Corrigendum: Tumor infiltrating T cell states and checkpoint inhibitor expression in hepatic and pancreatic malignancies.

[This corrects the article DOI: 10.3389/fimmu.2023.1067352.].

Tumor infiltrating T cell states and checkpoint inhibitor expression in hepatic and pancreatic malignancies.

Hepato-pancreatico-biliary (HPB) malignancies are difficult-to-treat and continue to to have a high mortality and significant therapeutic resistance to standard therapies. Immune oncology (IO) therapies have demonstrated efficacy in several solid malignancies when combined with chemotherapy, whereas response rates in pancreatic ductal adenocarcinoma (PDA) are poor. While promising in hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), there remains an unmet need to fully leverage IO therapies to treat HPB tumors. We therefore defined T cell subsets in the tumor microenvironment of HPB patients utilizing a novel, multiparameter flow cytometry and bioinformatics analysis. Our findings quantify the T cell phenotypic states in relation to checkpoint receptor expression. We demonstrate the presence of CD103+ tissue resident memory T cells (TRM), CCR7+ central memory T cells, and CD57+ terminally differentiated effector cells across all HPB cancers, while the anti-tumor function was dampened by expression of multiple co-inhibitory checkpoint receptors. Terminally exhausted T cells lacking co-stimulatory receptors were more prevalent in PDA, whereas partially exhausted T cells expressing both co-inhibitory and co-stimulatory receptors were most prevalent in HCC, especially in early stage. HCC patients had significantly higher TRM with a phenotype that could confer restored activation in response to immune checkpoint therapies. Further, we found a lack of robust alteration in T cell activation state or checkpoint expression in response to chemotherapy in PDA patients. These results support that HCC patients might benefit most from combined checkpoint therapies, whereas efforts other than cytotoxic chemotherapy will likely be necessary to increase overall T cell activation in CCA and PDA for future clinical development.

Impact of comprehensive family history and genetic analysis in the multidisciplinary pancreatic tumor clinic setting.

BACKGROUND: Genetic testing is recommended for all pancreatic ductal adenocarcinoma (PDAC) patients. Prior research demonstrates that multidisciplinary pancreatic cancer clinics (MDPCs) improve treatment- and survival-related outcomes for PDAC patients. However, limited information exists regarding the utility of integrated genetics in the MDPC setting. We hypothesized that incorporating genetics in an MDPC serving both PDAC patients and high-risk individuals (HRI) could: (1) improve compliance with guideline-based genetic testing for PDAC patients, and (2) optimize HRI identification and PDAC surveillance participation to improve early detection and survival. METHODS: Demographics, genetic testing results, and pedigrees were reviewed for PDAC patients and HRI at one institution over 45 months. Genetic testing analyzed 16 PDAC-associated genes at minimum. RESULTS: Overall, 969 MDPC subjects were evaluated during the study period; another 56 PDAC patients were seen outside the MDPC. Among 425 MDPC PDAC patients, 333 (78.4%) completed genetic testing; 29 (8.7%) carried a PDAC-related pathogenic germline variant (PGV). Additionally, 32 (9.6%) met familial pancreatic cancer (FPC) criteria. These PDAC patients had 191 relatives eligible for surveillance or genetic testing. Only 2/56 (3.6%) non-MDPC PDAC patients completed genetic testing (p < 0.01). Among 544 HRI, 253 (46.5%) had a known PGV or a designation of FPC, and were eligible for surveillance at baseline; of the remainder, 15/291 (5.2%) were eligible following genetic testing and PGV identification. CONCLUSION: Integrating genetics into the multidisciplinary setting significantly improved genetic testing compliance by reducing logistical barriers for PDAC patients, and clarified cancer risks for their relatives while conserving clinical resources. Overall, we identified 206 individuals newly eligible for surveillance or genetic testing (191 relatives of MDPC PDAC patients, and 15 HRI from this cohort), enabling continuity of care for PDAC patients and at-risk relatives in one clinic.

