Impact of surgery after endoscopically resected high-risk T1 colorectal cancer: results of an emulated target trial.

BACKGROUND AND AIMS: We aimed to compare the long-term outcomes of patients with high-risk T1 colorectal cancer (CRC) resected endoscopically who received either additional surgery or surveillance. METHODS: We used data from routine care to emulate a target trial aimed at comparing 2 strategies after endoscopic resection of high-risk T1 CRC: surgery with lymph node dissection (treatment group) versus surveillance alone (control group). All patients from 14 tertiary centers who underwent an endoscopic resection for high-risk T1 CRC between March 2012 and August 2019 were included. The primary outcome was a composite outcome of cancer recurrence or death at 48 months. RESULTS: Of 197 patients included in the analysis, 107 were categorized in the treatment group and 90 were categorized in the control group. From baseline to 48 months, 4 of 107 patients (3.7%) died in the treatment group and 6 of 90 patients (6.7%) died in the control group. Four of 107 patients (3.7%) in the treatment group experienced a cancer recurrence and 4 of 90 patients (4.4%) in the control group experienced a cancer recurrence. After balancing the baseline covariates by inverse probability of treatment weighting, we found no significant difference in the rate of death and cancer recurrence between patients in the 2 groups (weighted hazard ratio, .95; 95% confidence interval, .52-1.75). CONCLUSIONS: Our study suggests that patients with high-risk T1 CRC initially treated with endoscopic resection may not benefit from additional surgery.

Burden of grade 3 or 4 liver injury associated with immune checkpoint inhibitors.

Background & Aims: There is concern about the burden of liver injury in patients with cancer exposed to immune checkpoints inhibitors (ICIs). Methods: In a retrospective cohort study, we evaluated the likelihood of grade 3/4 liver injury, of grade 3/4 cholestatic liver injury, and of liver failure, as per the Common Terminology Criteria for Adverse Events (CTCAE) version 5, following treatment with ICIs. We compared these occurrences with a group of cancer patients who were propensity-matched and treated with conventional chemotherapy. For all ICI patients experiencing grade 3/4 liver injury, we conducted a causality assessment using the RUCAM method and examined patient outcomes. Results: Among 952 patients (median [IQR] age 66 [57-73] years, 64% males) who were treated with ICI between January 1, 2015, and December 31, 2019, a total of 86 (9%) progressed to grade 3/4 liver injury, and liver failure was not observed. Anti-PD-(L)1/anti-CTLA-4 antibodies combinations (adjusted hazard ratio 3.36 [95% CI: 1.67-6.79]; p <0.001), and chronic hepatitis B (adjusted hazard ratio 5.48 [95% CI: 1.62-18.5]; p = 0.006], were independent risk factors. Liver injury was attributed to ICI treatment in 19 (2.0%) patients. Patients with ICI toxicity typically presented with granulomatous hepatitis or cholangiocyte inflammation. ICI withdrawal was associated with cancer progression and mortality. Re-introduction of ICI was not associated with recurrent grade 3/4 liver injury. Compared with matched patients treated with conventional, non-ICI-based chemotherapy, anti-PD-(L)1/anti-CTLA-4 combinations (p <0.001) and anti-PD-(L)1 monotherapies (p = 0.053) increased the risk of grade 3/4 liver injury and of grade 3/4 cholestatic liver injury, respectively. Conclusions: An increased risk of grade 3/4 liver injury under anti-PD-(L)1/anti-CTLA-4 antibodies was observed, whereas no substantial increase in the likelihood of liver failure occurred even after treatment reintroduction. Impact and implications: There is concern about liver injury in patients with cancer exposed to immune checkpoints inhibitors (ICIs). We investigated the burden of grade 3/4 liver injury after treatment with ICIs in a multicentric cohort of patients with cancer. Overall, a 9% incidence of grade 3/4 liver injury was detected after ICIs, and direct ICI hepatotoxicity was demonstrated in 2% of patients. Anti-PD-(L)1/Anti-CTLA-4 antibody combinations, and chronic HBV infection were independent risk factors. ICI withdrawal for grade 3/4 liver injury was associated with cancer progression. Re-introduction of ICI treatment was not associated with recurrent grade 3/4 liver injury.

