs (as well as chemotherapeutics), mainly acting through the local and systemic immune system. Herein, we reviewed the highly dynamic and complex microbiome-immune system interface, its bidirectional relationship with cancer immunotherapies, and explored the future possibilities and risks in manipulating the gut microbiome., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Introduction: In the current study, we have investigated the effects of the different modalities of treatment (volume of radiotherapy [RT], previous surgery) as well as the Gleason score of prostate cancer (PC) on the lymphocyte composition of PC patients undergoing RT., Methods: This is a monoinstitutional study that prospectively included PC patients that underwent RT from January 2016 until December 2017. To compare the different evaluations, the Wilcoxon signed-rank test was used among 2 times (Timepoint 0 to Timepoint 1). Percentage variation was calculated for all the lymphocyte subpopulation and was correlated with clinical parameters (previous surgery, Gleason score, and pelvic irradiation) with the χ2 test. The statistical analysis was repeated also on the stratified dataset according to the above parameters (previous surgery, Gleason score, and whole pelvic radiotherapy [WPRT])., Results: One hundred and eleven patients were included in the present analysis. All the lymphocyte subpopulations resulted significantly lower after RT. The modifications of several lymphocyte subpopulations correlated with previous surgery, Gleason score, and WPRT, although stratified analysis demonstrated that WPRT showed the greatest correlation., Conclusion: Our results could be used to design a prospective trial in order to study the use of WPRT on the lymphocyte subpopulations., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Undifferentiated round cell sarcomas (URCS) of soft tissue and bone and tumours of uncertain differentiation (TUD) are commonly ascribed to a subset of neoplasms with low frequency of NTRK gene fusions. However, more recently NTRK-rearranged round and spindle cell tumours have been noted in case reports and in limited or heterogeneous cohorts. The aim of our study was to investigate the presence of NTRK gene fusions in a large retrospective cohort of paediatric URCS and TUD after a systematic review of the diagnosis, according to the recently updated WHO classification scheme. One-hundred and five patients with diagnosis of URCS or TUD, involving the bone or soft tissue, were retrospectively evaluated. After the case selection and the histopathological review of the case cohort, pan-Trk immunohistochemistry (IHC) testing was performed on formalin-fixed paraffin-embedded (FFPE) tissues. Tumour RNA was extracted from FFPE tissue and subjected to next-generation sequencing (NGS) library preparation, using a 10-gene NGS fusion panel, sequenced on an Illumina MiSeq. The NGS-positive cases were further confirmed by real-time PCR. On immunohistochemical screening, 12/105 (11.4%) cases were positive using the pan-Trk antibody, showing three different staining patterns with the cytoplasmic distribution being most common. Molecular analysis using NGS and confirmed by the real-rime PCR detected two positive cases for the ETV6-NTRK3 fusion. The histological pattern of the two positive cases, together with the demonstration of the NTRK rearrangement, leaded to re-classify these previously not otherwise specified sarcomas with uncertain differentiation into the emerging category of NTRK-rearranged neoplasms. In addition, we found the two NTRK fused neoplasms showing a clinical indolent course, in contrast with literature., Competing Interests: AL reports to be in a consulting role for Hoxo/Bayer and Ignyta/Genentech. DM has received honoraria for professional services and consultancy for Novartis, Bayer HealthCare Pharmaceuticals Inc., Pierre-Fabre, Sanofi Genzyme, MSD Italia S.r.l., Roche, Skyline Dx B.V. FD is founding scientist of FloNext Srl. The remaining 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 Nozzoli, Lazar, Castiglione, Campanacci, Beltrami, De Logu, Caporalini, Massi and Roviello.)

Rationale: Lung cancer is the most common cause of cancer-related deaths worldwide. Approximately 50% of patients is metastatic at diagnosis and the most common metastatic sites are bone, lungs, brain, adrenal glands, liver, and extra thoracic lymph nodes. The occurrence of gastrointestinal metastasis from lung carcinoma is rare and seems more commonly related to small cell lung cancer compared to non-small cell lung cancer (NSCLC)., Patient Information and Diagnosis: A 78-year-old man with completely surgically resected NSCLC and no initial evidence of distant metastases developed colon and gastric metastases 7 months after diagnosis, confirmed by serial radiological examinations and endoscopic biopsies., Interventions: The patient was subjected to total gastrectomy with D2 lymph node dissection plus partial colectomy for intraoperative detection of a transverse colon neoformation. Subsequent instrumental imaging showed bilateral lung tumor recurrence, treated with gemcitabine monotherapy for 8 months as first line chemotherapy for lung adenocarcinoma., Results: The patient presented complete response to therapy and was disease-free for 4 years., Lessons: Colonic and gastric metastasis are very infrequent in NSCLC. The resection of gastrointestinal metastasis may provide benefits in terms of both symptom control and survival in patients properly selected., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)

Gastric cancer (GC) patients with peritoneal metastasis tend to achieve poor clinical outcomes. Until recently, the treatment options were limited mainly to either palliative chemotherapy or radiation therapy in exceptional cases. Currently, these patients benefit from multimodal treatment, such as cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC). Despite good overall results, this treatment modality is still widely debated. The following study is designed to assess the papers about the possible application and utility of HIPEC in GC. A search in the PubMed, Web of Science, and Scopus databases was performed to assess the papers devoted to the role of HIPEC in GC treatment; a literature search was performed until March 21st; and, finally, 50 studies with a total number of 3946 patients were analyzed. According to the most recent data, it seems to be reasonable to limit the duration of HIPEC to the shortest effective time. Moreover, the drugs used in HIPEC need to have equal concentrations and the same solvent. Perioperative chemotherapy needs to be reported in detail and, furthermore, the term "morbidity" should be defined more clearly by the authors.

