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Gastric cancer (GC) is the fifth most frequently diagnosed malignant tumor and the third highest cause of cancer mortality worldwide. For advanced GC, many novel drugs and combinations have been tested, but results are still disappointing, and the disease is incurable in the majority of cases. In this regard, it is critical to investigate the molecular mechanisms underlying GC development. Angiogenesis is one of the hallmarks of cancer with a fundamental role in GC growth and progression. Ramucirumab, a monoclonal antibody that binds to vascular endothelial growth factor-2 (VEGFR-2), is approved in the treatment of advanced and pretreated GC. However, no predictive biomarkers for ramucirumab have been identified so far. Micro RNAs (miRNAs) are a class of evolutionarily-conserved single-stranded non-coding RNAs that play an important role (via post-transcriptional regulation) in essentially all biologic processes, such as cell proliferation, differentiation, apoptosis, survival, invasion, and migration. In our review, we aimed to analyze the available data on the role of angiogenesis-related miRNAs in GC.

Diarrhoea is one of the main side effects that cancer patients face. The literature showsthat the incidence of chemotherapy (CT)-induced diarrhoea (grade 3-4) in treated patients is in the range of 10-20%, particularly after 5-fluorouracil (5-FU) bolus or some combination therapies of irinotecan and fluoropyrimidines. The aim of the present study was to evaluate the clinical effectiveness of Lactobacillus kefiri LKF01 (Kefibios ® ) in the prevention or treatment of CT-related diarrhoea in the cancer population. We conducted a prospective observational study. Patients enrolled were adults treated for at least four months with 5-FU-based CT. Kefibios ® was administered to patients every day. The primary outcome was the evaluation of the incidence of grade 3-4 CT-induced diarrhoea. We included 76 patients in the final analysis. A 6.6% incidence of high-grade diarrhoea was found in the evaluated population (4.7% of patients treated with 5-FU-based therapy and 8.5% of patients treated with capecitabine-based CT). The overall incidence of high-grade diarrhoea observed was higher in the 1st and 2nd cycles (3.9%), with a subsequent sharp reduction from the 3rd cycle (1.3%) and negativisation from the 5th cycle. Lactobacillus kefiri LKF01 (Kefibios ® ) is safe and effective in preventing severe diarrhoea in cancer patients receiving 5-FU or capecitabine-based treatment.

Immunotherapy has revolutionized the treatment landscape in a number of solid tumors. In colorectal cancer, evidence suggests that microsatellite high (MSI-H) tumors are the most responsive to immune checkpoint blockade due to increased neo-antigen load and a favorable tumor microenvironment. Indeed, Pembrolizumab now represents a first-line option in such patients. However, MSI-H tumors represent the minority and a proportion of patients' progress despite initially responding. Trials are investigating different immunotherapy combinatorial strategies to enhance immune response in less immunogenic colorectal tumors. Such strategies include dual immune checkpoint blockade, combining immune checkpoint inhibitors with other treatment modalities such as radiotherapy, chemotherapy or other biological or targeted agents. Moreover, there is an increasing drive to identify biomarkers to better select patients most likely to respond to immunotherapy and understand intrinsic and acquired resistance mechanisms. Apart from MSI-H tumors, there is a strong rationale to suggest that tumors with alterations in DNA polymerase epsilon and DNA polymerase delta are also likely to respond to immunotherapy and trials in this subpopulation are underway. Other strategies such as priming O6-methylguanineDNA methyltransferase silenced tumors with alkylating agents to make them receptive to immune checkpoint blockade are also being investigated. Here we discuss different colorectal subpopulations together with their likelihood of response to immune checkpoint blockade and strategies to overcome barriers to a successful clinical outcome. We summarize evidence from published clinical trials and provide an overview of trials in progress whilst discussing newer immunotherapy strategies such as adoptive cell therapies and cancer vaccines., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: Bladder cancer (BC) usually metastasizes to the lymph nodes, bone, lung, liver and peritoneum, but rarely in the breast., Case Report: We present a case of a 66-year-old female diagnosed with a massive bladder tumor, who presented a right mammary nodule after neo-adjuvant chemotherapy. A biopsy of the nodule did not permit a definite diagnosis of metastatic spread, which was confirmed by excision of the nodule. In the literature, we found only 7 other similar cases of BC metastasis to the breast. Currently, a non-invasive method for differentiating a breast metastasis from primary cancer is lacking, although there are some clinical and radiological aspects that may help the diagnosis. Histological examination provides diagnostic certainty., Conclusion: Breast metastases from BC are unusual and consequently difficult to identify without non-invasive tools. Clinical history and histological study play a pivotal role in determining the correct diagnosis., (Copyright© 2021, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Circulating tumour DNA (ctDNA) is a novel tool that has been investigated in several types of tumours, including colorectal cancer (CRC). In fact, the techniques based on liquid biopsies are proposed as appealing non-invasive alternatives to tissue biopsy, adding more insights into tumour molecular profile, heterogeneity and for cancer detection and monitoring. Additionally, some analysis showed that in CRC patients, ctDNA seems to act as a biomarker able to predict the outcome (prognostic role) and the response to treatments (predictive role). In particular, in the early stage CRC (stage I-III), it could represent a time marker of adjuvant therapy as well as a marker of minimal residual disease and recurrence risk in addition to the already recognized risk factors. In metastatic CRC, the analysis of molecular tumour profile by ctDNA has shown to have high concordance with the tissue biopsy at diagnosis. Additionally, some studies demonstrated that ctDNA level during the treatment was linked with the early response to treatment and prognosis. Finally, the quantitative analysis of ctDNA and copy number alterations may be useful in order to detect resistance to therapy at the time of progression of disease and to help in finding new therapeutic targets., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Pancreatic cancer is one of the most aggressive malignancies with limited treatment options thus resulting in high morbidity and mortality. Among all cancers, with a five-year survival rates of only 2-9%, pancreatic cancer holds the worst prognostic outcome for patients. To improve the overall survival, an earlier diagnosis and stratification of cancer patients for personalized treatment options are urgent needs. A minority of pancreatic cancers belong to the spectrum of Lynch syndrome-associated cancers and are characterized by microsatellite instability (MSI). MSI is a consequence of defective mismatch repair protein functions and it has been well characterized in other gastrointestinal tumors such as colorectal and gastric cancer. In the latter, high levels of MSI are linked to a better prognosis and to an increased benefit to immune-based therapies. Therefore, the same therapies could offer an opportunity of treatment for pancreatic cancer patients with MSI. In this review, we summarize the current knowledge about immune-based therapies and MSI in pancreatic cancer.

Biliary tract cancers are anatomically distinct and genetically diverse tumors, evenly characterized by poor response to standard treatments and a bleak outlook. The advent of comprehensive genomic profiling using next-generation sequencing has unveiled a plethora of potentially actionable aberrations, changing the view of biliary tract cancers from an "orphan" to a "target-rich" disease. Recently, mutations in isocitrate dehydrogenase genes (IDH1/2) and fusions of the fibroblast growth factor receptor have emerged as the most amenable to molecularly targeted inhibition, with several compounds actively investigated in advanced-phase clinical trials. Specifically, the IDH1 inhibitor ivosidenib has been the first targeted agent to show a survival benefit in a randomized phase III trial of cholangiocarcinoma patients harboring IDH1 mutations. In this review article, we will focus on the IDH1/IDH2 pathway, discussing the preclinical rationale of its targeting as well as the promises and challenges of the clinical development of IDH inhibitors in biliary tract cancers.

