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.

Recurrent MALAT1-GLI1 oncogenic fusion and GLI1 up-regulation define a subset of plexiform fibromyxoma.

Plexiform fibromyxomas are rare neoplasms, being officially recognized as a distinct entity among benign mesenchymal gastric tumours in the 2010 WHO Classification of Tumours of the Digestive System. Characteristically, these tumours have a multinodular/plexiform growth pattern, and histologically contain variably cellular areas of bland myofibroblastic-type spindle cells embedded in an abundant myxoid matrix, rich in capillary-type vessels. As yet, the molecular and/or genetic features of these tumours are unknown. Here we describe a recurrent translocation, t(11;12)(q11;q13), involving the long non-coding gene metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) and the gene glioma-associated oncogene homologue 1 (GLI1) in a subgroup of these tumours. The presence of the fusion transcript in our index case was confirmed using polymerase chain reaction (PCR) on genomic DNA, followed by Sanger sequencing. We showed that the truncated GLI1 protein is overexpressed and retains its capacity to transcriptionally activate its target genes. A specific FISH assay was developed to detect the novel MALAT1-GLI1 translocation in formalin-fixed, paraffin-embedded (FFPE) material. This resulted in the identification of two additional cases with this fusion and two cases with polysomy of the GLI1 gene. Finally, immunohistochemistry revealed that the GLI1 protein is exclusively overexpressed in those cases that harbour GLI1/12q13 genomic alterations. In conclusion, overexpression of GLI1 through a recurrent MALAT1-GLI1 translocation or GLI1 up-regulation delineates a pathogenically distinct subgroup of plexiform fibromyxomas with activation of the Sonic Hedgehog signalling pathway. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Myeloid HIF-1 is protective in Helicobacter pylori-mediated gastritis.

Helicobacter pylori infection triggers chronic inflammation of the gastric mucosa that may progress to gastric cancer. The hypoxia-inducible factors (HIFs) are the central mediators of cellular adaptation to low oxygen levels (hypoxia), but they have emerged recently as major transcriptional regulators of immunity and inflammation. No studies have investigated whether H. pylori affects HIF signaling in immune cells and a potential role for HIF in H. pylori-mediated gastritis. HIF-1 and HIF-2 expression was examined in human H. pylori-positive gastritis biopsies. Subsequent experiments were performed in naive and polarized bone marrow-derived macrophages from wild-type (WT) and myeloid HIF-1α-null mice (HIF-1(Δmyel)). WT and HIF-1(Δmyel) mice were inoculated with H. pylori by oral gavage and sacrificed 6 mo postinfection. HIF-1 was specifically expressed in macrophages of human H. pylori-positive gastritis biopsies. Macrophage HIF-1 strongly contributed to the induction of proinflammatory genes (IL-6, IL-1ß) and inducible NO synthase in response to H. pylori. HIF-2 expression and markers of M2 macrophage differentiation were decreased in response to H. pylori. HIF-1(Δmyel) mice inoculated with H. pylori for 6 mo presented with a similar bacterial colonization than WT mice but, surprisingly, a global increase of inflammation, leading to a worsening of the gastritis, measured by an increased epithelial cell proliferation. In conclusion, myeloid HIF-1 is protective in H. pylori-mediated gastritis, pointing to the complex counterbalancing roles of innate immune and inflammatory phenotypes in driving this pathology.

Resection of Late Pulmonary Metastases from Pancreatic Adenocarcinoma: Is Surgery an Option?

Patients with recurrences from pancreas adenocarcinoma have a poor survival rate despite new chemotherapy treatment options. Recurrences are mainly hepatic metastases or peritoneal dissemination and surgical treatment is not recommended. Late and single metachronous pulmonary recurrences are uncommon and may mimic primary lung carcinoma. We report two patients with late and unique pulmonary metastasis from pancreatic cancer. These two patients underwent surgical resection; three and five years later, they did not experience recurrences. Cases called for a surgical approach in late and unique pulmonary metastases from pancreatic cancer, and paved the way for a prolonged chemotherapy free period.

Splenic vein tumor thrombosis is a major prognostic factor in distal pancreatic adenocarcinoma.