Cinematic Rendering of Gastrointestinal Stromal Tumors: A Review of Current Possibilities and Future Developments.

Gastrointestinal stromal tumors (GISTs) are defined as CD117-positive primary, spindled or epithelioid, mesenchymal tumors of the gastrointestinal tract, omentum, or mesentery. While computed tomography (CT) is the recommended imaging modality for GISTs, overlap in imaging features between GISTs and other gastrointestinal tumors often make radiological diagnosis and subsequent selection of the optimal therapeutic approach challenging. Cinematic rendering is a novel CT post-processing technique that generates highly photorealistic anatomic images based on a unique lighting model. The global lighting model produces high degrees of surface detail and shadowing effects that generate depth in the final three-dimensional display. Early studies have shown that cinematic rendering produces high-quality images with enhanced detail by comparison with other three-dimensional visualization techniques. Cinematic rendering shows promise in improving the visualization of enhancement patterns and internal architecture of abdominal lesions, local tumor extension, and global disease burden, which may be helpful for lesion characterization and pretreatment planning. This article discusses and illustrates the application of cinematic rendering in the evaluation of GISTs and the unique benefit of using cinematic rendering in the workup of GIST with a specific emphasis on tumor characterization and preoperative planning.

A preoperative computed tomography radiomics model to predict disease-free survival in patients with pancreatic neuroendocrine tumors.

IMPORTANCE: Imaging has demonstrated capabilities in the diagnosis of pancreatic neuroendocrine tumors (pNETs), but its utility for prognostic prediction has not been elucidated yet. OBJECTIVE: The aim of this study was to build a radiomics model using preoperative computed tomography (CT) data that may help predict recurrence-free survival (RFS) or OS in patients with pNET. DESIGN: We performed a retrospective observational study in a cohort of French patients with pNETs. PARTICIPANTS: Patients with surgically resected pNET and available CT examinations were included. INTERVENTIONS: Radiomics features of preoperative CT data were extracted using 3D-Slicer® software with manual segmentation. Discriminant features were selected with penalized regression using least absolute shrinkage and selection operator method with training on the tumor Ki67 rate (≤2 or >2). Selected features were used to build a radiomics index ranging from 0 to 1. OUTCOME AND MEASURE: A receiving operator curve was built to select an optimal cutoff value of the radiomics index to predict patient RFS and OS. Recurrence-free survival and OS were assessed using Kaplan-Meier analysis. RESULTS: Thirty-seven patients (median age, 61 years; 20 men) with 37 pNETs (grade 1, 21/37 [57%]; grade 2, 12/37 [32%]; grade 3, 4/37 [11%]) were included. Patients with a radiomics index >0.4 had a shorter median RFS (36 months; range: 1-133) than those with a radiomics index ≤0.4 (84 months; range: 9-148; P = .013). No associations were found between the radiomics index and OS (P = .86).

Impact of induction therapy in locally advanced intrahepatic cholangiocarcinoma.

INTRODUCTION: After local or systemic treatment, a small number of patients with primarily unresectable intrahepatic cholangiocarcinoma (ICC) may benefit from secondary resection. This study aimed to analyze the oncological outcome of patients who underwent radical surgery after preoperative treatment. METHODS: From 2000 to 2021, all patients who underwent curative-intent liver resection for ICC in three tertiary centers were selected. Patients were divided into two groups: upfront surgery (US) and preoperative treatment (POT). Oncologic data (preoperative treatment, histologic data, adjuvant chemotherapy, overall survival, and recurrence-free survival) were compared between the two groups. RESULTS: Among 198 included patients, 31 (15.7%) received POT including chemotherapy (74.2%), radioembolization (12.9%), chemoembolization (9.7%), or combined radiotherapy and chemotherapy (3.2%). Major resection was performed in 156 (78.8%) patients, and 53 (26.8%) had vascular and/or biliary reconstruction. Histological findings were similar between US and POT group and were not affected by the type of POT. After a median follow-up of 23 months, recurrence rate (58.1% POT vs. 55.1% US, p = 0.760) and type were similar between groups. Recurrence-free survival at 1 and 3 years (41.9% and 22.6% vs. 46.7 and 21.6% in the POT and US, respectively, p = 0.989) and overall survival at 1 and 3 years (77.4% and 32.3% vs. 69.5% and 34.7% in the POT and US respectively, p = 0.323) were similar and independent of the POT type. CONCLUSION: After POT, downstaged patients who underwent curative-intent resection for initially unresectable ICC have similar long-term outcomes as those undergoing upfront surgery.

