Identification of microenvironment features associated with primary resistance to anti-PD-1/PD-L1 + antiangiogenesis in gastric cancer through spatial transcriptomics and plasma proteomics.

Anti-angiogenic agents elicit considerable immune modulatory effects within the tumor microenvironment, underscoring the rationale for synergistic clinical development of VEGF and immune checkpoint inhibitors in advanced gastric cancer (AGC). Early phase studies involving Asian patients demonstrated encouraging anti-tumor efficacies. We report the results of the REGOMUNE phase II study, in which Caucasian patients were administered regorafenib, a multi-tyrosine kinase inhibitor, in combination with avelumab, a PD-L1-targeting monoclonal antibody. This therapeutic regimen resulted in deep and durable responses in 19% of patients, with the median duration of response not yet reached. Notwithstanding, a significant proportion of AGC patients exhibited no therapeutic advantage, prompting investigations into mechanisms of inherent resistance. Comprehensive biomarker profiling elucidated that non-responders predominantly exhibited an augmented presence of M2 macrophages within the tumor microenvironment and a marked overexpression of S100A10 by neoplastic cells, a protein previously implicated in macrophage chemotaxis. Additionally, peripheral biomarker assessments identified elevated levels of cytokines, including CSF-1, IL-4, IL-8, and TWEAK, correlating with adverse clinical outcomes, thereby accentuating the role of macrophage infiltration in mediating resistance. These insights furnish an invaluable foundation for elucidating, and potentially circumventing, resistance mechanisms in current AGC therapeutic paradigms, emphasizing the integral role of tumor microenvironmental dynamics and immune modulation.

Circulating tumor DNA landscape and prognostic impact of acquired resistance to targeted therapies in cancer patients: a national center for precision medicine (PRISM) study.

BACKGROUND: Despite the effectiveness of the various targeted therapies currently approved for solid tumors, acquired resistance remains a persistent problem that limits the ultimate effectiveness of these treatments. Polyclonal resistance to targeted therapy has been described in multiple solid tumors through high-throughput analysis of multiple tumor tissue samples from a single patient. However, biopsies at the time of acquired resistance to targeted agents may not always be feasible and may not capture the genetic heterogeneity that could exist within a patient. METHODS: We analyzed circulating tumor DNA (ctDNA) with a large next-generation sequencing panel to characterize the landscape of secondary resistance mechanisms in two independent prospective cohorts of patients (STING: n = 626; BIP: n = 437) with solid tumors who were treated with various types of targeted therapies: tyrosine kinase inhibitors, monoclonal antibodies and hormonal therapies. RESULTS: Emerging alterations involved in secondary resistance were observed in the plasma of up 34% of patients regardless of the type of targeted therapy. Alterations were polyclonal in up to 14% of patients. Emerging ctDNA alterations were associated with significantly shorter overall survival for patients with some tumor types. CONCLUSION: This comprehensive landscape of genomic aberrations indicates that genetic alterations involved in secondary resistance to targeted therapy occur frequently and suggests that the detection of such alterations before disease progression may guide personalized treatment and improve patient outcome.

FOLFIRI plus BEvacizumab or aFLIbercept after FOLFOX-bevacizumab failure for COlorectal cancer (BEFLICO): An AGEO multicenter study.

After failure of first line FOLFOX-bevacizumab for metastatic colorectal cancer (mCRC), adding either bevacizumab or aflibercept to second-line FOLFIRI increases survival compared to FOLFIRI alone. In this French retrospective multicentre cohort, we included patients with a mCRC treated with either FOLFIRI-aflibercept or FOLFIRI-bevacizumab. The primary endpoint was overall survival (OS), and secondary endpoints were progression-free survival (PFS), disease control rate (DCR: CR + PR + SD) and safety. We included 681 patients from 36 centers, 326 and 355 in the aflibercept and bevacizumab groups, respectively. Median age was 64.2 years and 45.2% of patients were men. Most patients had RAS-mutated tumors (80.8%) and synchronous metastases (85.7%). After a median follow up of 31.2 months, median OS was 13.0 months (95% CI: 11.3-14.7) and 10.4 months (95% CI: 8.8-11.4) in the bevacizumab and aflibercept groups, respectively (P < .0001). Median PFS was 6.0 months (95% CI: 5.4-6.5) and 5.1 months (95% CI: 4.3-5.6) (P < .0001). After adjustment on age, PS, PFS of first line, primary tumor resection, metastasis location and RAS/BRAF status, bevacizumab was still associated with better OS (HR: 0.71, 95% CI: 0.59-0.86, P = .0003). FOLFIRI-bevacizumab combination was associated with longer OS and PFS, and a better tolerability, as compared to FOLFIRI-aflibercept after progression on FOLFOX-bevacizumab.