BACKGROUND: The prognostic value of splenic vessel involvement in distal pancreatic adenocarcinoma remains controversial. The aim of the study was to assess its prognostic relevance in a large multicenter cohort. METHODS: Patients who underwent pancreatosplenectomy for distal pancreatic adenocarcinoma were identified from 5 pancreatic surgical centers. A pathology review of the surgical specimens was performed to assess splenic vessel involvement, defined as invasion of the vessel's adventitia or deeper, and confirm the presence of splenic vein tumor thrombosis. Prognostic factors associated with overall and relapse-free survival were evaluated. RESULTS: 149 patients underwent upfront surgery. Splenic vascular involvement was observed in 69 of them (46.3%). A parietal infiltration of the splenic artery or splenic vein was observed in 26 (17.5%) and 49 patients (32.8%), respectively. A pathologic tumor thrombosis of the splenic vein was identified in 22 patients (14.8%) and associated with larger tumors (>20 mm) (P = .023), more perineural (P = .017), and lymphovascular (P = .002) invasion, and more positive lymph node (P = .001). After a median follow-up of 50.8 months (95% confidence interval: 44.3-57.3), the cumulative 5-year overall and relapse-free survival were 46.2% and 33%, respectively. In multivariate analysis, in addition to lymph node metastasis (hazard ratio = 1.8; 95% confidence interval [1.1-3.1]; P = .023) and perineural invasion (hazard ratio = 3.5; 95% confidence interval [1.3-9.7]; P = .016), presence of splenic vein tumor thrombosis was the only splenic vascular involvement that affected independently the overall survival (HR = 2.3; 95% confidence interval [ 1.3-4.3]; P = .006). CONCLUSION: In resectable distal pancreatic adenocarcinoma, a pathologic tumor thrombosis of the splenic vein is an independent prognostic factor of overall survival. To define the perioperative oncological strategy, a preoperative evaluation of splenic vessel involvement and thrombosis is needed.

Diagnostic Yield of Repeat Endoscopic Ultrasound-Guided Fine Needle Biopsy for Solid Pancreatic Lesions.

PATIENTS AND METHODS: we performed a retrospective case-control study, including cases with repeat EUS FNB for a solid pancreatic lesion, matched on a 1:2 ratio on age, sex, tumor location and presence of chronic pancreatitis with cases diagnosed on the first EUS FNB. RESULTS: thirty-four cases and 68 controls were included in the analysis. Diagnostic accuracies were 80% and 88% in the repeat and single EUS FNB groups, respectively (p = 0.824). The second EUS FNB had a sensitivity of 80%, a specificity of 75%, a positive predictive value of 96%, and a negative predictive value of 33%. Of the 34 patients in the repeat EUS FNB group, 25 (74%) had a positive diagnosis with the second EUS FNB, 4 (12%) after surgery due to a second negative EUS FNB, 4 (12%) during clinical follow-up, and 1 (3%) after a third EUS FNB. Of the 25 patients diagnosed on the repeat EUS FNB, 17 (68%) had pancreatic adenocarcinomas, 2 (8%) neuroendocrine tumors, 2 (8%) other autoimmune pancreatitis, 2 (8%) chronic pancreatitis nodules, 1 (4%) renal cancer metastasis, and 1 (4%) other malignant diagnostic. There were no complications reported after the second EUS FNB in this study. CONCLUSION: repeat EUS FNB made a diagnosis in three fourths of patients with solid pancreatic lesions and a first negative EUS FNB, with 26% of benign lesions. This supports the repetition of EUS FNB sampling in this clinical situation.

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.

Endoscopic ultrasound efficacy in staging gastric linitis plastica lesion: a retrospective multicentric French study.

BACKGROUND: Endoscopic ultrasound (EUS) is a key imaging technique in gastric cancer (GC). The aim of this study was to evaluate the performance of EUS in the staging of parietal and lymph node involvement in linitis plastica (LP) compared to "classical" GC. METHODS: A retrospective multicentric French study was conducted on patients with no metastatic LP and operated by gastrectomy. A 2/1 matching based on pTNM stage and center was performed with GC. RESULTS: Forty-three patients were included, sixteen patients in the LP group and 27 in the control group. Sensitivity and specificity of EUS for diagnosis of T3-T4 parietal invasion were 77% and 100% respectively in the LP group and 89% and 56% respectively in the control group. Sensitivity and specificity of EUS for diagnosis of lymph node involvement were 73% and 80%, respectively in the LP group and 88% and 50%, respectively in the control group. Patients from LP group had significantly more advanced histological lesion, and frequent undiagnosed peritoneal carcinomatosis. CONCLUSIONS: This study evaluated for the first time in a European population, the preoperative EUS performance in LP. Our study identified a similar sensitivity and specificity of the EUS in LP compared to "classical" GC paving for a broader use of EUS in preoperative settings.