Histological Characteristics and Management of Hepatitis on Immune Checkpoint Inhibitors: A Retrospective Descriptive Study.

BACKGROUND AND AIMS: the side effects of immune checkpoint inhibitors (ICI) pose a problem for the clinical management of cancer patients. There is a lack of knowledge of the value of liver biopsy in patients with ICI-related drug-induced liver injury (ICI-DILI). The aim of this study was to explore the impact of liver biopsy on clinical management and response to corticosteroids, according to histological findings. METHODS: We conducted a retrospective, single-center study to evaluate the biochemical, histological and clinical data of 35 patients with ICI-DILI between 2015 and 2021 in a university hospital in France. RESULTS: Of the 35 patients with ICI-DILI (median [interquartile range] age 62 [48-73] years, 40% males) studied, 20 underwent a liver biopsy. There was no difference in the management of ICI-DILI according to liver biopsy in terms of ICI withdrawal, reduction or rechallenge. According to the histological profile, patients with toxic and granulomatous profiles had a better response to corticosteroids, while patients with cholangitic lesions had the worst response. CONCLUSION: In ICI-DILI, liver biopsy must not delay patient care but may be useful in identifying patients with a cholangitic profile who have a poorer response to corticosteroids.

Endoscopic submucosal dissection versus endoscopic mucosal resection for early esophageal adenocarcinoma.

OBJECTIVES: Endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD) allow endoscopic resection of early esophageal adenocarcinoma. The choice between the two techniques takes into account the morphology of the lesion, and the experience of the endoscopist. The aim of this study was to compare EMR to ESD for the treatment of early esophageal adenocarcinoma. METHODS: Patients who underwent an endoscopic resection for esophageal adenocarcinomas between March 2015 and December 2019 were included. ESD was compared to EMR in terms of clinical, procedural, histologic, and oncologic outcomes. RESULTS: 85 patients were included: 57 ESD and 28 EMR. The median (IQR) diameter of the lesion was 20(15-25) mm in the ESD group, and 15(8-16) mm in the EMR group, p<0.01. ESD allowed en bloc resection in 100% of cases, and EMR in 39% of cases, p<0.001. The R0 and curative resection rate in the ESD group versus the EMR group were 88% and 67%, respectively, versus 21% and 11%, p<0.001. We recorded one severe adverse event, in the EMR group. After a median (IQR) follow-up of 27.5 (14.5-38.7) months, the local recurrence rate was 23% vs. 18% (p = 0.63), and the overall survival 89% vs. 86% (p = 0.72), in the ESD and EMR groups, respectively. CONCLUSION: ESD was as safe as EMR and allowed higher en bloc, R0 and curative resection rates. Although these results did not translate into long-term outcomes, these data prompt for a broader adoption of ESD for the resection of esophageal lesions suspected of harboring early esophageal adenocarcinoma.

Azathioprine-induced vanishing bile duct syndrome: The value of early thiopurine metabolism assessment.

About 15% to 28% of patients treated with thiopurines experienced adverse drug reactions, such as haematological and hepatic toxicities. Some of these related to the polymorphic activity of the thiopurine S-methyltransferase (TPMT), the key detoxifying enzyme of thiopurine metabolism. We report here a case of thiopurine-induced ductopenia with a comprehensive pharmacological analysis on thiopurine metabolism. A 34-year-old woman, with a medical history of severe systemic lupus erythematosus with recent introduction of azathioprine therapy, presented with mild fluctuating transaminase blood levels consistent with a hepatocellular pattern, which evolved to a cholestatic pattern over the next weeks. A blood thiopurine metabolite assay revealed low 6-thioguanine nucleotides (6-TGN) level and a dramatically increased 6-methylmercaptopurine ribonucleotides (6-MMPN) level, together with an unfavourable [6-MMPN:6-TGN] metabolite ratio and a high TPMT activity. After a total of about 6 months of thiopurine therapy, a transjugular liver biopsy revealed a ductopenia, and azathioprine discontinuation led to further clinical improvement. In line with previous reports from the literature, our case supports the fact that ductopenia is a rare adverse drug reaction of azathioprine. The mechanism of reaction is unknown but may involve high 6-MMPN blood level, due to unusual thiopurine metabolism (switched metabolism). Early therapeutic drug monitoring with measurement of 6-TGN and 6-MMPN blood levels may help physicians to identify patients at risk of similar duct injury.

