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Retrospective studies and single center experiences suggest a role of capecitabine combined with temozolomide (CAPTEM) in neuroendocrine tumors (NENs).We performed a systematic review to assess the efficacy and safety of CAPTEM in patients affected with NENs, with the aim to better clarify the role of this regimen in the therapeutic algorithm of NENs.A total of 42 articles and 1818 patients were included in our review. The overall disease control rate was 77% (range 43.5%-100%). The median progression free survival ranged from 4 to 38.5 months, while the median overall survival ranged from 8 to 103 months. Safety analysis showed an occurrence of G3-G4 toxicities in 16.4% of the entire population. The most common toxicities were hematological (27.2%), gastrointestinal (8.3%,) and cutaneous (3.2%).This systematic review demonstrated that CAPTEM was an effective and relatively safe treatment for patients with advanced well-moderate differentiated NENs of gastroenteropancreatic, lung and unknown origin.

Background Prostate cancer local recurrence location and extent must be determined in an accurate and timely manner. Because of the lack of a standardized MRI approach after whole-gland treatment, a panel of international experts recently proposed the Prostate Imaging for Recurrence Reporting (PI-RR) assessment score. Purpose To determine the diagnostic accuracy of PI-RR for detecting local recurrence in patients with biochemical recurrence (BCR) after radiation therapy (RT) or radical prostatectomy (RP) and to evaluate the interreader variability of PI-RR scoring. Materials and Methods This retrospective observational study included patients who underwent multiparametric MRI between September 2016 and May 2021 for BCR after RT or RP. MRI scans were analyzed, and a PI-RR score was assigned independently by four radiologists. The reference standard was defined using histopathologic findings, follow-up imaging, or clinical response to treatment. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy were calculated to assess PI-RR performance for each reader. The intraclass correlation coefficient was used to determine interreader agreement. Results A total of 100 men were included: 48 patients after RT (median age, 76 years [IQR, 70-82 years]) and 52 patients after RP (median age, 70 years [IQR, 66-74 years]). After RT, with PI-RR of 3 or greater as a cutoff (assigned when recurrence is uncertain), diagnostic performance ranges were 71%-81% sensitivity, 74%-93% specificity, 71%-89% PPV, 79%-86% NPV, and 77%-88% accuracy across the four readers. After RP, with PI-RR of 3 or greater as a cutoff, performance ranges were 59%-83% sensitivity, 87%-100% specificity, 88%-100% PPV, 66%-80% NPV, and 75%-85% accuracy. The intraclass correlation coefficient was 0.87 across the four readers for both the RT and RP groups. Conclusion MRI scoring with the Prostate Imaging for Recurrence Reporting assessment provides structured, reproducible, and accurate evaluation of local recurrence after definitive therapy for prostate cancer. © RSNA, 2022

BACKGROUND: Doublets plus antiepidermal growth factor receptors monoclonal antibodies (EGFRi) are widely considered the preferable first-line regimen in patients with left-sided RAS/BRAF wild-type metastatic colorectal cancer (mCRC), resulting superior in terms of activity and efficacy compared to doublets plus bevacizumab. However, data comparing doublet plus EGFRi and triplet plus bevacizumab are lacking, and the relative benefit of an intensive regimen plus an antiangiogenic backbone in this population is debated. METHODS: This multicenter, retrospective study aimed at evaluating clinicians' attitude to triplet-bevacizumab and doublet-EGFRi as first-line regimen in patients with left-sided RAS/BRAF wild-type mCRC treated in clinical practice at 22 Oncology Units from March 2012 to October 2020. A random case-control matching was performed to compare activity (ORR), and effectiveness (PFS, OS, secondary resection rate of metastases with curative intent) between triplet-bevacizumab and doublet-EGFRi, on the basis of ECOG-PS, age, gender, and burden of disease. RESULTS: A total of 718 patients were consecutively treated with doublet-EGFRi (686, 95.5%) or triplet-bevacizumab (32, 4.5%). After case-control matching, median PFS was 13.6 (95% CI, 8.9-31.7) and 16.1 (95% CI, 12.1-36.8) months (P= .621), while median OS was 30.2 (95% CI, 14.4-69.5) and 38.1 (95% CI, 33.1-101.1) months (P= .0283) in the doublet-EGFRi and the triplet-bevacizumab cohort, respectively. The ORR was 65.6% and 90.6% (P= .016), while the secondary resection rate was 18.8% and 46.9% (P= .016), in the doublet-EGFRi and the triplet-bevacizumab cohort, respectively. Triplet-bevacizumab was associated with a higher incidence of G3/G4 neutropenia (25.0% vs. 12.5%, P= .041). CONCLUSION: Although a doublet-EGFRi remains the recommended upfront regimen in patients with left-sided RAS and BRAF wild-type mCRC, our real life data suggest a triplet-bevacizumab might be at least equally active and effective in properly selected cases.