Background: The role of immune-related adverse events (irAEs), as a surrogate predictor of the efficacy of checkpoint inhibitors, has not yet been described in the setting of first-line, single-agent pembrolizumab for patients with metastatic non-small-cell lung-cancer (NSCLC) with a programmed death-ligand 1 (PD-L1) expression of ≥ 50%., Patients and Methods: We previously conducted a multicenter retrospective analysis in patients with treatment-naive metastatic NSCLC and a PD-L1 expression of ≥ 50% receiving first-line pembrolizumab. Here, we report the results of the irAE analysis and the potential correlation between irAEs and clinical outcomes., Results: A total of 1010 patients were included in this analysis; after a 6-week landmark selection, 877 (86.8%) patients were included in the efficacy analysis. Any grade irAEs (P < .0001), grade 3/4 irAEs (P = .0025), leading to discontinuation irAEs (P = .0144), multiple-site and single-site irAEs (P < .0001), cutaneous irAEs (P = .0001), endocrine irAEs (P = .0227), pulmonary irAEs (P = .0479), and rheumatologic irAEs (P = .0018) were significantly related to a higher objective response rate. Any grade irAEs (P < .0001), single-site irAEs (P < .0001), multiple-site irAEs (P = .0005), cutaneous irAEs (P = .0042), endocrine irAEs (P < .0001), gastrointestinal irAEs (P = .0391), and rheumatologic irAEs (P = .0086) were significantly related to progression-free survival. Any grade irAEs (P < .0001), single-site irAEs (P < .0001), multiple-site irAEs (P = .0003), cutaneous irAEs (P = .0002), endocrine irAEs (P = .0001), and rheumatologic irAEs (P = .0214) were significantly related to overall survival., Conclusions: This study confirms the feasibility and the safety of first-line, single-agent pembrolizumab, in a large, real-world cohort of patients with NSCLC with PD-L1 expression ≥ 50%. The occurrence of irAEs may be a surrogate of clinical activity and improved outcomes in this setting., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background and Aims: Changes in single microRNA (miRNA) expression have been associated with chemo-resistance in biliary tract cancers (BTCs). However, a global assessment of the dynamic role of the microRNome has never been performed to identify potential therapeutic targets that are functionally relevant in the BTC cell response to chemotherapy., Approach and Results: High-throughput screening (HTS) of 997 locked nucleic acid miRNA inhibitors was performed in six cholangiocarcinoma cell lines treated with cisplatin and gemcitabine (CG) seeking changes in cell viability. Validation experiments were performed with mirVana probes. MicroRNA and gene expression was assessed by TaqMan assay, RNA-sequencing, and in situ hybridization in four independent cohorts of human BTCs. Knockout of microRNA was achieved by CRISPR-CAS9 in CCLP cells (MIR1249KO) and tested for effects on chemotherapy sensitivity in vitro and in vivo. HTS revealed that MIR1249 inhibition enhanced chemotherapy sensitivity across all cell lines. MIR1249 expression was increased in 41% of cases in human BTCs. In validation experiments, MIR1249 inhibition did not alter cell viability in untreated or dimethyl sulfoxide-treated cells; however, it did increase the CG effect. MIR1249 expression was increased in CD133+ biliary cancer cells freshly isolated from the stem cell niche of human BTCs as well as in CD133+ chemo-resistant CCLP cells. MIR1249 modulated the chemotherapy-induced enrichment of CD133+ cells by controlling their clonal expansion through the Wnt-regulator FZD8. MIR1249KO cells had impaired expansion of the CD133+ subclone and its enrichment after chemotherapy, reduced expression of cancer stem cell markers, and increased chemosensitivity. MIR1249KO xenograft BTC models showed tumor shrinkage after exposure to weekly CG, whereas wild-type models showed only stable disease over treatment., Conclusions: MIR1249 mediates resistance to CG in BTCs and may be tested as a target for therapeutics., (© 2020 The Authors. Hepatology published by Wiley Periodicals, Inc., on behalf of American Association for the Study of Liver Diseases.)

The novel coronavirus respiratory illness (COVID-19) is a public health emergency of global concern. Patients with cancer are at high risk of infections, due to an overall immunocompromised status. However, this connection is not straightforward for coronavirus (CoV) infection, in which the host immune response is the main driver of tissue damage. We performed a thorough review of data on CoV pathogenesis and morbidity rate in cancer patients, through the analysis of the previous CoV pandemics. Considering the interaction between CoV and the host immune system, cancer patients receiving immunotherapy might be more at risk for an aberrant immune response in case of infection, and might therefore deserve additional precautions. The limited available data do not allow us to provide practical indications for the management of cancer patients in this critical situation. Efforts should be made to prospectively collect data, to identify effective interventions to guide treatment decision., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: Although most of the analyses included transverse colon cancers (TCC) among right colon cancer (RCC), it is not completely clear if they present total similarities with RCC or if they have their specific features. Therefore, we present an observational study to evaluate clinicopathological characteristics and survival data of patients with TCC. Methods: We retrospectively reviewed 450 RCC, of whom 97 stages I-IV TCC were included in this multicenter study; clinicopathological and molecular parameters were analyzed to identify prognostic factors for disease-free survival (DFS) and overall survival (OS). Results: Most of TCC cases were male (61%), with ≤70 years old (62%), and good performance status (ECOG PS 0, 68%). According to WHO classification, 41 (49%) and 40 (48%) tumors were classified as well to moderate and poorly/undifferentiated respectively, regardless of mucinous component (30%). About molecular data, 8 (26%), 45 (63%), and 14 (24%) were MSI-H, KRAS wild-type, and BRAF V600E mutant, respectively. With a median follow-up of 34 months, there were 29 and 50 disease recurrences and deaths respectively. Charlson comorbidity index ≥5 was a significant prognostic factor for DFS (HR = 7.67, 95% CI 2.27-25.92). Colon obstruction/perforation (HR = 2.65, 95% CI 1.01-7.01), and BRAF mutant (HR = 3.03, 95% CI 0.97-9.50) cases showed a worst, despite not statistically significant, DFS. Whereas for OS, at the multivariate model, only tumor grade differentiation (HR = 5.26, 95% CI 1.98-14.01) and BRAF mutation status (3.71, 95% CI 1.07-12.89) were independent prognostic factors. Conclusions: Poorly/undifferentiated tumor grade and BRAF V600E mutation are independent prognostic factors for OS in TCC. Further prospective clinical trials are needed to better define TCC treatment in order to improve patient outcome.

The COVID-19 pandemic has inevitably caused those involved in cancer care to change clinical practice in order to minimize the risk of infection while maintaining cancer treatment as a priority. General advice during the pandemic suggests that most patients continue with ongoing therapies or planned surgeries, while follow-up visits may instead be delayed until the resolution of the outbreak. We conducted a literature search using PubMed to identify articles published in English language that reported on care recommendations for cancer patients during the COVID-19 pandemic from its inception up to 1st June 2020, using the terms "(cancer or tumor) AND (COVID 19)". Articles were selected for relevance and split into five categories: (1) personal recommendations of single or multiple authors, (2) recommendations of single authoritative centers, (3) recommendations of panels of experts or of multiple regional comprehensive centers, (4) recommendations of multicenter cooperative groups, (5) official guidelines or recommendations of health authorities. Of the 97 included studies, 10 were personal recommendations of single or multiple independent authors, 16 were practice recommendations of single authoritative cancer centers, 35 were recommendations provided by panel of experts or of multiple regional comprehensive centers, 19 were cooperative group position papers, and finally, 17 were official guidelines statements. The COVID-19 pandemic is a global emergency, and has rapidly modified our clinical practice. Delaying unnecessary treatment, minimizing toxicity, and identifying care priorities for surgery, radiotherapy, and systemic therapies must be viewed as basic priorities in the COVID-19 era.

Purpose: BRAF mutations represent the main negative prognostic factor for metastatic colorectal cancer and a supposed negative predictive factor of response to standard chemotherapy. We have explored survival difference in right-sided colon cancer (RCC) patients according to BRAF mutations, with the aim to identify any predictive factors of response to targeted-based therapy., Methods: A retrospective study of RCC patients, with BRAF known mutation status, treated with chemotherapy (CT) from October 2008 to June 2019 in 5 Italian centers, was conducted., Results: We identified 207 advanced RCC patients: 20.3% BRAF mutant and 79.7% BRAF wild type (wt). BRAF-mutant cancers were more likely to be pT4 (50.0% v 25.7%, p = 0.016), undifferentiated (71.4% v 44.0%, p = 0.004), KRAS wt (90.5% v 38.2%, p < 0.001), and MSI-H (41.7% v 16.2%, p = 0.019) tumors, with synchronous (52.4% v 31.5%, p = 0.018) and peritoneal metastases (38.1% v 22.4%, p = 0.003). Median overall survival (OS) was 16 v 27 months in BRAF mutant and BRAF wt (P = 0.020). In first-line setting, BRAF-mutant showed a 2ys OS of 80% in clinical trials, 32% in anti-VEGF, 14% in epidermial growth factor receptor (EGFR), and 0% in chemotherapy alone regimens (P = 0.009). BRAF-mutant patients demonstrated worse survival, regardless of targeted therapy administered. However, survival difference was statistically significant in the anti-EGFR-treated subgroup (16 v 28 months, P = 0.005 in BRAF mutant v BRAF wt, respectively)., Conclusions: Our study demonstrated that BRAF status makes the difference in treatment's outcome. Therefore, the anti-EGFR should not be excluded in all advanced RCC but considered on a case-by-case basis.

The novel coronavirus (CoV) pandemic is a serious threat for patients with cancer, who have an immunocompromised status and are considered at high risk of infections. Data on the novel CoV respiratory disease (coronavirus disease 2019 [COVID-19]) in patients with cancer are still limited. Unlike other common viruses, CoVs have not been shown to cause a more severe disease in immunocompromised subjects. Along with direct viral pathogenicity, in some individuals, CoV infection triggers an uncontrolled aberrant inflammatory response, leading to lung tissue damage. In patients with cancer treated with immunotherapy (e.g. immune checkpoint inhibitors), COVID-19 may therefore represent a serious threat. After a thorough review of the literature on CoV pathogenesis and cancer, we selected several shared features to define which patients can be considered at higher risk of COVID-19. We combined these clinical and laboratory variables, with the aim of developing a score to weight the risk of COVID-19 in patients with cancer., Competing Interests: Conflict of interest statement F.G. reports a consulting or advisory role for MSD Oncology, Bristol-Myers Squibb, AstraZeneca, Roche, Pfizer and Bayer; participates in the speakers' bureau of MSD Oncology, Bristol-Myers Squibb, AstraZeneca, Roche, Pierre Fabre, Amgen, Celgene, Eli Lilly and Pfizer; reports Funding from Bristol-Myers Squibb and reports travel, accommodation and expense fees from Bristol-Myers Squibb, MSD, Roche, AstraZeneca, Pierre Fabre, Celgene, Amgen, Eli Lilly and Novartis. All the remaining authors have declared no conflicts of interest., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Cholangiocarcinoma (CCC) is the most aggressive malignant tumor of the biliary tract. Perihilar CCC (pCCC) is the most common CCC and is burdened by a complicated diagnostic iter and its anatomical location makes surgical approach burden by poor results. Besides its clinical presentation, a multimodal diagnostic approach should be carried on by a tertiary specialized center to avoid miss-diagnosis. Preoperative staging must consider the extent of liver resection to avoid post-surgical hepatic failure. During staging iter, magnetic resonance can obtain satisfactory cholangiographic images, while invasive techniques should be used if bile duct samples are needed. Consistently, to improve diagnostic potential, bile duct drainage is not necessary in jaundice, while it is indicated in refractory cholangitis or when liver hypertrophy is needed. Once resecability criteria are identified, the extent of liver resection is secondary to the longitudinal spread of CCC. While in the past type IV pCCC was not considered resectable, some authors reported good results after their treatment. Conversely, in selected unresectable cases, liver transplantation could be a valuable option. Adjuvant chemotherapy is the standard of care for resected patients, while neoadjuvant approach has growing evidences. If curative resection is not achieved, radiotherapy can be added to chemotherapy. This multistep curative iter must be carried on in specialized centers. Hence, the aim of this review is to highlight the main steps and pitfalls of the diagnostic and therapeutic approach to pCCC with a peculiar attention to type IV pCCC., Competing Interests: Conflict-of-interest statement: Authors declare no conflict of interests for this article., (©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.)