Withholding the Introduction of Anti-Epidermal Growth Factor Receptor: Impact on Outcomes in RAS Wild-Type Metastatic Colorectal Tumors: A Multicenter AGEO Study (the WAIT or ACT Study).

BACKGROUND: Patients with RAS wild-type (WT) nonresectable metastatic colorectal cancer (mCRC) may receive either bevacizumab or an anti-epidermal growth factor receptor (EGFR) combined with first-line, 5-fluorouracil-based chemotherapy. Without the RAS status information, the oncologist can either start chemotherapy with bevacizumab or wait for the introduction of the anti-EGFR. Our objective was to compare both strategies in a routine practice setting. MATERIALS AND METHODS: This multicenter, retrospective, propensity score-weighted study included patients with a RAS WT nonresectable mCRC, treated between 2013 and 2016 by a 5-FU-based chemotherapy, with either delayed anti-EGFR or immediate anti-vascular endothelial growth factor (VEGF). Primary criterion was overall survival (OS). Secondary criteria were progression-free survival (PFS) and objective response rate (ORR). RESULTS: A total of 262 patients (129 in the anti-VEGF group and 133 in the anti-EGFR group) were included. Patients receiving an anti-VEGF were more often men (68% vs. 56%), with more metastatic sites (>2 sites: 15% vs. 9%). The median delay to obtain the RAS status was 19 days (interquartile range: 13-26). Median OS was not significantly different in the two groups (29 vs. 30.5 months, p = .299), even after weighting on the propensity score (hazard ratio [HR] = 0.86, 95% confidence interval [CI], 0.69-1.08, p = .2024). The delayed introduction of anti-EGFR was associated with better median PFS (13.8 vs. 11.0 months, p = .0244), even after weighting on the propensity score (HR = 0.74, 95% CI, 0.61-0.90, p = .0024). ORR was significantly higher in the anti-EGFR group (66.7% vs. 45.6%, p = .0007). CONCLUSION: Delayed introduction of anti-EGFR had no deleterious effect on OS, PFS, and ORR, compared with doublet chemotherapy with anti-VEGF. IMPLICATIONS FOR PRACTICE: For RAS/RAF wild-type metastatic colorectal cancer, patients may receive 5-fluorouracil-based chemotherapy plus either bevacizumab or an anti-epidermal growth factor receptor (EGFR). In daily practice, the time to obtain the RAS status might be long enough to consider two options: to start the chemotherapy with bevacizumab, or to start without a targeted therapy and to add the anti-EGFR at reception of the RAS status. This study found no deleterious effect of the delayed introduction of an anti-EGFR on survival, compared with the introduction of an anti-vascular endothelial growth factor from cycle 1. It is possible to wait one or two cycles to introduce the anti-EGFR while waiting for RAS status.

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.

Tumor-size responses to first-line is a predictor of overall survival in metastatic colorectal cancer.