High Prevalence of NASH and Advanced Fibrosis in Type 2 Diabetes: A Prospective Study of 330 Outpatients Undergoing Liver Biopsies for Elevated ALT, Using a Low Threshold.

OBJECTIVE: Most people with type 2 diabetes (T2DM) and nonalcoholic steatohepatitis (NASH) or advanced fibrosis (AF) remain undiagnosed, resulting in missed opportunities for early intervention. This multicenter, prospective study assessed the yield of using routinely available data to identify these patients. RESEARCH DESIGN AND METHODS: A total of 713 outpatients with T2DM, screened in four diabetology clinics for nonalcoholic fatty liver disease according to American Diabetes Association criteria, were referred to hepatologists for further work-up (Fibrosis-4 and vibration-controlled transient elastography [VCTE]). A liver biopsy was proposed when ALT levels were persistently >20 IU/L in female patients or >30 IU/L in male patients, in the absence of other liver disease. RESULTS: Liver biopsies were performed in 360 patients and considered adequate for reading after central review for 330 specimens (median patient age, 59 years; male patients, 63%; median BMI and HbA1c values, 32 and 7.5%, respectively). Prevalence of NASH, AF, and cirrhosis were 58%, 38%, and 10%, respectively. Liver lesions were independently associated with the components of metabolic syndrome but not with the micro- and macrovascular complications of T2DM. Models based on routinely available data with or without VCTE had good accuracy to predict AF (respectively: area under the receiver operating characteristic curve [AUROC], 0.84 and 0.77; and correctly classified 59% and 45%) and NASH (respectively: AUROC, 0.82 and 0.81; 44% and 42%). CONCLUSIONS: Despite the use of a low ALT threshold, prevalence of NASH (58%) or AF (38%) was high. Routinely available data had a high yield in identifying patients with T2DM with AF and/or NASH requiring further liver assessment.

Impact of Morphology in the Genotype and Phenotype Correlation of Bilateral Macronodular Adrenocortical Disease (BMAD): A Series of Clinicopathologically Well-Characterized 35 Cases.

Bilateral macronodular adrenocortical disease (BMAD) is characterized by the development of adrenal macronodules resulting in a pituitary-ACTH independent Cushing's syndrome. Although there are important similarities observed between the rare microscopic descriptions of this disease, the small series published are not representative of the molecular and genetic heterogenicity recently described in BMAD. We analyzed the pathological features in a series of BMAD and determined if there is correlation between these criteria and the characteristics of the patients. Two pathologists reviewed the slides of 35 patients who underwent surgery for suspicion of BMAD in our center between 1998 and 2021. An unsupervised multiple factor analysis based on microscopic characteristics divided the cases into 4 subtypes according to the architecture of the macronodules (containing or not round fibrous septa) and the proportion of the different cell types: clear, eosinophilic compact, and oncocytic cells. The correlation study with genetic revealed subtype 1 and subtype 2 are associated with the presence of ARMC5 and KDM1A pathogenic variants, respectively. By immunohistochemistry, all cell types expressed CYP11B1 and HSD3B1. HSD3B2 staining was predominantly expressed by clear cells whereas CYP17A1 staining was predominant on compact eosinophilic cells. This partial expression of steroidogenic enzymes may explain the low efficiency of cortisol production in BMAD. In subtype 1, trabeculae of eosinophilic cylindrical cells expressed DAB2 but not CYP11B2. In subtype 2, KDM1A expression was weaker in nodule cells than in normal adrenal cells; alpha inhibin expression was strong in compact cells. This first microscopic description of a series of 35 BMAD reveals the existence of 4 histopathological subtypes, 2 of which are strongly correlated with the presence of known germline genetic alterations. This classification emphasizes that BMAD has heterogeneous pathological characteristics that correlate with some genetic alterations identified in patients.