Combined 68Ga-DOTATOC and 18F-FDG PET Predicts a Double Component With Different Grade of a Pancreatic Neuroendocrine Tumor in a Patient With Multiple Endocrine Neoplasia Type 1.

Managing decisions of pancreatic neuroendocrine tumors (pNETs) can be challenging because of different clinical presentations and prognosis. A 31-year-old woman with multiple endocrine neoplasia type 1, including a suspicious pNET, was assessed with Ga-DOTATOC and F-FDG PET. A high Ga-DOTATOC uptake was visualized in the entire pNET, whereas a high F-FDG PET uptake was present only in the upper part of the tumor. After surgery, pathology confirmed the pNET with a double component: an upper grade 2 with a Ki67 of 11% with the high F-FDG PET uptake, and a lower grade 1 with a Ki67 of 2%. Combined Ga-DOTATOC/F-FDG PET predicts the grade in heterogeneous pNETs.

"Chronic Disseminated Aspergillosis," a Novel Fungal Immune Reconstitution Inflammatory Syndrome.

We report a case of chronic hepatosplenic aspergillosis following immune reconstitution complicating colic aspergillosis in an AIDS patient with multicentric Castleman disease. Symptoms mimicked the clinical presentation of chronic disseminated candidiasis and responded to corticosteroid. This emerging entity enlarges the spectrum of fungal immune reconstitution inflammatory syndrome in the HIV setting.

Tumor-infiltrating lymphocytes in colorectal cancers with microsatellite instability are correlated with the number and spectrum of frameshift mutations.

Colorectal cancers with microsatellite instability are characterized by an important density of tumor-infiltrating lymphocytes and a good prognosis. Microsatellite instability results from the inactivation of the DNA mismatch repair system and induces secondary somatic frameshift mutations within target genes harboring repeat sequences in their coding frame. By disrupting the open reading frame, frameshift mutations can result in the appearance of potentially immunogenic neopeptides. To determine the frameshift mutations inducing a T-cell response during the development of a tumor with microsatellite instability, we studied in 61 colorectal cancer patients with microsatellite instability, using a fluorescent multiplex PCR comparative analysis, the relative frequency of frameshift mutations within 19 target genes and analyzed the correlation of these frameshift mutations with the density of CD3+ tumor-infiltrating lymphocytes. The four most frequently mutated genes were ACVR2 (92%), TAF1B (84%), ASTE1/HT001 (80%) and TGFBR2 (77%). The vast majority (95%) of the tumors exhibited at least three frameshift mutations, and the number of frameshift mutations was associated with tumor progression (TNM stage, wall invasion and tumor diameter). Tumor-infiltrating lymphocyte density was associated with the overall number of frameshift mutations and with the presence of frameshift mutations within two target genes, namely ASTE1/HT001 and PTEN. These results strongly argue for the clinical relevance of immunotherapy of colorectal cancers with microsatellite instability.

EUS-guided pancreatic radiofrequency ablation: preclinical comparison of two currently available devices in a pig model.

Introduction Two devices are currently available to perform pancreatic radiofrequency ablation (P-RFA). Potential clinical indications might extend from the treatment of pancreatic cystic lesions to ablation of small pancreatic solid lesions or cytoreduction of advanced pancreatic adenocarcinomas, but more preclinical data from animal models are needed to optimize P-RFA operation. Methods P-RFA was performed under laparotomy and under endoscopic ultrasonographic guidance on the liver and pancreatic parenchyma of four live swine using the Habib EUS RFA (EMcision Ltd, London, UK) probe and the EUS-RA needle (Taewoong Medical, Gyeonggi-do, South Korea). Animals were sacrificed 2 hours after the procedure. Influence of tuning ablation time and power on tissue ablation were studied by histopathological assessment of the maximal depth of tissue damage on representative slides for each P-RFA shot. Results The Habib probe in the liver parenchyma resulted in tissue necrosis increasing within the range of 1.9 ±â€Š0.5 mm (Power = 8 W, Time = 120 s) to 2.5 ±â€Š1 mm (Power = 10 W, Time = 120 s). In the pancreatic parenchyma, tissue damage ranged from 3.1 ±â€Š0.4 mm (Power = 8 W, Time = 120 s) to 2.3 ±â€Š0.1 mm (12 W, 120 s) in depth. EUS RFA ablation of the liver parenchyma resulted in tissue damage ranging from 1.6 ±â€Š0.2 mm (Power = 30 W, Time = 11 s) to 1.5 ±â€Š0.1 mm (Power = 70 W, Time = 9 s); in the pancreas, ablation depth ranged from 3.6 ±â€Š0.5 mm (Power = 30 W, Time = 15 s) to 3.8 ±â€Š0.4 mm (Power = 70 W, Time = 11 s). Conclusion Both devices allow for effective ablation of pancreatic tissue within 1.5 to 3.8 mm around the RFA electrode, with a modest influence of tuning power settings. Specific settings are recommended for each of the devices studied. Ablation of larger lesions may require more repeat P-RFA shots in different locations rather than a simple modulation of ablation parameters.