Cancer surveillance awareness and practice among families at increased risk for pancreatic adenocarcinoma.

BACKGROUND: Early detection of pancreatic ductal adenocarcinoma (PDAC) is an important goal for improving survival. Individuals who meet published guidelines for surveillance may be underidentified, and family communication about risk represents a pathway to increasing participation in surveillance. We investigated the uptake of and barriers to surveillance in at-risk relatives of clinic patients. METHODS: We conducted a retrospective record review of patients with personal or family history of PDAC evaluated over 12 months. The first relative presenting to clinic (proband) reported surveillance status and reasons for nonparticipation for at-risk relatives. Descriptive analyses and Fisher's exact tests were conducted to evaluate differences in surveillance participation. RESULTS: Among 193 at-risk relatives, 21% were in surveillance. The primary reasons for nonparticipation were lack of awareness (36%) and lack of interest (24%). Neither the sex nor the cancer status of probands impacted surveillance. At-risk relatives with familial pancreatic cancer (FPC) who also carried relevant pathogenic germline variants (PGVs) were more likely to undergo surveillance than those with FPC or PGVs alone (P = .003). Among families with PGVs, 59% of relatives potentially eligible for surveillance had not completed genetic testing. CONCLUSION: PDAC surveillance is underutilized in high-risk families. Communication interventions to address informational needs and decisional support could improve outcomes.

Donning a New Approach to the Practice of Gastroenterology: Perspectives From the COVID-19 Pandemic Epicenter.

The COVID-19 pandemic seemingly is peaking now in New York City and has triggered significant changes to the standard management of gastrointestinal diseases. Priorities such as minimizing viral transmission, preserving personal protective equipment, and freeing hospital beds have driven unconventional approaches to managing gastroenterology (GI) patients. Conversion of endoscopy units to COVID units and redeployment of GI fellows and faculty has profoundly changed the profile of most GI services. Meanwhile, consult and procedural volumes have been reduced drastically. In this review, we share our collective experiences regarding how we have changed our practice of medicine in response to the COVID surge. Although we review our management of specific consults and conditions, the overarching theme focuses primarily on noninvasive measures and maximizing medical therapies. Endoscopic procedures have been reserved for those timely interventions that are most likely to be therapeutic. The role of multidisciplinary discussion, although always important, now has become critical. The support of our faculty and trainees remains essential. Local leadership can encourage well-being by frequent team check-ins and by fostering trainee development through remote learning. Advancing a clear vision and a transparent process for how to organize and triage care in the recovery phase will allow for a smooth transition to our new normal.

The Role of Endoscopic Ultrasound-Guided Ki67 in the Management of Non-Functioning Pancreatic Neuroendocrine Tumors.

BACKGROUND/AIMS: The management of small, incidentally discovered nonfunctioning pancreatic neuroendocrine tumors (NF-PNETs) has been a matter of debate. Endoscopic ultrasound with fine-needle aspiration (EUS-FNA) is a tool used to identify and risk-stratify PNETs. This study investigates the concordance rate of Ki67 grading between EUS-FNA and surgical pathology specimens in NFPNETs and whether certain NF-PNET characteristics are associated with disease recurrence and disease-related death. METHODS: We retrospectively reviewed the clinical history, imaging, endoscopic findings, and pathology records of 37 cases of NFPNETs that underwent pre-operative EUS-FNA and surgical resection at a single academic medical center. RESULTS: There was 73% concordance between Ki67 obtained from EUS-FNA cytology and surgical pathology specimens; concordance was the highest for low- and high-grade NF-PNETs. High-grade Ki67 NF-PNETs based on cytology (p=0.028) and histology (p=0.028) were associated with disease recurrence and disease-related death. Additionally, tumors with high-grade mitotic rate (p=0.005), tumor size >22.5 mm (p=0.104), and lymphovascular invasion (p=0.103) were more likely to have poor prognosis. CONCLUSION: NF-PNETs with high-grade Ki67 on EUS-FNA have poor prognosis despite surgical resection. NF-PNETs with intermediate-grade Ki67 on EUS-FNA should be strongly considered for surgical resection. NF-PNETs with low-grade Ki67 on EUSFNA can be monitored without surgical intervention, up to tumor size 20 mm.