[Well-differentiated neuroendocrine tumors of the digestive tract: Focus on pancreatic neuroendocrine tumors]. / Tumeurs neuroendocrines digestives bien différenciées: focus sur les tumeurs pancréatiques.

Pancreatic neuroendocrine tumors are rare tumors showing a rising incidence. They are well-differentiated tumors, classified by grade according to their Ki67 index value (grade 1 to 3). Pancreatic neuroendocrine tumors are mainly sporadic tumors but about 10% arise within endocrine tumor syndromes such as multiple endocrine neoplasia type 1. They can be responsible for functional syndromes or non-specific clinical symptoms depending on tumor extension. However, there is also an increase of incidental diagnoses of nonfunctional pancreatic neuroendocrine tumors with the widespread use of high-quality imaging techniques. About 50 % of pancreatic neuroendocrine tumors are diagnosed at a metastatic stage, with metastases often located in the liver. Chromogranin A, CT-scan and often an abdominal MRI, and functional imaging should be performed for tumor staging and follow-up. Imaging with PET/CT with 68Ga-labeled somatostatin analogues has the highest sensitivity for the diagnosis of pancreatic neuroendocrine tumors, while 18fluorodeoxyglucose PET/CT can sometimes be useful. Overall, they are rather indolent tumors with prolonged survival. Surgery is the recommended treatment in the localized setting, with the exception of small<2cm nonfunctional tumors that can be monitored with imaging techniques. For advanced tumors, there are several available treatments such as somatostatine analogues, chemotherapy, targeted therapies (sunitinib, everolimus), locoregional ablative therapies and Peptide Receptor Radiolabelled Therapy. The treatment strategy will depend on the initial tumor staging, tumor grade, aggressiveness and patient's choice.

Comparison between CT-enterography and MR-enterography for the diagnosis of right-sided deep infiltrating endometriosis of the bowel.

OBJECTIVE: To compare computed tomography-enterography (CTE) and magnetic resonance-enterography (MRE) in the detection of right-sided bowel deep infiltrating endometriosis (DIE). MATERIALS AND METHODS: Fifty women with DIE who underwent preoperatively CTE and MRE were included. CTE and MRE were first analyzed separately by two independent readers who analyzed five bowel segments (cecum, appendix, ileocecal junction, distal ileum and proximal small bowel [i.e., proximal ileum and jejunum]) for the presence of DIE and then interpreted in consensus. CTE, MRE and CTE with MRE were compared in terms of sensitivity, specificity and accuracy. Interobserver agreement was assessed with kappa (κ) test. RESULTS: Using the reference standard 25 out 250 bowel segments were involved by DIE in 18 women and 225 were free of DIE. Sensitivity, specificity, and accuracy of CTE were 60% (95% confidence interval [CI]: 39-79), 93% (95% CI: 89-96) and 90% (95% CI: 85-93) for Reader 1, respectively, and 52% (95% CI: 31-72), 99% (95% CI: 97-100) and 94% (95% CI: 91-97) for Reader 2, with no differences in sensitivity (P = 0.564) and specificity (P = 0.181) between readers and fair interobserver agreement (κ = 0.37). For MRE these figures were 52% (95% CI: 31-72), 92% (95% CI: 88-95) and 88% (95% CI: 84-92) for Reader 1 and 60% (95% CI: 39-79), 99% (95% CI: 96-100) and 95% (95% CI: 91-97) for Reader 2, with no differences in sensitivity (P = 0.157) and specificity (P = 0.061) between readers and fair interobserver agreement (κ = 0.31). Significant differences in sensitivity (20%; 95% CI: 7-41) were found between CTE + MRE vs. CTE alone for Reader 1 and vs. MRE alone for Reader 2 (P = 0.041 for both) CONCLUSION: CTE and MRE have not different sensitivities and convey only fair interobserver agreement but are highly specific for the diagnosis of right-sided bowel DIE. CTE and MRE are complementary because they improve the detection of DIE implants when used in combination.