McCune Albright syndrome is a genetic predisposition to intraductal papillary and mucinous neoplasms of the pancreas associated pancreatic cancer in relation with GNAS somatic mutation - a case report.

RATIONALE: Intraductal papillary and mucinous neoplasms of the pancreas (IPMN) are preneoplastic lesions diagnosed with an increasing incidence. Recently, several groups have described, in up to 70% of IPMN, activating mutations of the G-protein alpha stimulatory sub-unit (Gsα subunit) gene (GNAS). GNAS-activating somatic, post-zygotic, mutations are also associated with McCune-Albright syndrome (MCAS) characterized by fibrous dysplasia, precocious puberty, and café-au-lait spots. PATIENT CONCERNS: We herein report a patient with McCune Albright Syndrome that presented with malignant IPMN and underwent pancreatic resection. DIAGNOSES AND INTERVENTIONS: Leucocyte and duodenum juice DNA analysis, endoscopically collected from secretin-stimulated pancreatic juice revealed the same (GNAS) activating mutation also found in the invasive pancreatic colloid adenocarcinoma arising from intestinal subtype IPMN. OUTCOMES: Thirty months after surgery, the patient was alive with recurrence (bone only metastasis). LESSONS: In this observation, we show that MCAS should be view as a new genetic predisposition to IPMN associated pancreatic cancer, and consequently a targeted screening in this high-risk population might be proposed.

Ciliated hepatic foregut cyst discovered after kidney transplantation in a hepatitis C virus-infected patient: a report of one case and review of the literature.

Ciliated hepatic foregut cyst (CHFC) is a rare liver lesion derived from the embryonic foregut. In most cases, CHFC remains asymptomatic but some malignant transformations have been reported. Typical imaging features usually lead to diagnosis using ultrasonography, computed tomography scan examination or MRI. When the diagnosis remains uncertain, a fine needle aspiration with cytology is appropriate. The presence of ciliated epithelial cells with hepatocytes and mucous cells on aspiration cytology is enough to assess the diagnosis. Surgery is recommended when there is uncertain diagnosis or malignant lesion suspicion. We report herein, the case of a CHFC discovered in a hepatitis C virus-infected patient following a renal transplantation. To eliminate a lymphoma or a liver tumor arising because of patient's immunosuppression status, a surgical resection of the lesion was performed. The surgical outcome was uneventful. Regarding this case, embryogenesis, morphological characteristics and treatment of the lesions are discussed.

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

BACKGROUND: Computed tomography (CT) scan is a key imaging technique in the staging of gastric adenocarcinoma and therapeutic management of patients. The aim of this study was to evaluate the performance of CT scan in the staging of parietal and metastatic invasion in gastric linitis plastica group. METHODS: A retrospective multicentric French study was conducted from January 2006 to December 2015 on patients with no metastatic gastric linitis plastica and operated by gastrec-tomy. A 2/1 matching based on pTNM stage and center was performed. RESULTS: Fifty patients were included in the linitis plastica group and 100 in the control group. Patients from the linitis group were significantly different from those from the control group with a lower age at diagnosis, a more advanced histological lesion, a more frequent undiagnosed peritoneal carcinomatosis, and a higher risk of R1 resection. Sensitivity and specificity of CT scan for the diagnosis of lymph node involvement were 44% and 75%, respectively, in the linitis plastica group and 55% and 60%, respectively, in the control group. The sensitivity and specificity of CT scan for the T3-T4 parietal invasion were 26% and 100%, respectively, in the linitis group and 40% and 72%, respectively, in the control group. CONCLUSION: CT scan has an equal sensitivity and specificity for the evaluation of lymph node and parietal involvement in gastric adenocarcinoma, including linitis plastica. CT scan remains the cornerstone of preoperative evaluation in gastric adenocarcinoma, including linitis plastica. However, CT presents a lack of sensitivity to diagnose low-volume peritoneal carcinomatosis.