Background: Incidence of gastric cancer (GC) shows different distribution in Italy, with higher incidence in the north and center. We retrospectively analyzed the clinical data of patients resected at the Hospital of Cremona between January 2007 and December 2016. Available clinical variables were linked with survival to identify possible prognostic factors., Materials and Methods: Variables analyzed were age, sex, type of surgery, site, histology, invasion, nodal status, resection margins, grade, HER2 status, Helicobacter pylori infection (neo)adjuvant chemotherapy, adjuvant chemoradiotherapy, neutrophil-to-lymphocyte ratio, number of nodes removed and type of lymphadenectomy. Overall survival (OS) was estimated by the Kaplan-Meier method and differences between groups by the log-rank test. Data on OS were analyzed by Cox regression and the final model was obtained using the step-wise method., Results: 379 patients were considered, out of which 195 were operated from 2007 to 2011 and 184 from 2012 to 2016. Median follow-up was 25.5 months, median OS 31.3 months and time to recurrence 23.2 months. D2 resection rate increased from 36% (period 2007-2011) to 74% in 2012-2016 (p = 0.01) with a higher mean number of nodes collected (20.98 for 2007-2011 and 23.53 for 2012-2016, p = 0.040). Only 37% of patients received a postoperative treatment. At multivariate analysis, variables associated with OS were age (p = 0.002), stage (p < 0.001), resection margins status (p < 0.001), adjuvant chemotherapy (p < 0.010) and tumor location (cardia vs non-cardia) (p = 0.029)., Conclusions: Our analysis shows that completeness of resection and lower stage are strong predictors of long-term survival in GC, providing the rationale for adjuvant and neoadjuvant approaches (chemotherapy, radiotherapy or combined). Cardial GC has worse prognosis compared to distal cancers., Trial Registration Number: Service evaluation number 256, protocol 16821/17, date 05 June 2017.

Background: In TAGS, an international, double-blind, phase 3 trial, trifluridine/tipiracil significantly improved overall survival and progression-free survival compared with placebo in heavily pretreated metastatic gastric cancer patients. This paper reports pre-specified quality of life (QoL) outcomes for TAGS., Methods: Patients were randomized 2:1 to trifluridine/tipiracil (35 mg/m 2 twice daily on days 1-5 and 8-12 of each 28-day cycle) plus best supportive care (BSC) or placebo plus BSC. QoL was evaluated at baseline and at each treatment cycle, using the EORTC QLQ-C30 and EORTC QLQ-STO22 questionnaires; results were considered valid for analysis only if ≥ 10% of patients completed the questionnaires. Key QoL outcomes were mean changes from baseline and time to deterioration in QoL. A post hoc analysis assessed the association between QoL and time to deterioration of Eastern Cooperative Oncology Group performance score (ECOG PS) to ≥ 2., Results: Of 507 randomized patients, 496 had baseline QoL data available. The analysis cut-off was 6 cycles for trifluridine/tipiracil and 3 cycles for placebo. In both treatment groups, there were no clinically significant deteriorations in the mean QLQ-C30 Global Health Status (GHS) score, or in most subscale scores. In a sensitivity analysis including death and disease progression as events, there was a trend towards trifluridine/tipiracil reducing the risk of deterioration of QoL scores compared with placebo. Deterioration in the GHS score was associated with deterioration in ECOG PS., Conclusion: QoL was maintained in TAGS, and there was a trend towards trifluridine/tipiracil reducing the risk of QoL deterioration compared with placebo. Trial registration ClinicalTrials.gov number: NCT02500043.

Background: Data on spectrum and grade of immune-related adverse events (irAEs) in long-term responders to immune checkpoint inhibitors (ICIs) are lacking., Methods: We performed a retrospective multicenter study to characterized irAEs occurring after a 12-months minimum treatment period with PD-(L)1 ICIs in patients with advanced cancer. IrAEs were categorized into 'early' (≤12 months) and 'late' (>12 months)., Results: From September 2013 to October 2019, 436 consecutive patients were evaluated. Two hundred twenty-three experienced any grade early-irAEs (51.1%), whereas 132 experienced any grade late-irAEs (30.3%) (p < 0.0001). Among the latter, 29 (22%) experienced a recurrence of an early-irAEs, whereas 103 (78%) experienced de novo late-irAEs involving different system/organ. Among patients with late-irAEs, 21 experienced GIII/GIV irAEs (4.8%). Median time to onset of early-irAEs was 3.4 months (95% confidence interval [CI]: 2.8-4.2), whereas the median time to onset of late-irAEs was 16.6 months (95% CI: 15.8-17.6). Cumulative time-adjusted risk of disease progression according to both the early-irAEs (hazard ratio [HR] = 0.63 [95% CI: 0.30-1.29], p = 0.204) and late-irAEs occurrence revealed no statistically significant differences (HR = 0.75 [95% CI: 0.37-1.56], p = 0.452). In addition, the time-adjusted cumulative risk of death in accordance with both early-irAEs (HR = 0.79 [95% CI: 0.34-1.86], p = 0.598) and late-irAEs (HR = 0.92 [95% CI: 0.49-1.74], p = 0.811) did not show statistically significant differences., Conclusion: Although less frequent than early-irAEs, late-irAEs are quite common in long responders to PD-(L)1 ICIs and are different in terms of spectrum and grade. Time-adjusted analysis revealed that the cumulative risk of disease progression and death were not significantly reduced in patients who experienced late-irAEs., Competing Interests: Conflict of interest statement A.C. reports having received grants as speaker by MSD and Astra-Zeneca; grant consultancies by BMS, Roche, Novartis, Istituto Gentili and Ipsen. M.B. reports having received research funding by Roche, Pfizer, Seqirus, AstraZeneca, Bristol-Myers Squibb, Novartis and Sanofi; she also received honoraria for advisory role and as speaker at scientific events by Bristol-Myers Squibb, Novartis and Pfizer. M.R. reports having received honoraria for scientific events by Roche, Astrazeneca, Bristol-Myers Squibb, Merck Sharp & Dohme and Boehringer Ingelheim. R.G. reports to be a part of the advisory boards/Honoraria/Speakers’ fee/Consultant for: Astra Zeneca, Roche. All remaining authors declare no conflict of interest., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Importance: The mismatch repair (MMR) pathway plays a crucial role in repairing DNA replication errors in normal and cancer cells. Defects in DNA MMR proteins that determine the microsatellite instability-high (MSI-H) condition lead to the accumulation of mutations and the generation of neoantigens, which may stimulate the antitumor immune response. Clinical trials have demonstrated that MSI-H status is associated with long-term benefit in patients treated with immune checkpoint inhibitors (ICIs)., Objective: To evaluate the activity of ICIs in terms of overall response rate (ORR), disease control rate (DCR), overall survival (OS), and progression-free survival (PFS) in patients with MSI-H cancers., Data Sources: Published articles that evaluated ICIs in the treatment of advanced MSI-H tumors from inception to December 2019 were identified by searching the PubMed, EMBASE, and Cochrane Library databases., Study Selection: Prospective or retrospective studies, published in the English language, providing outcome data with ICIs in patients with MSI-H cancer were selected., Data Extraction and Synthesis: Author and year of publication, type of studies, diseases included, median follow up, type of ICI, median OS ,and PFS, ORR, DCR and 1-, 2-, and 3-year OS were retrieved. Analysis was performed in December 2019., Main Outcome and Measures: The primary outcome of interest was ORR. Secondary end points were median PFS, median OS, pooled rate of patients alive at 1, 2 ,and 3 years, and pooled rate of patients that attained disease control rate ([DCR] calculated as the sum of stable disease rate and ORR)., Results: Overall, 939 patients (14 studies) were analyzed mainly in pretreated settings. The pooled ORR was 41.5% (95% CI, 34.9%-48.4%). The pooled DCR was 62.8% (95% CI, 54.5%-70.3%). Pooled median PFS was 4.3 months (95% CI, 3-6.8 months). The pooled median OS was 24 months (95% CI, 20.1-28.5 months). The pooled 1- and 2-year OS were 75.6% (95% CI, 61.8%-85.5%) and 56.5% (95% CI, 46%-66.4%), respectively. Because only 1 study provided 3-year OS data, a formal pooled analysis for 3 years was not possible., Conclusions and Relevance: In this meta-analysis of patients with pretreated MSI-H cancer, ICIs were associated with high activity independent of tumor type and drug used. Among molecular biomarkers for selection of treatment, MMR proteins may have a predictive value for the activity of immunotherapy.

