Recent Articles on Pancreatobiliary #Pathology – 2020-10-01

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


  • Recurrent YAP1 and MAML2 Gene Rearrangements in Retiform and Composite Hemangioendothelioma

The American journal of surgical pathology 2020 Sep;():

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=32991341

Retiform and composite hemangioendotheliomas (CHEs) are both locally aggressive, rarely metastasizing vascular neoplasms characterized by arborizing vascular channels lined by endothelial cells with a hobnail morphology. CHE displays additional cytologic and architectural components, including often vacuolated epithelioid cells, solid areas, or features reminiscent of well-differentiated angiosarcoma. Triggered by an index case of a soft tissue retiform hemangioendothelioma (RHE) which revealed a YAP1-MAML2 gene fusion by targeted RNA sequencing, we sought to investigate additional cases in this morphologic spectrum for this genetic abnormality. A total of 24 cases, 13 RHE and 11 CHE involving skin and soft tissue were tested by fluorescence in situ hybridization using custom BAC probes for rearrangements involving these genes. An additional visceral CHE with neuroendocrine differentiation was tested by targeted RNA sequencing. Among the soft tissue cohort, 5/13 (38%) RHE and 3/11 (27%) CHE showed YAP1 gene rearrangements, with 5 cases showing a YAP1-MAML2 fusion, including all 3 CHE. The single neuroendocrine CHE showed the presence of a PTBP1-MAML2 fusion. All YAP1-positive CHE lesions occurred in female children at acral sites, compared with fusion-negative cases which occurred in adults, with a wide anatomic distribution. YAP1-positive RHE occurred preferentially in males and lower limb, compared with negative cases. These results suggest that RHE and CHE represent a morphologic continuum, sharing abnormalities in YAP1 and MAML2 genes. In contrast, the neuroendocrine CHE occurring in a 37-year-old male harbored a distinct PTBP1-MAML2 fusion and showed aggressive clinical behavior (pancreatic mass with multiple liver and lung metastases). These preliminary findings raise the possibility that neuroendocrine CHE may be genetically distinct from the conventional RHE/CHE spectrum. Further studies are needed to investigate the pathogenetic relationship of fusion-negative cases with this subset and, less likely, with other members of the HE family of tumors.

doi: https://doi.org/10.1097/PAS.0000000000001575



  • Critical thresholds: key to unlocking the door to the prevention and specific treatments for acute pancreatitis

Gut 2020 Sep;():

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=32973069

Acute pancreatitis (AP), an acute inflammatory disorder of the exocrine pancreas, is one of the most common gastrointestinal diseases encountered in emergency departments with no specific treatments. Laboratory-based research has formed the cornerstone of endeavours to decipher the pathophysiology of AP, because of the limitations of such study in human beings. While this has provided us with substantial understanding, we cannot answer several pressing questions. These are: (a) Why is it that only a minority of individuals with gallstones, or who drink alcohol excessively, or are exposed to other causative factors develop AP? (b) Why do only some develop more severe manifestations of AP with necrosis and/or organ failure? © Why have we been unable to find an effective therapeutic for AP? This manuscript provides a state-of-the-art review of our current understanding of the pathophysiology of AP providing insights into the unanswered clinical questions. We describe multiple protective factors operating in most people, and multiple stressors that in a minority induce AP, independently or together, via amplification loops. We present testable hypotheses aimed at halting progression of severity for the development of effective treatments for this common unpredictable disease.

doi: https://doi.org/10.1136/gutjnl-2020-322163



  • Outcomes of limited resection for patients with intraductal papillary mucinous neoplasm of the pancreas: A single-center experience

Pancreatology : official journal of the International Association of Pancreatology (IAP) … [et al.] 2020 Sep;():

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=32972836

BACKGROUND: /ObjectivesThe aim of this study was to clarify the oncological outcomes of patients with intraductal papillary mucinous neoplasm (IPMN) who underwent limited resection (LR).
METHODS: This retrospective study analyzed the data of 110 patients with IPMN. Patients with IPMN without a history of pancreatitis who had neither tumor infiltration nor regional lymph node swelling on imaging findings underwent LR. We assessed the oncological outcomes of LR for patients with IPMN by comparing the surgical outcomes of LR and standard resection.
RESULTS: LR was performed in 50 patients (45.5%), including duodenum-preserving pancreatic head resection (n = 31), middle-pancreatectomy (n = 12), spleen-preserving distal pancreatectomy (n = 3), total parenchymal pancreatectomy (n = 3), and partial resection (n = 1). In the LR group, 18 patients had postoperative complications of Clavien-Dindo classification ≥ IIIa. After histopathological examination, the presence of high-grade dysplasia (HGD) and invasive carcinoma (IC) were observed in nine and three patients, respectively, in the LR group, and eight and 22 patients, respectively, in the standard resection group. There was a significant difference in the histopathological diagnosis of IC between the two groups (p < 0.001). Finally, in the LR group, postoperative recurrences occurred in three patients, and the 5-, 10-, and 15-year disease-specific survival rates were all 97.0%.
CONCLUSIONS: For patients with IPMN judged to have no infiltrating lesions based on the detailed imaging examination, LR is acceptable and may be considered as an alternative to standard resection.

