Recent Articles on Pancreatobiliary #Pathology – 2020-07-24

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


  • CPA1 and REG1a as New Markers for Pancreatic Acinar Cell Carcinoma

Human pathology 2020 Jul;():

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=32702400

Acinar cell carcinoma (ACC) is a rare tumor that differentiates towards pancreatic acinar cells and shows evidence of pancreatic enzyme production. Mixed acinar-neuroendocrine carcinoma (MANC) is defined as having more than 30% of both acinar and neuroendocrine cell types by immunohistochemistry. Trypsin is currently the most commonly used stain for acinar differentiation. In this study, we investigate the utility of two novel markers, carboxypeptidase A1 (CPA1) and regenerating islet-derived 1α (REG1a), in diagnosing ACC/MANC. Immunohistochemical staining for CPA1 and REG1a was performed on 14 ACC and 5 MANC, as well as on 80 other pancreatic tumors including 20 cases each of: ductal adenocarcinoma, well differentiated neuroendocrine tumor, mucinous cystic neoplasm and solid pseudopapillary tumor. All ACC and MANC were positive for CPA1 (all diffuse) and REG1a (12 diffuse, 4 patchy, 3 focal). A diffuse or patchy staining pattern was significantly more common in ACC/MANC cases (100% diffuse/patchy for CPA1 and 84% for REG1a) compared to other pancreatic tumors (5% diffuse/patchy for CPA1 and 7.5% for REG1a) with a P value of <0.0001 for both CPA1 and REG1a. The sensitivity and specificity of diffuse/patchy staining for CPA1 and REG1a in diagnosing pancreatic ACC/MANC were 100% and 95% for CPA1 and 84% and 93% for REG1a. In conclusion, CPA1 and REG1a are sensitive markers for ACC that can be used as additional acinar cell differentiation markers to help in the diagnosis of pancreatic ACC and MANC. A negative result for CPA1 virtually excludes ACC/MANC.

doi: https://doi.org/10.1016/j.humpath.2020.07.019



  • Invasion inhibition in pancreatic cancer using the oral iron chelating agent deferasirox

BMC cancer 2020 Jul;20(1):681

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=32698792

BACKGROUND: Iron is required for cellular metabolism, and rapidly proliferating cancer cells require more of this essential nutrient. Therefore, iron regulation may well represent a new avenue for cancer therapy. We have reported, through in vitro and in vivo research involving pancreatic cancer cell lines, that the internal-use, next-generation iron chelator deferasirox (DFX) exhibits concentration-dependent tumour-suppressive effects, among other effects. After performing a microarray analysis on the tumour grafts used in that research, we found that DFX may be able to suppress the cellular movement pathways of pancreatic cancer cells. In this study, we conducted in vitro analyses to evaluate the effects of DFX on the invasive and migratory abilities of pancreatic cancer cells.
METHODS: We used pancreatic cancer cell lines (BxPC-3, Panc-1, and HPAF II) to examine the efficacy of DFX in preventing invasion in vitro, evaluated using scratch assays and Boyden chamber assays. In an effort to understand the mechanism of action whereby DFX suppresses tumour invasion and migration, we performed G-LISA to examine the activation of Cdc42 and Rac1 which are known for their involvement in cellular movement pathways.
RESULTS: In our scratch assays, we observed that DFX-treated cells had significantly reduced invasive ability compared with that of control cells. Similarly, in our Boyden chamber assays, we observed that DFX-treated cells had significantly reduced migratory ability. After analysis of the Rho family of proteins, we observed a significant reduction in the activation of Cdc42 and Rac1 in DFX-treated cells.
CONCLUSIONS: DFX can suppress the motility of cancer cells by reducing Cdc42 and Rac1 activation. Pancreatic cancers often have metastatic lesions, which means that use of DFX will suppress not only tumour proliferation but also tumour invasion, and we expect that this will lead to improved prognoses.

doi: https://doi.org/10.1186/s12885-020-07167-8



  • Molecular characterization of organoids derived from pancreatic intraductal papillary mucinous neoplasms

The Journal of pathology 2020 Jul;():