Non-coding RNAs represent a significant proportion of the human genome. After having been considered as 'junk' for a long time, non-coding RNAs are now well established as playing important roles in maintaining cellular homeostasis and functions. Some non-coding RNAs show cell- and tissue-specific expression patterns and are specifically deregulated under pathological conditions (e.g. cancer). Therefore, non-coding RNAs have been extensively studied as potential biomarkers in the context of different diseases with a focus on microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) for several years. Since their discovery, miRNAs have attracted more attention than lncRNAs in research studies; however, both families of non-coding RNAs have been established to play an important role in gene expression control, either as transcriptional or post-transcriptional regulators. Both miRNAs and lncRNAs can regulate key genes involved in the development of cancer, thus influencing tumour growth, invasion, and metastasis by increasing the activation of oncogenic pathways and limiting the expression of tumour suppressors. Furthermore, miRNAs and lncRNAs are also emerging as important mediators in drug-sensitivity and drug-resistance mechanisms. In the light of these premises, a number of pre-clinical and early clinical studies are exploring the potential of non-coding RNAs as new therapeutics. The aim of this review is to summarise the latest knowledge of the use of miRNAs and lncRNAs as therapeutic tools for cancer treatment.

Introduction: Anaplastic lymphoma kinase (ALK) inhibitors are potent oral anti-cancer agents acting as tyrosine kinase inhibitors (TKIs), which are approved for the treatment of ALK+ non-small cell lung cancer (NSCLC). Over the last years, several new molecules have been developed and are currently under clinical investigation., Areas Covered: In this paper, the authors review the most relevant clinical findings of ALK inhibitors in the treatment of ALK+ NSCLC. The authors discuss differences in the efficacy and treatment-related adverse events (AEs) incidence of distinct ALK inhibitors, molecular mechanisms of acquired resistance, and ongoing clinical studies assessing the use of ALK inhibitors in innovative settings and novel combinations., Expert Commentary: ALK inhibitors have dramatically improved the prognosis of patients with ALK+ NSCLC and revolutionized therapy options. Nowadays, several molecules are approved for the treatment of ALK+ NSCLC, either in first or further lines of systemic treatment. Several clinical trials are currently ongoing in order to define a potential role of ALK inhibitors in combination with novel anti-cancer agents, as well as monotherapy in neo- and adjuvant settings.

: Background: The optimal anti-angiogenic strategy as second-line treatment in RAS wild-type metastatic colorectal cancer (mCRC) treated with anti-EGFR (Epidermal Growth Factor Receptor) based first-line treatment is still debated., Methods: This multicenter, real-world, retrospective study is aimed at evaluating the effectiveness of second-line Bevacizumab- and Aflibercept-based treatments after an anti-EGFR based first-line regimen. Clinical outcomes measured were: objective response rate (ORR), progression free survival (PFS), overall survival (OS) and adverse events (AEs) profiles., Results: From February 2011 to October 2019, 277 consecutive mCRC patients received Bevacizumab-based (228, 82.3%) or Aflibercept-based (49, 17.7%) regimen. No significant difference was found regarding ORR. The median follow-up was 27.7 months (95%CI: 24.7-34.4). Aflibercept-treated group had a significantly shorter PFS compared to Bevacizumab-treated group (5.6 vs. 7.1 months, respectively) (HR = 1.34 (95%CI: 0.95-1.89); p = 0.0932). The median OS of the Bevacizumab-treated group and Aflibercept-treated group was 16.2 (95%CI: 15.3-18.1) and 12.7 (95%CI: 8.8-17.5) months, respectively (HR= 1.31 (95%CI: 0.89-1.93) p = 0.16). After adjusting for the key covariates (age, gender, performance status, number of metastatic sites and primary tumor side) Bevacizumab-based regimens revealed to be significantly related with a prolonged PFS (HR = 1.44 (95%CI: 1.02-2.03); p = 0.0399) compared to Aflibercept-based regimens, but not with a prolonged OS (HR = 1.47 (95%CI: 0.99-2.17); p = 0.0503). The incidence of G3/G4 VEGF inhibitors class-specific AEs was 7.5% and 26.5% in the Bevacizumab-treated group and the Aflibercept-treated group, respectively ( p = 0.0001)., Conclusion: Our analysis seems to reveal that Bevacizumab-based regimens have a slightly better PFS and class-specific AEs profile compared to Aflibercept-based regimen as second-line treatment of RAS wild-type mCRC patients previously treated with anti-EGFR based treatments. These results have to be taken with caution and no conclusive considerations are allowed., Competing Interests: Alessio Cortellini received grants as a speaker by MSD and Astra-Zeneca, grant consultancies by BMS, Roche, Novartis and Astellas. Dr. Daniele Rossini received personal fees from Takeda. Dr. Ingrid Garajova received grants as a speaker by Amgen and Takeda. The other authors declare no conflict of interest.

Antibiotics (ABs) are common medications used for treating infections. In cancer patients treated with immune checkpoint inhibitors (ICIs), concomitant exposure to ABs may impair the efficacy of ICIs and lead to a poorer outcome compared to AB non-users. We report here the results of a meta-analysis evaluating the effects of ABs on the outcome of patients with solid tumours treated with ICIs. PubMed, the Cochrane Library and Embase were searched from inception until September 2019 for observational or prospective studies reporting the prognoses of adult patients with cancer treated with ICIs and with or without ABs. Overall survival (OS) was the primary endpoint, and progression-free survival (PFS) was the secondary endpoint. The effect size was reported as hazard ratios (HRs) with a 95% confidence interval (CI) and an HR > 1 associated with a worse outcome in ABs users compared to AB non-users. Fifteen publications were retrieved for a total of 2363 patients. In the main analysis ( n = 15 studies reporting data), OS was reduced in patients exposed to ABs before or during treatment with ICIs (HR = 2.07, 95%CI 1.51-2.84; p < 0.01). Similarly, PFS was inferior in AB users in n = 13 studies with data available (HR = 1.53, 95%CI 1.22-1.93; p < 0.01). In cancer patients treated with ICIs, AB use significantly reduced OS and PFS. Short duration/course of ABs may be considered in clinical situations in which they are strictly needed.

Purpose: Established that the only approved agents in previously treated metastatic colorectal cancer (CRC) are trifluoridine/tipiracil and regorafenib, we conducted a systematic review of all the published phase 2-3 trials, with the scope to evaluate the benefit of any later-line regimens in refractory metastatic CRC., Methods: Phase 2-3 studies that enrolled patients with stage IV disease receiving salvage therapies for refractory CRC were identified using electronic databases (Pubmed, EMBASE, and Cochrane Library). Clinical outcomes were pooled using a point estimates for the weighted values of median overall survival (OS), progression-free survival (PFS), response rate (ORR), stable disease rate (SD), and 6-month and 1-year OS., Results: Overall, 7556 patients were included from 67 studies (n = 70 arms). Overall, the pooled ORR and SD were 15.4% (95% CI 13-18%) and 36.9% (95% CI 33.5-40.6%). Median PFS, 6-month and 1-year OS, and median OS were 3.2 (95% CI 2.9-3.3) months, 65.4% (95% CI 61.9-68.8%), 36% (95% CI 32.3-39.9%) and 8.8 (95% CI 8.3-9.2) months. Overall survival was different in the monochemotherapy, polychemotherapy, chemotherapy + targeted therapy, and targeted therapy alone arms (7.6, 9.5, 10.3, and 7.9 months, respectively, P for difference = 0.01). Median PFS were respectively 2.3, 3.9, 3.8, and 2.6, respectively (P for difference < 0.01)., Conclusions: Overall, combination therapy (polychemotherapy with or without targeted agents) is associated with a higher control of disease and better outcome than approved agents. Treatment, if possible, should be personalized according to the patients' conditions, physician preference and molecular profile of disease.