doi: https://doi.org/10.1016/j.pan.2020.09.008



  • Prediction of clinically relevant pancreatic fistula after pancreatic surgery using preoperative CT scan: A systematic review and meta-analysis

Pancreatology : official journal of the International Association of Pancreatology (IAP) … [et al.] 2020 Sep;():

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=32972835

BACKGROUND: Body composition analysis has emerged as a practical tool for predicting outcomes following pancreatic surgery. However, the impact of body composition disorders on clinically relevant postoperative pancreatic fistula (CR-POPF) remains inconclusive. The aim of this study was to review and analyse whether radiographically assessed body composition is predictive of CR-POPF.
METHODS: PubMed, MEDLINE, Web of Science, and the Cochrane Library databases were searched up to January 2020 to identify relevant studies. CR-POPF was defined according to the definition and grading system proposed by the International Study Group on Pancreatic Surgery (ISGPS). Pooled odds ratios (OR) for CR-POPF were calculated to evaluate the predictive values of radiographically assessed body composition.
RESULTS: Fifteen studies published between 2008 and 2019 with a total of 3136 patients were included. There was a significant increase in the incidence of CR-POPF in patients with visceral obesity (OR 2.97, 95% CI 2.05-4.29, P < 0.00001) and sarcopenic obesity (OR 2.88, 95% CI 1.31-6.34, P = 0.009). Conversely, the impact of sarcopenia (OR 0.91, 95% CI 0.65-1.28, P = 0.59) and low muscle attenuation (MA) on CR-POPF did not reach statistical significance.
CONCLUSION: Preoperative visceral obesity and sarcopenic obesity are more effective at predicting CR-POPF than decreased muscle quantity and quality. This finding may lead to appropriate management and early intervention of patients at risk of CR-POPF.

doi: https://doi.org/10.1016/j.pan.2020.09.009



  • Elucidating the Causes of Improved Survival in Clinical Trials of Randomized Adjuvant Pancreatic Ductal Adenocarcinoma (PDAC)

Annals of surgical oncology 2020 Sep;():

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=32968957

BACKGROUND: Overall survival (OS) has increased in recent adjuvant clinical trials of pancreatic ductal adenocarcinoma (PDAC). Although oncologists have taken notice, the root causes have not been fully examined.
METHODS: All phase 3 adjuvant PDAC clinical trials were screened (n = 13), and eight trials (2007-2019) that met a study requirement of having a gemcitabine monotherapy arm to serve as a uniform comparative anchor across trials were identified. Patient enrollment eligibility criteria were compared across trials and categorized as tumor- or patient-related factors. Disease-free survival (DFS) and OS in the gemcitabine-only and non-gemcitabine arms were plotted and compared over time using linear regression.
RESULTS: In the non-gemcitabine arms, OS increased over time, but the slope did not achieve statistical significance (p = 0.0815). Interestingly, OS improved for patients receiving only gemcitabine (slope, 1.99 months; p = 0.0018), whereas DFS remained constant (p = 0.897). Carbohydrate antigen (CA) 19-9 values and pathologic profiles of tumors were only marginally different across all cohorts. Recent adjuvant trials had stricter inclusion criteria (i.e., more patients were excluded for medical reasons; linear regression, p = 0.010).
CONCLUSION: Survival for patients with resected PDAC has roughly doubled in phase 3 adjuvant trials during the past decade. Improved outcomes likely are attributable to improved adjuvant therapeutic regimens, but also reflect healthier patients enrolled in the more recent trials.

doi: https://doi.org/10.1245/s10434-020-08859-y



  • Low serum trypsinogen levels in chronic pancreatitis: Correlation with parenchymal loss, exocrine pancreatic insufficiency, and diabetes but not CT-based cambridge severity scores for fibrosis

Pancreatology : official journal of the International Association of Pancreatology (IAP) … [et al.] 2020 Sep;():

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=32967795

BACKGROUND: Chronic pancreatitis (CP) is a complex inflammatory disorder of the pancreas affecting acinar cells, duct cells, islet cells and inflammatory cells including fibrosis-producing stellate cells. Serum trypsinogen is a biomarkers of acinar cell function.
AIM: To define the degree of correlation between low trypsinogen levels as a marker of acinar cell function and variable features of CP.
METHODS: Serum samples from previously ascertained and well phenotyped case and control subjects from the North American Pancreatitis Study II (NAPS2) were used to measure serum trypsinogen levels in a commercial laboratory. Control samples were used to define normal ranges and compared with levels in CP patients with defined features.
RESULTS: A final cohort of 279 CP patients and 262 controls from the NAPS2 studies were evaluated. In controls trypsinogen had a mean of 34.96 ng/ml and SD = 11.99. Cut-off values for low trypsinogen ranged from <20 to 10 ng/ml and very low trypsinogen at <10 ng/ml. Compared to controls, CP was associated with very low trypsinogen levels (p < 0.0001). Within CP, very low trypsinogen levels correlated with parenchymal loss (pancreatic surgery [p < 0.05]; atrophy with calcifications, [p < 0.001]), EPI (p < 0.01, trend p < 0.001) and diabetes (trend p < 0.01) but not CT-based criteria for fibrosis (pancreatic duct dilation, irregularity, strictures).
CONCLUSIONS: Very low serum trypsinogen levels correlate with measures of acinar cell loss including surgical resection, atrophic-calcific CP, diabetes and functional symptoms EPI but not duct morphology criteria. Serum trypsinogen levels correlate with decreased acinar cell function and therefore have biomarker utility clinical management.

