A systematic comparison of pan-Trk immunohistochemistry assays among multiple cancer types

AIMS NTRK rearranged tumours are rare but can be successfully treated using anti-TRK-targeted therapies, making NTRK testing important for treatment choices in patients with advanced cancers. Pan-Trk immunohistochemistry (IHC) has become a valuable and affordable screening tool in many laboratories. Unfortunately, the choice of antibodies and IHC protocols to investigate biomarkers is not standardised. In this study, we compared the performance of four pan-Trk IHC methods, using three different clones, primarily in NTRK fusion-positive tumours. METHODS AND RESULTS We studied the performance of four pan-Trk IHC methods using three different clones: EPR17341 (Abcam and Ventana), EP1058Y (Abcam) and A7H6R (Cell Signaling) in 22 molecularly confirmed NTRK rearranged tumours. Additionally, selected NTRK fusion-negative tumours were further included: NTRK mutated (n = 8) and amplified (n = 15) tumours as well as NTRK fusion-negative tumours driven by other gene fusions, such as ALK, ROS1 and BCOR (n = 20), as well as salivary gland tumours (n = 16). Inter-rater agreement of three pathologists was additionally calculated, including H-score. With clone EPR17341 (Abcam in-house and ready-to-use Ventana protocol), all molecularly confirmed NTRK1-3 rearranged tumours were positively detected by immunohistochemistry, while the other clones missed NTRK2-3 rearranged tumours. For the fusion-negative cohort we found the best performance (least false-positive cases) using the clone A7H6R (Cell Signalling). CONCLUSION Given the therapeutic importance, testing for NTRK rearrangements in daily practice has become necessary and, despite IHC being a fast and affordable tool, using it in routine diagnostics is complicated and requires a high level of expertise

Effects of carbohydrate sugars and artificial sweeteners on appetite and the secretion of gastrointestinal satiety peptides

In vitro, both carbohydrate sugars and artificial sweeteners (AS) stimulate the secretion of glucagon-like peptide-1 (GLP-1). It has been suggested that the gut tastes sugars and AS through the same mechanisms as the tongue, with potential effects on gut hormone release. We investigated whether the human gut responds in the same way to AS and carbohydrate sugars, which are perceived by lingual taste as equisweet. We focused on the secretion of gastrointestinal (GI) satiety peptides in relation to appetite perception. We performed a placebo-controlled, double-blind, six-way, cross-over trial including twelve healthy subjects. On separate days, each subject received an intragastric infusion of glucose, fructose or an AS (aspartame, acesulfame K and sucralose) dissolved in 250ml of water or water only (control). In a second part, four subjects received an intragastric infusion of the non-sweet, non-metabolisable sugar analogue 2-deoxy-d-glucose. Glucose stimulated GLP-1 (P=0·002) and peptide tyrosine tyrosine (PYY; P=0·046) secretion and reduced fasting plasma ghrelin (P=0·046), whereas fructose was less effective. Both carbohydrate sugars increased satiety and fullness (albeit not significantly) compared with water. In contrast, equisweet loads of AS did not affect gastrointestinal peptide secretion with minimal effects on appetite. 2-Deoxy-d-glucose increased hunger ratings, however, with no effects on GLP-1, PYY or ghrelin. Our data demonstrate that the secretion of GLP-1, PYY and ghrelin depends on more than the detection of (1) sweetness or (2) the structural analogy to glucos

β6-Integrin Serves as a Potential Serum Marker for Diagnosis and Prognosis of Pancreatic Adenocarcinoma

INTRODUCTION Despite enormous efforts during the past decades, pancreatic adenocarcinoma (PAC) remains one of the most deleterious cancer entities. A useful biomarker for early detection or prognosis of PAC does not yet exist. The goal of our study was the characterization of β6-integrin (ITGB6) as a novel serum tumor marker for refined diagnosis and prognosis of PAC. Serum ITGB6 levels were analyzed in 3 independent PAC cohorts consisting of retrospectively and prospectively collected serum and/or (metastatic) PAC tissue specimens. METHODS Using 2 independent cohorts, we measured serum ITGB6 concentrations in 10 chronic pancreatitis patients, 10 controls, as well as in 27 (cohort 1) and 24 (cohort 2) patients with PAC, respectively. In these patients, we investigated whether ITGB6 serum levels correlate with known clinical and prognostic markers for PAC and whether they might differ between patients with PAC or benign inflammatory diseases of the pancreas. RESULTS We found that elevated serum ITGB6 levels (≥0.100 ng/mL) in patients suffering from metastasizing PAC presented an unfavorable prognostic outcome. By correlating the ITGB6 tissue expression in primary and metastatic PAC with clinical parameters, we found that positive ITGB6 expression in the tumor tissue is linked to increased serum ITGB6 levels in nonmetastatic PAC and correlates with carbohydrate antigen 19-9 and clinical outcome. DISCUSSION Our findings suggest that ITGB6 might serve as a novel serum biomarker for early diagnosis and prognosis of PAC. Given the limited specificity and sensitivity of currently used carbohydrate antigen 19-9-based assays, ITGB6 may have the potential to improve the diagnostic accuracy for PAC