Exchange-bias has been reported in bulk nanocrystalline Fe 2 MnAl, but individual thin films of this Heusler alloy have never been studied so far. Here we study the structural and magnetic properties of nanocrystalline thin films of Fe 2- x Mn 1+ x Al ( x = -0.25, 0 and 0.25) obtained by sputtering and ex situ post-deposition annealing. We find that Fe 2 MnAl films display exchange-bias, and that varying Mn concentration determines the magnitude of the effect, which can be either enhanced (in Fe 1.75 Mn 1.25 Al) or suppressed (in Fe 2.25 Mn 0.75 Al). X-ray diffraction shows that our films present a mixed L2 1 -B2 Heusler structure where increasing Mn concentration favors the partial transformation of the L2 1 phase into the B2 phase. Scanning transmission electron microscopy (STEM) and energy dispersive X-ray spectroscopy (EDX) reveal that this composition-driven L2 1 → B2 transformation is accompanied by phase segregation at the nanoscale. As a result, the Fe 2- x Mn 1+ x Al films that show exchange-bias ( x = 0, 0.25) are heterogeneous, with nanograins of an Fe-rich phase embedded in a Mn-rich matrix (a non-negative matrix factorisation algorithm was used to give an indication of the phase composition from EDX data). Our comparative analysis of XRD, magnetometry and X-ray magnetic circular dichroism (XMCD), shows that the Fe-rich nanograins and Mn-rich matrix are composed of a ferromagnetic L2 1 phase and an antiferromagnetic B2 phase, respectively, thus revealing that exchange-coupling between these two phases is the cause of the exchange-bias effect. Our work should inspire the development of single-layer, environmentally friendly spin valve devices based on nanocomposite Heusler films., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Immune checkpoint inhibitors have revolutionized treatment and outcome of melanoma and many other solid malignancies including non-small cell lung cancer (NSCLC) and renal cell carcinoma (RCC). Unfortunately, only a minority of patients have a long-term benefit, while the remaining demonstrate primary or acquired resistance. Recently, it has been demonstrated that the prevalence of programmed death-ligand 1 (PD-L1) and tumor-infiltrating lymphocytes (TILs) varies based on the anatomical site of metastases. In particular, liver seems to have more immunosuppressive microenvironment while both the presence of lymph nodal disease and lung metastases seem to have the highest prevalence of PD-L1 and TILs. The aim of the present study is to investigate the possible role of site of metastases as a predictive factor for response or resistance to immunotherapy in several types of cancer. In this multicenter retrospective study, we enrolled patients with metastatic NSCLC, melanoma, RCC, urothelial, merkel carcinoma, and colon cancer who received immunotherapy from April 2015 to August 2019. Major clinicopathological parameters were retrieved and correlated with patients' survival outcomes in order to assess their prognostic value and build a useful tool to assist in the decision-making process. A total of 291 patients were included in this study. One hundred eighty-seven (64%) patients were male and 104 (36%) female. The tumor histology was squamous NSCLC in 56 (19%) patients, non-squamous NSCLC in 99 (34%) patients, melanoma in 101 (35%) patients, RCC in 28 (10%) patients, and other tumors in the remaining 7 (2%) patients. The number of metastatic sites was 1 in 103 patients (35%), 2 in 104 patients (36%) and 3 in 84 patients (29%). Out of 183 valuable patients, the entity of response was complete response (CR), partial response (PR), stable disease (SD), and progression disease (PD) in 15, 53, 31, and 79 patients, respectively. Using an univariate analysis (UVA), tumor burden ( p = 0.0004), the presence of liver ( p = 0.0009), bone ( p = 0.0016), brain metastases ( p < 0.0001), the other metastatic sites ( p = 0.0375), the number of metastatic sites ( p = 0.0039), the histology ( p = 0.0034), the upfront use of immunotherapy ( p = 0.0032), and Eastern Cooperative Oncology Group (ECOG) Perfomance status (PS) ≥ 1 ( p < 0.0001) were significantly associated with poor overall survival (OS). Using a multivariate analysis (MVA) the presence of liver ( p = 0.0105) and brain ( p = 0.0026) metastases, the NSCLC diagnosis ( p < 0.0001) and the ECOG PS ( p < 0.0001) resulted as significant prognostic factors of survival. Regarding the progression free survival (PFS), using a UVA of the tumor burden ( p = 0.0004), bone ( p = 0.0098) and brain ( p = 0.0038) metastases, the presence of other metastatic sites ( p = 0.0063), the number of metastatic sites ( p = 0.0007), the histology ( p = 0.0007), the use of immunotherapy as first line ( p = 0.0031), and the ECOG PS ≥ 1 ( p ≤ 0.0001) were associated with a lower PFS rate. Using an MVA, the presence of brain ( p = 0.0088) and liver metastases ( p = 0.024) and the ECOG PS ( p < 0.0001) resulted as predictors of poor PFS. Our study suggests that the site of metastases could have a role as prognostic and predictive factor in patients treated with immunotherapy. Indeed, regardless of the histology, the presence of liver and brain metastases was associated with a shorter PFS and OS, but these results must be confirmed in further studies. In this context, a deep characterization of microenvironment could be crucial to prepare patients through novel strategies with combination or sequential immunotherapy in order to improve treatment response.

We performed a systematic review and meta-analysis to evaluate the role of gastric acid suppressant use on outcomes of tyrosine kinase inhibitors (TKIs) and oral chemotherapy. We identified all research evaluating the effect of GAS (gastric acid suppressants) use on patients receiving oral chemotherapy or TKIs for solid tumors. The pooled hazard ratios (HRs) and 95% confidence interval (95%CI) for overall survival (OS) and progression-free survival (PFS) were calculated with a fixed-effects or a random effects model. The study population included n = 16 retrospective studies and 372,418 patients. The series concerned gastrointestinal tract tumors ( n = 5 studies), renal cell carcinomas (RCC, n = 3 studies), non-small cell lung cancers (NSCLC, n = 5 studies), and soft tissue sarcomas or mixed histologies solid tumors in n = 3 studies. The pooled HRs for OS and PFS were 1.31 (95%CI: 1.20-1.43; p < 0.01) and 1.3 (95%CI 1.07-1.57; p < 0.01) for GAS and no GAS users, respectively. Only studies of EGFR (epidermal growth factor receptor) mutated NSCLC patients receiving TKIs and those with colorectal cancer receiving oral chemotherapy showed a significant correlation between GAS and poor survival. Our study supports the evidence of a possible negative impact of concomitant GAS therapy on survival outcomes of patients receiving oral anti-cancer drugs.

Breast cancer-related lymphedema (BCRL) occurs in a significant number of breast cancer survivors as a consequence of the axillary lymphatics' impairment after therapy (mainly axillary surgery and irradiation). Despite the recent achievements in the clinical management of these patients, BCRL is often diagnosed at its occurrence. In most cases, it remains a progressive and irreversible condition, with dramatic consequences in terms of quality of life and on sanitary costs. There are still no validated pre-surgical strategies to identify individuals that harbor an increased risk of BCRL. However, clinical, therapeutic, and tumor-specific traits are recurrent in these patients. Over the past few years, many studies have unraveled the complexity of the molecular and transcriptional events leading to the lymphatic system ontogenesis. Additionally, molecular insights are coming from the study of the germline alterations involved at variable levels in BCRL models. Regrettably, there is a substantial lack of predictive biomarkers for BCRL, given that our knowledge of its molecular milieu remains extremely puzzled. The purposes of this review were (i) to outline the biology underpinning the ontogenesis of the lymphatic system; (ii) to assess the current state of knowledge of the molecular alterations that can be involved in BCRL pathogenesis and progression; (iii) to discuss the present and short-term future perspectives in biomarker-based patients' risk stratification; and (iv) to provide practical information that can be employed to improve the quality of life of these patients., (Copyright © 2020 Invernizzi, Lopez, Michelotti, Venetis, Sajjadi, De Mattos-Arruda, Ghidini, Runza, de Sire, Boldorini and Fusco.)

Using photoemission electron microscopy (PEEM) to image ferromagnetism in polycrystalline Ni disks, and ferroelectricity in their single-crystal BaTiO 3 substrates, we find that voltage-driven 90° ferroelectric domain switching serves to reversibly annihilate each magnetic vortex via uniaxial compressive strain, and that the orientation of the resulting bi-domain reveals the chirality of the annihilated vortex. Micromagnetic simulations reveal that only 60% of this strain is required for annihilation. Voltage control of magnetic vortices is novel, and should be energetically favourable with respect to the use of a magnetic field or an electrical current. In future, stray field from bi-domains could be exploited to read vortex chirality. Given that core polarity can already be read via stray field, our work represents a step towards four-state low-power memory applications.

Background: The addition of induction chemotherapy to concomitant neoadjuvant chemoradiation in locally advanced rectal cancer could increase pathological downstaging and act on occult micrometastatic disease, leading ultimately to a better outcome. A systematic review was carried out of the existing literature on the treatment outcomes of total neoadjuvant therapy (TNT) on locally advanced rectal cancer. TNT was defined as chemotherapy using cycles of induction and/or consolidation in conjunction with standard chemoradiotherapy prior to surgery., Methods: A systematic search of PubMed, Embase, and the Cochrane Library was performed according to the PRISMA statement up until January 2019. The primary endpoints were complete pathologic response (pCR), disease-free survival, and overall survival rates., Results: A total of 28 studies (3 retrospective and 25 prospective for a total of 3579 patients) were included in the final analysis (n = 2688 treated with TNT and n = 891 with neoadjuvant chemoradiotherapy therapy). The pooled pCR rate was 22.4% (95% CI 19.4%-25.7%) in all patients treated with TNT (n = 27 studies with data available). In n = 10 comparative studies with data available, TNT was found to increase the odds of pCR by 39% (1.40, 95% CI 1.08-1.81, P = 0.01)., Conclusions: The addition of induction or consolidation chemotherapy to standard neoadjuvant chemoradiotherapy results in a higher pCR rate. Given that the comparative analysis was derived from few randomized publications, large confirmatory trials should be carried out before a strong recommendation is made in favor of TNT.

