These are the recent articles on Pancreatobiliary Pathology:
To see all journal watch articles please visit: http://pbpath.org/journal-watch-upcoming-issue/
New Pancreas Articles
- A preclinical trial and molecularly-annotated patient cohort identify predictive biomarkers in homologous recombination deficient pancreatic cancer
Clinical cancer research : an official journal of the American Association for Cancer Research 2020 Aug;():
PURPOSE: Pancreatic ductal adenocarcinoma (PDAC) arising in patients with a germline BRCA1 or BRCA2 (gBRCA) mutation may be sensitive to platinums and poly(adenosine diphosphate-ribose) polymerase inhibitors (PARPi). However, treatment stratification based on gBRCA mutational status alone is associated with heterogeneous responses.
EXPERIMENTAL DESIGN: We performed a 7-arm preclinical trial consisting of 471 mice, representing 12 unique PDAC patient-derived xenografts, of which 9 were gBRCA-mutated. From 179 patients whose PDAC was whole genome and transcriptome sequenced, we identified 21 cases with homologous recombination deficiency (HRD), and investigated prognostic biomarkers.
RESULTS: We found that biallelic inactivation of BRCA1/BRCA2 is associated with genomic hallmarks of HRD and required for cisplatin and talazoparib (PARPi) sensitivity. However, HRD genomic hallmarks persisted in xenografts despite the emergence of therapy resistance, indicating the presence of a genomic scar. We identified tumour polyploidy and a low Ki67 index as predictors of poor cisplatin and talazoparib response. In HRD PDAC patients, tumour polyploidy and a basal-like transcriptomic subtype were independent predictors of shorter survival. To facilitate clinical assignment of transcriptomic subtype, we developed a novel pragmatic two-marker assay (GATA6:KRT17).
CONCLUSIONS: In summary, we propose a predictive and prognostic model of gBRCA-mutated PDAC based on HRD genomic hallmarks, Ki67 index, tumour ploidy and transcriptomic subtype.
- CDK1/2/5 inhibition overcomes IFNG-mediated adaptive immune resistance in pancreatic cancer
Gut 2020 Aug;():
OBJECTIVE: Adaptive immune resistance mediated by the cytokine interferon gamma (IFNG) still constitutes a major problem in cancer immunotherapy. We develop strategies for overcoming IFNG-mediated adaptive immune resistance in pancreatic ductal adenocarcinoma cancer (PDAC).
DESIGN: We screened 429 kinase inhibitors for blocking IFNG-induced immune checkpoint (indoleamine 2,3-dioxygenase 1 (IDO1) and CD274) expression in a human PDAC cell line. We evaluated the ability of the cyclin-dependent kinase (CDK) inhibitor dinaciclib to block IFNG-induced IDO1 and CD274 expression in 24 human and mouse cancer cell lines as well as in primary cancer cells from patients with PDAC or ovarian carcinoma. We tested the effects of dinaciclib on IFNG-induced signal transducer and activator of transcription 1 activation and immunological cell death, and investigated the potential utility of dinaciclib in combination with IFNG for pancreatic cancer therapy in vivo, and compared gene expression levels between human cancer tissues with patient survival times using the Cancer Genome Atlas datasets.
RESULTS: Pharmacological (using dinaciclib) or genetic (using shRNA or siRNA) inactivation of CDK1/2/5 not only blocks JUN-dependent immune checkpoint expression, but also triggers histone-dependent immunogenic cell death in immortalised or primary cancer cells in response to IFNG. This dual mechanism turns an immunologically 'cold' tumour microenvironment into a 'hot' one, dramatically improving overall survival rates in mouse pancreatic tumour models (subcutaneous, orthotopic and transgenic models). The abnormal expression of CDK1/2/5 and IDO1 was associated with poor patient survival in several cancer types, including PDAC.
CONCLUSION: CDK1/2/5 kinase activity is essential for IFNG-mediated cancer immunoevasion. CDK1/2/5 inhibition by dinaciclib provides a novel strategy to overcome IFNG-triggered acquired resistance in pancreatic tumour immunity.
- Diagnosis of pancreatic solid pseudopapillary neoplasms using cell blocks and immunohistochemical evaluation of endoscopic ultrasound-guided fine-needle aspiration biopsy specimens
Cytopathology : official journal of the British Society for Clinical Cytology 2020 Aug;():
BACKGROUND AND AIMS: Preoperative diagnostic imaging of pancreatic solid pseudopapillary neoplasms (SPN) is challenging. A few studies have investigated the role of endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) for the diagnosis of SPN. We investigated the diagnostic yield of cell blocks and immunohistochemistry (IHC) for SPN using EUS-FNA specimens without cytological evaluation.
