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A simple and rapid access to fluorinated dithioesters was developed by a one-pot sequence corresponding to a Grignard reaction—Mitsunobu type substitution. These activated dithioesters have shown excellent reactivity in an aminolysis reaction from simple or more complex primary amines such as cinchona alkaloids. A stoichiometric amount of amine was sufficient to prepare various thioamides, including a 4-styrenylthioamide cinchonidine monomer, under environmentally friendly conditions, at room temperature, and in a very short time.

Objectives: Hospital admission (HA) in cancer history is a common, repeated and frequently unplanned event. The emergency departments (EDs) and the oncological outpatient service (OOS) are the ordinary way of entry. We studied the reasons of admission, pathways of access and discharge and prognostic factors in a population of admitted patients with cancer., Methods: The health records of the admitted patients in the oncological ward of a referral hospital in a 6-month period were retrieved and analysed. The characteristics of those admitted in the last 3 months of life were compared with the other group., Results: Among the 147 HA, 79.5% were unplanned, 48.9% passing through the ED and 30.6% through the OOS; 56.5% were due to cancer-related symptoms; 50.3% occurred in the last 3 months of life. Median overall survival was 90 days (95% IC 53.1-126.9). Independent prognostic factors for survival were: being admitted for symptoms, referral through the ED and not being discharged at home., Conclusions: Hospital is a turning point in the cancer care pathway. Patients needing HA have a dismal prognosis, half of them being in the last 3 months of life. This group can be identified using universally available variables., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Randomised controlled trials (RCTs) are usually considered the highest level of evidence for clinical practice. Patients assigned to control arm in RCTs should always receive the best available treatments to protect participants while also allowing for proper interpretation and applicability of study results. Here we analysed RCTs published in oncology between 2017 and 2021 to describe the frequency of suboptimal control arms., Methods: We identified phase III studies testing active treatments in patients with solid tumours among 11 major oncology journals. Each control arm was analysed, and the standard of care was determined according to international guidelines and scientific evidence at accrual beginning and until accrual completion. We identified studies with suboptimal control arm from the beginning (type 1) and studies with an initially optimal control arm which became outdated during the accrual period (type 2)., Results: This analysis included 387 studies. Forty-three (11.1%) control arms were judged as suboptimal: 24 (6.2%) type 1 and 19 (4.9%) type 2. These rates were higher in industry-sponsored compared to academic trials: 9.3% versus 1.9% for type 1 (p = 0.003); 7.9% versus 0.6% for type 2 (p = 0.001). Rates of suboptimal control arms were higher in studies with positive results: 8.1% versus 4.0% for type 1 (p = 0.09); 7.6% versus 1.7% for type 2 (p = 0.007)., Conclusions: Many trials have suboptimal control arms, even in journals with high-impact factors, leading to suboptimal treatment of control patients and biased evaluation of trial results., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper, RDL reports honoraria from Astellas Pharma and Janssen. LM reports honoraria from Gilead and Merck; research grant from AstraZeneca; travel expenses from Janssen. CP reports support for attending meetings and/or travel from Eli Lilly and Takeda; institutional research grant from IQVIA. MLR reports honoraria from Eli Lilly, AstraZeneca and Janssen. AF reports honoraria from Roche, Pfizer, Novartis, Dompè , Astra Zeneca, Seagen, Gilead, Exact Science, Eli Lilly; support for attending meetings and/or travel from Roche, Pfizer, Novartis, Dompè , Astra Zeneca, Seagen, Gilead, Exact Science, Eli Lilly; participation on advisory boards for Roche, Pfizer, Novartis, Astra Zeneca, Seagen, Gilead, Eli Lilly. FP reports honoraria from Bayer, Pierre Fabre, AstraZeneca, Incyte, Ipsen, Clovis, Astellas, Sanofi, Roche, Pfizer; institutional funding for work in clinical trials/contracted research from Roche, Bayer, AstraZeneca, Pfizer, Incyte, Tesaro/GlaxoSmithKline and Merck. MDM reports honoraria from AstraZeneca, Boehringer Ingelheim, Janssen, Merck Sharp & Dohme (MSD), Novartis, Pfizer, Roche, Takeda for consultancy or participation to advisory boards institutional research funding from Tesaro/GlaxoSmithKline, institutional funding for work in clinical trials/contracted research from Beigene, Exelixis, MSD, Pfizer and Roche. Other authors declare no relationships or activities that could appear to have influenced the submitted work., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Fluoropyrimidines (FP) are the backbone chemotherapy in colorectal cancer (CRC) treatment; however, their use is associated with cardiotoxicity, which is underreported. In the present study, it was aimed to prospectively determine the incidence rates and related risk factors of FP‑induced cardiotoxicity (FIC) in CRC patients and at identifying predictive biomarkers. A total of 129 consecutive previously untreated CRC patients underwent active cardiological monitoring, including 5‑items simplified questionnaire on symptoms, electrocardiogram (ECG) and plasma sample collection during FP chemotherapy. FIC was defined as the presence of ECG alterations and/or the arising of at least one symptom of chest pain, dyspnoea, palpitations or syncope. The primary objective was the evaluation of FIC incidence. Secondary objectives were the correlation of FIC with well‑known cardiological risk factors and the identification of circulating biomarkers (serum levels of troponin I, pro hormone BNP; miRNA analysis) as predictors of FIC. A total of 20 out of 129 (15.5%) patients experienced FIC. The most common symptoms were dyspnoea (60%) and chest pain (40%), while only 15% of patients presented ECG alterations, including one acute myocardial infarction. Retreatment with FP was attempted in 90% of patients with a favourable outcome. Despite 48% of patients having cardiological comorbidities, an increased FIC was not observed in this subgroup. Only the subgroup of females with the habit of alcohol consumption showed an increased risk of FIC. None of the circulating biomarkers evaluated demonstrated a clinical utility as FIC predictors. FIC can be an unexpected, life‑threatening adverse event that can limit the subsequent treatment choices in patients with CRC. In this prospective study, well‑known cardiological comorbidities were not related to higher FIC risk and circulating biomarkers predictive of toxicity could not be found. With careful monitoring, mainly based on symptoms, almost all patients completed the FP treatment.