Colorectal cancer (CRC) patients frequently develop liver metastases. Different treatment strategies are available according to the timing of appearance, the burden of metastatic disease, and the performance status of the patient. Systemic treatment (ST) represents the cornerstone of metastatic disease management. However, in select cases, combined ST and surgical resection can lead to remarkable survival outcomes. In the present multicentric cohort study, we explored the efficacy of a conversion strategy in a selected population of left-sided RAS/BRAF wild-type CRC patients with liver-limited metastatic disease. Methods: The primary endpoint was to compare survival outcomes of patients undergoing ST not leading to surgery, liver resection after conversion ST, and hepatic resection with perioperative ST. Furthermore, we explored survival outcomes depending on whether the case was discussed within a multidisciplinary team. Results: Between 2012 and 2020, data from 690 patients respecting the inclusion criteria were collected. Among these, 272 patients were deemed eligible for the analysis. The conversion rate was 24.1% of cases. Fifty-six (20.6%) patients undergoing surgical resection after induction treatment (i.e., ultimately resectable) had a significant survival advantage compared to those receiving systemic treatment not leading to surgery (176 pts, 64.7%) (5-year OS 60.8% and 11.7%, respectively, Log Rank test p < 0.001; HR = 0.273; 95% CI: 0.16–0.46; p < 0.001; 5-year PFS 22.2% and 6.3%, respectively, Log Rank test p < 0.001; HR = 0.447; 95% CI: 0.32–0.63; p < 0.001). There was no difference in survival between ultimately resectable patients and those who had liver resection with perioperative systemic treatment (potentially resectable—40 pts) (5-year OS 71.1%, Log Rank test p = 0.311. HR = 0.671; 95% CI: 0.31–1.46; p = 0.314; 5-year PFS 25.7%, Log Rank test p = 0.305. HR = 0.782; 95% CI: 0.49–1.25; p = 0.306). Conclusions: In our selected population of left-sided RAS/BRAF wild-type colorectal cancer patients with liver-limited disease, a conversion strategy was confirmed to provide a survival benefit. Patients not deemed surgical candidates at the time of diagnosis and patients judged resectable with perioperative systemic treatment have similar survival outcomes.

Background. Personalized therapy is becoming increasingly popular in oncological scenarios, not only based on molecular pharmacological targets, but also preventing any drug–drug–gene interaction (DDGI), which could lead to severe toxicities. Single nucleotide polymorphisms (SNPs), the individual germline sequence variations in genes involved in drug metabolism, are correlated to interindividual response to drugs and explain both efficacy and toxicity profiles reported by patients. Case presentation. We present the case of a woman suffering from triple-positive breast cancer; she had early-stage disease at the onset and after four years developed metastatic disease. During her history, she presented different toxicities due to antineoplastic treatments. Particularly, hypertransaminasemia was found during every line of treatment. Nevertheless, we were able to guarantee the patient an excellent therapeutic adhesion thanks to the supportive treatments and the reduction of drug dosage. Moreover, we conducted a simultaneous analysis of the patient’s biochemical and genomic data thanks to Drug-PIN software, and we found several significant SNPs of the main enzymes and transporters involved in drug metabolism. Conclusion. Our case report demonstrated the relevance of DDGI in clinical practice management of a patient treated for advanced breast cancer, suggesting the role of Drug-PIN software as an easy-to-use tool to prevent adverse events during cancer treatment and to help physicians in therapeutic algorithms. However, further studies are needed to confirm these results.

Background: Sarcopenia is a well know prognostic factor in oncology, influencing patients’ quality of life and survival. We aimed to investigate the role of sarcopenia, assessed by a Computed Tomography (CT)-based artificial intelligence (AI)-powered-software, as a predictor of objective clinical benefit in advanced urothelial tumors and its correlations with oncological outcomes. Methods: We retrospectively searched patients with advanced urothelial tumors, treated with systemic platinum-based chemotherapy and an available total body CT, performed before and after therapy. An AI-powered software was applied to CT to obtain the Skeletal Muscle Index (SMI-L3), derived from the area of the psoas, long spine, and abdominal muscles, at the level of L3 on CT axial images. Logistic and Cox-regression modeling was implemented to explore the association of sarcopenic status and anthropometric features to the clinical benefit rate and survival endpoints. Results: 97 patients were included, 66 with bladder cancer and 31 with upper-tract urothelial carcinoma. Clinical benefit outcomes showed a linear positive association with all the observed body composition variables variations. The chances of not experiencing disease progression were positively associated with ∆_SMI-L3, ∆_psoas, and ∆_long spine muscle when they ranged from ~10–20% up to ~45–55%. Greater survival chances were matched by patients achieving a wider ∆_SMI-L3, ∆_abdominal and ∆_long spine muscle. Conclusions: A CT-based AI-powered software body composition and sarcopenia analysis provide prognostic assessments for objective clinical benefits and oncological outcomes.