PATIENTS AND METHODS: We retrospectively analyzed the histopathology records of patients with suspected SPN, who underwent EUS-FNA biopsy between January 1997 and January 2020. Diagnosis based on cell blocks (hematoxylin-eosin staining with complementary IHC) was compared with the definitive surgical diagnosis.
RESULTS: This study included 25 patients (24 were women). Patients' mean age was 33.7 years (range 12-78 years). The most common symptom was abdominal pain. SPN was an incidental finding in 52% of the patients. The mean lesion size was 4.3 cm (range 1.2-11.4 cm), and the most common endosonographic features included solid-cystic (56%) or solid (40%) tumors. Final diagnoses included SPNs (23) and non-functioning neuroendocrine tumors (2). The overall accuracy of EUS-FNA was 80%. Tumor cells showed immunopositivity for beta-catenin, CD10, CD99, and progesterone receptor (PR) in 93.7%, 87.5%, 83.3%, and 66.6% of patients, respectively. No SPN showed immunopositivity for chromogranin A.
CONCLUSIONS: Intention-to-diagnose analysis showed that the diagnostic accuracy of EUS-FNA for SPNs using cell blocks and complementary IHC without cytological evaluation was fairly good. Evaluation of beta-catenin, CD 10, CD99, and PR expression must be included in the IHC panel for diagnostic confirmation of SPNs using EUS-FNA biopsy specimens.
- Effects of Diet versus Gastric Bypass on Metabolic Function in Diabetes
The New England journal of medicine 2020 Aug;383(8):721-732
BACKGROUND: Some studies have suggested that in people with type 2 diabetes, Roux-en-Y gastric bypass has therapeutic effects on metabolic function that are independent of weight loss.
METHODS: We evaluated metabolic regulators of glucose homeostasis before and after matched (approximately 18%) weight loss induced by gastric bypass (surgery group) or diet alone (diet group) in 22 patients with obesity and diabetes. The primary outcome was the change in hepatic insulin sensitivity, assessed by infusion of insulin at low rates (stages 1 and 2 of a 3-stage hyperinsulinemic euglycemic pancreatic clamp). Secondary outcomes were changes in muscle insulin sensitivity, beta-cell function, and 24-hour plasma glucose and insulin profiles.
RESULTS: Weight loss was associated with increases in mean suppression of glucose production from baseline, by 7.04 μmol per kilogram of fat-free mass per minute (95% confidence interval [CI], 4.74 to 9.33) in the diet group and by 7.02 μmol per kilogram of fat-free mass per minute (95% CI, 3.21 to 10.84) in the surgery group during clamp stage 1, and by 5.39 (95% CI, 2.44 to 8.34) and 5.37 (95% CI, 2.41 to 8.33) μmol per kilogram of fat-free mass per minute in the two groups, respectively, during clamp stage 2; there were no significant differences between the groups. Weight loss was associated with increased insulin-stimulated glucose disposal, from 30.5±15.9 to 61.6±13.0 μmol per kilogram of fat-free mass per minute in the diet group and from 29.4±12.6 to 54.5±10.4 μmol per kilogram of fat-free mass per minute in the surgery group; there was no significant difference between the groups. Weight loss increased beta-cell function (insulin secretion relative to insulin sensitivity) by 1.83 units (95% CI, 1.22 to 2.44) in the diet group and by 1.11 units (95% CI, 0.08 to 2.15) in the surgery group, with no significant difference between the groups, and it decreased the areas under the curve for 24-hour plasma glucose and insulin levels in both groups, with no significant difference between the groups. No major complications occurred in either group.
CONCLUSIONS: In this study involving patients with obesity and type 2 diabetes, the metabolic benefits of gastric bypass surgery and diet were similar and were apparently related to weight loss itself, with no evident clinically important effects independent of weight loss. (Funded by the National Institutes of Health and others; ClinicalTrials.gov number, NCT02207777.).