ROS1 genomic rearrangements are rare actionable drivers in microsatellite stable colorectal cancer

c-Ros oncogene 1, receptor tyrosine kinase (ROS1) genomic rearrangements have been reported previously in rare cases of colorectal cancer (CRC), yet little is known about the frequency, molecular characteristics, and therapeutic vulnerabilities of ROS1-driven CRC. We analyzed a clinical dataset of 40 589 patients with CRC for ROS1 genomic rearrangements and their associated genomic characteristics (Foundation Medicine, Inc [FMI]). We moreover report the disease course and treatment response of an index patient with ROS1-rearranged metastatic CRC. ROS1 genomic rearrangements were identified in 34 (0.08%) CRC samples. GOPC-ROS1 was the most common ROS1 fusion identified (11 samples), followed by TTC28-ROS1 (3 samples). Four novel 5' gene partners of ROS1 were identified (MCM9, SRPK1, EPHA6, P4HA1). Contrary to previous reports on fusion-positive CRC, ROS1-rearrangements were found exclusively in microsatellite stable (MSS) CRCs. KRAS mutations were significantly less abundant in ROS1-rearranged vs ROS1 wild type cases. The index patient presented with chemotherapy-refractory metastatic right-sided colon cancer harboring GOPC-ROS1. Molecularly targeted treatment with crizotinib induced a rapid and sustained partial response. After 15 months on crizotinib disseminated tumor progression occurred and KRAS Q61H emerged in tissue and liquid biopsies. ROS1 rearrangements define a small, yet therapeutically actionable molecular subgroup of MSS CRC. In summary, the high prevalence of GOPC-ROS1 and noncanonical ROS1 fusions pose diagnostic challenges. We advocate NGS-based comprehensive molecular profiling of MSS CRCs that are wild type for RAS and BRAF and patient enrollment in precision trials. Keywords: ROS1 rearrangement; acquired resistance; colorectal cancer; crizotinib; molecular subgroups; precision treatmen

ROS1 genomic rearrangements are rare actionable drivers in microsatellite stable colorectal cancer.

c-Ros oncogene 1, receptor tyrosine kinase (ROS1) genomic rearrangements have been reported previously in rare cases of colorectal cancer (CRC), yet little is known about the frequency, molecular characteristics, and therapeutic vulnerabilities of ROS1-driven CRC. We analyzed a clinical dataset of 40 589 patients with CRC for ROS1 genomic rearrangements and their associated genomic characteristics (Foundation Medicine, Inc [FMI]). We moreover report the disease course and treatment response of an index patient with ROS1-rearranged metastatic CRC. ROS1 genomic rearrangements were identified in 34 (0.08%) CRC samples. GOPC-ROS1 was the most common ROS1 fusion identified (11 samples), followed by TTC28-ROS1 (3 samples). Four novel 5' gene partners of ROS1 were identified (MCM9, SRPK1, EPHA6, P4HA1). Contrary to previous reports on fusion-positive CRC, ROS1-rearrangements were found exclusively in microsatellite stable (MSS) CRCs. KRAS mutations were significantly less abundant in ROS1-rearranged vs ROS1 wild type cases. The index patient presented with chemotherapy-refractory metastatic right-sided colon cancer harboring GOPC-ROS1. Molecularly targeted treatment with crizotinib induced a rapid and sustained partial response. After 15 months on crizotinib disseminated tumor progression occurred and KRAS Q61H emerged in tissue and liquid biopsies. ROS1 rearrangements define a small, yet therapeutically actionable molecular subgroup of MSS CRC. In summary, the high prevalence of GOPC-ROS1 and noncanonical ROS1 fusions pose diagnostic challenges. We advocate NGS-based comprehensive molecular profiling of MSS CRCs that are wild type for RAS and BRAF and patient enrollment in precision trials

Vollwandresektion eines Pylorusdrüsenadenoms im proximalen Duodenum bei einem 67-jährigen Patienten mit attenuierter Polyposis coli