Capecitabine is an oral prodrug of 5-fluorouracil with a relevant role in the treatment of breast cancer. Severe and unexpected toxicities related to capecitabine are not rare, and the identification of biomarkers is challenging. We evaluate the relationship between dihydropyrimidine dehydrogenase, thymidylate synthase enhancer region and methylenetetrahydrofolate reductase polymorphisms, 5-fluorouracil degradation rate and the onset of G3–4 toxicities in breast cancer patients. Genetic polymorphisms and the 5-fluorouracil degradation rate of breast cancer patients treated with capecitabine were retrospectively studied. Genetic markers and the 5-fluorouracil degradation rate were correlated with the reported toxicities. Thirty-seven patients with a median age of 58 years old treated with capecitabine for stages II–IV breast cancer were included in this study. Overall, 34 (91.9%) patients suffered from at least an episode of any grade toxicity while nine patients had G3–4 toxicity. Homozygous methylenetetrahydrofolate reductase 677TT was found to be significantly related to haematological toxicity (OR = 6.5 [95% IC 1.1–37.5], P = 0.04). Three patients had a degradation rate less than 0.86 ng/mL/106 cells/min and three patients greater than 2.1 ng/mL/106 cells/min. At a univariate logistic regression analysis, an altered value of 5-fluorouracil degradation rate (values 2.10 ng/mL/106 cells/min) increased the risk of G3–4 adverse events (OR = 10.40 [95% IC: 1.48–7.99], P = 0.02). A multivariate logistic regression analysis, adjusted for age, comorbidity and CAPE-regimen, confirmed the role of 5-fluorouracil degradation rate as a predictor of G3–4 toxicity occurrence (OR = 10.9 [95% IC 1.2–96.2], P = 0.03). The pre-treatment evaluation of 5-fluorouracil degradation rate allows to identify breast cancer patients at high risk for severe 5-FU toxicity.

Background Electrochemotherapy (ECT) is a minimally invasive and safe treatment gaining positive and long-lasting antitumoral results that are receiving the attention of the scientific community. It is a local treatment that combines the use of electroporation and the administration of cytotoxic drugs to induce cell death in the target tissue. ECT is largely used for the treatment of cutaneous and subcutaneous lesions, and good results have been reported for the treatment of deep visceral tumors. The latest literature review is provided. Moreover, in line with its development for the treatment of visceral tumors in this article, we describe a novel approach of ECT: endoscopic treatment of colorectal cancer. Endoscopic ECT application was combined with systemic chemotherapy in the treatment of obstructing rectal cancer without prospective surgery. A good response after ECT was described: concentric involvement of the rectum was reduced, and no stenosing lesions were detected. Conclusions Clinical studies have demonstrated that ECT is a very effective treatment for tumors of different histologic types and localizations. Endoscopic treatment for gastrointestinal cancer is an innovative application of ECT. The combination of systemic treatment and ECT was safe and highly effective in the treatment of colorectal cancer, especially when obstructive, giving the patient a significant gain in quality of life.

Background: The combination of radiotherapy (RT) and programmed death 1 inhibitors seems to increase antitumor immune responses. Objective: To assess the outcome and the role of the best combination sequence, i.e. immunotherapy given before, during, and/or after RT, in patients with non-small cell lung cancer (NSCLC). Methods: We conducted an observational, retrospective analysis of 95 consecutive patients with advanced NSCLC who received any radiotherapy treatment and nivolumab, as clinically indicated. Median overall survival (OS) and the 95% confidence interval (CI) were estimated with the Kaplan-Meier method. Cox model was used to obtain hazard ratio (HR) and associated 95% CI with statistical inference by log-rank statistic. Results: Median OS was 11.9 months (95% CI, 6.6–17.2). Patients who received radiotherapy during an immune checkpoint inhibitor treatment started more than 60 days before showed a better outcome than patients who started immunotherapy over 60 days after RT ending (HR, 2.90 [1.37–6.12], p = 0.005; median OS, 22.4 months vs 8.6 months, p = 0.005). Median progression-free survival was 6.3 months (95% CI, 4.6–8.0). Conclusions: This study shows that combining irradiation with nivolumab for the treatment of advanced NSCLC leads to improved OS. The optimal time window for the combination of RT and immunotherapy seems to play a critical role for therapeutic antitumor response derived by abscopal effect.