- Clinical Routine Application of the Second-generation Neuroendocrine Markers ISL1, INSM1, and Secretagogin in Neuroendocrine Neoplasia: Staining Outcomes and Potential Clues for Determining Tumor Origin
Endocrine pathology 2020 Aug;():
Neuroendocrine neoplasms (NENs) have traditionally been identified via expression of proteins associated to the regulation of secretory vesicles and granules. We report the clinical usage of the “second-generation” proteins ISL LIM homeobox 1 (ISL1), INSM transcriptional repressor 1 (INSM1), and secretagogin (SECG) as immunohistochemical markers of neuroendocrine differentiation since their introduction in clinical routine and compare the results with the established proteins chromogranin A (CGA) and synaptophysin (SYP). In total, 161 tumors, including 139 NENs and 22 “non-NENs” (unrelated tumors with an initial suspicion of NEN), were informatively stained for ISL1, and subsets were also interrogated for INSM1 and/or SECG. Diffuse or focal positive immunoreactivity was noted for ISL1 in 91/139 NENs (65%) and in 6/22 (27%) non-NENs, for INSM1 in 76/85 NENs (89%) and in 2/5 (40%) non-NENs, and for SECG in 49 out of 64 NENs (77%) and in 0/5 non-NENs (0%). Generally, ISL1, INSM1, and SECG exhibited sensitivities in line with or slightly below that of CGA and SYP-largely attributable to tissue-specific patterns regarding tumoral origin. Moreover, for pancreatic and small intestinal NENs, the two largest subgroups, ISL1 staining results were consistent irrespectively of tumor source and WHO grade. We verify previously suggested immunohistochemical schemes of neuroendocrine markers of first- and second-generations to facilitate the diagnostic process for NENs and confirm that the second-generation neuroendocrine markers display tissue-specific patterns. We therefore recommend their implementation in tertiary endocrine pathology centers, not least to aid in the identification of primary tumors when analyzing metastases.
- Left-sided portal hypertension caused by peripancreatic lymph node tuberculosis misdiagnosed as pancreatic cancer: a case report and literature review
BMC gastroenterology 2020 Aug;20(1):276
BACKGROUND: Left-sided portal hypertension (LSPH) is an extremely rare clinical syndrome, and it is the only form of curable portal hypertension. It is primarily caused by pancreatic disease, and is associated with complications that cause spleen vein compression. Specific symptoms are often lacking, rendering it difficult to diagnose. Splenectomy is the main treatment for cases complicated by variceal bleeding, and the effects of treatment primarily depend on the condition of the primary disease.
CASE PRESENTATION: The patient was a 29-year-old woman who was admitted to the hospital for repeated hematemesis and black stool. She had been misdiagnosed with pancreatic cancer 7 years prior. Combined imaging and endoscopic examination indicated varicose gastric fundus veins, a pancreatic mass, and enlarged peripancreatic lymph nodes. Laboratory investigations revealed reduced erythrocyte, platelet, and leukocyte counts, the interferon gamma release assay was positive, and liver function was normal. Abdominal exploration, splenectomy, varicose vein dissection, and lesion resection were performed via laparotomy. Postoperative biopsy analysis confirmed the diagnosis of lymph node tuberculosis. Based on the above-described factors, LSPH caused by peripancreatic lymph node tuberculosis was a diagnosed.
CONCLUSIONS: Herein we describe the first reported case of LSPH caused by peripancreatic lymph node tuberculosis. When left portal hypertension occurs simultaneously, peripancreatic lymph node tuberculosis is often misdiagnosed as pancreatic cancer. Further studies are necessary to develop a more favorable diagnostic method for pancreas masses and more advantageous therapy for LSPH, especially in cases caused by mechanical compression.
New GallBladder Articles
- Post-mortem viral dynamics and tropism in COVID-19 patients in correlation with organ damage
Virchows Archiv : an international journal of pathology 2020 Aug;():
The persistence of SARS-CoV-2 after death of infected individuals is unclear. The aim of this study was to investigate the presence of SARS-CoV-2 RNA in different organs in correlation with tissue damage and post-mortem viral dynamics in COVID-19 deceased. Twenty-eight patients (17 males, 11 females; age 66-96 years; mean 82.9, median 82.5 years) diagnosed with COVID-19 were studied. Swabs were taken post-mortem during autopsy (N = 19) from the throat, both lungs, intestine, gallbladder, and brain or without autopsy (N = 9) only from the throat. Selective amplification of target nucleic acid from the samples was achieved by using primers for ORF1a/b non-structural region and the structural protein envelope E-gene of the virus. The results of 125 post-mortem and 47 ante-mortem swabs were presented as cycle threshold (Ct) values and categorized as strong, moderate, and weak. Viral RNA was detected more frequently in the lungs and throat than in the intestine. Blood, bile, and the brain were negative. Consecutive throat swabs were positive up to 128 h after death without significant increase of Ct values. All lungs showed diffuse alveolar damage, thrombosis, and infarction and less frequently bronchopneumonia irrespective of Ct values. In 30% the intestine revealed focal ischemic changes. Nucleocapsid protein of SARS-CoV-2 was detected by immunohistochemistry in bronchial and intestinal epithelium, bronchial glands, and pneumocytes. In conclusion, viral RNA is still present several days after death, most frequently in the respiratory tract and associated with severe and fatal organ damage. Potential infectivity cannot be ruled out post-mortem.
New BileDuct Articles
Today there is no new Bile Duct Article.
New Ampulla Articles
Today there is no new Ampulla Article.
To see all journal watch articles please visit: http://pbpath.org/journal-watch-upcoming-issue/