Background: Chemotherapy-induced peripheral neuropathy (CIPN) is one of the most frequent adverse events observed with taxane use, whose disability often required modification or treatment discontinuation. The aim of this study was to assess the value of several variables as risk factors for CIPN development., Material and Methods: Eligible patients with metastatic pancreatic cancer receiving chemotherapy with nab-paclitaxel and gemcitabine were assessed in a multicenter study. Peripheral neuropathy was categorized using the National Cancer Institute Common Toxicity Criteria scale, version 4.02, and a physical/neurological examination. Univariate and multivariate regression analyses were used to identify blood-based and clinical factors associated with CIPN., Results: Data were available from 153 patients from five Italian centers. Key risk factors of CIPN in univariate regression models included age, number of chemotherapy cycles, statin assumption, and concomitant comorbidities. However, in the multivariate analysis, only for age (OR 1.0, p < 0.01, 95% CI: 1.01-1.11) and the number of cycles (OR 1.22, p < 0.01, 95% CI: 1.09-1.36), the correlation with CIPN development has been confirmed., Conclusion: Our study confirms age and the number of chemotherapy cycles as CIPN risk factors. The identification and validation of different risk factors could be advantageous to prevent or optimize management of CIPN which outstandingly affect the patient's quality of life., (© 2022 S. Karger AG, Basel.)

Background: Cabozantinib improves survival in metastatic renal cell carcinoma (mRCC) after prior antiangiogenics. The best treatment at disease progression (PD) is unknown. Being also a AXL/MET inhibitor, involved in acquired resistance, we hypothesized a prolonged tumor growth control in patients continuing cabozantinib despite PD., Research Design and Methods: This retrospective multicenter study enrolled patients receiving cabozantinib after the first line between 2014 and 2020. We compared patients maintaining cabozantinib after first PD due to clinical benefit and good tolerability with those who changed therapy. The postprogression survival (PPS) of both was our primary endpoint., Results: We analyzed 89 patients: 45 received cabozantinib beyond PD and 44 switched therapy. 40.4%, 31.5%, and 28.1% of patients received 1, 2, or >2 prior treatment, respectively. 84.3% were intermediate-poor International Metastatic Renal Cell Carcinoma Database risk. Patients continuing cabozantinib showed a higher response rate to cabozantinib before PD (46.7% vs 25%, p = 0.03) and were more heavily pretreated. Continuing cabozantinib showed a significantly longer PPS compared with switching therapy (median PPS 16.9 vs 13.2 months, HR 0.66, 95%CI 0.48-0.92, p = 0.011)., Conclusions: We observed longer PPS in patients continuing cabozantinib beyond PD, suggesting that this could be an effective option.

Introduction: Cancer aggravates COVID-19 prognosis. Nosocomial transmission of SARS-CoV-2 is particularly frequent in cancer patients, who need to attend hospitals regularly. Since March 2020, all cancer patients having access to the Oncology Unit at the "Andrea Tortora" Hospital (Pagani, Salerno - referred to as "the Hospital") as inpatients or outpatients receiving intravenous therapy have been screened for SARS-CoV-2 using RT-PCR nasal swab. The ongoing COICA (COVID-19 infection in cancer patients) study is an ambispective, multicenter, observational study designed to assess the prognosis of SARS-CoV-2 infection in cancer patients. The aim of the study presented here was to explore potential differences in COVID-19-related outcomes among screening-detected versus nonscreening-detected SARS-CoV-2-infected patients. Methods: The COICA study enrolled cancer patients who had received any anticancer systemic therapy within 3 months since the day they tested positive for SARS-CoV-2 on RT-PCR. The target accrual is 128 patients, and the study was approved by the competent Ethics Committee. Only the subgroup of patients enrolled at the Hospital was considered in this unplanned interim analysis. Logistic regression analysis was used to evaluate the association of screening-based versus nonscreening-based diagnosis. Results: Since March 15, 2020, until August 15, 2021, a total of 931 outpatients and 230 inpatients were repeatedly screened for SARS-CoV-2 using RT-PCR nasal swab at the Hospital. Among these, 71 asymptomatic patients were positive on routine screening and 5 patients were positive for SARS-CoV-2 outside the institutional screening. Seven patients died because of COVID-19. At univariate analysis, nonscreening- versus screening-detected SARS-CoV-2 infection was associated with significantly higher odds of O 2 therapy (OR = 16.2; 95% CI = 2.2-117.1; p = 0.006), hospital admission (OR = 31.5; 95% CI = 3.1-317.8; p = 0.003), admission to ICU (OR = 23.0; 95% CI = 2.4-223.8; p = 0.007), and death (OR = 8.8; 95% CI = 1.2-65.5; p = 0.034). Conclusion: Routine screening with RT-PCR may represent a feasible and effective strategy in reducing viral circulation and possibly COVID-19 mortality in patients with active cancer having repeated access to hospital facilities., (© 2021 S. Karger AG, Basel.)

Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoma representing approximately one third of all non-Hodgkin lymphomas and about 40% of patients do not benefit of the standard first-line immune-chemotherapeutic treatment (i.e., R-CHOP - rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) that is administered as upfront therapy to substantially all patients independently from the stage of disease and other prognostic parameters. The administration of other pharmacological treatments is in fact limited to selected patients, unfitting for R-CHOP. Although clinical prognostic scores, i.e. International Prognostic Index (IPI), and molecular classifiers based on the cell of origin are available, at present no biomarkers predictive of R-CHOP response has been identified and validated. Constitutional polymorphisms of genes involved in the mechanism of action of drugs included in R-CHOP have been suggested by many authors to play a role in the efficacy and in some case in the toxicity of this treatment. Thus, it is conceivable that in the future, after proper validation, some polymorphisms can be used as pharmacogenetic biomarkers of therapeutic outcome in this disease setting. This review discusses the status of the art on molecular biomarkers predictive of DLBCL prognosis and deals with the relevant issue of the variability in response to DLBCL drug treatment. Overall, this review focuses on single nucleotide polymorphisms (SNPs) that, based on a candidate gene approach or on a genome-wide association study (GWAS) analysis, have been suggested to play a role in response to R-CHOP. In particular, SNPs discovered by a candidate gene approach are related to genes involved in drug transport (i.e., ATP-binding cassette transporters), drug metabolism, drug detoxification enzymes, oxidative stress, apoptosis, DNA repair, immunity and angiogenesis. Data from a GWAS analysis performed in DLBCL patients treated with R-CHOP, identified two SNPs associated with clinical outcomes related to genes involved in pivotal cellular processes and in transcriptional regulation and cell cycle progression, respectively. Ongoing prospective pharmacogenetic clinical trials, including a GWAS study we performed, have also been discussed., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Currently, gastric cancer is one of the leading death-related cancer globally. The etiopathogenesis of gastric cancer is multifactorial and includes among others dysbiotic alterations of gastric microbiota. Molecular techniques revealed that stomach is not a sterile organ and it is resides with ecosystem of microbes. Due to the fact that the role of Helicobacter pylori infection in development of gastric cancer is established and well-studied, this paper is mainly focused on the role of other bacterial as well as viral and fungal gut microbiota imbalance in gastric carcinogenesis. Notably, not only the composition of gastric microbiota may play an important role in development of gastric cancer, but also its activity. Microbial metabolites, such as short-chain fatty acids, polyamines, N-nitroso compounds, and lactate, may significantly affect gastric carcinogenesis. Therefore, this paper discussed aforementioned aspects with the interdisciplinary insights (regarding also immunological point of view) into the association between gut microbiome and gastric carcinogenesis based on up-to-date studies., (© 2021. The Author(s).)