714 Background: Intermediate IMDC group is the largest and most heterogeneous group of mRCC. Current first-line (1L) therapy options for these patients (pts) are based on either an anti-angiogenic agent (VEGFR-TKI) combined with immunotherapy (IO), or a combo of IO (ipilimumab+nivolumab [I/N]). No biomarkers (BM) for selecting the most effective regimen have been identified so far. Methods: Immunohistochemical expression of PBRM1, PD-L1, CD31, and CD4/CD8 ratio was evaluated on histological samples of intermediate-risk mRCC pts treated with VEGFR-TKI monotherapy, and then in pts receiving a VEGFR-TKI-based therapy or the immune doublet I/N. PBRM1 positivity score was based on the percentage of positive cells and on the intensity of nuclear expression; PD-L1 positivity was defined as CPS≥10; CD31 high-density had moderate to strong nuclear staining; and the CD4/CD8 ratio cut-off for positivity was >0.2. Cox model was used to assess the correlation between BM and outcomes; PFS and OS were estimated by Kaplan-Meier method. Results: After screening of tumor tissues from 150 pts, a total of 111 were included in the final analysis (Table). In pts treated with VEGFR-TKI monotherapy, a significant correlation with PFS was observed with loss of PBRM1 expression (HR 0.58, p=0.035), PD-L1 negativity (HR 0.44, p=0.048), and high CD4/CD8 ratio (HR 0.62, p=0.073). CD31 density did not significantly correlate with PFS. A profile potentially predictive of angiogenesis (AP+) was defined based on the PBRM1 loss, PD-L1 negative, and high CD4/CD8. In pts treated with VEGFR-TKI monotherapy, tumors with the AP+ (43% of all cases) had a significantly longer median PFS (mPFS 23.8 vs. 11.8 months, p=0.003) and mOS (41.5 vs. 26.9 months, p=0.024) compared to the others. The AP+ retained its significant correlation with PFS (mPFS 23.8 vs. 11.1 months, p

Simple Summary Our analysis of a 17-gene expression signature resulted in being significantly different among patients with clear cell renal cancer cell (ccRCC) who reported a recurrence-free survival (RFS) >5 years and patients with a RFS < 1 year. This Genomic Signatures could be useful to better identify good prognosis (with favorable genomic signature) against poor prognosis (with unfavorable genomic signature) ccRCC. Accordingly, both follow-up and treatment could be profoundly personalized for patients with neodiagnosis of ccRCC in the near future. Abstract The Identification of reliable Biomarkers able to predict the outcome after nephrectomy of patients with clear cell renal cell carcinoma (ccRCC) is an unmet need. The gene expression analysis in tumor tissues represents a promising tool for better stratification of ccRCC subtypes and patients’ evaluation. Methods: In our study we retrospectively analyzed using Next-Generation expression analysis (NanoString), the expression of a gene panel in tumor tissue from 46 consecutive patients treated with nephrectomy for non-metastatic ccRCC at two Italian Oncological Centres. Significant differences in expression levels of selected genes was sought. Additionally, we performed a univariate and a multivariate analysis on overall survival according to Cox regression model. Results: A 17-gene expression signature of patients with a recurrence-free survival (RFS) < 1 year (unfavorable genomic signature (UGS)) and of patients with a RFS > 5 years (favorable genomic signature (FGS)) was identified and resulted in being significantly correlated with overall survival of the patients included in this analysis (HR 51.37, p < 0.0001). Conclusions: The identified Genomic Signatures may serve as potential biomarkers for prognosis prediction of non-metastatic RCC and could drive both follow-up and treatment personalization in RCC management.

Objectives: Oral potentially malignant disorders (OPMDs) are lesions that may undergo malignant transformation to oral cancer. The early diagnosis and surveillance of OPMDs reduce the morbidity and mortality of patients. Diagnostic techniques based on medical images analysis have been developed to diagnose clinical conditions. This systematic review and meta-analysis aimed to evaluate the efficacy of imaging-based techniques compared to the gold standard of histopathology to assess their ability to correctly identify the presence of OPMDs. Design: Literature searches of free text and MeSH terms were performed using MedLine (PubMed), Scopus, Google Scholar, and the Cochrane Library (from 2000 to 30 June 2020). The keywords used in the search strategy were: (“oral screening devices” or “autofluorescence” or “chemiluminescence” or “optical imaging” or “imaging technique”) and (“oral dysplasia” or “oral malignant lesions” or “oral precancerosis”). Results: The search strategy identified 1282 potential articles. After analyzing the results and applying the eligibility criteria, the remaining 43 papers were included in the qualitative synthesis, and 34 of these were included in the meta-analysis. Conclusions: None of the analyzed techniques based on assessing oral images can replace the biopsy. Further studies are needed to explore the role of techniques-based imaging analysis to identify an early noninvasive screening method.