doi: https://doi.org/10.1016/j.pan.2020.08.025



  • The economic burden of metastatic pancreatic cancer

Pancreatology : official journal of the International Association of Pancreatology (IAP) … [et al.] 2020 Sep;():

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=32967794

BACKGROUND: Objectives: Pancreatic cancer (PC) is a costly disease with a limited life-expectancy as it generally presents as an advanced, metastatic disease. Though current literature suggests cost varies by first line treatment, there is limited real-world knowledge about the economic burden of pancreatic cancer. This study describes the economic burden of pancreatic cancer patients overall and by observed first line treatments.
METHODS: The IBM MarketScan databases were used to identify adult metastatic PC patients from January 1, 2010 through 3/31/2017. Those without other primary cancers, pregnancy, or prior PC treatment, and with 6 months of continuous enrollment prior to PC were included. Treatment patterns and healthcare utilization and expenditures were measured during the variable-length follow-up period. Continuous measures were presented as per patient per month (PPPM).
RESULTS: A total of 6,360 patients met all inclusion criteria. Almost half (46.8%) of patients were untreated. Gemcitabine alone (15.6%) and FOLFIRINOX (11.4%) were the most commonly observed first line regimens. Treated patients incurred $17,513 PPPM (Gemcitabine alone) to $27,889 PPPM (FOLFIRINOX) during follow-up. Untreated patients incurred the highest unadjusted ($30,777 PPPM) and adjusted ($20,392 PPPM) cost.
CONCLUSIONS: Metastatic PC patients incur a high economic burden driven by high utilization of healthcare resources, which varies by first line treatment. Also, the high proportion of untreated patients is alarming as these patients may be the most expensive of all patients. There is an unmet need in these patients for effective treatments that also reduce their economic burden.

doi: https://doi.org/10.1016/j.pan.2020.09.002



  • Interferon-beta enhances sensitivity to gemcitabine in pancreatic cancer

BMC cancer 2020 Sep;20(1):913

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=32967656

BACKGROUND: Adjuvant gemcitabine for pancreatic cancer has limited efficacy in the clinical setting. Impaired drug metabolism is associated with treatment resistance. We aimed to evaluate the chemosensitising effect of interferon-beta (IFN-β).
METHODS: BxPC-3, CFPAC-1, and Panc-1 cells were pre-treated with IFN-β followed by gemcitabine monotherapy. The effect on cell growth, colony formation, and cell cycle was determined. RT-qPCR was used to measure gene expression. BxPC-3 cells were used in a heterotopic subcutaneous mouse model.
RESULTS: IFN-β increased sensitivity to gemcitabine (4-, 7.7-, and 1.7-fold EC50 decrease in BxPC-3, CFPAC-1, and Panc-1, respectively; all P < 0.001). Findings were confirmed when assessing colony formation. The percentage of cells in the S-phase was significantly increased after IFN-β treatment only in BxPC-3 and CFPAC-1 by 12 and 7%, respectively (p < 0.001 and p < 0.05, respectively). Thereby, IFN-β upregulated expression of the drug transporters SLC28A1 in BxPC-3 (252%) and SLC28A3 in BxPC-3 (127%) and CFPAC-1 (223%) (all p < 0.001). In vivo, combination therapy reduced tumor volume with 45% (P = 0.01). Both ex vivo and in vivo data demonstrate a significant reduction in the number of proliferating cells, whereas apoptosis was increased.
CONCLUSIONS: For the first time, we validated the chemosensitising effects of IFN-β when combined with gemcitabine in vitro, ex vivo, and in vivo. This was driven by cell cycle modulation and associated with an upregulation of genes involving intracellular uptake of gemcitabine. The use of IFN-β in combination with gemcitabine seems promising in patients with pancreatic cancer and needs to be further explored.

doi: https://doi.org/10.1186/s12885-020-07420-0



  • GLUT-1 as a predictor of worse prognosis in pancreatic adenocarcinoma: immunohistochemistry study showing the correlation between expression and survival

BMC cancer 2020 Sep;20(1):909

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=32967636

BACKGROUND: Various parameters have been considered for predicting survival in pancreatic ductal adenocarcinoma. Information about western population is missing. The aim of this study is to assess the association between Glucose transporter type 1 (GLUT-1) expression and prognosis for patients with PDAC submitted for surgical resection in a European cohort.
METHODS: Retrospective analysis of PDAC specimens after pancreatoduodenectomy assessing GLUT-1 expression according to intensity (weak vs strong) and extension (low if < 80% cells were stained, high if > 80%) was performed. Statistical analysis was performed using the exact Fisher test, Student t test or the Mann-Whitney U test. Survival was analysed using the Kaplan-Meier method and compared with the Log-rank test. The differences were considered significant at a two-sided p value of < 0.05. All statistical analyses were performed using SPSS® 23.0 for Windows (SPSS Inc., Chicago, IL, USA).
RESULTS: Our study consisted of 39 patients of which 58.9% presented with weak and 41.1% with strong intensity. The median extension was 90%: 28.2% cases presented with a low extension and 71.8% with a high extension. No significant differences related to intensity were found. The high-extension group showed a higher percentage of T3 PDAC (92.9% vs 63.6%, p = 0.042) and LNR20 (35.7% vs 0%, p = 0.037) as well as shorter disease-free survival (17.58 vs 54.46 months; p = 0.048).
CONCLUSIONS: Our findings suggest that GLUT-1 could be related to higher aggressivity in PDAC and could be used as a prognostic marker, identifying patients with a worse response to current therapies who could benefit from more aggressive treatments.

