Autologous T cell responses to primary human colorectal cancer spheroids are enhanced by ectonucleotidase inhibition.

OBJECTIVE: T cells are major effectors of the antitumoural immune response. Their activation by tumour-associated antigens can unleash their proliferation and cytotoxic functions, leading to tumour cell elimination. However, tumour-related immunosuppressive mechanisms including the overexpression of immune checkpoints like programmed cell death protein-1 (PD-1), are also engaged, promoting immune escape. Current immunotherapies targeting these pathways have demonstrated weak efficacy in colorectal cancer (CRC). It is thus crucial to find new targets for immunotherapy in this cancer type. DESIGN: In a prospective cohort of patients with CRC, we investigated the phenotype of tumour-related and non-tumour related intestinal T cells (n=44), particularly the adenosinergic pathway, correlating with clinical phenotype. An autologous coculture model was developed between patient-derived primary tumour spheroids and their autologous tumour-associated lymphocytes. We used this relevant model to assess the effects of CD39 blockade on the antitumour T cell response. RESULTS: We show the increased expression of CD39, and its co-expression with PD-1, on tumour infiltrating T cells compared with mucosal lymphocytes. CD39 expression was higher in the right colon and early-stage tumours, thus defining a subset of patients potentially responsive to CD39 blockade. Finally, we demonstrate in autologous conditions that CD39 blockade triggers T cell infiltration and tumour spheroid destruction in cocultures. CONCLUSION: In CRC, CD39 is strongly expressed on tumour infiltrating lymphocytes and its inhibition represents a promising therapeutic strategy for treating patients.

Oral therapies in digestive oncology (Review).

Targeted therapy and oral chemotherapy indications are increasing in the realm of digestive oncology. Oral intake of cancer agents is sometimes compulsory (no i.v. equivalent) or is preferred by the patient or the physician. Although oral chemotherapy facilitates the treatment of oncology patients, the treatment diversity, risk of pharmaceutical interactions and monitoring of side effects are potentially challenging and need to be fully acknowledged by the physician. We offer here a literature review of the indications, doses, side effects and monitoring of every oral therapy indicated in Digestive Oncology. We suggest a prescription algorithm including therapeutic education by the physician or a trained nurse, and pharmaceutical counseling.

Early esophageal signet ring cell carcinoma: A contraindication to endoscopic resection?

INTRODUCTION: Endoscopic resection is a standard-of-care for early esophageal neoplasia. Early gastric signet ring cell carcinoma (SRCC) can be safely managed by endoscopic resection, if the early SRCC is limited to the mucosa and less than 15mm, with a low lymph node metastasis rate. It is not known if esophageal signet ring cell carcinoma is amenable to endoscopic resection. METHODS: We retrospectively collected demographic, procedural, oncologic and follow-up data from all patients with esophageal SRCC resected endoscopically at our institution, and compared them to those of patients with endoscopically resected poorly differentiated esophageal adenocarcinomas. RESULTS: Between 2016 and 2018, 170 endoscopic resections were performed for esophageal neoplasms, among which 7 patients with SRCC and 6 patients with poorly differentiated early adenocarcinomas were identified. The histologically complete (R0) resection rate was 28.6% (2/7) for SRCC vs. 100% for poorly differentiated adenocarcinomas (P=0.04). The presence of lymphovascular invasion or deep submucosal invasion led to curative resection rates of 14.2% (1/7) and 66.6% (4/6) for SRCC and poorly differentiated adenocarcinomas, respectively (P=0.1). CONCLUSION: Endoscopic resection of early esophageal SRCC is neither histologically complete, nor curative in the majority of cases. These data argue against upfront endoscopic resection when SRCC is evidenced on esophageal biopsies.

Non-Pharmacological Therapeutic Options for Liver Metastases in Advanced Neuroendocrine Tumors.

The incidence of liver metastasis in digestive neuroendocrine tumors is high. Their presence appears as an important prognostic factor in terms of quality of life and survival. These tumors may be symptomatic because of the tumor burden itself and/or the hormonal hyper-secretion induced by the tumor. Surgery is the treatment of choice for resectable tumors and metastasis. Nevertheless, surgery is only possible in a small number of cases. The management of non-resectable liver metastasis is a challenge. The literature is rich but consists predominantly in small retrospective series with a low level of proof. Thus, the choice of one technique over another could be difficult. Local ablative techniques (radiofrequency) or trans-catheter intra-arterial liver-directed treatments (hepatic artery embolization, chemo-embolization, and radio-embolization) are frequently considered for liver metastasis. In the present review, we focus on these different therapeutic approaches in advanced neuroendocrine tumors, results (clinical and radiological), and overall efficacy, and summarize recommendations to help physicians in their clinical practice.

[Identification and management of patients with Lynch syndrome]. / Syndrome de LYNCH : identification et prise en charge.

About 5% of colorectal cancer (CRC) cases occurred in the context of an underlying hereditary predisposition syndrome. Lynch syndrome is the main causes of hereditary CRC but is also associated with a higher risk of other cancers (such as endometrial cancer and ovarian cancer). It is the consequence of constitutional mutation in a MisMatch Repair (MMR) gene, involved in DNA repair: MLH1, MSH2, MSH6 or PMS2; or of the EPCAM gene (MSH2 promotor). If a mutation predisposing to Lynch Syndrome is identified in an individual, special monitoring should be initiated, adapted to estimated cancer risk. Clinical criteria (Amsterdam II and Bethesda) have been validated to identify the patients who should be referred for genetic counseling in order to initiate constitutional DNA testing. Furthermore, the French National Cancer Institute (INCa) systematically recommend tumoral testing looking for MMR system failure in case of CRC diagnosed under 60, endometrial cancer diagnosed under 50 or whatever the age in patients diagnosed with CRC or endometrial cancer harbouring personal or familal history of Lunch Syndrome cancers. In this review, we will discuss how to detect Lynch syndrome (identification of the index case and family screening) and how to monitor it in 2019.

Local Therapy in Advanced Cholangiocarcinoma: A Review of Current Endoscopic, Medical, and Oncologic Treatment Options.

Endoscopic decompression of bile duct stenosis in unresectable cholangiocarcinoma (CC) may be difficult due to localization of the tumor, but it is important for pursuing oncologic treatment afterwards. Besides the initial diagnosis, jaundice and cholangitis are the most important indications for immediate endoscopic treatment. Endoscopic retrograde cholangiopancreatography is the favored approach for biliary access and stent placement. Hilar tumors are more difficult to treat and sometimes need higher endoscopic or radiologic expertise. In general, biliary decompression is accompanied by antibiotic treatment. Oncologic treatment of CC remains difficult, as it has to be interrupted when -infectious complications occur. For chemotherapy, a gemcitabine/cisplatin-based regime is favored. A validated -second-line treatment does not exist. Several therapeutic options are therefore offered to patients, including photodynamic therapy, selective internal radiotherapy, and high-dose radiotherapy. Exact treatment recommendations do not exist due to tumor rarity and lack of randomized controlled trials. In the present article, we take a look at current endoscopic, medical, and oncologic challenges from the endoscopist's point of view.