Immune checkpoint inhibitors (ICIs) can elicit toxicities by inhibiting negative regulators of adaptive immunity. Sometimes, management of toxicities may require systemic glucocorticoids. We performed a systematic review and meta-analysis of published studies to evaluate the correlation between steroids use, overall survival (OS), and progression-free survival (PFS) in cancer patients treated with ICIs. Publications that compared steroids with non-steroid users in cancer patients treated with ICIs from inception to June 2019 were identified by searching the EMBASE, PubMed, SCOPUS, Web of Science, and Cochrane Library databases. The pooled hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using a random-effects model. Patients (studies, n = 16; patients, n = 4045) taking steroids were at increased risk of death and progression compared to those not taking steroids (HR = 1.54, 95% CI: 1.24-1.91; p = 0.01 and HR = 1.34, 95% CI: 1.02-1.76; p = 0.03, respectively). The main negative effect on OS was associated with patients taking steroids for supportive care (HR = 2.5, 95% CI 1.41-4.43; p < 0.01) or brain metastases (HR = 1.51, 95% CI 1.22-1.87; p < 0.01). In contrast, steroids used to mitigate adverse events did not negatively affect OS. In conclusion, caution is needed when steroids are used for symptom control. In these patients, a negative impact of steroid use was observed for both OS and PFS., Competing Interests: The authors declare no conflict of interest.

Neoadjuvant hormonal therapy (NEO-HT) is a possible treatment option for breast cancer (BC) patient with estrogen receptor positive (ER+) and HER2 negative (HER2-) disease. The absence of solid data on the type of drugs to be used and duration of treatment as well as lack of clear evidence of effectiveness of NEO-HT compared to chemotherapy (CT) reserve its use for patients with old age or frail conditions. However, the low pathologic complete response rate (pCR) obtained with tamoxifen or aromatase inhibitors (AIs) alone does not make NEO-HT as a suitable option for the neoadjuvant treatment of HR+ HER2-. The use of the cyclin-dependent kinase 4 and 6 (CDK 4/6) inhibitors palbociclib, ribociclib and abemaciclib of the mammalian target of rapamycin (mTOR) inhibitor everolimus and of the phosphoinositide 3 kinase (PI3K) inhibitor taselisib together with endocrine therapy (ET) has become a standard in advanced breast cancer, showing clinical effectiveness and significantly prolonging median progression-free survival compared to ET only. In the early phase disease, the use of ET together with CDK 4/6, mTOR and PI3K inhibitors is still investigational. Data from recent studies are promising even though less impressive than in metastatic setting. In this context, the use of genomic-transcriptomic tools (such as ONCOTYPE, PAM50) and the identification of novel biomarkers (ESR1, PI3Kca, PDGF-R) on tissue or with liquid biopsy could help to select patient prone to respond to endocrine-combined therapy and able to achieve pCR. With our review, we aimed at evaluating the current state of the art in the treatment of locally advanced breast cancer with NEO-HT., Competing Interests: The authors report no conflicts of interest in this work., (© 2020 Grizzi et al.)

Importance: Trifluridine/tipiracil (FTD/TPI) treatment has shown clinical benefit in patients with pretreated metastatic gastric cancer or gastroesophageal junction cancer (mGC/GEJC). Patients who have undergone gastrectomy constitute a significant proportion of patients with mGC/GEJC., Objective: To assess the efficacy and safety of FTD/TPI among patients with previously treated mGC/GEJC who had or had not undergone gastrectomy., Design, Setting, and Participants: This preplanned subgroup analysis of TAGS (TAS-102 Gastric Study), a phase 3, randomized, placebo-controlled, clinical trial included patients with mGC/GEJC who had received at least 2 previous chemotherapy regimens, and was conducted at 110 academic hospitals in 17 countries in Europe, Asia, and North America, with enrollment between February 24, 2016, and January 5, 2018; the data cutoff was March 31, 2018., Interventions: Patients were randomized 2:1 to receive oral FTD/TPI 35 mg/m2 twice daily or placebo twice daily with best supportive care on days 1 through 5 and days 8 through 12 of each 28-day treatment cycle., Main Outcomes and Measures: The primary end point was overall survival. This subgroup analysis was conducted to examine potential trends and was not powered for statistical significance. Efficacy and safety end points were evaluated in the subgroups., Results: Of 507 randomized patients (369 [72.8%] male; mean [SD] age, 62.5 [10.5] years), 221 (43.6%) had undergone gastrectomy (147 randomized to FTD/TPI and 74 to placebo) and 286 (56.4%) had not undergone gastrectomy (190 randomized to FTD/TPI and 96 to placebo). In the gastrectomy subgroup, the overall survival hazard ratio (HR) in the FTD/TPI group vs placebo group was 0.57 (95% CI, 0.41-0.79), and the progression-free survival HR was 0.48 (95% CI, 0.35-0.65). In the no gastrectomy subgroup, the overall survival HR in the FTD/TPI group vs placebo group was 0.80 (95% CI, 0.60-1.06), and the progression-free survival HR was 0.65 (95% CI, 0.49-0.85). Among FTD/TPI-treated patients, grade 3 or higher adverse events of any cause occurred in 122 of 145 patients (84.1%) in the gastrectomy subgroup and 145 of 190 (76.3%) in the no gastrectomy subgroup: 64 (44.1%) in the gastrectomy subgroup and 50 (26.3%) in the no gastrectomy subgroup had grade 3 or higher neutropenia, 31 (21.4%) in the gastrectomy subgroup and 33 (17.4%) in the no gastrectomy subgroup had grade 3 or higher anemia, and 21 (14.5%) in the gastrectomy subgroup and 10 (5.3%) in the no gastrectomy subgroup hD grade 3 or higher leukopenia. In the gastrectomy subgroup, 94 (64.8%) had dosing modifications because of adverse events vs 101 (53.2%) in the no gastrectomy subgroup; 15 (10.3%) in the gastrectomy group and 28 (14.7%) in the no gastrectomy group discontinued treatment because of adverse events. Treatment exposure was similar between groups., Conclusions and Relevance: The FTD/TPI treatment was tolerable and provided efficacy benefits among patients with pretreated mGC/GEJC regardless of previous gastrectomy., Trial Registration: ClinicalTrials.gov identifier: NCT02500043.

Immune-related adverse events (irAEs) are autoimmune-toxic effects associated with immune checkpoint inhibitors (ICIs) used for the treatment of advanced solid tumors. We performed a systematic review and meta-analysis of the published literature to assess the outcome for cancer patients treated with ICIs who develop irAEs. Two independent reviewers selected prospective or retrospective studies from PubMed, EMBASE, and the Cochrane Library database from their inception to November 2018. Data were pooled using hazard ratios (HRs) for overall survival or progression-free survival or odds ratio for overall response rate of irAEs versus no irAEs according to fixed or random-effect model. HRs for OS (the primary outcome measure) were pooled to provide an aggregate value. A total of 30 studies that included a total of 4324 patients treated with ICIs were selected. Patients who developed irAEs presented a reduced risk of death [HR=0.49, 95% confidence interval (CI): 0.38-0.62; P<0.001]. Similarly, the occurrence of irAEs was associated with a reduced risk of progression (HR=0.51, 95% CI: 0.42-0.64; P<0.001). The odds of response was 4.56 (95% CI: 3.72-5.59; P<0.001). In patients treated with ICIs, irAEs predict survival and response. Although this correlation cannot be fully explained, it may be related to the strongest T-cell activation.

Introduction: An accurate assessment of renal function is needed in the majority of clinical settings. Unfortunately, the most used estimated glomerular filtration rate (eGFR) formulas are affected by significant errors in comparison to gold standards methods of measured GFR (mGFR)., Objective: The objective of the study is to determine the extent of the error of eGFR formulas compared to the mGFR in different specific clinical settings., Methods: A total retrospectively consecutive cohort of 1,320 patients (pts) enrolled in 2 different European Hospitals (Center 1: 470 pts; Center 2: 850 pts) was collected in order to compare the most common eGFR formulas used by physicians with the most widespread mGFR methods in daily clinical practice (Iohexol Plasma Clearance -Center 1 [mGFR-iox] and Renal Scintigraphy -Center 2 [mGFR-scnt]). The study cohort was composed by urological, oncological, and nephrological pts. The agreement between eGFR and mGFR was evaluated using bias (as median of difference), precision (as interquartile range of difference) accuracy (as P30), and total deviation index., Results: The most accurate eGFR formula in the comparison with gold standard method (Iohexol plasma clearance) in Center 1 was represented by s-creatinine and cystatin C combined Chronic Kidney Disease-Epidemiology Collaboration-cr-cy, even though the P30 is reduced (84%) under the threshold of 60 mL/min/1.73 m2. Similar results were found in Center 2, with a wider discrepancy between mGFR-scnt and eGFR formulas due to the minor accuracy of the nuclear tool in respect to the mGFR-iox., Conclusions: The loss of accuracy observed for the formulas at lower values of GFR suggests the mandatory use of gold standards methods as Iohexol Plasma Clearance to assess the correct status of renal function for critical cases. The center 2 showed lower levels of agreement between mGFR and eGFR suggesting that the errors are partially accounted for the Renal Scintigraphy technique too. In particular, we suggest the use of mGFR-iox in oncological urological and nephrological pts with an eGFR lower than 60 mL/min/1.73 m2., (© 2020 The Author(s) Published by S. Karger AG, Basel.)