Atypical Spitz tumors (AST) deviate from stereotypical Spitz nevi for one or more atypical features and are now regarded as an intermediate category of melanocytic tumors with uncertain malignant potential. Activating NTRK1/NTRK3 fusions elicit oncogenic events in Spitz lesions and are targetable with kinase inhibitors. However, their prevalence among ASTs and the optimal approach for their detection is yet to be determined. A series of 180 ASTs were screened with pan-TRK immunohistochemistry and the presence of NTRK fusions was confirmed using FISH, two different RNA-based NGS panels for solid tumors, and a specific real time RT-PCR panel. Overall, 26 ASTs showed pan-TRK immunostaining. NTRK1 fusions were detected in 15 of these cases showing cytoplasmic immunoreaction, whereas NTRK3 was detected in one case showing nuclear immunoreaction. Molecular tests resulted all positive in only two ASTs (included the NTRK3 translocated), RNA-based NGS and real time RT-PCR were both positive in three cases, and FISH and real time RT-PCR in another two cases. In seven ASTs NTRK1 fusions were detected only by FISH and in two cases only by real time RT-PCR. The frequency of NTRK fusions in ASTs is 9%, with a clear prevalence of NTRK1 compared to NTRK3 alterations. Pan-TRK immunohistochemistry is an excellent screening test. Confirmation of NTRK fusions may require the use of different molecular techniques.

Introduction: : The evolving therapeutic landscape of advanced hepatocellular carcinoma (HCC) includes the increasing implementation of target-therapy and immunotherapy. Lenvatinib, a multi-target tyrosine kinase inhibitor (TKI), is an emerging first-line therapy for hepatocellular carcinoma. Its approval has changed the scenario of first-line therapies for advanced HCC, where just sorafenib proved clinical efficacy for over a decade., Areas Covered: : The current evidence on the role of lenvatinib for patients with advanced HCC is reviewed in this article. Particularly, therapeutic mechanisms and clinical efficacy of lenvatinib are summarized and the management of adverse events is discussed. In addition, future perspectives on the emerging role of combine therapy for HCC are highlighted., Expert Opinion: In the first line, lenvatinib was found to be non-inferior to sorafenib for overall survival, with significantly better progression-free survival and objective response rate. Immune checkpoint inhibitors (ICIs) are now part of HCC treatment, and recently the combination of atezolizumab plus bevacizumab has become the recommended standard of care first-line therapy for selected patients. The antitumor and immunomodulatory activities that lenvatinib shows in preclinical studies, and the positive outcomes achieved using a combination of lenvatinib plus ICIs, open new perspectives for advanced HCC treatment.

Background: In recent years, new therapeutic combinations based on immunotherapy provided significant benefits as a first-line treatment for patients with advanced renal cell carcinoma (mRCC)., Objective: This work aims to address the lack of head-to-head comparisons and the uncertainty of the benefit from immunotherapy-based combinations in all the International Metastatic RCC Database Consortium (IMDC) subgroups., Design Setting and Participants: A systematic review and a network meta-analysis were performed. Overall survival (OS) in the intention-to-treat (ITT) population was the primary endpoint. OS according to IMDC subgroups (favorable, intermediate, poor), PD-L1 expression, and grade ⩾3 adverse events (AEs) were secondary endpoints. A SUCRA analysis was performed., Results and Limitations: Six randomized phase III trials with 5121 patients were included. There was a high likelihood (82%) that nivolumab-cabozantinib was the preferred treatment in OS. The benefit of ICI-based combinations over sunitinib was unclear in the favorable-risk subgroup. Nivolumab-ipilimumab had the best risk/benefit ratio among all the ICI-based combinations. The limitations were the lack of individual patient data; the heterogeneity of patients' characteristics, trial designs, and follow-up times; and a limited number of studies for indirect comparisons., Conclusions: A customized approach for the first-line treatment of patients with mRCC should consider the risk/benefit profile of each treatment option, especially considering the likeliness of long-term survival finally reached in this setting., Competing Interests: Conflict of interest statement: The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: C.C. received Travel/Accommodation/Expenses from Novartis, Pfizer, Janssen, and Ipsen; advisory board from Janssen. C.M. received honoraria as a speaker for scientific events from Astellas and Ipsen. S.B. received honoraria as a speaker at scientific events and advisory role from Bristol-Myers Squibb (BMS), Pfizer, MSD, Ipsen, Roche, Eli-Lilly, AstraZeneca, and Novartis; he also received research funding from Novartis. O.C. received honoraria as advisor/speaker from Astellas, AstraZeneca, Bayer, Janssen, MSD, Pfizer, and Sanofi. A.G. has declared consulting/advisory role for Roche, MSD, Eli Lilly, Pierre Fabre, EISAI, and Daichii Sankyo; Speakers Bureau from Eisai, Novartis, Eli Lilly, Roche, Teva, Gentili, Pfizer, Astra Zeneca, Celgene, and Daichii Sankyo; and research funds from EISAI, Eli Lilly, and Roche. M.B. received research funding from Roche S.p.A., Seqirus UK, Pfizer, Novartis, BMS, Astra Zeneca, and Sanofi Genzyme; honoraria as a speaker at scientific events from Bristol-Myers Squibb (BMS), Novartis, Astra Zeneca, Pierre Fabre, and Pfizer; fees as a consultant for advisory role from Novartis, BMS, IPSEN, and Pfizer; and fees for copyright transfer and consultancies from Sciclone Pharmaceuticals. All the other authors declare no conflicts of interest., (© The Author(s), 2021.)