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=32696980

Intraductal papillary mucinous neoplasms (IPMNs) are a commonly identified non-invasive cyst-forming pancreatic neoplasms with the potential to progress into invasive pancreatic adenocarcinoma. There are few in vitro models with which to study the biology of IPMNs and their progression to invasive carcinoma. Therefore, we generated a living biobank of organoids from 7 normal pancreatic ducts and 10 IPMNs. We characterized 8 IPMN organoid samples using whole genome sequencing and characterized 5 IPMN organoids and 7 normal pancreatic duct organoids using transcriptome sequencing. We identified an average of 11 344 somatic mutations in the genomes of organoids derived from IPMNs, with one sample harboring 61 537 somatic mutations enriched for T- > C transitions and T- > A transversions. Recurrent coding somatic mutations were identified in 15 genes, including KRAS, GNAS, RNF43, PHF3, and RBM10. The most frequently mutated genes were KRAS, GNAS, and RNF43, with somatic mutations identified in 6 (75%), 4 (50%), and 3 (37.5%) IPMN organoid samples respectively. On average, we identified 36 structural variants in IPMN derived organoids, and none had an unstable phenotype (>200 structural variants). Transcriptome sequencing identified 28 genes differentially expressed between normal pancreatic duct organoid and IPMN organoid samples. The most significantly upregulated and downregulated genes were CLDN18 and FOXA1. Immunohistochemical analysis of FOXA1 expression in 112 IPMNs, 113 mucinous cystic neoplasms, and 145 pancreatic ductal adenocarcinomas demonstrated statistically significant loss of expression in low-grade IPMNs (p < 0.0016), mucinous cystic neoplasms (p < 0.0001), and pancreatic ductal adenocarcinoma of any histologic grade (p < 0.0001) compared to normal pancreatic ducts. These data indicate that FOXA1 loss of expression occurs early in pancreatic tumorigenesis. Our study highlights the utility of organoid culture to study the genetics and biology normal pancreatic duct and IPMNs. This article is protected by copyright. All rights reserved.

doi: https://doi.org/10.1002/path.5515



  • Phase 1b study of Wnt inhibitor ipafricept (IPA) with gemcitabine and nab-paclitaxel in patients with previously untreated stage IV pancreatic cancer (mPDAC)

Clinical cancer research : an official journal of the American Association for Cancer Research 2020 Jul;():

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=32694153

BACKGROUND: The recombinant fusion protein ipafricept (IPA) blocks Wnt signaling, and in combination with gemcitabine (G) and nab-paclitaxel (Nab-P) caused tumor regression in xenografts. This phase 1b study evaluated the combination of IPA with Nab-P+G in untreated metastatic PDAC (mPDAC) patients.
METHODS: Dose escalation started with standard dose Nab-P+G and IPA (3.5 mg/kg days 1, 15). Due to fragility fractures seen with different anti-Wnt agents, following cohorts had >=6 patients treated with IPA 3 – 5 mg/kg on day 1, and included bone marker monitoring and prophylactic bisphosphonates as indicated. Based on pre-clinical data sequential dosing was evaluated in cohort 4 (IPA day 1 followed Nab-P+G day 3). Objectives included safety, MTD, RP2D, pharmacokinetics, immunogenicity, pharmacodynamics, and efficacy.
RESULTS: 26 patients were enrolled, 5 in the cohort 1 and 7 each in cohorts 2-4. IPA-related AEs of any grade included fatigue, nausea, vomiting, anorexia and pyrexia. IPA-related AEs >=grade3 included 2 events of AST elevation, and 1 each of nausea, rash, vomiting and leucopenia. No DLTs or fragility fractures were observed. Nine patients (34.6%) had PR, 12 (46.2%) SD as best response, with clinical benefit rate of 81%. Median PFS was 5.9m (95%CI 3.4-18.4), median OS was 9.7m (95%CI: 7.0-14). The study was terminated by the sponsor due to bone-related toxicity within this therapeutic program and concerns for commercial viability. One patient remains on therapy under compassionate use.
CONCLUSIONS: IPA can be administered with Nab-P+G with reasonable tolerance. Wnt pathway remains a therapeutic target of interest in mPDAC.

doi: https://doi.org/10.1158/1078-0432.CCR-20-0489


New GallBladder Articles


  • Extended Resections for Advanced Gallbladder Cancer: Results from a Nationwide Cohort Study

Annals of surgical oncology 2020 Jul;():

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=32696306

BACKGROUND: Extended resections (i.e., major hepatectomy and/or pancreatoduodenectomy) are rarely performed for gallbladder cancer (GBC) because outcomes remain inconclusive. Data regarding extended resections from Western centers are sparse. This Dutch, multicenter cohort study analyzed the outcomes of patients who underwent extended resections for locally advanced GBC.
METHODS: Patients with GBC who underwent extended resection with curative intent between January 2000 and September 2018 were identified from the Netherlands Cancer Registry. Extended resection was defined as a major hepatectomy (resection of ≥ 3 liver segments), a pancreatoduodenectomy, or both. Treatment and survival data were obtained. Postoperative morbidity, mortality, survival, and characteristics of short- and long-term survivors were assessed.
RESULTS: The study included 33 patients. For 16 of the patients, R0 resection margins were achieved. Major postoperative complications (Clavien Dindo ≥ 3A) occurred for 19 patients, and 4 patients experienced postoperative mortality within 90 days. Recurrence occurred for 24 patients. The median overall survival (OS) was 12.8 months (95% confidence interval, 6.5-19.0 months). A 2-year survival period was achieved for 10 patients (30%) and a 5-year survival period for 5 patients (15%). Common bile duct, liver, perineural and perivascular invasion and jaundice were associated with reduced survival. All three recurrence-free patients had R0 resection margins and no liver invasion.
CONCLUSION: The median OS after extended resections for advanced GBC was 12.8 months in this cohort. Although postoperative morbidity and mortality were significant, long-term survival (≥ 2 years) was achieved in a subset of patients. Therefore, GBC requiring major surgery does not preclude long-term survival, and a subgroup of patients benefit from surgery.

