Cetuximab in combination with irinotecan/5-fluorouracil/folinic acid (FOLFIRI) in the initial treatment of metastatic colorectal cancer: a multicentre two-part phase I/II study

This study was designed to investigate the efficacy and safety of the epidermal growth factor receptor (EGFR) inhibitor cetuximab combined with irinotecan, folinic acid (FA) and two different doses of infusional 5-fluorouracil (5-FU) in the first-line treatment of EGFR-detectable metastatic colorectal cancer.Clinical Trial, Phase IClinical Trial, Phase IIJournal ArticleMulticenter StudyResearch Support, Non-U.S. Gov'tinfo:eu-repo/semantics/publishe

Medical Treatment of Advanced Pancreatic Neuroendocrine Neoplasms

Pancreatic neuroendocrine neoplasms (panNENs) are relatively rare but their incidence has increased almost sevenfold over the last four decades. Neuroendocrine neoplasms are classified according to their histologic differentiation and their grade. Their grade is based on their Ki-67 proliferation index and mitotic index. Their prognosis is highly variable according to these elements and treatments also vary according to their classification. Surgery is the only curative treatment for localized and advanced panNENs and offers a better prognosis than non-surgical treatments. In the case of an advanced panNEN without the possibility of resection and/or ablation, medical treatment remains the cornerstone for improving survival and preserving quality-of-life. PanNENs are considered as chemosensitive tumors, unlike midgut neuroendocrine tumors. Thus, panNENs can be treated with chemotherapy, but targeted therapies and somatostatin analogs are also treatment options. The scarcity and heterogeneity of NENs make their management difficult. The present review aims to clarify the medical treatments currently available for advanced panNENs, based on their characteristics, and to propose a treatment algorithm

Therapeutic Management of Advanced Hepatocellular Carcinoma: An Updated Review

Hepatocellular carcinoma (HCC) usually occurs in the setting of liver cirrhosis and more rarely in a healthy liver. Its incidence has increased in the past years, especially in western countries with the rising prevalence of non-alcoholic fatty liver disease. The prognosis of advanced HCC is low. In the first-line setting of advanced HCC, sorafenib, a tyrosine kinase inhibitor, was the only validated treatment for many years. In 2020, the combination of atezolizumab, an immune checkpoint inhibitor, and bevacizumab showed superiority to sorafenib alone in survival, making it the first-line recommended treatment. Regorafenib and lenvatinib, other multikinase inhibitors, were also validated in the second and first-line settings, respectively. Transarterial chemoembolization can be an alternative treatment for patients with intermediate-stage HCC and preserved liver function, including unresectable multinodular HCC without extrahepatic spread. The current challenge in advanced HCC lies in the selection of a patient for the optimal treatment, taking into account the underlying liver disease and liver function. Indeed, all trial patients present with a Child–Pugh score of A, and the optimal approach for other patients is still unclear. Furthermore, the combination of atezolizumab and bevacizumab should be considered in the absence of medical contraindication. Many trials testing immune checkpoint inhibitors in association with anti-angiogenic agents are ongoing, and primary results are promising. The landscape in advanced HCC management is undergoing profound change, and many challenges remain for optimal patient management in the years to come. This review aimed to provide an overview of current systemic treatment options for patients with advanced unresectable HCC who are not candidates for liver-directed therapy

Impact of Sarcopenia on Patients with Localized Pancreatic Ductal Adenocarcinoma Receiving FOLFIRINOX or Gemcitabine as Adjuvant Chemotherapy