OBJECTIVES: Early tumor shrinkage (ETS) has been reported to be associated with survival of metastatic colorectal cancer (mCRC) patients. Our aim was to analyze long-term tumor-size evolution, according to early mCRC best responses during the first-line therapy, to evaluate first best response-survival links. METHODS: Sixty-five patients with unresectable mCRCs, treated between 2010 and 2015, were included retrospectively in this descriptive monocenter study and grouped according to their RECIST 1.1 first-line best responses: progressive disease (PDfl), stable disease with tumor-size evolution between 0 and + 19% (SDfl+) or 0 and - 29% (SDfl-), and partial responders (PRs), who were classed PR with ETS (ETSfl) or without (PRfl). Tumor-size evolution and best tumor responses to each chemotherapy line were analyzed. RESULTS: Tumor loads of ETSfl or PRfl mCRCs tended to remain inferior to their initial values: 60% of patients died with target lesion sums below baseline. For first-line SDfl+ or PDfl mCRCs, rapid tumor load increases continued during successive lines: > 80% died with target lesion sums above baseline. ETSfl mCRCs responded better to subsequent lines (37.5% second-line PR), whereas PDfl mCRCs remained refractory to other therapies (0% second- and third-line PR). Overall survival rates were significantly (p = 0.03) longer for the ETSfl group (29.9 [95% CI: 12.6-47.1] months) and shorter for the PDfl group (17.1 [95% CI: 1.5-37.5] months). CONCLUSION: Tumors responding to first-line chemotherapy also responded better to subsequent lines, whereas PDfl mCRCs remained refractory, which may explain the better survival associated with ETSfl. KEY POINTS: • Early shrinking tumors under first-line chemotherapy responded better to subsequent lines, maintaining low tumor loads, potentially explaining the link between early tumor shrinkage and overall survival of metastatic colorectal cancer (mCRC) patients. • mCRCs progressing under first-line chemotherapy remained refractory to other therapies and their tumor loads increased rapidly. • Even outside a clinical trial, an early first CT scan reevaluation with RECIST criteria 8 weeks after starting first-line therapy is crucial to determine long-term mCRC evolution.

Echoendoscopic ultrasound pancreatic adenocarcinoma diagnosis and theranostic approach: should KRAS mutation research be recommended in everyday practice?

Background: The impact of KRAS mutation testing on pancreatic ductal adenocarcinoma (PDAC) samples by endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) for reducing the need to repeat EUS-FNA has been demonstrated. Such testing however is not part of standard practice for endoscopic ultrasound-guided fine-needle biopsy (EUS-FNB). Objectives: We aim to analyse the proportion of non-contributive samples by EUS-FNB and to evaluate the impact of KRAS mutation testing on the diagnosis, theranostics and survival. Design: In this retrospective study, the impact on diagnosis and survival of KRAS testing for contributive and non-contributive samples by EUS-FNB was analysed. Methods: The EUS-FNB samples, combined with KRAS testing using the Idylla® technique on liquid-based cytology from patients with PDAC between February 2019 and May 2023, were retrospectively reviewed. The cytology results were classified according to the guidelines of the World Health Organization System for Reporting Pancreaticobiliary Cytopathology (WHOSRPC). Results: A total of 85 EUS-FNB specimens were reviewed. In all, 25 EUS-FNB samples did not lead to a formal diagnosis of PDAC according to the WHOSRPC (30.2%). Out of these 25, 11 (44%) could have been considered positive for a PDAC diagnosis thanks to the KRAS mutation test without carrying out further diagnosis procedures. The sensitivity of KRAS mutation testing using the Idylla technique was 98.6%. According to the available data, survival rates were not statistically different depending on the type of mutation. Conclusion: KRAS mutation testing on liquid-based cytology using the Idylla or equivalent technique, combined with the PDAC EUS-FNB sample, should become a standard for diagnosis to avoid delaying treatment by doing another biopsy. Furthermore, knowledge of the KRAS status from treatment initiation could be used to isolate mutations requiring targeted treatments or inclusion in clinical research trials, especially for wild-type KRAS PDAC.