doi: https://doi.org/10.1245/s10434-020-08858-z



  • Lymph node involvement by enteropathy-like indolent NK-cell proliferation

Virchows Archiv : an international journal of pathology 2020 Jul;():

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=32696224

Natural killer (NK)-cell enteropathy (NKCE) and lymphomatoid gastropathy (LG) are closely related lymphoproliferative disorders (LPDs) composed of mature and Epstein-Barr virus (EBV)-negative NK-cells. Although these uncommon and indolent lymphoid proliferations mostly arise within the gastrointestinal (GI) tract as their designations implies, a few cases have been reported outside the GI tract. We hereby describe a unique case of lymph node infiltration by such EBV-negative NK-cell proliferation fortuitously found during routine examination of a gallbladder resected for biliary lithiasis. The histologic, phenotypic, and molecular features of this NK-cell proliferation, which were very similar if not identical to those previously reported in NKCE or LG, suggest that similar indolent EBV-negative NK-cell LPDs may also occasionally involve lymph nodes.

doi: https://doi.org/10.1007/s00428-020-02892-8


New BileDuct Articles


  • Extended Resections for Advanced Gallbladder Cancer: Results from a Nationwide Cohort Study

Annals of surgical oncology 2020 Jul;():

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=32696306

BACKGROUND: Extended resections (i.e., major hepatectomy and/or pancreatoduodenectomy) are rarely performed for gallbladder cancer (GBC) because outcomes remain inconclusive. Data regarding extended resections from Western centers are sparse. This Dutch, multicenter cohort study analyzed the outcomes of patients who underwent extended resections for locally advanced GBC.
METHODS: Patients with GBC who underwent extended resection with curative intent between January 2000 and September 2018 were identified from the Netherlands Cancer Registry. Extended resection was defined as a major hepatectomy (resection of ≥ 3 liver segments), a pancreatoduodenectomy, or both. Treatment and survival data were obtained. Postoperative morbidity, mortality, survival, and characteristics of short- and long-term survivors were assessed.
RESULTS: The study included 33 patients. For 16 of the patients, R0 resection margins were achieved. Major postoperative complications (Clavien Dindo ≥ 3A) occurred for 19 patients, and 4 patients experienced postoperative mortality within 90 days. Recurrence occurred for 24 patients. The median overall survival (OS) was 12.8 months (95% confidence interval, 6.5-19.0 months). A 2-year survival period was achieved for 10 patients (30%) and a 5-year survival period for 5 patients (15%). Common bile duct, liver, perineural and perivascular invasion and jaundice were associated with reduced survival. All three recurrence-free patients had R0 resection margins and no liver invasion.
CONCLUSION: The median OS after extended resections for advanced GBC was 12.8 months in this cohort. Although postoperative morbidity and mortality were significant, long-term survival (≥ 2 years) was achieved in a subset of patients. Therefore, GBC requiring major surgery does not preclude long-term survival, and a subgroup of patients benefit from surgery.

doi: https://doi.org/10.1245/s10434-020-08858-z


New Ampulla Articles


  • Acute duodenal obstruction secondary to intussusception caused by the duodenal diverticulum: a case report

BMC gastroenterology 2020 Jul;20(1):234

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=32698796

BACKGROUND: The duodenal intussusception is rarely reported and usually occurs secondary to organic diseases of the duodenum such as polyps, tumors and duplication cysts. Herein we report a case of duodenal intussusception caused by duodenal diverticulum.
CASE PRESENTATION: A 21-year old male patient presented with abdominal pain and vomiting for one day. A contrast enhanced computed tomography of the abdomen revealed duodenal intussusception. On emergency laparotomy, the intussusception had reduced spontaneously while an invaginated diverticulum was seen at the junction of the descending and horizontal segments of the duodenum. The diverticulum was resected and the patient had uneventful recovery.
CONCLUSION: Duodenal intussusception is a rare complication of duodenal diverticulum. Being aware of this complication of diverticulum can help in timely diagnosis and treatment.

doi: https://doi.org/10.1186/s12876-020-01379-9


To see all journal watch articles please visit: http://pbpath.org/journal-watch-upcoming-issue/