Kaposi's sarcoma (KS) is a rare inflammation- based vascular cancer involving the skin. The viral aetiology of KS is the Human Herpesvirus 8. KS may be frequently diagnosed in immunosuppressed kidneytransplanted patients, while is less common in patients with dialysis. It is known that various immunological abnormalities can lead to impaired immune status in uremic patients. It is noteworthy that despite the incidence of KS in patients with renal impairment, only few cases have reported efficacy and safety profile of KS targeting anti-cancer drugs in this kidney disease population. Herein, we report the first case of a symptomatic KS patient with renal disease in haemodialysis and focus on its therapeutic management. We also review the main data available from literature regarding the safety of KS therapy in dialysis patients., Competing Interests: Conflict of interest: The authors declare no potential conflict of interest., (©Copyright: the Author(s).)

Importance : The protein p53 is an unequivocal tumor suppressor that is altered in half of all cancers. The immune system produces systemic p53 autoantibodies (p53 Abs) in many cancer patients. Objective : This systemic review and meta-analysis focuses on the prognostic value of p53 Abs expressed in the serum of patients with solid tumors. Data Sources : All the clinical investigations were searched on PubMed from the first study dated 1993 until May 2021 (date of submission of the manuscript). Study Selection : Studies were included that met the following criteria: (1) participants with cancer; (2) outcome results expressed in relation to the presence of a p53 antibody; (3) a primary outcome (disease-free survival, overall survival or progression-free survival) expressed as hazard ratio (HR). The following exclusion criteria were used: (1) insufficient data available to evaluate outcomes; (2) animal studies; (3) studies with less than 10 participants. As a result, 12 studies were included in the analysis. Data Extraction and Synthesis : PRISMA guidelines were used for abstracting and assessing data quality and validity by three independent observers. The summary estimates were generated using a fixed-effect model (Mantel-Haenszel method) or a random-effect model (DerSimonian-Laird method), depending on the absence or presence of heterogeneity (I 2 ). Main Outcome(s) and Measure(s) : The primary study outcome was to determine the prognostic value of p53 Abs from a large population of patients with solid tumors, as determined before data collection. Results: In total, 12 clinical studies involving 2094 patients were included in the meta-analysis, and it was determined that p53 Abs expression in the serum significantly correlated with poorer survival outcomes of cancer patients (95% CI 1.48 [1.24, 1.77]; p < 0.00001). Conclusions and Relevance: This is the first meta-analysis proving the diagnostic utility of p53-Abs for cancer patients in predicting poorer outcomes. The serum-p53 value (s-p53-value) may be useful for future theranostics.

Purpose: Immune checkpoint inhibitors have opened a new scenario in the treatment of cancer. These agents can elicit adverse events, which may affect different systems and organs, including the endocrine system. The aims of this study were to evaluate the impact of the anti-PD-1 molecules nivolumab and pembrolizumab on endocrine toxicity and on patient outcome., Methods: A retrospective and multicentre study was designed, which involved a total of 251 patients affected by different tumors (mostly non-small cell lung cancer, 68.92% and melanoma, 24.30%) and treated with the PD-1 inhibitors nivolumab (61.35%) or pembrolizumab (38.65%) for up to 60 months. Clinical and biochemical data were recorded until July 31, 2020., Results: Endocrine toxicity occurred in 70 out of 251 patients (27.89%). It was mostly related to thyroid dysfunction and in 75% of cases occurred within 6 months from the beginning of therapy. A previous endocrine morbidity and female gender were predictors of endocrine toxicity. There was no association between endocrine dysfunction and patient outcome. However, when all toxicities (i.e., endocrine and non endocrine) were considered, a significant association with progression-free survival and overall survival was found., Conclusions: Thyroid alterations are frequently observed in cancer patients treated with anti PD-1 drugs, particularly in women and in the presence of a previous endocrinopathy. We suggest that regular thyroid assessment should be performed in these patients, especially in the first months of therapy. Finally, the onset of side effects, related to anti PD-1 agents, appears to be associated with a better outcome., (© 2021. The Author(s).)

Introduction : Although standard doublet chemotherapy represents the upfront gold standard to increase survival and improve quality of life of gastric cancer patients, overall improvements in long-term outcomes are modest and novel treatments are urgently needed. Among these, immunotherapy is an increasingly attractive option. Areas covered : A number of clinical trials have shown that checkpoint inhibitors may be of value, but many unclear issues remain controversial and should be promptly untangled. In our short review, we offer the current available data regarding immunotherapies in gastric cancers, discuss potential limits of the reported trials, compare outcomes of checkpoints inhibitor to those of standard chemotherapy or other novel treatments, and present basic principles of immune surveillance and immune escape that may be embraced in the near future with novel drug combinations. Expert opinion : Gastric cancer patients may benefit from immunotherapy, both given alone in advanced lines and upfront in combination with chemotherapy. We believe that appropriate patients' and tumor's selection are crucial issues to maximize its potential efficacy. In addition, we think that assay standardization, biomarker agreement, and translational studies will improve the benefit-to-risk ratio of these agents in the clinical practice.

Nowadays, allogenic hematopoietic stem cell transplantation (allo-HSCT) is a curative therapy that is mainly recommended for hematologic malignancies. However, complications (such as graft-versus-host disease, mucositis, disease relapse, and infections) associated with the HSCT procedure contribute to the development of gut microbiota imbalance, gut-barrier disruption, and increased intestinal permeability. In the present narrative review, the crosstalk between gut microbiota products and intestinal homeostasis is discussed. Notably, gut-microbiota-related aspects have an impact on patients' clinical outcomes and overall survival. In accordance with the most recent published data, gut microbiota is crucial for the treatment effectiveness of many diseases, not only gastrointestinal cancers but also hematologic malignancies. Therefore, it is necessary to indicate a therapeutic method allowing to modulate gut microbiota in HSCT recipients. Currently, fecal microbiota transplantation (FMT) is the most innovative method used to alter/restore gut microbiota composition, as well as modulate its activity. Despite the fact that some previous data have shown promising results, the knowledge regarding FMT in HSCT is still strongly limited, except for the treatment of Clostridium difficile infection. Additionally, administration of prebiotics, probiotics, synbiotics, and postbiotics can also modify gut microbiota; however, this strategy should be considered carefully due to the high risk of fungemia/septicemia (especially in case of fungal probiotics).