CDKN2A Germline Rare Coding Variants and Risk of Pancreatic Cancer in Minority Populations.

Background: Pathogenic germline mutations in the CDKN2A tumor suppressor gene are rare and associated with highly penetrant familial melanoma and pancreatic cancer in non-Hispanic whites (NHW). To date, the prevalence and impact of CDKN2A rare coding variants (RCV) in racial minority groups remain poorly characterized. We examined the role of CDKN2A RCVs on the risk of pancreatic cancer among minority subjects.Methods: We sequenced CDKN2A in 220 African American (AA) pancreatic cancer cases, 900 noncancer AA controls, and 183 Nigerian controls. RCV frequencies were determined for each group and compared with that of 1,537 NHW patients with pancreatic cancer. Odds ratios (OR) and 95% confidence intervals (CI) were calculated for both a case-case comparison of RCV frequencies in AAs versus NHWs, and case-control comparison between AA cases versus noncancer AA controls plus Nigerian controls. Smaller sets of Hispanic and Native American cases and controls also were sequenced.Results: One novel missense RCV and one novel frameshift RCV were found among AA patients: 400G>A and 258_278del. RCV carrier status was associated with increased risk of pancreatic cancer among AA cases (11/220; OR, 3.3; 95% CI, 1.5-7.1; P = 0.004) compared with AA and Nigerian controls (17/1,083). Further, AA cases had higher frequency of RCVs: 5.0% (OR, 13.4; 95% CI, 4.9-36.7; P < 0.001) compared with NHW cases (0.4%).Conclusions: CDKN2A RCVs are more common in AA than in NHW patients with pancreatic cancer and associated with moderately increased pancreatic cancer risk among AAs.Impact: RCVs in CDKN2A are frequent in AAs and are associated with risk for pancreatic cancer. Cancer Epidemiol Biomarkers Prev; 27(11); 1364-70. ©2018 AACR.

Optical coherence tomography (OCT) prior to peroral endoscopic myotomy (POEM) reduces procedural time and bleeding: a multicenter international collaborative study.

BACKGROUND: Per-oral endoscopic myotomy (POEM) has emerged as an endoscopic treatment of achalasia. There are no pre-procedural imaging modalities to predict the safest and the most efficacious approach. AIM: To evaluate the use of optimal coherence tomography (OCT) in providing a pre-procedural esophageal assessment. METHODS: Patients undergoing POEM from July 2013 to November 2015 were captured in a multicenter, international registry. Patients who underwent OCT pre-POEM ("OCT arm") were compared to patients without pre-POEM OCT ("control arm"). OCT images were assessed for the degree of vascularity and the thickness of the circular muscular layer, and an approach was determined. RESULTS: A total of 84 patients were captured in the registry. Fifty-one patients underwent pre-POEM OCT. Using OCT as a guide, 24 (47 %) of patients underwent anterior POEM while 27 (53 %) underwent posterior POEM. Technical success was achieved in 96 % of patients. Significantly less bleeding occurred in the OCT arm when compared to the control group [4 (8 %) vs. 14 (43 %), p = 0.0001]. As a result, procedural time was significantly lower in the OCT group as compared to the control group (85.8 vs. 121.7 min, p = 0.000097). CONCLUSION: Pre-POEM OCT results in a reduction in procedural bleeding which contributes to a reduction in overall procedural time. CLINICAL TRIAL REGISTRATION: NCT01438385.

Gadofosveset trisodium-enhanced MR angiography for detection of lower gastrointestinal bleeding.