Background: Coronavirus disease 2019 (COVID-19) has triggered the disruption of health care on a global scale. With Italy tangled up in the pandemic response, oncology care has been largely diverted and cancer screenings suspended. Our multicenter Italian study aimed to evaluate whether COVID-19 has impacted access to diagnosis, staging, and treatment for patients newly diagnosed with colorectal cancer (CRC), compared with pre-pandemic time., Methods: All consecutive new CRC patients referred to 8 Italian oncology institutions between March and December 2020 were included. Access rate and temporal intervals between date of symptoms onset, radiological and cytohistological diagnosis, treatment start and first radiological evaluation were analyzed and compared with the same months of 2019., Results: A reduction (29%) in newly diagnosed CRC cases was seen when compared with 2019 (360 vs 506). New CRC patients in 2020 were less likely to be diagnosed with early stage (stages I-II-III) CRC (63% vs 78%, P < .01). Gender and sidedness were similar regardless of the year. The percentage of tumors with any mutation among BRAF, NRAS, and KRAS genes were significantly different between the 2 years (61% in 2020 vs 50% in 2019, P = .04). Timing of access to cancer diagnosis, staging, and treatment for patients with CRC has not been negatively affected by the pandemic. Significantly shorter temporal intervals were observed between symptom onset and first oncological appointment (69 vs 79 days, P = .01) and between histological diagnosis and first oncological appointment (34 vs 42 days, P < .01) during 2020 compared with 2019. Fewer CRC cases were discussed in multidisciplinary meetings during 2020 (38% vs 50%, P = .01)., Conclusions: Our data highlight a significant drop in CRC diagnosis after COVID-19, especially for early stage disease. The study also reveals a remarkable setback in the multidisciplinary management of patients with CRC. Despite this, Italian oncologists were able to ensure diagnostic-therapeutic pathways proper operation after March 2020., (© The Author(s) 2022. Published by Oxford University Press.)

Background: 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., Aim and Methods: 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)., Results: 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)., Conclusion: 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., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

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., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background and Aims: In the last few years, there has been increasing interest in non-cancer medications and their potential anti-cancer activity. Data are not available in cholangiocarcinoma (CCA) patients. The aim of this study is to fill this gap by investigating the potential impact in terms of clinical outcome of the common non-cancer medications., Methods: All consecutive patients with CCAs were retrospectively identified from 7 Italian medical institutions. We investigated the role of intake of vitamin D, aspirin, metformin, statins, and diuretics., Results: A total of 537 patients with CCAs were identified; 197 patients undergoing surgery were evaluated for disease-free survival (DFS), and 509 patients with an advanced stage were evaluated for overall survival (OS). A longer DFS was found in patients with intake of vitamin D versus never users (HR 0.55, 95% CI 0.32-0.92, p = 0.02). In an advanced stage an association with OS was found in patients with intake of metformin versus never users (HR 0.70, 95% CI 0.52-0.93, p = 0.0162), and in patients who have started taking metformin after chemotherapy versus before chemotherapy and never users (HR 0.44, 95% CI 0.26-0.73, p = 0.0016)., Conclusions: Our results highlighted that vitamin D intake improves DFS in patients undergoing surgery. Metformin intake after starting chemotherapy can improve the clinical outcome in advanced disease. These results could open up new therapeutic strategies in cholangiocarcinoma patients. We are planning to undertake a prospective study to validate these data., (© 2021 S. Karger AG, Basel.)