doi: https://doi.org/10.1186/s12885-020-07409-9



  • Surufatinib in advanced pancreatic neuroendocrine tumours (SANET-p): a randomised, double-blind, placebo-controlled, phase 3 study

The Lancet. Oncology 2020 Sep;():

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=32966810

BACKGROUND: Surufatinib showed superior efficacy in extrapancreatic neuroendocrine tumours (NETs) in the phase 3 SANET-ep study. In SANET-p, we aimed to assess the efficacy and safety of surufatinib in patients with advanced pancreatic NETs.
METHODS: SANET-p was a multicentre, randomised, double-blind, placebo-controlled, phase 3 study, done in 21 hospitals across China. Eligible patients were adults (aged 18 years or older) with progressive, advanced, well differentiated pancreatic NETs, Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and progression on up to two kinds of previous systemic regimens for advanced disease. Patients were randomly assigned (2:1) via an interactive web response system to receive 300 mg of surufatinib or placebo, taken orally once per day in consecutive 4-week treatment cycles until disease progression, intolerable toxicity, withdrawal of consent, poor compliance, use of other antitumour medication, pregnancy, loss to follow-up, or if the investigator deemed discontinuation in the patient's best interest. Randomisation was done centrally using stratified block randomisation (block size three), stratified by pathological grade, previous systemic antitumour treatment, and ECOG performance status score. Patients, investigators, research staff, and the sponsor study team were masked to treatment allocation. Crossover to surufatinib was permitted for patients in the placebo group with disease progression. The primary endpoint was investigator-assessed progression-free survival in the intention-to-treat population, which included all patients in randomisation. A pre-planned interim analysis was done at 70% of the predicted progression-free survival events. This study is registered at ClinicalTrials.gov, NCT02589821.
FINDINGS: Between Feb 18, 2016, and Nov 11, 2019, of 264 patients who were screened, 172 (65%) patients were randomly assigned to receive surufatinib (n=113) or placebo (n=59). The median follow-up was 19·3 months (95% CI 9·3-19·4) in the surufatinib group and 11·1 months (5·7-35·9) in the placebo group. The median investigator-assessed progression-free survival was 10·9 months (7·5-13·8) for surufatinib versus 3·7 months (2·8-5·6) for placebo (hazard ratio 0·49, 95% CI 0·32-0·76; p=0·0011). The trial met the early stopping criteria at the interim analysis and was terminated on recommendation from the independent data monitoring committee. The most common grade 3 or worse treatment-related adverse events were hypertension (43 [38%] of 113 with surufatinib vs four [7%] of 59 with placebo), proteinuria (11 [10%] vs one [2%]), and hypertriglyceridaemia (eight [7%] vs none). Treatment-related serious adverse events were reported in 25 (22%) patients in the surufatinib group and four (7%) patients in the placebo group. There were three on-treatment deaths in the surufatinib group, including two deaths due to adverse events (gastrointestinal haemorrhage [possibly treatment-related] and cerebral haemorrhage [unlikely to be treatment-related]), and one death attributed to disease progression. One on-treatment death in the placebo group was attributed to disease progression.
INTERPRETATION: Surufatinib significantly improves progression-free survival and has an acceptable safety profile in patients with progressive, advanced pancreatic NETs, and could be a potential treatment option in this patient population.
FUNDING: Hutchison MediPharma.

doi: https://doi.org/10.1016/S1470-2045(20)30493-9



  • World Health Organization grading classification for pancreatic neuroendocrine neoplasms: a comprehensive analysis from a large Chinese institution