Skin toxicity in patients affected by metastatic colorectal cancer (mCRC) treated with epidermal growth factor receptor (EGFR) inhibitors is well known. However, ad hoc ESMO guidelines have only recently been published. To describe the management (pre-emptive or reactive) of anti-EGFR-related cutaneous adverse events (AEs), in a real-life clinical context, in a selected population of patients with left-sided, metastatic RAS/BRAF wild-type mCRC treated with doublet chemotherapy plus anti-EGFR monoclonal antibody (i.e., panitumumab or cetuximab) as first-line regimen at 22 Institutions. The measured clinical outcomes were treatment-related adverse events, objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). Of 515 patients included in the analysis, 173 (33.6%) received a pre-emptive and 342 (66.4%) a reactive treatment. The median follow-up period for the overall population was 30.0 months. A significantly lower incidence of any grade acneiform rash was found in the pre-emptive compared to the reactive cohort both in the overall population (78.6% vs 94.4%, p < 0.001) and in patients treated with panitumumab (76.1% vs 93.7%, p < 0.001) or cetuximab (83.3% vs 95.4%, p = 0.004), respectively. A lower incidence of any grade (41.6% vs 50.9%, p = 0.047) but a higher incidence of G3-G4 (9.2% vs 4.7%, p = 0.042) paronychia/nail disorders were found in the pre-emptive compared to the reactive cohort. Nevertheless, a lower rate of patients within the reactive compared to the pre-emptive cohort was referred to dermatological counseling (21.4% vs 15.3%, respectively, p = 0.001). A higher rate of anti-EGFR therapy modification was needed in the pre-emptive compared to the reactive cohort (35.9% vs 41.6%, respectively, p < 0.001). The pre-emptive approach did not reduce the efficacy of antineoplastic therapy compared to the reactive in terms of ORR (69.2% vs 72.8%), median PFS (12.3 vs 13.0 months), and median OS (28.8 vs 33.5 months). Although recommended by international guidelines, the pre-emptive approach of anti-EGFR-related skin toxicity in mCRC patients still appears less adopted in daily clinical practice, compared to the reactive one. A wider reception and application of this indication is desirable to improve patients’ quality of life without compromising the continuity and efficacy of antineoplastic therapy.

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.

Drug&ndash, drug interactions (DDIs) can affect both treatment efficacy and toxicity. We used Drug-PIN&reg, (Personalized Interactions Network) software in colorectal cancer (CRC) patients to evaluate drug&ndash, drug&ndash, gene interactions (DDGIs), defined as the combination of DDIs and individual genetic polymorphisms. Inclusion criteria were: (i) stage II-IV CRC, (ii) ECOG PS (Performance status sec. Eastern coperative oncology group) &le, 2, (iii) &ge, 5 concomitant drugs, and (iv) adequate renal, hepatic, and bone marrow function. The Drug-PIN&reg, system analyzes interactions between active and/or pro-drug forms by integrating biochemical, demographic, and genomic data from 110 SNPs. We selected DDI, DrugPin1, and DrugPin2 scores, resulting from concomitant medication interactions, concomitant medications, and SNP profiles, and DrugPin1 added to chemotherapy drugs, respectively. Thirty-four patients, taking a median of seven concomitant medications, were included. The median DrugPin1 and DrugPin2 scores were 42.6 and 77.7, respectively. In 13 patients, the DrugPin2 score was two-fold higher than the DrugPin1 score, with 7 (54%) of these patients experiencing severe toxicity that required hospitalization. On chi-squared testing for any toxicity, a doubled DrugPin2 score (p = 0.001) was significantly related to G3&ndash, G4 toxicity. Drug-PIN&reg, software may prevent severe adverse events, decrease hospitalizations, and improve survival in cancer patients.

Simple Summary The recent addition of cyclin-dependent kinase 4 (CDK4) and CDK6 inhibitors (palbociclib, ribociclib, abemaciclib) to endocrine therapy have remarkably improved the outcome of patients with HR+ advanced breast cancer. However, some points of reflections are still undiscussed. To answer these questions, we revised the mechanism of action of CDK4-6 inhibitors, clinical data available from pivotal studies, and summarized potential future strategies to overcome resistance to CDK4-6 inhibitors, thus improving patient’s survival. Abstract Hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer is the most common breast cancer subtype, and endocrine therapy (ET) remains its therapeutic backbone. Although anti-estrogen therapies are usually effective initially, approximately 50% of HR+ patients develop resistance to ET within their lifetime, ultimately leading to disease recurrence and limited clinical benefit. The recent addition of cyclin-dependent kinase 4 (CDK4) and CDK6 inhibitors (palbociclib, ribociclib, abemaciclib) to ET have remarkably improved the outcome of patients with HR+ advanced breast cancer (ABC) compared with anti-estrogens alone, by targeting the cell-cycle machinery and overcoming some aspects of endocrine resistance. However, which patients are the better candidates for these drugs, which are the main characteristics for a better selection of patients or if there are predictive biomarkers of response, is still unknown. In this review we reported the mechanism of action of CDK4/6 inhibitors as well as their potential mechanism of resistance, their implications in clinical practice and the forthcoming strategies to enhance their efficacy in improving survival and quality of life of patients affected with HR+, HER2−, ABC.

Background The response to immunotherapy can be impaired by several factors including external intervention such as drug interactions with immune system. We aimed to examine the immunomodulatory action of opioids, since immune cells express opioid receptors able to negatively influence their activities. Methods This observational, multicenter, retrospective study, recruited patients with different metastatic solid tumors, who have received immunotherapy between September 2014 and September 2019. Immunotherapy was administered according to the standard schedule approved for each primary tumor and line of treatment. The concomitant intake of antibiotics, antifungals, corticosteroids and opioids were evaluated in all included patients. The relationship between tumor response to immunotherapy and the oncological outcomes were evaluated. A multivariate Cox-proportional hazard model was used to identify independent prognostic factors for survival. Results One hundred ninety-three patients were recruited. Overall, progression-free survival (PFS) and overall survival (OS) were significantly shorter in those patients taking opioids than in those who didn’t (median PFS, 3 months vs. 19 months, HR 1.70, 95% CI 1.37–2.09, p p Discussion Our study suggests that the concomitant administration of drugs as well as some clinical features could negatively predict the outcomes of cancer patients receiving immunotherapy. In particular, opioids use during immunotherapy is associated with early progression, potentially representing a predictive factor for PFS and negatively influencing OS as well. Conclusions A possible negative drug interaction able to impair the immune response to anti-PD-1/PD-L1 agents has been highlighted. Our findings suggest the need to further explore the impact of opioids on immune system modulation and their role in restoring the response to immunotherapy treatment, thereby improving patients' outcomes.