Biology and Management of High-Grade Chondrosarcoma: An Update on Targets and Treatment Options.

This review provides an overview of histopathology, clinical presentation, molecular pathways, and potential new systemic treatments of high-grade chondrosarcomas (CS), including grade 2−3 conventional, dedifferentiated, and mesenchymal CS. The diagnosis of CS combines radiological and histological data in conjunction with patient clinical presentations. Conventional CS is the most frequent subtype of CS (85%) and represents about 25% of primary bone tumors in adults; they can be categorized according to their bone location into central, peripheral, and periosteal chondrosarcomas. Central and peripheral CS differ at the molecular level with either IDH1/2 mutations or EXT1/2 mutations, respectively. CDKN2A/B deletions are also frequent in conventional CS, as well as COL2A1 mutations. Dedifferentiated CS develops when low-grade conventional CS transforms into a high-grade sarcoma and most frequently exhibits features of osteosarcoma, fibrosarcoma, or undifferentiated pleomorphic sarcoma. Their molecular characteristics are similar to conventional CS. Mesenchymal CS is a totally different pathological entity exhibiting recurrent translocations. Their clinical presentation and management are different too. The standard treatment of CSs is wide en-bloc resection. CS are relatively radiotherapy resistant; therefore, doses >60 Gy are needed in an attempt to achieve local control in unresectable tumors. Chemotherapy is possibly effective in mesenchymal chondrosarcoma and is of uncertain value in dedifferentiated chondrosarcoma. Due to resistance to standard anticancer agents, the prognosis is poor in patients with metastatic or unresectable chondrosarcomas. Recently, the refined characterization of the molecular profile, as well as the development of new treatments, allow new therapeutic options for these rare tumors. The efficiency of IDH1 inhibitors in other malignancies suggests that these inhibitors will be part of IDH1/2 mutated conventional CS management soon. Other treatment approaches, such as PIK3-AKT-mTOR inhibitors, cell cycle inhibitors, and epigenetic or immune modulators based on improving our understanding of CS molecular biology, are emerging.

Axin1 Protects Colon Carcinogenesis by an Immune-Mediated Effect.

BACKGROUND & AIMS: Axin1 is a negative regulator of wingless-type MMTV integration site family, member 1 (Wnt)/ß-catenin signaling with tumor-suppressor function. The Wnt pathway has a critical role in the intestine, both during homeostasis and cancer, but the role of Axin1 remains elusive. METHODS: We assessed the role of Axin1 in normal intestinal homeostasis, with control, epithelial-specific, Axin1-knockout mice (Axin1ΔIEC) and Axin2-knockout mice. We evaluated the tumor-suppressor function of Axin1 during chemically induced colorectal tumorigenesis and dextran sulfate sodium-induced colitis, and performed comparative gene expression profiling by whole-genome RNA sequencing. The clinical relevance of the Axin1-dependent gene expression signature then was tested in a database of 2239 clinical colorectal cancer (CRC) samples. RESULTS: We found that Axin1 was dispensable for normal intestinal homeostasis and redundant with Axin2 for Wnt pathway down-regulation. Axin1 deficiency in intestinal epithelial cells rendered mice more susceptible to chemically induced colon carcinogenesis, but reduced dextran sulfate sodium-induced colitis by attenuating the induction of a proinflammatory program. RNA-seq analyses identified an interferon γ/T-helper1 immune program controlled by Axin1 that enhances the inflammatory response and protects against CRC. The Axin1-dependent gene expression signature was applied to human CRC samples and identified a group of patients with potential vulnerability to immune checkpoint blockade therapies. CONCLUSIONS: Our study establishes, in vivo, that Axin1 has redundant function with Axin2 for Wnt down-regulation and infers a new role for Axin1. Physiologically, Axin1 stimulates gut inflammation via an interferon γ/Th1 program that prevents tumor growth. Linked to its T-cell-mediated effect, the colonic Axin1 signature offers therapeutic perspectives for CRC.