BMC cancer 2020 Sep;20(1):906

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=32962649

BACKGROUND: Pancreatic neuroendocrine neoplasms (p-NENs) are a group of highly heterogeneous tumors with distinct clinicopathological features and long-term prognosis. In 2017, in order to better stratify patients into prognostic groups and predicting their outcomes, World Health Organization (WHO) officially updated its grading system for p-NENs which distinguished these neoplasms among Grading 1 (G1) pancreatic neuroendocrine tumors (p-NETs), G2 p-NETs, G3 p-NETs and G3 pancreatic neuroendocrine carcinomas (p-NECs). However, this new grading classification for p-NENs has not yet been rigorously validated.
METHODS: Data of patients who were surgically treated and histopathologically diagnosed as p-NENs at West China Hospital of Sichuan University from January 2002 to December 2018 were retrospectively collected and analyzed according the novel WHO 2017 grading classification.
RESULTS: We eventually enrolled 480 eligible patients with p-NENs in our present study, in which 150 patients with WHO 2017 G1 p-NETs, 158 with G2 p-NETs, 64 with G3 p-NETs and 108 with G3 p-NECs were identified. The estimated 5-year overall survival for patients with G1 p-NETs, G2 p-NETs, G3 p-NETs and G3 p-NECs was 75.8, 58.4, 35.1 and 11.1%, with a median survival time of 85.3mons, 67.4mons, 51.3mons and 26.8mons, respectively. Patients with G2 p-NETs present notably worse survival than those with G1 p-NETs (P = 0.03). Survival of G3 p-NETs were significantly worse than that of G1 p-NETs or G2 p-NETs (P < 0.001, P = 0.023, respectively), as well as that when comparing G3 p-NECs with G1 p-NETs or G2 p-NETs (P < 0.001, P < 0.001, respectively). Patients with G3 p-NECs showed statistically shorter survival than those with G3 p-NETs (P < 0.001). Both WHO 2017 and 2010 grading criteria could be independent predictor for the OS of p-NENs (P = 0.016, P = 0.022; respectively). The 95% confidence intervals of WHO 2017 grading classification (0.983-9.454) was slightly smaller than that of WHO 2010 criteria (0.201-13.374), indicating a relatively more accurate predicting ability for the prognosis of p-NENs.
CONCLUSION: The WHO 2017 grading classification for p-NENs could successfully allocate patients into four groups with distinct clinical features and significant survival differences, which might be superior to the WHO 2010 criteria for its better prognostic stratification and more accurate predicting ability.

doi: https://doi.org/10.1186/s12885-020-07356-5



  • Delving into Early Onset Pancreatic Ductal Adenocarcinoma: How Does Age Fit In?

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

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=32958704

PURPOSE: With the rising incidence of early-onset pancreatic cancer (EOPC), molecular characteristics that distinguish early onset pancreatic ductal adenocarcinoma (PDAC) tumors from those arising at a later age are not well understood.
EXPERIMENTAL DESIGN: We performed bioinformatic analysis of genomic and transcriptomic data generated from 269 advanced (metastatic or locally advanced) and 277 resectable PDAC tumor samples. Patient samples were stratified into EOPC (age of onset ≤55 years; n=117), intermediate (age of onset 55-70 years; n=264) and average (age of onset ≥70 years; n=165) groups. Frequency of somatic mutations affecting genes commonly implicated in PDAC, as well as gene expression patterns, were compared between EOPC and all other groups.
RESULTS: EOPC tumors showed significantly lower frequency of somatic SNV/indels in CDKN2A (p=0.0017), and were more likely to achieve bi-allelic mutation of CDKN2A through homozygous copy loss as opposed to heterozygous copy loss coupled with a loss-of-function SNV/indel mutation, the latter of which was more common for tumors with later ages of onset (p=1.5e-4). Transcription factor FOXC2 was significantly up-regulated in EOPC tumors (p=0.032). Genes significantly correlated with FOXC2 in PDAC samples were enriched for gene sets related to epithelial-mesenchymal transition (EMT) and included VIM (p=1.8e-8), CDH11 (p=6.5e-5) and CDH2 (p=2.4e-2).
CONCLUSIONS: Our comprehensive analysis of sequencing data generated from a large cohort of PDAC patient samples highlights a distinctive pattern of bi-allelic CDKN2A mutation in EOPC tumors. Increased expression of FOXC2 in EOPC, with the correlation between FOXC2 and EMT pathways, represent novel molecular characteristics of EOPC.

doi: https://doi.org/10.1158/1078-0432.CCR-20-1042



  • KRASG12C Inhibition with Sotorasib in Advanced Solid Tumors

The New England journal of medicine 2020 09;383(13):1207-1217

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=32955176

BACKGROUND: No therapies for targeting KRAS mutations in cancer have been approved. The KRAS p.G12C mutation occurs in 13% of non-small-cell lung cancers (NSCLCs) and in 1 to 3% of colorectal cancers and other cancers. Sotorasib is a small molecule that selectively and irreversibly targets KRASG12C.
METHODS: We conducted a phase 1 trial of sotorasib in patients with advanced solid tumors harboring the KRAS p.G12C mutation. Patients received sotorasib orally once daily. The primary end point was safety. Key secondary end points were pharmacokinetics and objective response, as assessed according to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1.
RESULTS: A total of 129 patients (59 with NSCLC, 42 with colorectal cancer, and 28 with other tumors) were included in dose escalation and expansion cohorts. Patients had received a median of 3 (range, 0 to 11) previous lines of anticancer therapies for metastatic disease. No dose-limiting toxic effects or treatment-related deaths were observed. A total of 73 patients (56.6%) had treatment-related adverse events; 15 patients (11.6%) had grade 3 or 4 events. In the subgroup with NSCLC, 32.2% (19 patients) had a confirmed objective response (complete or partial response) and 88.1% (52 patients) had disease control (objective response or stable disease); the median progression-free survival was 6.3 months (range, 0.0+ to 14.9 [with + indicating that the value includes patient data that were censored at data cutoff]). In the subgroup with colorectal cancer, 7.1% (3 patients) had a confirmed response, and 73.8% (31 patients) had disease control; the median progression-free survival was 4.0 months (range, 0.0+ to 11.1+). Responses were also observed in patients with pancreatic, endometrial, and appendiceal cancers and melanoma.
CONCLUSIONS: Sotorasib showed encouraging anticancer activity in patients with heavily pretreated advanced solid tumors harboring the KRAS p.G12C mutation. Grade 3 or 4 treatment-related toxic effects occurred in 11.6% of the patients. (Funded by Amgen and others; CodeBreaK100 ClinicalTrials.gov number, NCT03600883.).