e14529 Background: PD-L1 is the only biomarker that has been accepted to identify patients who could potentially benefit from immune checkpoint inhibitors (ICIs) administration, but also PD-L1 negative tumors respond to immunotherapy. However, other biomarkers have been proposed but they are too expensive and actually, there is not a consensus for detection and analytical methods. Thus, there is an urgent need for inexpensive and reproducible tests to better optimize the clinical use of ICIs. Recent findings suggest that host parameters may help to select patients to treat with ICIs: performance status (PS) and some laboratory parameters, such as lactate dehydrogenase (LDH) and blood cells count. Inflammation and inflammatory response have been considered surrogate biomarkers of host immunity. An elevated neutrophil-to-lymphocyte (NLR), myeloid-to-lymphocyte (MLR) and platelet-to-lymphocyte (PLR) ratio have been associated with systemic inflammation and some evidences suggest that these biomarkers could play a role as prognostic factors. Methods: We performed a retrospective analysis of 250 patients treated with ICIs at our institution. The associations between basal NLR, MLR and PLR, clinicopathological features and their impact on progression free survival (PFS), overall survival (OS) and toxicities were assessed. Results: From May 2015 to January 2022, 250 patients were screened, of whom 66 were excluded from the analysis. A total of 184 patients (64.7% men), with a median age of 68 years (37-90) a PS 0 (52.2%), 1 (39.7%) and 2 (8.1%), were enrolled. The primary tumor origin was lung (93 adenocarcinoma, 19 squamous, 14 small cell lung cancer), urothelial (33), melanoma (4) and renal (21). Nivolumab was used in 103 patients, Pembrolizumab in 67 and atezolizumab in 18. At 24 months median follow up there were 131 progression diseases and 122 deaths. Overall, the median value of NLR, PLR and MLR was 3.15 (1-41), 168 (4-797) and 3.5 (0-245), respectively. Lower values of NLR and PLR were associated with a better median PFS (HR for NLR 1.7, 95% CI 1.2-2.4, p = 0.002; HR for PLR 2.2, 95% CI, 1.6 - 3.2, p < 0.0001) and OS (HR for NLR 1.5, 95%CI 1.1-2.2, p = 0.017; HR for PLR 1.9, 95%CI 1.3-2.7 p < 0.0001). MLR was not statistically significant. According to primary tumor origin, renal cancer reported a value significantly under the median of NLR and PLR (p = 0.015 and p = 0.021 respectively). Toxicity and clinico-pathological factors showed a significant association between female sex and both severe fatigue (p = 0.002) and pain (p = 0.018). Pain was also related to younger age (p = 0.009) and to a PS ≥2 (p = 0.003). Conclusions: Our study shows that NLR and PLR represent inexpensive, reproducible and reliable markers that may help identifying patients who can have a greater benefit from immunotherapy.

Drug–drug interactions (DDIs) can affect both treatment efficacy and toxicity. We used Drug-PIN® (Personalized Interactions Network) software in colorectal cancer (CRC) patients to evaluate drug–drug–gene interactions (DDGIs), defined as the combination of DDIs and individual genetic polymorphisms. Inclusion criteria were: (i) stage II-IV CRC; (ii) ECOG PS (Performance status sec. Eastern coperative oncology group) ≤2; (iii) ≥5 concomitant drugs; and (iv) adequate renal, hepatic, and bone marrow function. The Drug-PIN® system analyzes interactions between active and/or pro-drug forms by integrating biochemical, demographic, and genomic data from 110 SNPs. We selected DDI, DrugPin1, and DrugPin2 scores, resulting from concomitant medication interactions, concomitant medications, and SNP profiles, and DrugPin1 added to chemotherapy drugs, respectively. Thirty-four patients, taking a median of seven concomitant medications, were included. The median DrugPin1 and DrugPin2 scores were 42.6 and 77.7, respectively. In 13 patients, the DrugPin2 score was two-fold higher than the DrugPin1 score, with 7 (54%) of these patients experiencing severe toxicity that required hospitalization. On chi-squared testing for any toxicity, a doubled DrugPin2 score (p = 0.001) was significantly related to G3–G4 toxicity. Drug-PIN® software may prevent severe adverse events, decrease hospitalizations, and improve survival in cancer patients.