Background: Pyloric gland adenomas (PGAs) are very rare and underdiagnosed, mostly be founded in the stomach. Similar to colorectal adenomas they have a high risk of malignant transformation to adenocarcinoma up to 12-47 %. Endoscopic resections in the duodenum harbor a significant risk of complications. EMR is the current standard technique for treatment of duodenal non-ampullary adenomas. Complete resection rates are considerably high at about 90 %. Adverse events as bleeding was reported up to 25 %. ESD is not recommended for resection of duodenal lesions since the perforation rate may be as high as 35 %. Use of EFTR in the duodenum are limited to a single case study of 20 patients. Case: A 67 year old patient with attenuated polyposis coli presented for screening. Gastroscopy showed a 20 mm large, non-ampullary lesions in the proximal duodenum (pars I). The margins of the duodenal lesions were marked with a high-frequency (HF) probe. An integrated balloon dilatation (20 mm) of the upper esophageal sphincter and the pylorus was performed to facilitate advancing of the gastroduodenal FTRD® (Ovesco Endoscopy AG). After pulling the duodenal lesion into the cap with a grasper the FTRD clip was deployed and the lesion immediately resected with the preloaded snare. A single-shot antibiotic prophylaxis with 2 g ceftriaxone i. v. was administered during the intervention. Second-look endoscopy was scheduled 24 h after resection. The resectat showed histologically a gastric type adenoma of 18 mm in the proximal duodenum (immunohistochemistry positive for Mucin-1, Mucin-5, Mib 1). Conclusion: Herein we present the first case of duodenal EFTR in a patient with attenuated FAP and a PGA. There are currently no specific guidelines for the removal and surveillance. ASGE recommends resection and surveillance endoscopy at 3-5 years interval

Effects of carbohydrate sugars and artificial sweeteners on appetite and the secretion of gastrointestinal satiety peptides

In vitro, both carbohydrate sugars and artificial sweeteners (AS) stimulate the secretion of glucagon-like peptide-1 (GLP-1). It has been suggested that the gut tastes sugars and AS through the same mechanisms as the tongue, with potential effects on gut hormone release. We investigated whether the human gut responds in the same way to AS and carbohydrate sugars, which are perceived by lingual taste as equisweet. We focused on the secretion of gastrointestinal (GI) satiety peptides in relation to appetite perception. We performed a placebo-controlled, double-blind, six-way, cross-over trial including twelve healthy subjects. On separate days, each subject received an intragastric infusion of glucose, fructose or an AS (aspartame, acesulfame K and sucralose) dissolved in 250 ml of water or water only (control). In a second part, four subjects received an intragastric infusion of the non-sweet, non-metabolisable sugar analogue 2-deoxy-d-glucose. Glucose stimulated GLP-1 (P = 0·002) and peptide tyrosine tyrosine (PYY; P = 0·046) secretion and reduced fasting plasma ghrelin (P = 0·046), whereas fructose was less effective. Both carbohydrate sugars increased satiety and fullness (albeit not significantly) compared with water. In contrast, equisweet loads of AS did not affect gastrointestinal peptide secretion with minimal effects on appetite. 2-Deoxy-d-glucose increased hunger ratings, however, with no effects on GLP-1, PYY or ghrelin. Our data demonstrate that the secretion of GLP-1, PYY and ghrelin depends on more than the detection of (1) sweetness or (2) the structural analogy to glucose

Direct intraoperative assessment of total mesorectal excision specimens by expert pathologists in patients with very low rectal cancer prevents unnecessary abdominoperineal resections

PURPOSE In patients with low rectal cancer, the intraoperative assessment of sufficient distal resection margins can be challenging. The assessment determines whether reconstruction can be performed or whether permanent colostomy is required. The goal of the present study was to evaluate intraoperative assessment of the total mesorectal excision (TME) specimen during an interruption of the operation. METHODS The intraoperative strategy of eight patients with low rectal cancer was evaluated. In all cases, intraoperative pathological assessment of the TME specimen by an expert pathologist together with the surgeon was performed. Assessment of the distance of the tumor to the resection margin was measured macroscopically as well as microscopically. RESULTS All patients underwent neoadjuvant chemoradiation. The tumor was located at an average 4.8 ± 1.4 cm from the anal verge. In all cases, preoperative MRI revealed mrT3 tumors. The intraoperative assessment showed a median distal resection margin of 10 mm (2-15 mm). In six patients, sufficient margins allowed for reconstruction while in two patients APR was needed. In three patients (37.5%), the pathological assessment changed the operative strategy: In one patient APR could be avoided while two patients required APR instead of the anticipated TME. CONCLUSION The intraoperative assessment of the TME specimen by an expert pathologist together with the surgeon is a valuable tool to avoid unnecessary APR or R1 resections. We therefore suggest routine intraoperative pathological assessment in all operations for borderline low rectal cancers