Diagnostic and theranostic interest of searching for a KRAS mutation in echoendoscopic ultrasound biopsies of pancreatic adenocarcinomas The echoendoscopic ultrasound diagnostic of pancreatic adenocarcinomas sometimes remains difficult due to the nature of these tumors with a particular microenvironment. For more than 30 years, several authors have underlined the importance of searching for a KRAS mutation on samples taken by echoendoscopic ultrasound to improve diagnostic performance. However, this research is not common practice. Our retrospective study made it possible to review the files of 85 patients with pancreatic adenocarcinoma in whom an echoendoscopic ultrasound biopsy was performed with a search for the KRAS mutation (with second-generation fine needle biopsy). Forty-four percent could have been considered positive for the diagnosis of PDAC thanks to the search for the KRAS mutation without repeating new samples. Furthermore, knowledge of the KRAS mutation type from diagnosis would make it possible to isolate mutations justifying possible targeted treatments.

Impact on survival without chemotherapy of local treatments of lung metastasis of colorectal cancers: Analysis on REPULCO cohort.

BACKGROUND: The impact of local management of pulmonary metastases on the disease course of patients with metastatic colorectal cancer is poorly assessed. METHODS: REPULCO database was a retrospective cohort on 18 years that included all patients treated for lung metastases from colorectal cancer who received local and/or systemic treatments. AIMS: Primary objective was overall survival, secondary were progression-free survival and survival without chemotherapy. RESULTS: Three hundred and fifteen patients were analyzed, 157 with only systemic treatments, 78 with only local treatments, and 80 with local and systemic treatments. Overall survival at 5 years was 26.9% (IC95%: [17.7-36.9]) for systemic treatments only, 61.0% (IC95%: [40.8-76.1]) for local treatments only, and 77.8% (IC95%: [60.1-88.3]) for local and systemic treatments. Progression-free survival at 2 years was 4.8% (IC95%: [2.1-9.2]) for systemic treatment only, 28.3% (IC95%: [17.7-39.9]) for local treatments only, and 21.8% (IC95%: [13.1-31.9]) for local and systemic treatments. Median survival without chemotherapy was 2.99 months (IC95%: [2.33-3.68]) for systemic treatments, 33.97 months (IC95%: [19.06-NA]) for local treatments, and 12.85 months (IC95%: [8.18-21.06]) for local and systemic treatments. CONCLUSION: Local treatments of lung metastasis led to prolonged survival and allowed long periods of time without chemotherapy in this cohort.

[Oesogastric cancer - new therapeutic targets]. / Adénocarcinome œsogastrique ­ nouvelles cibles thérapeutiques.

The median overall survival of metastatic esophagogastric adenocarcinoma is approximately twelve months. In fifteen years, major breakthrough have been the targeting of HER2 overexpression and more recently immunotherapy in patients with CPS≥5. Recent advances in molecular biology have identified some molecular alterations in esophageal adenocarcinoma, interesting to target. FGFR2 is overexpressed in one third of patients, and its targeting with a specific monoclonal antibody bemarituzumab showed a significant improvement in survival. Claudin 18.2 (CLDN 18.2) is overexpressed in at least a third of esophagogastric adenocarcinomas. The combination of zolbetuximab and chemotherapy provides a survival benefit, correlated with the intensity of CLDN 18.2 expression. The potential interest of targeting other pathways is under investigation in several trials with some encouraging preliminary data, and early trials in these indications, justifying considering large molecular screening in patients who might be candidate for early phase trial. Finally, with the recent advent of immunotherapy, one of the future challenges will be to optimize it through combination strategies with targeted therapies. The combination of anti-angiogenic and immunotherapy seems promising in gastric cancer.

Chemotherapy-induced ileitis associated or not with colitis in digestive oncology patients: An AGEO multicentre study.

BACKGROUND: The characteristics and management of ileitis induced by chemotherapy in cancer patients are poorly described in the literature. METHODS: This retrospective multicentre study enroled patients hospitalized in a digestive oncology unit for a symptomatic chemotherapy-induced ileitis. RESULTS: Forty-three patients were included, with a regimen based on fluoropyrimidine and/or irinotecan in 95% of cases. Five patients were excluded due to the diagnosis of infectious ileitis (Clostridium difficile in 3 patients, Campylobacter jejuni in 1 patient and cytomegalovirus in 1 patient). The most frequently described symptoms were diarrhoea (77% including 54% of grade 3-4 diarrhoea), abdominal pain (58%), fever (51%) and vomiting (56%). An ileo-colonoscopy was performed in 35% of patients and did not show any specific results or severity criteria. The ileitis was complicated by bowel perforation and/or obstruction in 3 patients. Disease progression was favourable in 1-2 weeks in the vast majority of cases, on symptomatic treatment, allowing resumption of the chemotherapy regimen involved in 67% of patients. CONCLUSION: Chemotherapy-induced ileitis is a rare complication that most often involves fluoropyri-midine- and/or irinotecan-based regimens. In most cases, endoscopic examinations were not contributory and do not seem useful in the event of non-severe symptomatology which most often develops favourably on symptomatic therapy, allowing resumption of the chemotherapy involved.