The role of induction chemotherapy in the multidisciplinary treatment of locally advanced, nonlaryngeal high-risk human papilloma virus (HPV)-negative head and neck squamous cells carcinoma (HNSCC) is uncertain in terms of overall survival (OS). The primary objective of this study was to identify possible predictive factors of survival and outcome in patients with HNSCC who were treated with induction chemotherapy. Fifty-nine patients with stage IVa/b HPV-negative non-laryngeal HNSCC (mostly originating from the oral cavity) who underwent induction chemotherapy at Policlinico Umberto I were reviewed. Treatment outcomes in term of objective response rate (ORR), progression-free survival (PFS), OS and toxicities were analyzed. A significant association between nodal status, ORR, ongoing smoking use, toxicities and OS was demonstrated. ORR (obtained in 61% of patients) was associated with a reduction in mortality of 80% (P< 0.0001). Early discontinuation after just one cycle of induction chemotherapy was associated to a significantly shorter OS. In oral cavity radical surgery with negative margins was obtained in 15/16 patients. In 42% of patients G3-G4 toxicity occurred. Toxicity requiring hospitalization occurred in 42% and 21% of patients with oropharyngeal and oral cavity carcinoma, respectively. Five patients died of treatment-related causes. No treatment-related mortality occurred in oral cavity patients. G5 toxicities were different according to the sub-sites of disease (P = 0.05). Induction chemotherapy in non-laryngeal high-risk HNSCC is an active strategy, most importantly in oral cavity cancer, even though burdened with a high (G ≥ 3) toxicity and early discontinuation rate. These data will however need to be confirmed in further and larger studies.

Pathological complete response (pCR) after neoadjuvant chemotherapy (NACT) can predict better survival outcomes in patients with early triple negative breast cancer (TNBC). Tumor infiltrating lymphocytes (TILs), Programmed Death-Ligand 1 (PD-L1), and Cluster of Differentiation 73 (CD73) are immune-related biomarkers that can be evaluated in the tumor microenvironment. We investigated if the contemporary expression of these biomarkers combined in a tissue immune profile (TIP) can predict pCR better than single biomarkers in TNBC. Tumor infiltrating lymphocytes (TILs), CD73 expression by cancer cells (CC), and PD-L1 expression by immune cells (IC) were evaluated on pre-NACT biopsies. We defined TIP positive (TIP+) as the simultaneous presence of TILS &ge, 50%, PD-L1 &ge, 1%, and CD73 &le, 40%. To consider the effects of all significant variables on the pCR, multivariate analysis was performed. Akaike information criterion (AIC) and Bayesian information criterion (BIC) were used for model selection. We retrospectively analyzed 60 biopsies from patients with TNBC who received standard NACT. Pathological complete response was achieved in 23 patients (38.0%). Twelve (20.0%) cases resulted to be TIP+. The pCR rate was significantly different between TIP+ (91.7%) and TIP&minus, (25.0%) (p &lt, 0.0001). Using a multivariate analysis, TIP was confirmed as an independent predictive factor of pCR (OR 49.7 (6.30&ndash, 392.4), p &lt, 0.0001). Finally, we compared the efficacy of TIP versus each single biomarker in predicting pCR by AIC and BIC. The combined immune profile is more accurate in predicting pCR (AIC 68.3, BIC 74.5) as compared to single biomarkers. The association between TIP+ and pCR can be proposed as a novel link between immune background and response to chemotherapy in TNBC, highlighting the need to consider an immunological patients&rsquo, profile rather than single biomarkers.

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&ndash, 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 &le, 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 &ge, 5 was a significant prognostic factor for DFS (HR = 7.67, 95% CI 2.27&ndash, 25.92). Colon obstruction/perforation (HR = 2.65, 95% CI 1.01&ndash, 7.01), and BRAF mutant (HR = 3.03, 95% CI 0.97&ndash, 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&ndash, 14.01) and BRAF mutation status (3.71, 95% CI 1.07&ndash, 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.

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&ndash, 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&ndash, 1.89), p = 0.0932). The median OS of the Bevacizumab-treated group and Aflibercept-treated group was 16.2 (95%CI: 15.3&ndash, 18.1) and 12.7 (95%CI: 8.8&ndash, 17.5) months, respectively (HR= 1.31 (95%CI: 0.89&ndash, 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&ndash, 2.03), p = 0.0399) compared to Aflibercept-based regimens, but not with a prolonged OS (HR = 1.47 (95%CI: 0.99&ndash, 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.