Background: Despite its toxicity, modified FOLFIRINOX is the main chemotherapy for localized, operable pancreatic adenocarcinomas. Sarcopenia is known as a factor in lower overall survival (OS). The purpose of this study was to assess the impact of sarcopenia on OS in patients with localized pancreatic ductal adenocarcinoma (PDAC) who received modified FOLFIRINOX or gemcitabine as adjuvant chemotherapy. Methods: Patients with operated PDAC who received gemcitabine-based (GEM group) or oxaliplatin-based (OXA group) adjuvant chemotherapy between 2008 and 2021 were retrospectively included. Sarcopenia was estimated on a baseline computed tomography (CT) examination using the skeletal muscular index (SMI). The primary evaluation criterion was OS. Secondary evaluation criteria were disease-free survival (DFS) and toxicity. Results: Seventy patients treated with gemcitabine-based (n = 49) and oxaliplatin-based (n = 21) chemotherapy were included, with a total of fifteen sarcopenic patients (eight in the GEM group and seven in the OXA group). The median OS was shorter in sarcopenic patients (25 months) compared to non-sarcopenic patients (158 months) (p = 0.01). A longer OS was observed in GEM non-sarcopenic patients (158 months) compared to OXA sarcopenic patients (14.4 months) (p < 0.01). The median OS was 157.7 months in the GEM group vs. 34.1 months in the OXA group (p = 0.13). No differences in median DFS were found between the GEM group and OXA group. More toxicity events were observed in the OXA group (50%) than in the GEM group (10%), including vomiting (p = 0.02), mucositis (p = 0.01) and neuropathy (p = 0.01). Conclusion: Sarcopenia is associated with a worse prognosis in patients with localized operated PDAC whatever the delivered adjuvant chemotherapy

Gene expression profiling provides insights into pathways of oxaliplatin-related sinusoidal obstruction syndrome in humans

Sinusoidal obstruction syndrome (SOS; formerly veno-occlusive disease) is a well-established complication of hematopoietic stem cell transplantation, pyrrolizidine alkaloid intoxication, and widely used chemotherapeutic agents such as oxaliplatin. It is associated with substantial morbidity and mortality. Pathogenesis of SOS in humans is poorly understood. To explore its molecular mechanisms, we used Affymetrix U133 Plus 2.0 microarrays to investigate the gene expression profile of 11 human livers with oxaliplatin-related SOS and compared it to 12 matched controls. Hierarchical clustering analysis showed that profiles from SOS and controls formed distinct clusters. To identify functional networks and gene ontologies, data were analyzed by the Ingenuity Pathway Analysis Tool. A total of 913 genes were differentially expressed in SOS: 613 being upregulated and 300 downregulated. Reverse transcriptase-PCR results showed excellent concordance with microarray data. Pathway analysis showed major gene upregulation in six pathways in SOS compared with controls: acute phase response (notably interleukin 6), coagulation system (Serpine1, THBD, and VWF), hepatic fibrosis/hepatic stellate cell activation (COL3a1, COL3a2, PDGF-A, TIMP1, and MMP2), and oxidative stress. Angiogenic factors (VEGF-C) and hypoxic factors (HIF1A) were upregulated. The most significant increase was seen in CCL20 mRNA. In conclusion, oxaliplatin-related SOS can be readily distinguished according to morphologic characteristics but also by a molecular signature. Global gene analysis provides new insights into mechanisms underlying chemotherapy-related hepatotoxicity in humans and potential targets relating to its diagnosis, prevention, and treatment. Activation of VEGF and coagulation (vWF) pathways could partially explain at a molecular level the clinical observations that bevacizumab and aspirin have a preventive effect in SOS

Helpfulness of the combination of acetic acid and FICE in the detection of Barrett's epithelium and Barrett's associated neoplasias

AIM: To investigate the mucosal morphology in Barrett’s oesophagus by chromo and magnifying endoscopy

Impact of Sarcopenia on Survival in Patients Treated with FOLFIRINOX in a First-Line Setting for Metastatic Pancreatic Carcinoma

International audienceSarcopenia, defined as decreased muscle mass and strength, can be evaluated by a computed tomography (CT) examination and might be associated with reduced survival in patients with carcinoma. The prognosis of patients with metastatic pancreatic carcinoma is poor. The FOLFIRINOX (a combination of 5-fluorouracil, irinotecan, and oxaliplatin) chemotherapy regimen is a validated first-line treatment option. We investigated the impact of sarcopenia on overall survival (OS) and progression-free survival (PFS) in patients with metastatic pancreatic carcinoma. Clinical data and CT examinations of patients treated with FOLFIRINOX were retrospectively reviewed. Sarcopenia was estimated using baseline CT examinations. Seventy-five patients were included. Forty-three (57.3%) were classified as sarcopenic. The median OS of non-sarcopenic and sarcopenic patients were 15.6 and 14.1 months, respectively (p = 0.36). The median PFS was 10.3 in non-sarcopenic patients and 9.3 in sarcopenic patients (p = 0.83). No differences in toxicity of FOLFIRINOX were observed. There was a trend towards a higher probability of short-term death (within 4 months of diagnosis) in sarcopenic patients. In this study, the detection of sarcopenia failed to predict a longer OS or PFS in selected patients deemed eligible by a physician for triplet chemotherapy and receiving the FOLFIRINOX regimen in a first-line setting, confirming the major importance of a comprehensive patient assessment by physicians in selecting the best treatment option