Background: The role of immune checkpoint inhibitors (ICI) rechallenge in cancer patients is not defined. When ICIs are discontinued due to treatment completion or toxicity, another course of ICIs is feasible in clinical practice, but the amount of data is still quite limited to draw definitive conclusions. Here we report the results of a meta-analysis evaluating efficacy and safety of ICI rechallenge., Methods: PubMed, Embase, and Cochrane library were searched for studies reporting efficacy and safety of ICI rechallenge. Pooled analysis of response rate (ORR), median progression-free survival (mPFS) and median overall survival (mOS) were calculated., Results: A total of 49 studies were included in qualitative and quantitative pooled analysis Overall response rate, mPFS and mOS were 21.8 % (range 0-70 %), 4.9 months (range 0-19.1 months) and 15.6 months (range 5.1-39 months), respectively. Incidence of any grade and grade 3-4 adverse events were 52.2 % (range 4-100 %) and 21.5 % (range 0-97.8 %), respectively. In the subgroup of patients who had previously discontinued ICI because of disease progression ORR, mPFS and mOS were 15.2 %, 2.9 and 7.9 months. Patients who had previously discontinued ICI because of toxicity achieved an ORR of 44 % and a mPFS of 13.2 months with the rechallenge., Conclusions: Our results suggest that rechallenge ICI is an active and feasible strategy, and it could be considered on an individual basis. However, this analysis is based on non-randomized studies. Prospective studies are needed to clarify the role of rechallenge after disease progression or adverse events., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Hepatitis B virus (HBV) has been considered a significant cause of human reproductive failure in different studies; however, there is a considerable disagreement on the true impacts of HBV on female reproduction. This study has evaluated the impact of HBV infection on pregnancy complications in natural pregnancy and also on pregnancy outcomes in women undergoing in vitro fertilization (IVF) treatment., Method: We searched Embase, Web of Science, PubMed and Google Scholar databases to identify the potentially relevant studies. Summary odds ratio (OR) or standardized mean difference (SMD) with 95% confidence interval (CI) was applied to assess the relationship. Heterogeneity testing, sensitivity analysis and publication bias testing were also performed., Results: A total of 42 studies concerning the effect of HBV infection on the natural and IVF pregnancy were included in this study. Our meta-analysis results revealed that HBV infection had a positive correlation to gestational diabetes mellitus (GDM) [OR = 1.32 (1.17-1.48) (p < 0.01)] and preterm birth [OR = 1.26 (1.14-1.40) (p < 0.01)] in natural pregnancy; however, HBV infection was not significantly associated with decreased fertility rates among the patients who underwent IVF., Conclusion: This study revealed a strong association of GDM and preterm birth with higher rates of HBV infection in pregnant women. Also, our results suggested that HBV infection in patients undergoing IVF may not negatively influence the pregnancy outcome. It may be rational to conclude that IVF might be rather a safe and effective method for HBV+ females who desire to have children., (© 2021 John Wiley & Sons Ltd.)

Bladder cancer (BC) is the most common malignancy of the genitourinary tract, with high morbidity and mortality rates. Until recently, the treatment of locally advanced or metastatic urothelial BC was based on the use of chemotherapy alone. Since 2016, five immune checkpoint inhibitors (ICIs) have been approved by the Food and Drug Administration (FDA) in different settings, i.e., first-line, maintenance and second-line treatment, while several trials are still ongoing in the perioperative context. Lately, pembrolizumab, a programmed death-1 (PD-1) inhibitor, has been approved for Bacillus Calmette-Guérin (BCG)-unresponsive high-risk non-muscle invasive bladder cancer (NMIBC), using immunotherapy at an early stage of the disease. This review investigates the current state and future perspectives of immunotherapy in BC, focusing on the rationale and results of combining immunotherapy with other therapeutic strategies.

In this systematic review and network meta-analysis (NMA), we aimed to assess the benefits and harms of third-line (L3) treatments in randomized controlled trials (RCTs) of patients with metastatic castration-resistant prostate cancer (mCRPC). Two reviewers searched for publications from 1 January 2006 to 30 June 2021. The review analyzed seven RCTs that included 3958 patients and eight treatments. Treatment with prostate-specific membrane antigen (PSMA)-based radioligand therapy (PRLT) resulted in a 1.3-times-higher rate of median PSA decline ≥50% than treatment with abiraterone, enzalutamide, mitoxantrone, or cabazitaxel ( p = 0.00001). The likelihood was 97.6% for PRLT to bring about the best PSA response, out of the examined treatments. PRLT resulted in a 1.1-times-higher six-month rate of median radiographic progression-free survival. Treatment with PRLT in the VISION trial resulted in 1.05-times-higher twelve-month median overall survival than L3 treatment with cabazitaxel in other RCTs. PRLT more often resulted in severe thrombocytopenia and less often in severe leukopenia than did cabazitaxel. In conclusion, for patients with mCRPC, L3 treatment with PRLT is highly effective and safe.

Background: Severe immune-related Adverse Events (irAEs) develop in 10-27% of patients treated with Immune-Oncology (IO) [Powles (Lancet 391:748-757, 2018); Galsky (Lancet 395:1547-1557, 2020); Haanen (Ann Oncol 28:119-142, 2017)]. The aim of our study was to evaluate efficacy and clinical outcome of metastatic renal cell carcinoma (mRCC) patients who stopped Immune Checkpoint Inhibitors (ICIs) due to early Grade (G) 3-G4 irAEs., Methods: We retrospectively collected data from 204 mRCC patients treated with ICIs in 6 Italian referral centers adhering to the Meet-Uro group, between February 2017 and January 2020. To properly weight the results, patients who did not report early G3-G4 toxicities have been included as control group. Primary endpoint was to evaluate 6 months Progression Free Survival (PFS) after early treatment interruption for Grade (G) 3-4 toxicities compared to the control group. Secondary endpoints were to evaluate Time to treatment failure (TTF) and overall survival (OS) in both groups. All statistical analyses were performed using SPSS software (version 19.00, SPSS, Chicago)., Results: 18/204 (8.8%) patients had early treatment interruption for serious (G3-G4) irAEs. Early was defined as interruption of IO after only one or two administrations. Immune related nephritis and pancreatitis were the most common irAE that lead to treatment interruption. 6/18 patients received IO-IO combination whereas 12/18 patients antiPD1. In the study group, 12/18 (66.6%) were free from progression at 6 months since IO interruption, TTF was 1.6 months (95% CI 1.6-2.1), mPFS was 7.4 months (95% CI 3.16-11.6) and mOS was 15.5 months (5.1-25.8). In the control group 111/184 (60.3%) patients were free from progression at 6 months, TTF was 4.6 months (95% CI 3.5-5.6), mPFS was 4.6 months (95% CI 3.5-5.6) and mOS was 19.6 months (95% CI 15.1-24.0). In the overall population, mPFS was 5.0 months (95% CI 4.0-5.9) and mOS was 19.6 months (95% CI 15.1-24.0)., Conclusions: ICIs seem to maintain efficacy even after early interruption due to severe irAE., (© 2021. The Author(s).)