Radiotherapy (RT) represents a mainstay in the treatment of brain metastases (BMs) from solid tumors. Immunotherapy (IT) has improved survival of metastatic cancer patients across many tumor types. The combination of RT and IT for the treatment of BMs has a strong rationale, but data on efficacy and safety of this combination is still limited. A systematic search of PubMed, the Cochrane Central Register of Controlled Trials, and EMBASE was conducted. 33 studies were included for a total of 1520 patients, most of them with melanoma (87%). Median pooled OS was 15.9 months (95%CI 13.9-18.1). One- and 2-year OS rates were 55.2% (95% CI 49.3-60.9) and 35.7% (95% CI 30.4-41.3), respectively. Addition of IT to RT was associated with improved OS (HR = 0.54, 95%CI 0.44-0.67; P < 0.001). For patients with BMs from solid tumors, addition of concurrent IT to brain RT is able to increase survival and provide long term control., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background/aim: About 15-20% of colorectal cancers (CRCs) have deficiency in a mismatch repair (MMR) protein. MMR has a high level of microsatellite instability (MSI-H). We have conducted this review and meta-analysis to determine the prognostic role of MSI-H status in stage II CRC., Materials and Methods: We searched PubMed, EMBASE, The Cochrane Library, Web of Science, and SCOPUS for studies reporting data on overall survival (OS) and disease-free or relapse-free survival (DFS or RFS) for MSI-H compared to microsatellite stable (MSS) CRC., Results: A total of 39 studies were analysed, including 12,110 patients. MSI-H status was associated with a significantly reduced risk of death (HR=0.64, 95%CI=0.52-0.8, p<0.01) and relapse (HR=0.59, 95%CI=0.45-0.77, p<0.01) in stage II CRC., Conclusion: MSI-H represents an important prognostic determinant in stage II CRC and may be considered when estimating the risk of recurrence in stage II CRC., (Copyright© 2019, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Because of a lack of large-scale prospective studies there is no clear indication about the management of patients with small bowel adenocarcinoma (SBA). This study evaluated clinical outcome of patients diagnosed with SBA at our institution., Methods: Clinicopathologic features, treatments, and clinical outcome of patients diagnosed with SBA between 2006 and 2017 were retrospectively analyzed. Median time of survival was calculated and compared using the log-rank test. Multivariate Cox regression was used to test independence of significant factors in univariate analysis., Results: Forty patients were included in the study; the majority (82.5%) had a tumor in the duodenum (including ampulla of Vater) and an early stage disease at the diagnosis. Median overall survival (OS) in the whole study population was 26.5 months. Patients with a tumor of the lower part of the small intestine (jejunum, ileum, and appendix) showed a better OS compared with that of patients with upper SBA (40 months vs 26 months, respectively; P =0.09). Primary tumor site and stage were independent predictors of OS., Conclusions: Our results suggest a prognostic role for the primary tumor site. This finding deserves to be further investigated to ensure better classification as well as more effective management strategies for SBA.

Immunotherapy has become the standard-of-care in many solid tumors. Despite the significant recent achievements in the diagnosis and treatment of cancer, several issues related to patients' selection for immunotherapy remain unsolved. Multiple lines of evidence suggest that, in this setting, the vision of a single biomarker is somewhat naïve and imprecise, given that immunotherapy does not follow the rules that we have experienced in the past for targeted therapies. On the other hand, additional immune-related biomarkers that are reliable in real-life clinical practice remain to be identified. Recently, the immune-checkpoint blockade has been approved in the US irrespective of the tumor site of origin. Further histology-agnostic approvals, coupled with with tumor-specific companion diagnostics and guidelines, are expected in this field. In addition, immune-related biomarkers can also have a significant prognostic value. In this review, we provide an overview of the role of these biomarkers and their characterization in the management of lung cancer, melanoma, colorectal cancer, gastric cancer, head and neck cancer, renal cell carcinoma, urothelial cancers, and breast cancer.

Background: Hyponatremia in cancer patients is often caused by the syndrome of inappropriate antidiuretic hormone secretion (SIADH). The aim of this observational multicenter study was to analyze the medical and economic implications of SIADH in this setting., Methods: This study included 90 oncological patients from 28 Italian institutions that developed SIADH between January 2010 and September 2015. Data on clinical-pathological characteristics, anticancer therapies, hyponatremia, and related treatments were statistically analyzed., Results: The majority were lung cancer patients (73%) with metastatic disease at the onset of hyponatremia (83%). A total of 76 patients (84%) were hospitalized because of SIADH and less than half (41%) received tolvaptan for SIADH treatment. The duration of hospitalization was significantly longer in patients who did not receive tolvaptan and in those who do not reach sodium normalization during hospitalization. Patients who experienced a second episode of hyponatremia following tolvaptan dose modification/discontinuation presented a significantly lower serum sodium value at the time of hospitalization and minimum sodium value during hospitalization compared with patients who had not experienced another episode. The severity of hyponatremia, defined as minimum sodium value during hospitalization with a cut-off value of 110 mmol/l, and not obtaining sodium correction during hospitalization significantly correlated with overall survival rate., Conclusions: Hyponatremia due to SIADH could result in longer hospitalization and in a decreased overall survival when not adequately treated, and tolvaptan represents an effective treatment with a potential effect of both improving overall survival and decreasing duration of hospitalization., Competing Interests: Conflict of interest statement: The author(s) declare that there is no conflict of interest., (© The Author(s), 2019.)

Aims and Methods: This multicenter retrospective study aims to evaluate the correlations between Body Weight Loss (BWL), Body Mass Index (BMI) and clinical outcomes (ORR, PFS, and OS) of advanced gastric cancer (aGC) patients treated with second-line ramucirumab-based therapy in a "real-life" setting., Results: From December 2014 to October 2018, 101 consecutive aGC patients progressed to a first-line chemotherapy were treated with ramucirumab alone (10.9%) or in combination with paclitaxel (89.1%). Median BMI was 21.2 kg/m 2 and mBWL since first-line treatment commencement was 4.5%. Among 53 patients who underwent primary tumor resection (PTR), 73.6% experienced BWL, while 26.4% did not experience BWL (p = 0.0429). Patients who underwent PTR had a significantly higher probability of experiencing BWL (yes vs no) [OR = 2.35 (95% CI 1.02-5.42), p = 0.0439]. Among the 89 evaluable patients, ORR was 26.9% (95% CI 17.2-40.1). At a median follow-up of 17.3 months, mPFS was 5.4 months (95% CI 3.6-6.8) and mOS was 8.7 months (95% CI 7.3-11.9). In the multivariate analysis, only ECOG-PS and BMI were confirmed independent predictors for shorter PFS [HR = 1.69 (95% CI 1.01-2.82), p = 0.04] [HR = 1.97 (95% CI 1.12-3.46), p = 0.01] and OS [HR = 1.69 (95% CI 1.01-2.83), p = 0.04] [HR = 2.08 (95% CI 1.17-3.70), p = 0.01]., Conclusion: Efficacy of ramucirumab is confirmed in this "real-life" analysis. BWL seems not to have correlations with clinical outcomes in these patients, while BMI and ECOG-PS remain major prognostic factors. A possible explanation for the lack of prognostic effect of BWL might be the proportion of patients subjected to PTR in this series (52.5%).

The association between antibiotic use and risk of cancer development is unclear, and clinical trials are lacking. We performed a systematic review and meta-analysis of observational studies to assess the association between antibiotic use and risk of cancer. PubMed, the Cochrane Library and EMBASE were searched from inception to 24 February 2019 for studies reporting antibiotic use and subsequent risk of cancer. We included observational studies of adult subjects with previous exposure to antibiotics and available information on incident cancer diagnoses. For each of the eligible studies, data were collected by three reviewers. Risk of cancer was pooled to provide an adjusted odds ratio (OR) with a 95% confidence interval (CI). The primary outcome was the risk of developing cancer in ever versus non-antibiotic users. Cancer risk's association with antibiotic intake was evaluated among 7,947,270 participants ( n = 25 studies). Overall, antibiotic use was an independent risk factor for cancer occurrence (OR 1.18, 95%CI 1.12-1.24, p < 0.001). The risk was especially increased for lung cancer (OR 1.29, 95%CI 1.03-1.61, p = 0.02), lymphomas (OR 1.31, 95%CI 1.13-1.51, p < 0.001), pancreatic cancer (OR 1.28, 95%CI 1.04-1.57, p = 0.019), renal cell carcinoma (OR 1.28, 95%CI 1.1-1.5, p = 0.001), and multiple myeloma (OR 1.36, 95%CI 1.18-1.56, p < 0.001). There is moderate evidence that excessive or prolonged use of antibiotics during a person's life is associated with slight increased risk of various cancers. The message is potentially important for public health policies because minimizing improper antibiotic use within a program of antibiotic stewardship could also reduce cancer incidence.

Despite extensive research, pancreatic ductal adenocarcinoma (PDAC) remains a difficult-to-treat cancer associated with poor survival. Due to the known aggressive disease biology, palliative chemotherapy is the only routinely recommended treatment in the metastatic setting in patients with adequate performance status. However, in a subset of patients with oligometastatic disease, multimodality treatment with surgery and/or locoregional approaches may provide long-term disease control and prolong survival. In fact, in highly selected cases, median overall survival has been reported to extend to 56 months in patients treated with surgery. In particular, liver and extraregional nodal resections may provide long-term tumor control with acceptable morbidity. Current guidelines do not recommend surgery for patients with metastatic PDAC and, in the case of PDAC with oligometastases, there are no published randomized controlled trials regarding locoregional or surgical approaches. Here we review the literature on surgical and locoregional approaches including radiofrequency ablation, irreversible electroporation, and stereotactic body radiation, and focus on patients with hepatic oligometastatic pancreatic cancer. We provide a summary regarding survival outcomes, morbidity and mortality and discuss selection criteria that may be useful to predict the best outcomes for such strategies.