Impact of Delaying the Addition of Anti-EGFR in First Line of RAS Wild-Type Metastatic Colorectal Cancer: A Propensity-Weighted Pooled Data Analysis.

The first-line therapy of patients with RAS wild-type (WT) non-resectable metastatic colorectal cancer (mCRC) is usually 5-fluorouracil-based chemotherapy with either bevacizumab or an anti-epidermal growth factor receptor (EGFR). The addition of anti-EGFR antibodies is commonly delayed in clinical practice because of late RAS testing results. Our objective was to evaluate the impact on overall survival (OS) of a delayed anti-EGFR introduction strategy. This study pooled the data of two large retrospective studies. Patients with RAS WT non-resectable mCRC, treated in first line by a doublet chemotherapy with an anti-EGFR introduced with a delay of 2 to 4 cycles, were compared to an anti-EGFR and to an anti-VEGF that was introduced immediately. Patients numbering 305 in the delayed anti-EGFR group, 401 in the immediate anti-EGFR group, and 129 in the immediate anti-VEGF group were analyzed. After propensity scoring, there was no difference between the characteristics of the three groups. Median OS was 28.6 months (95% CI: 23.5-34.1) in the immediate anti-EGFR group, 35.1 (95% CI: 29.9-43.5) in the delayed anti-EGFR group, and 32.4 (95% CI: 25.4-44.8) in the immediate anti-VEGF group. There was no significant difference concerning median OS (p = 0.24) or progression-free survival (p = 0.56). This study suggests that delaying the introduction of an anti-EGFR has no deleterious impact on survival compared to the immediate introduction of an anti-VEGF or of an anti-EGFR.

Endoscopic ultrasound guided fine needle biopsy in patients with suspected gastric linitis plastica.

BACKGROUND: Gastric linitis plastica (GLP) is a diffuse infiltrating type of gastric adenocarcinoma. It is associated with a poor prognosis and a five-year survival of 3-10%. The infiltrating profile of this tumor explains the low yield of the superficial mucosal biospies. The objective of this study was to investigate the role of endoscopic ultrasound-fine needle biopsy (EUS-FNB) in the diagnosis of GLP. METHODS: We performed a retrospective analysis including all patients who had an EUS-FNB, at a tertiary referral center, over the last 3 years. The primary outcome was the sensitivity of EUS-FNB in patients with suspected GLP. RESULTS: Between January 2017 and December 2020, 34 patients had an EUS-FNB for suspected GLP. Ten patients had a diagnostic of GLP. This diagnosis was obtained by EUS-FNB in 90% (9/10) of the cases. Eight patients had at least one previous esophagogastroduodenoscopy (EGD) with negative mucosal biopsies. Gastric EUS-FNB helped diagnose other serious conditions in 47% (16/34) of cases with inconclusive mucosal biopsies. CONCLUSION: Gastric EUS-FNB in patients with suspected GLP and normal endoscopic mucosal biopsies may lead to a positive diagnosis of GLP in 90% of cases without notable adverse events. This technique should be considered as a second step in the setting of suspicion of GLP after inconclusive mucosal biopsies.

First-line chemotherapy with raltitrexed in metastatic colorectal cancer: an Association des Gastro-entérologues Oncologues (AGEO) multicentre study.