Accumulating evidence has revealed the critical roles of commensal microbes in cancer progression and recently several investigators have evaluated the therapeutic effectiveness of targeting the microbiota. This gut microbiota-related approach is especially attractive in the treatment of gastrointestinal cancers. Probiotics supplementation is a microbiota-targeted strategy that appears to improve treatment efficacy; Lactobacillus spp. and Bifidobacterium spp. are among the most commonly used probiotic agents. These bacteria seem to exert immunomodulatory effects, impacting on the immune system both locally and systemically. The gut microbiota are able to affect the efficiency of immunotherapy, mainly acting as inhibitors at immune checkpoints. The effects of immunotherapy may be modulated using traditional probiotic strains and/or next generation probiotics, such as Akkermansia municiphila . It is possible that probiotics might enhance the efficiency of immunotherapy based on PD-1/PD-L1 and CTLA-4 but more data are needed to confirm this speculation. Indeed, although there is experimental evidence for the efficacy of several strains, the health-promoting effects of numerous probiotics have not been demonstrated in human patients and furthermore the potential risks of these products, particularly in oncologic patients, are rarely mentioned.

The addition of aflibercept to FOLFIRI has been demonstrated to improve survival in patients with metastatic colorectal cancer (mCRC) who progressed after receiving a standard oxaliplatin-based regimen. In this retrospective, single-institution, observational study we collected clinical data from mCRC patients who received aflibercept in combination with FOLFIRI in routine clinical practice from October 2012 to March 2021 to describe feasibility and efficacy of this regimen in a real-world population. Forty-nine patients receiving aflibercept-FOLFIRI as second-line treatment were identified, 40.8% of whom were aged over 65 years. The majority of patients had multi-organ metastases (73.5%), and had previously received bevacizumab in combination with chemotherapy (CT) as first-line treatment (79.6%). Median overall survival (OS) and progression-free survival (PFS) were 13 and 6 months, respectively; overall response rate (ORR) and disease control rate (DCR) were 12.3% and 49.1%, respectively. Several factors were associated with survival in univariate analysis, including PFS in first-line therapy, number of metastatic sites, bone metastases and others. However, in multivariate analysis, only PFS in first-line CT over 12 months was significantly associated with better OS (HR 0.32; 95% CI 0.13-0.79; p = 0.01). Hypertension was the most commonly reported grade (G) 3-4 adverse event (AE), affecting 18.4% of the overall population. Thromboembolic events were observed in 16.3% of patients, hemorrhagic events in 10.2%, and proteinuria in 8.2%. Neutropenia was the most frequently observed hematological G3-4 AE with an incidence of 10.2%. Aflibercept-FOLFIRI has been confirmed as a feasible second-line treatment for mCRC in a re-al-life setting, and PFS in first-line therapy >12 months resulted as the only predictive marker of better survival.

Objectives: The incidence of prostate cancer in renal transplant recipients (RTRs) is increasing, but few data are available in the literature. In this study, we reviewed the 25-year experience in the management of prostate cancer after kidney transplantation at the Florence Transplant Centre. Methods: We retrospectively reviewed the data from 617 RTR male patients who underwent renal transplantation at our institute between July 1996 and September 2016. Data regarding demographics, renal transplantation, prostate cancer and immunosuppressive treatment were analyzed. The probability of death was estimated by using the Kaplan-Meier method and differences between patients' groups were assessed by the log-rank test. Results: From July 1991 to September 2016, 617 kidney transplantations of male patients were performed at our institute. Among these, 20 patients were subsequently diagnosed with prostate cancer accounting for a cumulative incidence of 3.24%. After a median follow-up of 59 months, 10 patients underwent radical prostatectomy whereas 10 patients underwent primary radiotherapy. A biochemical recurrence was identified in five (25%) patients while a fatal event occurred in 11 (55%) patients. Univariate Cox regression showed that the basal value of PSA >10 ng/ml was the only significant factor negatively affecting the survival of patients. Conclusions: Standard treatments can be proposed to RTR with satisfactory results on both post-operative and oncological outcomes. Further studies are needed to address the issue of prostate cancer screening based on PSA levels and the optimal management of prostate cancer in RTRs., 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. The reviewer JGR declared a past co-authorship with the authors FS and SS to the handling editor., (Copyright © 2021 Spatafora, Sessa, Caroassai Grisanti, Bisegna, Saieva, Roviello, Polverino, Rivetti, Verdelli, Zanazzi, Beatrice, Vignolini, Nesi, Nicita, Serni and Villari.)

Competing Interests: Conflict of interest statement: The author(s) declare that there is no conflict of interest.

ALTERTASTE is a prospective study to evaluate changes in taste/flavor perception and food preferences in patients treated with adjuvant or neoadjuvant chemotherapy for breast or colorectal cancer. The study adopts a longitudinal approach. Taste and odor responsiveness, food preferences and habits, emotions elicited by foods, and quality of life will be measured at six-time points: before chemotherapy (T0), after two cycles (T1, after around 1 month), after four cycles (T2, after around 2 months), after six cycles (T3, after around 4 months), at the end of chemotherapy (T4, after around 6 months) and 3 months after the conclusion of the therapy (T5). In addition, patients will be characterized for oral responsiveness and their psychological traits and attitudes toward food. The ALTERTASTE trial is expected to improve the understanding of the impact of chemotherapy on taste and smell and the repercussions of these alterations on food behaviors. Furthermore, the trial aims to develop an easy and reliable procedure to test smell, taste and food behavior alterations to allow a routine measure with patients. Clinical trial registration: NCT04495387 (ClinicalTrials.gov).