doi: https://doi.org/10.1056/NEJMoa1917239



  • Histological diagnosis and grading of pancreatic neuroendocrine tumor by endoscopic ultrasound-guided fine needle biopsy using a 25-gauge needle with a core trap: A multicenter prospective trial

Pancreatology : official journal of the International Association of Pancreatology (IAP) … [et al.] 2020 Sep;():

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=32952043

OBJECTIVES: Preoperative grading of pancreatic neuroendocrine tumors (PanNET) is challenging. The aim of this study was to prospectively evaluate the use of a 25-gauge needle with a core trap for diagnosis and grading of PanNET.
METHODS: This multicenter prospective trial was registered with the University Hospital Medical Information Network (UMIN000021409). Consecutive patients with suspected PanNET between June 2016 and November 2017 were enrolled. All patients underwent endoscopic ultrasound-guided fine needle biopsy (EUS-FNB) using a 25-gauge needle with a core trap. Samples obtained after the first needle pass were used for central pathological review. EUS-FNB was evaluated in terms of (i) technical success rate, (ii) adequacy for histological evaluation, (iii) complication rate during the procedure, and (iv) concordance between PanNET grading on EUS-FNB and that after analysis of the resected tumor.
RESULTS: Fifty-two patients were enrolled. Of the 36/52 patients who underwent surgical resection, 31 were finally diagnosed with PanNET and were eligible for analysis. The technical success rate of EUS-FNB was 100%. The rate of adequacy for histological evaluation was 90.3%. There were no complications related to EUS-FNB. The concordance rate between PanNET grading on EUS-FNB and that after analysis of the resected tumor was 82.6% (95% confidence interval = 61.22-95.05, P = 0.579).
CONCLUSIONS: EUS-FNB using a 25-gauge needle with a core trap is feasible, providing histological samples are of sufficient quality for diagnosis and grading of PanNET.

doi: https://doi.org/10.1016/j.pan.2020.08.023



  • Analysis of T lymphocyte-related biomarkers in pancreatic cancer

Pancreatology : official journal of the International Association of Pancreatology (IAP) … [et al.] 2020 Sep;():

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=32952042

BACKGROUND: Pancreatic cancer remains one of the most lethal cancers.
OBJECTIVE: This study aimed to analyze T cell-related biomarkers and their molecular network in pancreatic cancer.
METHODS: RNAseq sequencing data and clinical data of pancreatic cancer were obtained from TCGA database. The STromal and Immune cells in MAlignant Tumours using Expression data (ESTIMATE) algorithm was used to screen the DEGs related to the tumor immune cells. The pearson correlation analysis were used to analyze the relationships between DEGs and T cells. Additionally, the T cell-related DEGs were subjected to protein-protein interaction, competing endogenous RNA (ceRNA), and chemical small molecule-target network construction. Furthermore, the prognosis-associated DEGs were screened.
RESULTS: A total of 412 stromal score-associated and 312 immune score-associated DEGs were obtained. From these DEGs, 50 CD4+ T cell-related genes and 13 CD8+ T cell-related genes were selected. The PPI networks associated with immune cell-related genes were constructed and found that CD22, SELL, and OLR1 had higher degrees in the PPI network. The number of ceRNA regulatory relation pairs obtained from CD4+ T cells and CD8+ T cells were 59 and 48, respectively. Additionally, both CD4+ T cell- and CD8+ T cell-related genes predicted 29 small molecules. CXCL9 and GIMAP7 were screened out from CD4+ T cell-related genes, which were related with the survival of pancreatic cancer.
CONCLUSION: We mapped T cell-related gene profile in pancreatic cancer and constructed their potential regulatory network.

doi: https://doi.org/10.1016/j.pan.2020.09.005



  • Pancreatic resections in patients who refuse blood transfusions. The application of a perioperative protocol for a true bloodless surgery

Pancreatology : official journal of the International Association of Pancreatology (IAP) … [et al.] 2020 Sep;():

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=32950387

BACKGROUND: The refusal of blood transfusions compels surgeons to face ethical and clinical issues. A single-institution experience with a dedicated perioperative blood management protocol was reviewed to assess feasibility and short-term outcomes of true bloodless pancreatic surgery.
METHODS: The institutional database was reviewed to identify patients who refused transfusion and were scheduled for elective pancreatic surgery from 2010 through 2018. A protocol to optimize the hemoglobin values by administration of drugs stimulating erythropoiesis was systematically used.
RESULTS: Perioperative outcomes of 32 Jehovah's Witnesses patients were included. Median age was 67 years (range, 31-77). Nineteen (59.4%) patients were treated with preoperative erythropoietin. Twenty-four (75%) patients underwent pylorus-preserving pancreaticoduodenectomy, 4 (12.5%) distal pancreatectomy (DP) with splenectomy, 3 (9.4%) spleen-preserving DP, and 1 (3.1%) total pancreatectomy. Median estimated blood loss and surgical duration were 400 mL (range, 100-1000) and 470 min (range, 290-595), respectively. Median preoperative hemoglobin was 13.9 g/dL (range, 11.7-15.8) while median postoperative nadir hemoglobin was 10.5 g/dL (range, 7.1-14.1). The most common histological diagnosis (n = 15, 46.9%) was pancreatic ductal adenocarcinoma. Clavien-Dindo grade I-II complications occurred in fourteen (43.8%) patients while one (3.1%) patient had a Clavien-Dindo grade IIIa complication wich was an abdominal collection that required percutaneous drainage. Six (18.8%) patients presented biochemical leak or postoperative pancreatic fistula grade B. Median hospital stay was 16 days (range, 8-54) with no patient requiring transfusion or re-operation and no 90-day mortality.
CONCLUSIONS: A multidisciplinary approach and specific perioperative management allowed performing pancreatic resections in patients who refused transfusion with good short-term outcomes.