BACKGROUND: In case of contraindication or intolerance to fluoropyrimidines, raltitrexed is a validated alternative in metastatic colorectal cancer (mCRC), associated or not with oxaliplatin. Little is known about the outcomes of raltitrexed combined with irinotecan or targeted therapies. METHODS: This retrospective multicentre study enroled mCRC patients treated with first-line raltitrexed-based chemotherapy. Treatment-related toxicities were recorded. Progression-free survival (PFS) and overall survival (OS) were calculated from treatment start. RESULTS: 75 patients were treated with raltitrexed alone, TOMOX, or TOMIRI with or without bevacizumab. Grade 3-4 adverse events were seen in 31% of patients, without significant difference between the different treatment schedules. amongst the 36 patients with a history of fluoropyrimidine-induced cardiac toxicity, none developed cardiovascular events on raltitrexed. Median PFS and OS were 10.6 (95% CI 8.2 - 13.1) and 27.4 months (95% CI 24.1-38.1), respectively. Considering the chemotherapy regimen, TOMOX was significantly associated with better PFS and OS compared to TOMIRI and raltitrexed alone. CONCLUSIONS: In patients with mCRC not eligible for fluoropyrimidines, first-line raltitrexed-based chemotherapy had an acceptable safety profile. PFS and OS were consistent with usual survival data in mCRC, and significantly better in patients treated with TOMOX, independently of associated targeted therapies.

Systemic therapy in metastatic pancreatic adenocarcinoma: current practice and perspectives.

Major breakthroughs have been achieved in the management of metastatic pancreatic ductal adenocarcinoma (PDAC) with FOLFIRINOX (5-fluorouracil + irinotecan + oxaliplatin) and gemcitabine plus nab-paclitaxel approved as a first-line therapy, although the prognosis is still poor. At progression, patients who maintain a good performance status (PS) can benefit from second-line chemotherapy. To address the concern of achieving tumor control while maintaining a good quality of life, maintenance therapy is a concept that has now emerged. After a FOLFIRINOX induction treatment, maintenance with 5-fluorouracil (5-FU) seems to offer a promising approach. Although not confirmed in large, prospective trials, gemcitabine alone as a maintenance therapy following induction treatment with gemcitabine plus nab-paclitaxel could be an option, while a small subset of patients with a germline mutation of breast cancer gene (BRCA) can benefit from the polyadenosine diphosphate-ribose polymerase (PARP) inhibitor olaparib. The rate of PDAC with molecular alterations that could lead to a specific therapy is up to 25%. The Food and Drug Administration (FDA) recently approved larotrectinib for patients with any tumors harboring a neurotrophic tyrosine receptor kinase (NTRK) gene fusion, and pembrolizumab for patients with a mismatch repair deficiency in a second-line setting, including PDAC. Research focused on targeted therapy and immunotherapy is active and could improve patients' outcomes in the near future.

Digestive Well-Differentiated Grade 3 Neuroendocrine Tumors: Current Management and Future Directions.

Digestive well-differentiated grade 3 neuroendocrine tumors (NET G-3) have been clearly defined since the 2017 World Health Organization classification. They are still a rare category lacking specific data and standardized management. Their distinction from other types of neuroendocrine neoplasms (NEN) not only lies in morphology but also in genotype, aggressiveness, functional imaging uptake, and treatment response. Most of the available data comes from pancreatic series, which is the most frequent tumor site for this entity. In the non-metastatic setting, surgical resection is recommended, irrespective of grade and tumor site. For metastatic NET G-3, chemotherapy is the main first-line treatment with temozolomide-based regimen showing more efficacy than platinum-based regimen, especially when Ki-67 index <55%. Targeted therapies, such as sunitinib and everolimus, have also shown some positive therapeutic efficacy in small samples of patients. Functional imaging plays a key role for detection but also treatment selection. In the second or further-line setting, peptide receptor radionuclide therapy has shown promising response rates in high-grade NEN. Finally, immunotherapy is currently investigated as a new therapeutic approach with trials still ongoing. More data will come with future work now focusing on this specific subgroup. The aim of this review is to summarize the current data on digestive NET G-3 and explore future directions for their management.