Background /Objectives: Pancreatic ductal adenocarcinoma (PDAC) has a higher incidence in men compared to women, although the difference in known risk factors cannot explain this disparity completely. Reproductive and hormonal factors have been demonstrated in pre-clinical studies to influence pancreatic carcinogenesis, but the few published data on the topic are inconsistent. The aim was to investigate the role of reproductive and hormonal factors on PDAC occurrence in women. Methods We conducted a unicenter case-control study; PDAC cases were matched to controls by age with a 1:2 ratio. Risk factors were screened through questionnaires about gynecologic and medical history. Comparisons were made using Chi-square and Fisher’s exact tests where appropriate for categorical variables and Student’s t-test for continuous variables. Logistic regression was used to calculate Odds Ratios (ORs) and their 95% confidence intervals (CI). Multivariable logistic regression models were adjusted for potential confounders. Results 253 PDAC and 506 matched controls were enrolled. At logistic regression multivariable analysis adjusted for confounding factors, older age at menopause (OR:0.95 per year; 95% CI:0.91–0.98; p = 0.007), use of Oral Contraceptives (OR:0.52; 95% CI:0.30–0.89; p = 0.018), use of Hormonal Replacement Therapy (OR:0.31; 95% CI:0.15–0.64; p = 0.001), and having had two children (OR:0.57; 95% CI:0.38–0.84; p = 0.005) were significant, independent protective factors for the onset of PDAC. Conclusions These data confirm some previous findings on menopause age and number of births while, to our knowledge, this is the first study to show a protective effect of HRT and OC use. The results collectively support the hypothesis that exposure to estrogens plays a protective role towards PDAC.

With the advent of immunotherapy, the life expectancy of patients with advanced non-small cell lung cancer (NSCLC) is dramatically improved. As described in the most recent clinical trials, the addition of immunotherapy to the available therapeutic strategies, restoring an efficient immune response against neoplasms and establishing an immunological memory, is able to improve both patient's survival and quality of life. This paved the way for new therapeutic algorithms, new combination strategies, as well as the possible use of adoptive immunotherapy. Although the use of immunotherapy is now widely employed in the different phases of lung cancer, we have not yet fully understood what are both the actual mechanisms of action and resistance to checkpoint inhibitors, predictive factors of response, immuno-related response criteria, and interferences between immunotherapy and tumor microenvironment, as well as angiogenesis and its interactions with conventional therapies, such as chemotherapy. The objective of this critical review is to frame the relevant results obtained with immunotherapy in NSCLC, providing insights to help overcome decision-making for a better therapeutic choice. In addition, returning to the study of pulmonary physiology and preclinical data, we will address the new issues on the heterogeneity of response to anti-PD1/anti-PD-L1, including their combinations, in NSCLC. Moreover, to date, we are facing with patterns of response different from those previously seen with cytotoxic or target therapies. Indeed, different radiological evaluation criteria have been proposed to evaluate response to immunotherapy and further efforts are needed to identify a unique system of evaluation and other than PDL1 biomarkers, to integrate radiology in the assessment of response.

Background: Clinical trials showed that only a subset of patients benefits from immunotherapy, suggesting the need to identify new predictive biomarker of resistance. Indoleamine-2,3-dioxygenase (IDO) has been proposed as a mechanism of resistance to anti-PD-1 treatment, and serum kynurenine/tryptophan (kyn/trp) ratio represents a possible marker of IDO activity.Methods: Metastatic non-small cell lung cancer (NSCLC), renal cell carcinoma (RCC), and head and neck squamous cell carcinoma (HNSCC) treated with nivolumab as second-line treatment were included in this prospective study. Baseline serum kyn and trp levels were measured by high-performance liquid chromatography to define the kyn/trp ratio. The χ2-test and t-test were applied to compare frequencies and mean values of kyn/trp ratio between subgroups with distinct clinical/pathological features, respectively. Median baseline kyn/trp ratio was defined and used as cutoff in order to stratify the patients. The association between kyn/trp ratio, clinical/pathological characteristics, response, progression-free survival (PFS), and overall survival (OS) was analyzed.Results: Fifty-five patients were included. Mean baseline serum kyn/trp ratio was significantly lower in female than in male patients (0.048 vs. 0.059, respectively, p = 0.044) and in patients with lung metastasis than in others (0.053 vs. 0.080, respectively, p = 0.017). Mean baseline serum kyn/trp ratio was significantly higher in early progressor patients with both squamous and non-squamous NSCLC (p = 0.003) and with a squamous histology cancer (19 squamous NSCLC and 14 HNSCC, p = 0.029). The median value of kyn/trp ratio was 0.06 in the overall population. With the use of median value as cutoff, patients with kyn/trp ratio > 0.06 had a higher risk to develop an early progression (within 3 months) to nivolumab with a trend toward significance (p = 0.064 at multivariate analysis). Patients presenting a baseline kyn/trp ratio ≤0.06 showed a longer PFS [median 8 vs. 3 months; hazard ratio (HR): 0.49; 95% confidence interval (CI) 0.24–1.02; p = 0.058] and a significantly better OS than did those with a kyn/trp ratio > 0.06 (median 16 vs. 4 months; HR: 0.39; 95% CI 0.19–0.82; p = 0.013).Conclusion: Serum kyn/trp ratio could have both prognostic and predictive values in patients with solid tumor treated with immunotherapy, probably reflecting a primary immune-resistant mechanism regardless of the primary tumor histology. Its relative weight is significantly related to gender, site of metastasis, NSCLC, and squamous histology, although these suggestive data need to be confirmed in larger studies.