doi: https://doi.org/10.1016/j.pan.2020.08.020


New GallBladder Articles


  • Incidence and Significance of GATA3 Positivity in Gallbladder Adenocarcinoma

Human pathology 2020 Sep;():

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=32991930

GATA3 immunostain is a sensitive marker for mammary and urothelial carcinomas. It is routinely used in surgical pathology during workup of carcinomas of unknown origin. To the best of our knowledge, this is the first focused study of GATA3 expression in gallbladder adenocarcinomas. In this study we evaluated GATA3 expression in 38 gallbladder adenocarcinomas. 8 of 38 (21%) gallbladder adenocarcinomas were positive for GATA3. The expression of GATA3 tended to be moderate to strong when present. It was patchy (50% positivity) in the other 4 cases. GATA3 expression did not show any significant correlation with clinicopathologic features such as sex, histologic grade, perineural invasion, vascular invasion, pathologic stage or distance metastasis. The results of our study show that a subset of gallbladder adenocarcinomas (21%) can be GATA3 positive. Awareness of this phenomenon is important while working up GATA3 positive carcinomas immunohistochemically.

doi: https://doi.org/10.1016/j.humpath.2020.09.012


New BileDuct Articles


  • Morphology of tumor and nontumor tissue in liver resection specimens for hepatocellular carcinoma following nivolumab therapy

Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 2020 Sep;():

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=32989224

Nivolumab is an immune checkpoint inhibitor (ICI) approved for treatment of many cancers, including hepatocellular carcinoma (HCC). Liver injury is a known complication in patients treated with nivolumab for nonliver tumors. To date, the morphologic changes to tumor and nontumor liver have not been well-characterized in HCC patients. We identified 20 patients who underwent partial hepatectomy or liver transplantation after receiving nivolumab for HCC. Demographics, laboratory values, and imaging results were obtained from medical records. All available slides from resection specimens were evaluated for tumor necrosis, tumor-infiltrating lymphocytes (TILs), and features of liver injury. Patients in the study included 16 males and 4 females with median age of 56 years. The underlying liver disease was HBV in 10, HCV in 6, and unknown/other in 4. Twelve patients were treated with nivolumab in the neoadjuvant setting, whereas eight were treated with nivolumab, usually along with other therapies, before undergoing liver transplantation. On review of resection specimens, three patients (all from the neoadjuvant group) demonstrated marked treatment response attributable to nivolumab. TILs were present in 17/20 cases. One case that showed treatment response in the neoadjuvant group demonstrated non-necrotizing granulomas and prominent bile duct intraepithelial lymphocytes (IELs) in the nontumor liver. One case from the transplant group showed bile duct damage and prominent ductular reaction after long-term nivolumab therapy (32 doses). Our findings indicate that nivolumab is effective in a subset of patients, including in the neoadjuvant setting. Granulomas and bile duct IELs are rare findings in cases treated with nivolumab but, when seen, may indicate potential response to therapy. Bile duct damage and ductular reaction may be manifestations of long-term nivolumab therapy. Future prospective and longitudinal studies with pretreatment tumor biopsies may help identify patients apt to respond to ICI therapy and further characterize patterns of ICI-related liver injury.

doi: https://doi.org/10.1038/s41379-020-00679-5



  • Oncologic Reappraisal of Bile Duct Resection for Middle-Third Cholangiocarcinoma

Annals of surgical oncology 2020 Sep;():

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=32960392

BACKGROUND: Although bile duct resection (BDR) in addition to pancreaticoduodenectomy (PD) is considered a surgical approach in patients with middle-third cholangiocarcinoma (MCC), available prognostic information after BDR remains very limited. The aim of this study was to reappraise BDR from the viewpoint of surgical oncology.
METHODS: Patients who underwent BDR or PD for MCC between 2001 and 2010 at 32 Japanese hospitals were included. Clinicopathological factors were retrospectively compared according to surgical procedure to identify a subset cohort who benefited most from BDR.
RESULTS: During the study, 92 patients underwent BDR (n = 38) or PD (n = 54). BDR was characterized by a shorter operation time, less blood loss, less frequent complications, and lower mortality, than PD. The incidence of positive surgical margins was 26.3% versus 5.6% (P = 0.007). The survival rate after BDR was significantly worse than that after PD: 38.8% versus 54.8% at 5 years (P = 0.035), and BDR was independently associated with deteriorated survival [hazard ratio (HR), 1.76; P = 0.023] by multivariable analysis. In the BDR group, tumor length < 15 mm (HR, 3.38; P = 0.017) and ductal margin length ≥ 10 mm (HR, 2.54; P = 0.018) were independent positive prognostic factors. Stratified by these two favorable factors, the 5-year survival rate was 63.0% in patients with ½ factors and 6.7% in those with 0 factors (P < 0.001).
CONCLUSION: In patients with MCC, BDR provided a better short-term and a worse long-term outcome than PD. However, patient selection using tumor length and ductal margin length may allow a favorable survival probability even after BDR.