Indications of Peptide Receptor Radionuclide Therapy (PRRT) in Gastroenteropancreatic and Pulmonary Neuroendocrine Tumors: An Updated Review.

Radionuclide therapy for neuroendocrine tumors is a form of systemic radiotherapy that allows the administration of targeted radionuclides into tumor cells that express a large quantity of somatostatin receptors. The two most commonly used radio-peptides for radionuclide therapy in neuroendocrine tumors are 90Y-DOTATOC and 177Lu-DOTATATE. Radio-peptides have been used for several years in the treatment of advanced neuroendocrine tumors. Recently, the randomized Phase III study NETTER-1 compared177Lu-DOTATATE versus high-dose (double-dose) octreotide LAR in patients with metastatic midgut neuroendocrine tumors, and demonstrated its efficacy in this setting. Strong signals in favor of efficiency seem to exist for other tumors, in particular for pancreatic and pulmonary neuroendocrine tumors. This focus on radionuclide therapy in gastroenteropancreatic and pulmonary neuroendocrine tumors addresses the treatment modalities, the validated and potential indications, and the safety of the therapy.

Outcomes of endoscopic submucosal dissection for early esophageal and gastric cardia adenocarcinomas.

OBJECTIVES: Adenocarcinomas of the esophagus and of the gastric cardia are regarded as a same clinical entity in oncology. For endoscopic resection however, endoscopic mucosal resection is recommended for esophageal adenocarcinoma, while endoscopic submucosal dissection (ESD) is advocated for gastric adenocarcinomas. Our aim was to compare the outcomes of ESD in both types of esophagogastric junction adenocarcinomas. METHODS: Between March 2015 and December 2019, we included all patients who underwent an ESD for early adenocarcinoma of the esophagogastric junction at a French tertiary referral center. Esophageal and gastric cardia adenocarcinomas were compared in terms of clinical, procedural and histological outcomes. RESULTS: 57 esophageal and 19 gastric cardia adenocarcinomas were included in the analysis, for a total of 76 patients. The median (IQR) size of the resections was 40 (40-57.5) and 50 (35-55)mm, p=0.96, respectively. En bloc resection was achieved in 100% and 89% for adenocarcinomas of the esophagus and the gastric cardia, p=0.06. Late adverse events occurred in 14% and 5.3%, respectively, p=0.44, with no severe adverse event. Curative resection rates were 67% and 63% for adenocarcinomas of the esophagus and the gastric cardia, respectively, p=0.89. CONCLUSION: ESD is a safe treatment for T1 adenocarcinomas of the esophagogastric junction, curative in two thirds of the patients, in tumors arising from the esophagus or from the stomach. ESD should be considered for the routine resection of esophageal adenocarcinomas.

Management of esophageal strictures after endoscopic resection for early neoplasia.

BACKGROUND: Endoscopic resection of extensive esophageal neoplastic lesions is associated with a high rate of esophageal stricture. Most studies have focused on the risk factors for post-endoscopic esophageal stricture, but data on the therapeutic management of these strictures are scarce. Our aim is to describe the management of esophageal strictures following endoscopic resection for early esophageal neoplasia. METHODS: We included all patients with an endoscopic resection for early esophageal neoplasia followed by endoscopic dilatation at a tertiary referral center. We recorded the demographic, endoscopic, and histological characteristics, and the outcomes of the treatment of the strictures. RESULTS: Between January 2010 and December 2019, we performed 166 endoscopic mucosal resections and 261 endoscopic submucosal dissections for early esophageal neoplasia, and 34 (8.0%) patients developed an esophageal stricture requiring endoscopic treatment. The indication for endoscopic resection was Barrett's neoplasia in 15/34 (44.1%) cases and squamous cell neoplasia (SCN) in 19/34 (55.9%) cases. The median [(interquartile range) (IQR)] number of endoscopic dilatations was 2.5 (2.0-4.0). Nine of 34 (26.5%) patients required only one dilatation, and 22/34 (65%) had complete dysphagia relief following three endoscopic treatment sessions. The median number of dilatations was significantly higher for SCN [3.0 (2-7); range 1-17; p = 0.02], and in the case of circumferential resection [4.0 (3.0-7.0); p = 0.03]. Endoscopic dilatation allowed a sustained dysphagia relief in 33/34 (97.0%) patients after a mean follow-up of 25.3 ± 22 months. CONCLUSION: Refractory post-endoscopic esophageal stricture is a rare event. After a median of 2.5 endoscopic dilatations, 97.0% of patients were permanently relieved of dysphagia. Circumferential endoscopic esophageal resections should be considered when indicated.