Gastric cancer is one of the most common malignancy worldwide. In unresectable or metastatic disease, the prognosis is poor and in generally less than a year. HER2 expression remains an important biomarker to lead the addition of trastuzumab to first-line systemic chemotherapy in unresectable or metastatic gastroesophageal adenocarcinoma. To date, a major issue is represented by resistance to trastuzumab developed during treatment, considering the not improved outcomes in this molecular subtype of gastroesophageal adenocarcinoma to other HER2 target strategies. In this review, we summarize the available data on the mechanisms underlying primary and secondary resistance to HER2-targeted therapy and current challenges in the treatment of HER2-positive advanced gastric cancer refractory to trastuzumab. Furthermore, we describe the prognostic value of new non-invasive screening methods, under development novel agents (e.g., HER2 antibody-drug conjugates and bispecific antibodies) and strategies with antitumor activity in early studies.

Background: Immune-Oncology (IO) improves Overall Survival (OS) in metastatic Renal Cell Carcinoma (mRCC). The prognostic impact of previous Cytoreductive Nephrectomy (CN) and radical nephrectomy (RN), with curative intent, in patients treated with IO is not well defined. The aim of our paper is to evaluate the impact of previous nephrectomy on outcome of mRCC patients treated with IO., Methods: 287 eligible patients were retrospectively collected from 16 Italian referral centers adhering to the MeetUro association. Patients treated with IO as second and third line were included, whereas patients treated with IO as first line were excluded. Kaplan-Meier method and log-rank test were performed to compare Progression Free Survival (PFS) and OS between groups. In our analysis, both CN and RN were included. The association between nephrectomy and other variables was analyzed in univariate and multivariate setting using the Cox proportional hazard model., Results: 246/287 (85.7%) patients had nephrectomy before IO treatment. Median PFS in patients who underwent nephrectomy (246/287) was 4.8 months (95%CI 3.9-5.7) vs 3.7 months (95%CI 1.9-5.5) in patients who did not it (HR log rank 0.78; 95%CI 0.53 to 1.15; p = 0.186). Median OS in patients who had previous nephrectomy (246/287) was 20.9 months (95%CI 17.6-24.1) vs 13 months (95%CI 7.7-18.2) in patients who did not it (HR log rank 0.504; 95%CI 0.337 to 0.755; p = 0.001). In the multivariate model, nephrectomy showed a significant association with OS (HR log rank 0.638; 95%CI 0.416 to 0.980), whereas gland metastases were still associated with better outcome in terms of both OS (HR log rank 0.487; 95%CI 0.279 to 0.852) and PFS (HR log rank 0.646; 95%CI 0.435 to 0.958)., Conclusions: IO treatment, in patients who had previously undergone nephrectomy, was associated with a better outcome in terms of OS. Further prospective trials would assess this issue in order to guide clinicians in real word practice., 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 © 2021 Stellato, Santini, Verzoni, De Giorgi, Pantano, Casadei, Fornarini, Maruzzo, Sbrana, Di Lorenzo, Soraru, Naglieri, Buti, De Vivo, Napolitano, Vignani, Mucciarini, Grillone, Roviello, Di Napoli and Procopio.)

Non-small cell lung cancer (NSCLC) is one of the most frequent causes of mortality in the western world. v-raf murine sarcoma viral oncogene homolog B (BRAF) is a member of the Raf kinase family and plays a critical role in cellular growth, proliferation, and differentiation through the mitogen-activated protein kinase pathway. The incidence of BRAF mutations in NSCLC is low, accounting for 0-3% of all cases of lung cancer. Given the results obtained in metastatic melanoma, several studies have reported the efficacy of anti-BRAF therapies in NSCLC treatment. In this review, we describe changes in the landscape of BRAF-mutated lung cancer treatment and analyze insights from major clinical trials in the context of future therapeutic prospects.

Metastatic prostate cancer is the most common cancer in males and the fifth cause of cancer mortality worldwide. Despite the major progress in this field, leading to the approval of novel anti-androgens, the prognosis is still poor. A significant number of patients acquire an androgen receptor splice variant 7 (AR-V7), which is constitutively activated and lacks the ligand-binding domain (LBD) while maintaining the nuclear localization signal and DNA-binding domain (DBD). This conformational change, even in the absence of the ligand, allows its retention within the nucleus, where it acts as a transcription factor repressing crucial tumor suppressor genes. AR-V7 is an important oncogenic driver and plays a role as an early diagnostic and prognostic marker, as well as a therapeutic target for antagonists such as niclosamide and TAS3681. Anti-AR-V7 drugs have shown promise in recent clinical investigations on this subset of patients. This mini-review focuses on the relevance of AR-V7 in the clinical manifestations of castration-resistant prostate cancer (CRPC) and summarizes redemptive therapeutic strategies.

In the last few years the advent of targeted therapies against oncogenic drivers significantly improved the survival of non small cell lung cancer (NSCLC) patients with a favourable toxicity profile. Therefore, genetic testing, including at least EGFR mutations and ALK/ROS1 rearrangements, should be performed in all NSCLC patients (in particular with adenocarcinoma) who received a diagnosis of advanced disease. This review focuses on novel druggable oncogenic drivers, such as MET exon 14 mutations/MET amplification, RET fusions, BRAF V600E mutations, KRAS G12C mutations, NTRK rearrangements, and HER2 alterations., 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 © 2021 Tartarone, Lapadula, Di Micco, Rossi, Ottanelli, Marini, Giorgione, Ferrari, Catalano, Voltolini, Mini and Roviello.)