doi: https://doi.org/10.1245/s10434-020-09157-3



  • Dabrafenib plus trametinib in patients with BRAFV600E-mutated biliary tract cancer (ROAR): a phase 2, open-label, single-arm, multicentre basket trial

The Lancet. Oncology 2020 09;21(9):1234-1243

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=32818466

BACKGROUND: Effective treatments for patients with cholangiocarcinoma after progression on gemcitabine-based chemotherapy are urgently needed. Mutations in the BRAF gene have been found in 5% of biliary tract tumours. The combination of dabrafenib and trametinib has shown activity in several BRAFV600E-mutated cancers. We aimed to assess the activity and safety of dabrafenib and trametinib combination therapy in patients with BRAFV600E-mutated biliary tract cancer.
METHODS: This study is part of an ongoing, phase 2, open-label, single-arm, multicentre, Rare Oncology Agnostic Research (ROAR) basket trial in patients with BRAFV600E-mutated rare cancers. Patients were eligible for the biliary tract cancer cohort if they were aged 18 years or older, had BRAFV600E-mutated, unresectable, metastatic, locally advanced, or recurrent biliary tract cancer, an Eastern Cooperative Oncology Group performance status of 0-2, and had received previous systemic treatment. All patients were treated with oral dabrafenib 150 mg twice daily and oral trametinib 2 mg once daily until disease progression or intolerance of treatment. The primary endpoint was the overall response rate, which was determined by Response Evaluation Criteria in Solid Tumors version 1.1 in the intention-to-treat evaluable population, which comprised all enrolled patients regardless of receiving treatment who were evaluable (ie, had progression, began a new anticancer treatment, withdrew consent, died, had stable disease for 6 weeks or longer, or had two or more post-baseline assessments). The ROAR trial is registered with ClinicalTrials.gov, NCT02034110. These results are based on an interim analysis; the study is active but not recruiting.
FINDINGS: Between March 12, 2014, and July 18, 2018, 43 patients with BRAFV600E-mutated biliary tract cancer were enrolled to the study and were evaluable. Median follow-up was 10 months (IQR 6-15). An investigator-assessed overall response was achieved by 22 (51%, 95% CI 36-67) of 43 patients. An independent reviewer-assessed overall response was achieved by 20 (47%, 95% CI 31-62) of 43 patients. The most common grade 3 or worse adverse event was increased γ-glutamyltransferase in five (12%) patients. 17 (40%) patients had serious adverse events and nine (21%) had treatment-related serious adverse events, the most frequent of which was pyrexia (eight [19%]). No treatment-related deaths were reported.
INTERPRETATION: Dabrafenib plus trametinib combination treatment showed promising activity in patients with BRAFV600E-mutated biliary tract cancer, with a manageable safety profile. Routine testing for BRAFV600E mutations should be considered in patients with biliary tract cancer.
FUNDING: GlaxoSmithKline and Novartis.

doi: https://doi.org/10.1016/S1470-2045(20)30321-1


New Ampulla Articles


  • Outcomes of limited resection for patients with intraductal papillary mucinous neoplasm of the pancreas: A single-center experience

Pancreatology : official journal of the International Association of Pancreatology (IAP) … [et al.] 2020 Sep;():

PubMed: https://www.ncbi.nlm.nih.gov/pubmed/?term=32972836

BACKGROUND: /ObjectivesThe aim of this study was to clarify the oncological outcomes of patients with intraductal papillary mucinous neoplasm (IPMN) who underwent limited resection (LR).
METHODS: This retrospective study analyzed the data of 110 patients with IPMN. Patients with IPMN without a history of pancreatitis who had neither tumor infiltration nor regional lymph node swelling on imaging findings underwent LR. We assessed the oncological outcomes of LR for patients with IPMN by comparing the surgical outcomes of LR and standard resection.
RESULTS: LR was performed in 50 patients (45.5%), including duodenum-preserving pancreatic head resection (n = 31), middle-pancreatectomy (n = 12), spleen-preserving distal pancreatectomy (n = 3), total parenchymal pancreatectomy (n = 3), and partial resection (n = 1). In the LR group, 18 patients had postoperative complications of Clavien-Dindo classification ≥ IIIa. After histopathological examination, the presence of high-grade dysplasia (HGD) and invasive carcinoma (IC) were observed in nine and three patients, respectively, in the LR group, and eight and 22 patients, respectively, in the standard resection group. There was a significant difference in the histopathological diagnosis of IC between the two groups (p < 0.001). Finally, in the LR group, postoperative recurrences occurred in three patients, and the 5-, 10-, and 15-year disease-specific survival rates were all 97.0%.
CONCLUSIONS: For patients with IPMN judged to have no infiltrating lesions based on the detailed imaging examination, LR is acceptable and may be considered as an alternative to standard resection.

doi: https://doi.org/10.1016/j.pan.2020.09.008


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