Patterns of ICU admissions and outcomes in patients with solid malignancies over the revolution of cancer treatment.

BACKGROUND: Major therapeutic advances including immunotherapy and targeted therapies have been changing the face of oncology and resulted in improved prognosis as well as in new toxic complications. The aim of this study is to appraise the trends in intensive care unit (ICU) admissions and outcomes of critically ill patients with solid malignancies. We performed a retrospective single-centre study over a 12-year period (2007-2018) including adult patients with solid malignancies requiring unplanned ICU admission. Admission patterns were classified as: (i) specific if directly related to the underlying cancer; (ii) non-specific; (iii) drug-related or procedural adverse events. RESULTS: 1525 patients were analysed. Lung and gastro-intestinal tract accounted for the two main tumour sites. The proportion of patients with metastatic diseases increased from 48.6% in 2007-2008 to 60.2% in 2017-2018 (p = 0.004). Critical conditions were increasingly related to drug- or procedure-related adverse events, from 8.8% of ICU admissions in 2007-2008 to 16% in 2017-2018 (p = 0.01). The crude severity of critical illness at ICU admission did not change over time. The ICU survival rate was 77.4%, without any significant changes over the study period. Among the 1279 patients with complete follow-up, the 1-year survival rate was 33.2%. Independent determinants of ICU mortality were metastatic disease, cancer in progression under treatment, admission for specific complications and the extent of organ failures (invasive and non-invasive ventilation, inotropes/vasopressors, renal replacement therapy and SOFA score). One-year mortality in ICU-survivors was independently associated with lung cancer, metastatic disease, cancer in progression under treatment, admission for specific complications and decision to forgo life-sustaining therapies. CONCLUSION: Advances in the management and the prognosis of solid malignancies substantially modified the ICU admission patterns of cancer patients. Despite underlying advanced and often metastatic malignancies, encouraging short-term and long-term outcomes should help changing the dismal perception of critically ill cancer patients.

Reasons for chemotherapy discontinuation and end-of-life in patients with gastrointestinal cancer: A multicenter prospective AGEO study.

BACKGROUND: Previous research on chemotherapy discontinuation has mainly focused on predictive factors and outcomes. Few data are available on the reasons for chemotherapy discontinuation. The main objective was to identify the reasons for chemotherapy discontinuation in patients with gastrointestinal cancer. The secondary objectives were to describe the announcement of chemotherapy discontinuation and the time between chemotherapy discontinuation and death. METHODS: This prospective multicenter French cohort included patients with advanced gastrointestinal cancer, for whom chemotherapy was discontinued between May 2016 and January 2018. RESULTS: One hundred and fourteen patients were analyzed. The first cause of chemotherapy discontinuation was the impairment of general condition (asthenia, cachexia). Complications such as sepsis, jaundice or occlusion, were the second most frequent cause. Progression was observed at chemotherapy discontinuation in two-thirds of cases. The announcement of the chemotherapy discontinuation was made formally in 74% of cases, with a follow-up by a palliative care team initiated in 50% of cases. Sixty-nine percent of the patients received chemotherapy during the last three months of life and 26% during the last month. The median time between chemotherapy discontinuation and death was 65 days (IQR: 36.5-109): 44% of patients died at the hospital, 39% in a palliative care unit and 16% at home. CONCLUSION: Impairment of general condition was the major reason for chemotherapy discontinuation in patients with gastrointestinal cancers. Complications such as jaundice, sepsis or occlusion, were important reasons for discontinuation and could explain our shorter time between chemotherapy discontinuation and death, compared to other oncology sub-specialties.