Impact of a dedicated multidisciplinary meeting on the management of superficial cancers of the digestive tract.

Background The recent development of endoscopic resection for superficial gastrointestinal cancers could justify the need for a dedicated oncological multidisciplinary meeting (MDM). The aim of our study was to evaluate the impact of the dedicated MDM on the management of superficial cancers of the digestive tract. Methods A dedicated MDM was developed at our tertiary referral center. A retrospective review of the MDM conclusions for all patients referred from March 2015 to March 2017 was performed. Outcomes measurements were the outcomes of endoscopic resection, and the concordance rate between the MDM recommendations, European Society of Gastrointestinal Endoscopy (ESGE) guidelines, and final patient management. Results In total, 153 patients with a median age of 69 years were included. Half of the patients had major comorbidities. The mean lesion size was 25 mm, and R0 and curative resection rate were 73.9 % and 56.9 %, respectively. Forty-three patients had an indication for surgery after endoscopic resection. The concordance rate between ESGE guidelines and MDM recommendation was 92.2 %, and 12 patients did not receive the treatment recommended due to comorbidities. Conclusion A MDM dedicated to superficial tumors helped tailor the ESGE guidelines to each patient in order to avoid unnecessary surgery.

Optimization of the generator settings for endobiliary radiofrequency ablation.

AIM: To determine the optimal generator settings for endobiliary radiofrequency ablation. METHODS: Endobiliary radiofrequency ablation was performed in live swine on the ampulla of Vater, the common bile duct and in the hepatic parenchyma. Radiofrequency ablation time, "effect", and power were allowed to vary. The animals were sacrificed two hours after the procedure. Histopathological assessment of the depth of the thermal lesions was performed. RESULTS: Twenty-five radiofrequency bursts were applied in three swine. In the ampulla of Vater (n = 3), necrosis of the duodenal wall was observed starting with an effect set at 8, power output set at 10 W, and a 30 s shot duration, whereas superficial mucosal damage of up to 350 µm in depth was recorded for an effect set at 8, power output set at 6 W and a 30 s shot duration. In the common bile duct (n = 4), a 1070 µm, safe and efficient ablation was obtained for an effect set at 8, a power output of 8 W, and an ablation time of 30 s. Within the hepatic parenchyma (n = 18), the depth of tissue damage varied from 1620 µm (effect = 8, power = 10 W, ablation time = 15 s) to 4480 µm (effect = 8, power = 8 W, ablation time = 90 s). CONCLUSION: The duration of the catheter application appeared to be the most important parameter influencing the depth of the thermal injury during endobiliary radiofrequency ablation. In healthy swine, the currently recommended settings of the generator may induce severe, supratherapeutic tissue damage in the biliary tree, especially in the high-risk area of the ampulla of Vater.

A new device to expedite endoscopic submucosal dissection procedures: a randomized animal study of efficacy and safety (with videos).

BACKGROUND AND STUDY AIMS: Endoscopic submucosal dissection (ESD) is a recognized method for the curative treatment of superficial neoplasia, but its use is limited by lengthy procedures and the lack of versatility of existing knives. We developed a prototype ESD device with the ability to work as a needle, hook, or "scythe." This new device was compared to regular ESD knives in a randomized animal study. PATIENTS AND METHODS: Eight pigs underwent two gastric ESD procedures each, similar in size and difficulty, one with a regular ESD device and the other with the new device. The order and location of each ESD, as well as the performing operator, were randomized. Primary judgment criterion was safety of procedures. Overall and submucosal dissection procedure times were measured. Time-to-surface ratios were measured and estimated for ESDs larger than those performed. Histopathology of the resected tissue and remaining stomach was done after each experiment. RESULTS: No complications were observed throughout the study and all resections were completed en-bloc and uneventfully. The submucosal extension of resections was similar with both the standard and the new devices. A comparison of time-consumption between groups did not show statistically significant differences, but a dramatic reduction of procedure duration was observed in some procedures with the new device; based on observed data, a potential time-saving of up to 66 % was anticipated, with a relatively short learning curve. CONCLUSIONS: This new versatile device proved to be as safe as regular ESD knives, and seems likely to help reduce the duration of the procedure.