Computed tomography scan efficacy in staging gastric linitis plastica lesion: a retrospective multicentric French study

International audienc

J. M. Coetzee et la littérature européenne

Auteur majeur des lettres anglaises depuis une trentaine d'années, désormais traduit et commenté dans le monde entier, J. M. Coetzee est encore peu étudié en France et souvent perçu à travers le filtre post-colonial. Or, le romancier sud-africain est aussi un lecteur assidu des plus grands écrivains européens de l'Antiquité au XXe siècle. Depuis ses débuts, il entretient un dialogue constant avec ses prédécesseurs. Les douze essais de ce volume cernent les contours de cet intertexte qui se développe de Terres de crépuscule à L'Homme ralenti et l'analysent. Virgile, Defoe, Dostoïevski, Kafka, Beckett apparaissent comme les interlocuteurs les plus importants, derrière lesquels se profilent Nietzsche, Rilke, T. S. Eliot et bien d'autres : poètes, romanciers, autobiographes, philosophes. L'intérêt proprement critique du repérage de ces sources est évident. Mais, s'agissant d'un auteur qui a vécu la plus grande partie de sa vie sous l'apartheid, le travail critique même oblige à s'interroger sur les rapports de la littérature et de l'histoire. À leur carrefour se situe le classique : l'ensemble des œuvres humaines que J. M. Coetzee définit comme ce qui survit à la barbarie parce qu'hommes et femmes ne peuvent s'en passer à aucun prix. Sous l'apartheid et dans la nouvelle Afrique du Sud, il affirme la nécessité du classique et celle d'une littérature qui, tendue elle-même vers un devenir-classique, transmette ses pouvoirs éthiques et politiques

Sinusoidal obstruction syndrome and nodular regenerative hyperplasia are frequent oxaliplatin-associated liver lesions and partially prevented by bevacizumab in patients with hepatic colorectal metastasis

AIMS: Because of its efficacy, oxaliplatin (OX) is increasingly used as a chemotherapeutic agent in the treatment of colorectal liver metastases (CRLM). Oxaliplatin-associated liver toxicity has been reported and can affect clinical practice, but studies on its prevalence and a full pathological description are lacking. The aims of this study were to fill this gap by providing, from a pathologist's perspective, a detailed assessment of the spectrum of hepatic lesions associated with OX, to suggest a scoring system to quantify them, and to investigate the protective effect of bevacizumab against OX-associated damage. METHODS AND RESULTS: The spectrum of oxaliplatin-associated liver lesions was investigated in a multi-institutional series of surgically resected CRLM (n = 385). Among 274 patients treated by OX, 54% had moderate/severe sinusoidal obstruction syndrome (SOS). Peliosis, centrilobular perisinusoidal/venular fibrosis and nodular regenerative hyperplasia (NRH) developed in 10.6%, 47% and 24.5%, respectively. The 111 patients treated by surgery alone had no lesions. Hepatic lesions were less severe in patients treated with OX/bevacizumab (n = 70) compared with the group treated by OX alone (n = 204), with an incidence of moderate/severe SOS (31.4% versus 62.2%), peliosis (4.3% versus 14.6%), NRH (11.4% versus 28.9%, respectively) and centrilobular/venular fibrosis (31.4% versus 52%, respectively) (P < 0.001). CONCLUSIONS: Pathologists should be aware of the distinctive lesions associated with OX and of their high prevalence. OX-related lesions are less frequent in patients treated with bevacizumab, suggesting that this drug has a preventive effect. Uniform criteria for diagnosis and grading of OX-associated lesions should help to include histological data in the optimal multidisciplinary management of CRLM