Background: Despite the survival advantage, not all metastatic renal cell carcinoma (mRCC) patients achieve a long-term benefit from immunotherapy. Moreover, the identification of prognostic biomarkers is still an unmet clinical need., Methods: This multicenter retrospective study investigated the prognostic role of peripheral-blood inflammatory indices and clinical factors to develop a novel prognostic score in mRCC patients receiving at least second-line nivolumab. The complete blood count before the first cycle of therapy was assessed by calculating neutrophil-to-lymphocyte ratio (NLR), derived NLR (dNLR), lymphocyte-to-monocyte ratio (LMR), platelet-to-lymphocyte ratio (PLR), systemic inflammation index (SII), and systemic inflammation response index (SIRI). Clinical factors included pre-treatment International Metastatic RCC Database Consortium (IMDC) score, line of therapy, and metastatic sites., Results: From October 2015 to November 2019, 571 mRCC patients received nivolumab as second- and further-line treatment in 69% and 31% of cases. In univariable and multivariable analyses all inflammatory indices, IMDC score, and bone metastases significantly correlated with overall survival (OS). The multivariable model with NLR, IMDC score, and bone metastases had the highest c-index (0.697) and was chosen for the developing of the score (Schneeweiss scoring system). After internal validation (bootstrap re-sampling), the final index (Meet-URO score) composed by NLR, IMDC score, and bone metastases had a c-index of 0.691. It identified five categories with distinctive OSs: group 1 (median OS - mOS = not reached), group 2 (mOS = 43.9 months), group 3 (mOS = 22.4 months), group 4 (mOS = 10.3 months), and group 5 (mOS = 3.2 months). Moreover, the Meet-URO score allowed for a fine risk-stratification across all three IMDC groups., Conclusion: The Meet-URO score allowed for the accurate stratification of pretreated mRCC patients receiving nivolumab and is easily applicable for clinical practice at no additional cost. Future steps include its external validation, the assessment of its predictivity, and its application to first-line combinations., Competing Interests: Conflict of interest statement: Dr Fornarini services advisory boards for Astellas, Janssen, Pfizer, Bayer, MSD, and Merck, and received travel accommodation from Astellas, Janssen, and Bayer. Dr Buti received honoraria as a speaker at scientific events and in an advisory role by BMS, Pfizer; MSD, Ipsen, Roche, Eli Lilly, AstraZeneca, Pierre-Fabre, Novartis. Dr Banna reports personal fees from AstraZeneca, Janssen-Cilag, Boehringer Ingelheim, Roche, and non-financial support from Bristol-Myers Squibb, AstraZeneca, MedImmune, Pierre Fabre, IPSEN, outside the submitted work. Dr De Giorgi services as an advisory/board member of Astellas, Bayer, Bristol-Myers Squibb, IPSEN, Janssen, Merck, Pfizer, and Sanofi, received research grant/funding to the institution from AstraZeneca, Roche, Sanofi, and travel/accommodations/expenses from Bristol-Myers Squibb, IPSEN, Janssen, and Pfizer. Dr Zucali services advisory boards/consulting for Pfizer, Bristol-Myers Squibb, MSD, IPSEN, Novartis, Roche, Amgen, AstraZeneca, Sanofi, Janssen, and Astellas. Dr Masini received personal fees as a speaker from Astellas, as a consultant from IPSEN, MSD, and Janssen, and for travel accommodation from BMS, Pfizer, Astellas, Janssen, and IPSEN. Dr Procopio services advisory boards/consulting for Astellas, AstraZeneca, Bayer, Bristol-Myers Squibb, Janssen, IPSEN, Merk, MSD, Novartis, and Pfizer. Dr Cortellini receives speaker fees/grant consultancies from Astrazeneca, BMS, MSD, Roche, Novartis, and Astellas. Dr Morelli received grants from MSD and Pfizer. Dr Bersanelli received research funding to the institution from Roche, Pfizer, Seqirus UK, AstraZeneca, Bristol-Myers Squibb, Novartis, and Sanofi, and received personal fees for advisory role, copyright transfer, consultancies, and as speaker at scientific events from Sciclone Pharmaceuticals, Bristol-Myers Squibb, AstraZeneca, Pierre-Fabre, Novartis, and Pfizer. The other authors have no conflicts of interest to disclose., (© The Author(s), 2021.)

A new class of zirconium and hafnium complexes coordinated by linear dianonic tetradentate NSSN ligands is reported. The ligands feature two amide functions coupled with two thioether groups linked by a central flexible ethane bridge and two lateral rigid phenylene bridges and differ for the substituents on the aniline nitrogen atoms, i.e., isopropyl, cyclohexyl, or mesityl substituents: NSSN- i Pr, NSSN-Cy, or NSSN-Mes. They were prepared by reacting 2-aminothiophenol with dibromoethane to afford the NSSN ligands without substituents on the aniline nitrogen atoms, which were subsequently alkylated through a reductive amination of acetone or cyclohexanone or palladium-catalyzed cross-coupling reaction with mesityl bromide. The corresponding zirconium and hafnium complexes 1 - 5 were obtained through a transamination reaction between the neutral ligands and Zr(NMe 2 ) 4 or Hf(NMe 2 ) 4 [(NSSN- i Pr)Zr(NMe 2 ) 2 ( 1 ), (NSSN-Cy)Zr(NMe 2 ) 2 ( 2 ), (NSSN-Mes)Zr(NMe 2 ) 2 ( 3 ), (NSSN- i Pr)Hf(NMe 2 ) 2 ( 4 ), and (NSSN-Cy)Hf(NMe 2 ) 2 ( 5 )]. They were characterized in solution by NMR spectroscopy and in solid state by X-ray diffraction analysis (except for 3 ). All complexes present an octahedral coordination geometry with a fac - fac ligand wrapping and a cis relationship between the other two monodentate ligands. The catalytic performances of 1 - 5 in the ring-opening polymerization of cyclic esters were investigated. Complex 1 was the most active: its polymerization activity was superior to those generally displayed by zirconium complexes featuring OSSO ligands and compared well with those of the most active group 4 complexes operating in a toluene solution.

Introduction : Important changes in the treatment of prostate cancer have taken place in recent years. Non-metastatic castration-resistant prostate cancer (nmCRPC) has been clinically delineated. In this setting, three drugs have been approved in high-risk disease: apalutamide, enzalutamide and darolutamide. Areas covered: This manuscript aims to profile darolutamide, its clinical development, pharmacologic properties, efficacy and safety. We presented the results of published clinical studies, but we also investigated ongoing ones. Expert opinion: An indirect comparison with the other two aforementioned drugs emerged. While the clinical efficacy is comparable, the toxicity profile is different for darolutamide, resulting in greater tolerance. We must wait for the results of the trials that study darolutamide in hormone-sensitive disease, both in the metastatic phase and in the localized phase. Clinical experience will also be important to determine ever more personalized treatments for patients.