Patients with unresectable biliary tract carcinomas (BTCs) have a poor prognosis with a median overall survival of fewer than 12 months following systemic chemotherapy. In recent years, the identification of distinct molecular alterations with corresponding targeted therapies is modifying this therapeutic algorithm. The aim of this review is to present an overview of targeted therapy for BTCs, describing published available data and potential future challenges in ongoing trials. From clinicaltrials.gov online database all ongoing trials for BTCs (any stage) was examinated in July 2021, and data regarding study design, disease characteristics and type of treatments were registered. Oncogenic-driven therapy (targeted therapy) was investigated in 67 trials. According to research, 15 ongoing trials (22.4%) are investigating fibroblast growth factor (FGF) receptor (FGFR)-inhibitors in BTCs. Three (18.7%) are open-label randomized multicenter phase 3 trials, 8 (50%) are single-arm phase two trials, and 4 (25%) are phase one studies. Twelve (17.9%) clinical trials dealt with isocitrate dehydrogenase (IDH) 1/2 targeting therapy either in combination with cisplatin (Cis) and gemcitabine (Gem) as first-line treatment for BTCs or in monotherapy in patients with IDH1 mutant advanced malignancies, including cholangiocarcinoma (CCA). Nine (13.4%) clinical trials tested human epidermal growth factor receptor (HER) 2 targeting therapy. Four (44.4%) studies are phase I trials, two (22.2%) are phase I/II trials, and three (33.3%) phase II trials. Rare molecular alterations in BTCs, such as anaplastic lymphoma kinase (ALK), c-ros oncogene1 receptor tyrosine kinase (ROS1), and v-RAF murine sarcoma viral oncogene homologue B1 (BRAF), are also under investigation in a few trials. Forty-four clinical trials (17.2%) are investigating not oncogenic-driven multitarget therapy like multireceptor tyrosin kinase inhibitors and antiangiogenetic agents. In conclusion, this review shows that BTCs management is experiencing important innovations, especially in biomarker-based patient selection and in the new emerging therapeutic approach. Many ongoing trials could answer questions regarding the role of molecular inhibitors leading to new therapeutic frontiers for molecular subcategories of BTCs., Competing Interests: The authors declare the following financial interests/personal relationships that may be considered as potential competing interests: Massimo Di Maio received honoraria and had roles as consultant or advisor for AstraZeneca, Pfizer, Novartis, Roche, Takeda, Eisai, Janssen, Astellas; received institutional research grant by Tesaro e GlaxoSmithKline, outside the submitted work. All remaining authors declared no conflicts of interest., (© The Author(s) 2021.)

Introduction : Biliary tract cancer (BTC), which comprises gallbladder cancer, ampullary cancer, and cholangiocarcinoma, is a rare and heterogeneous entity, with limited approved therapeutic options. However, interest in this disease has grown exponentially in recent years, as a mounting body of evidence has shed light on the complex molecular and microenvironmental background of BTC, and clinical investigations have explored a variety of new agents and combinations, with promising results. Areas covered : This review describes the standard of care in advanced BTC and summarizes the most recent evidence available on the pharmacological treatment of resected and advanced disease, focusing on chemotherapy, targeted therapy, and immunotherapy. Expert opinion : The therapeutic armamentarium of BTC has made radical progress after almost a decade of very few positive results. Phase-III evidence now supports the use of adjuvant capecitabine after resection of localized disease, while investigations into improved regimens in the advanced setting are underway, exploring alternative options to the standard gemcitabine-cisplatin doublet. The first positive phase-III trial supports the use of the mFOLFOX6 regimen as a second-line chemotherapy. Targeted therapy against specific genomic alterations can combine with chemotherapy in specific subsets of patients. Despite recent advancements, conducting clinical trials for BTC is still a real challenge.

Surgical resection remains the only treatment that offers a potential chance of long-term survival. Unfortunately, about 80% of patients treated with curative intent will develop recurrence. Since 2001, adjuvant therapy with gemcitabine or 5-fluorouracyle was recommended. This approach allows a median overall survival (OS) of around 23 months, and 5-year survival of 22%. In recent years, two phase-3 trials investigating new chemotherapy regimens resulted in considerably improved survival times. The doublet gemcitabine-capecitabine has shown improvement in OS from 25.5 to 28 months ( p = 0.032) compared to gemcitabine, in the ESPAC-4 trial. Later, preliminary results of PRODIGE 24 trial presented at the 2018 ASCO meeting showed a superiority of a combination chemotherapy regimen with fluorouracil, leucovorin, irinotecan, and oxaliplatin (mFOLFIRINOX) when compared to gemcitabine alone, both in terms of median disease-free survival (21.6 vs. 12.8 months, p < 0.0001) and OS (54.4 vs. 35 months, p = 0.003). Contrary to chemotherapy, the role of adjuvant radiotherapy is still controversial, even in the case of R1 surgery. A randomized trial exploring the role of chemoradiotherapy in this setting is now ongoing in the US (RTOG-0848). Overall, the management of localized pancreatic adenocarcinoma is evolving. In this review, we summarize the current status and the most up-to-date developments in adjuvant treatment., Competing Interests: The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.