Large changes in the magnetization of ferromagnetic films can be electrically driven by non-180° ferroelectric domain switching in underlying substrates, but the shear components of the strains that mediate these magnetoelectric effects have not been considered so far. Here we reveal the presence of these shear strains in a polycrystalline film of Ni on a 0.68Pb(Mg 1/3 Nb 2/3 )O 3 -0.32PbTiO 3 substrate in the pseudo-cubic (011) pc orientation. Although vibrating sample magnetometry records giant magnetoelectric effects that are consistent with the hitherto expected 90° rotations of a global magnetic easy axis, high-resolution vector maps of magnetization (constructed from photoemission electron microscopy data, with contrast from X-ray magnetic circular dichroism) reveal that the local magnetization typically rotates through smaller angles of 62-84°. This shortfall with respect to 90° is a consequence of the shear strain associated with ferroelectric domain switching. The non-orthogonality represents both a challenge and an opportunity for the development and miniaturization of magnetoelectric devices.

The association of folinate salts with 5-fluorouracil (5-FU) represents a gold standard in the treatment of many cancers. In several clinical trials, the simultaneous administration of calcium-folinic acid (Ca-FA) and the prolonged infusion of 5-FU resulted in a better clinical response compared with fluoropyrimidine alone and 5-FU bolus. However, the simultaneous infusion of 5-FU and Ca-FA mixed in the same infusion pump is hindered by the crystallization of calcium salts, which eventually leads to catheter obstruction and damage. The sodium salt of leucovorin-disodium levofolinate (Na-Lv) is a novel molecule with a pharmacological profile similar to Ca-FA. Owing to its higher solubility, it can be safely mixed with 5-FU in a single pump without the risk of precipitation and catheter occlusion. The efficacy and safety of Na-Lv have been widely examined in preclinical and clinical phase II studies in combination with various schedules of 5-FU and in several cancer types. PubMed, EMBASE, SCOPUS and Web of Science databases were searched from inception to November 2018 to retrieve available published phase I and II series, including Western patients. Compared with Ca-FA, Na-Lv shows a more favourable efficacy and toxicity profile in terms of overall response rate, progression-free survival, time to progression and occurrence of severe adverse events. Moreover, it allows treatment time to be shortened, decreasing the number of required human resources for drug administration and limiting the occurrence of catheter damage., Competing Interests: Conflict of interest statement: The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: Content Ed Net and Elisa Sala, PhD for linguistic revision, paper formatting and submission work; these activities were supported by Medac Pharma.

Introduction: Gastrointestinal stromal tumors (GISTs) are rare mesenchymal tumors arising in the gastrointestinal tract. Second primary tumors (SPTs) have been reported frequently, either synchronously or during follow-up, in patients diagnosed with GISTs., Methods: We carried out an electronic search of PubMed, SCOPUS, Web of Science, EMBASE, and the Cochrane Library seeking articles investigating the incidence of SPTs in patients with concomitant GIST. All studies were evaluated for heterogeneity before meta-analysis and for publication bias. Pooled incidence rate was estimated using fixed- and random-effects models. Subsite of SPTs was also investigated., Results: A total of 32 studies met the inclusion criteria, for a total of 19,627 patients with a diagnosis of GIST. The pooled prevalence of SPTs was 20%, with 14% and 3% being synchronous and metachronous tumors, respectively. We found a risk for several specific cancer sites, in particular gastrointestinal (5%) and genitourinary tract cancers (3%). The most frequently associated malignancies were: colorectal (17%), prostate (14%), gastric (9%), esophageal (5.5%), lung (5.4%), hepato-biliopancreatic (4.7%), breast (4.6%), lymphoma (4.4%), kidney (4.35%), and sarcomas (3.3%). Regression analyses revealed a significant positive association for all SPTs with follow-up and Miettinen risk., Conclusions: Our results indicate that 20% of patients with GIST experienced a SPT, primarily synchronously with a diagnosis of GIST. In particular, we observed an excess of incident gastrointestinal tumors. These findings have important implications for both pathologists, who should perform extensive molecular analysis of surgical non-GIST specimens in resected patients, and for oncologists, who should continue to follow up GIST patients., (Copyright © 2019. Published by Elsevier Ltd.)

Merkel cell carcinoma (MCC) is a rare and aggressive cutaneous malignancy with a high propensity for local recurrence and regional and distant metastases. The main treatment is surgery with narrow excision margins and draining nodes, plus or minus adjuvant radiotherapy (RT) on the surgical bed and/or lymph nodes. We performed a systematic review and meta-analysis of the benefits of adjuvant RT in MCC treatment. PubMed, EMBASE, and the Cochrane Library were systematically searched to identify relevant studies published before September 2018. Prospective trials and retrospective series comparing adjuvant RT vs. no RT in resected primary MCCs were included. Primary endpoint was to evaluate the outcomes of MCC patients who received adjuvant RT in term of overall survival (OS) and disease-free survival (DFS). Hazard ratios (HRs) for OS and DFS were aggregated according to a fixed or random effect model. Secondary endpoints were local, locoregional, and distant DFS. A total of 17,179 MCCs across 29 studies were analysed. There was a significant difference in OS between the RT and no RT arms (HR = 0.81, 95%CI 0.75-0.86, P < 0.001). There was also a significant difference in DFS in favour of adjuvant RT (HR = 0.45, 95%CI 0.32-0.62, P < 0.001). Adjuvant RT improved locoregional DFS and local DFS but not distant DFS (HR = 0.3, 95%CI 0.22-0.42; HR = 0.21, 95%CI 0.14-0.33, and HR = 0.79, 95%CI 0.49-1.14, respectively). Meta-regression analysis showed that high Newcastle-Ottawa scale scores, stage I-II MCCs, shorter follow-up durations, size >2 cm, and being of a younger age were associated with increased OS. This systematic review and meta-analysis suggests a survival and DFS benefit for postoperative radiation of MCCs. Intermediate stage MCCs derive the maximum benefit with local and regional relapses reduced by 80% and 70%, respectively. Conversely, distant metastases were not significantly prevented., (Copyright © 2019 Elsevier B.V. All rights reserved.)

(1) Background: The optimal timing of adjuvant chemotherapy (CT) in gastrointestinal malignancies is still a matter of debate. For colorectal cancer, it is recommended to start post-operative treatment within eight weeks. The objective of this study was to assess the clinical effects of starting adjuvant CT within or after 6-8 weeks post-surgery in colorectal, gastric, and pancreatic cancer. (2) Methods: MEDLINE, EMBASE, and the Cochrane Library were searched in December 2018. Publications comparing the outcomes of patients treated with adjuvant CT administered before (early) or after (delayed) 6-8 weeks post-surgery for colorectal, gastric, and pancreatic cancer were identified. The primary endpoint was overall survival (OS). (3) Results: Out of 8752 publications identified, 34 comparative studies assessing a total of 141,853 patients were included. Meta-analysis indicated a statistically significant increased risk of death with delayed CT (>6-8 weeks post-surgery) in colorectal cancer (hazard ratio (HR) = 1.27, 95% confidence interval (CI) 1.21-1.33; p <0.001). Similarly, for gastric cancer, delaying adjuvant CT was associated with inferior overall survival (HR = 1.2, 95% CI 1.04-1.38; p = 0.01). Conversely, the benefit of earlier CT was not evident in pancreatic cancer (HR = 1, 95% CI 1-1.01; p = 0.37). Conclusions: Starting adjuvant CT within 6-8 weeks post-surgery is associated with a significant survival benefit for colorectal and gastric cancer, but not for pancreatic cancer., Competing Interests: The authors declare no conflict of interest.

Gemcitabine and nab-paclitaxel (GEM-NAB) and the combination of 5-fluorouracil, oxaliplatin, and irinotecan (FOLFIRINOX) are valid first-line options for advanced or metastatic pancreatic cancer (mPC). However, no randomized trials comparing the two schemes have been performed. This meta-analysis aims to compare GEM-NAB and FOLFIRINOX in terms of safety and effectiveness, taking into account data from real-life studies on mPC. We systematically searched PubMed, EMBASE and Cochrane library up to November 2018 to identify retrospective or cohort studies on mPC comparing GEM-NAB and FOLFIRINOX. We included 16 retrospective studies, including 3813 patients (2123 treated with GEM-NAB and 1690 treated with FOLFIRINOX). Despite a median weighted overall survival (OS) difference in favor of FOLFIRINOX (mean difference: 1.15, 95% confidence interval CI 0.08⁻2.22, p = 0.03), in whole population OS was similar (hazard ratio (HR = 0.99, 95% CI 0.84⁻1.16; p = 0.9). PFS was also not different between the two arms (HR = 0.88, 95% CI 0.71⁻1.1; p = 0.26). The overall response rate was similar (25 vs. 24% with GEM-NAB and FOLFIRINOX). Among grade 3⁻4 toxicities, neutropenia, febrile neutropenia, and nausea were lower with GEM-NAB, while neurotoxicity and anemia were lower with FOLFIRINOX. In conclusion, despite a numerically longer median OS with FOLFIRINOX as compared to GEM-NAB, the overall risk of death and progression were similar. Their toxicity was different with less nausea, neutropenia, and febrile neutropenia with GEM-NAB, as compared to less neurotoxicity and anemia with FOLFIRINOX. Therefore, analysis of non-randomized "real world" studies to date has not provided evidence of a major benefit of one regimen over the other.