The purpose of our study is to determine if Gadofosveset trisodium-enhanced magnetic resonance angiography (MRA) could be used for detection and localization of acute lower gastrointestinal (LGI) bleed. Four patients underwent MRA (4 females, mean age of 65 years) for suspected LGI bleeding. MRA detected an active rectal bleed in one patient. All other patients did not demonstrate active bleeding and these true negatives were confirmed by computed tomography angiography, endoscopy, and tagged-red blood cell scan or digital subtraction angiography. Preliminary results suggest that MRA may serve as an alternative technique for detecting acute LGI bleeding when nuclear scintigraphy is unavailable or in the younger radiosensitive population but further investigation in a larger cohort is required.

Preoperative evaluation of oesophageal adenocarcinoma.

The preoperative evaluation of oesophageal adenocarcinoma involves endoscopic ultrasound (EUS), computed tomography (CT), and positron emission tomography (PET). With routine Barrett's oesophagus surveillance, superficial cancers are often identified. EUS, CT and PET have a limited role in the staging of superficial tumours. Standard EUS has limited accuracy, but high frequency ultrasound miniprobes are valuable for assessing tumour stage in superficial tumours. However, the best method for determining depth of invasion, and thereby stage of disease, is endoscopic mucosal resection. In contrast, in advanced oesophageal cancers, a multi-modality approach is crucial. Accurate tumour staging is very important since the treatment of advanced cancers involves a combination of chemotherapy, radiation, and surgery. EUS is very useful for staging of the tumour and nodes. High frequency ultrasound miniprobes provide the ability to perform staging when the lesion is obstructing the oesophageal lumen. CT and PET provide valuable information regarding node and metastasis staging.

Absence of pancreatic intraepithelial neoplasia predicts poor survival after resection of pancreatic cancer.

OBJECTIVES: Pancreatic intraepithelial neoplasia (PanIN), thought to represent the dominant precursor of pancreatic adenocarcinoma (PDAC), is often found synchronously adjacent to resected PDAC tumors. However, its prognostic significance on outcome after PDAC resection is unknown. METHODS: A total of 342 patients who underwent resection for PDAC between 2005 and 2010 at a single institution were identified and stratified according to highest grade of PanIN demonstrated surrounding the tumor. Clinical and pathologic characteristics of each patient and tissue were recorded and analyzed. The primary outcome was length of survival after resection. RESULTS: An absence of PanIN lesions was identified in 32 patients (9%), low grade PanIN without synchronous high grade lesions was identified in 52 patients (15%), and high grade PanIN was found in 258 patients (75%). Median survival were 12.8 months for the non-PanIN group, 26.3 months for the low-grade PanIN group, and 23.8 months for the high-grade PanIN groups (P = 0.043). In multivariable analysis, absence of PanIN was independently associated with poor survival (P = 0.002). CONCLUSIONS: The patients who demonstrate an absence of PanIN in the pancreatic tissue adjacent to the resected PDAC tumor have shorter postresection survival compared with those who demonstrate a PanIN lesion.

BRCA1 and BRCA2 germline mutations are frequently demonstrated in both high-risk pancreatic cancer screening and pancreatic cancer cohorts.

BACKGROUND: Approximately 10% of pancreatic ductal adenocarcinoma (PDAC) is due to a genetic predisposition, including the breast and ovarian cancer syndrome germline mutations BRCA1 and BRCA2. Knowledge of specific genetic mutations predisposing to PDAC may enable risk stratification, early detection, and the development of effective screening and surveillance programs. In the current study, the authors attempted to determine the diagnostic yield of testing for BRCA1/2 germline mutations in a PDAC screening cohort and a PDAC cohort referred for genetic testing. METHODS: Patients in a high-risk PDAC prevention and genetics program or those with a personal history of PDAC who were referred for genetic evaluation underwent testing for BRCA1/2 germline mutations. Clinical BRCA1/2 genetic testing included testing for the 3 Ashkenazi Jewish founder mutations or BRCA1/2 comprehensive testing. RESULTS: A total of 37 patients without PDAC underwent BRCA1/2 testing at the study institution. Genetic testing identified 7 patients who were BRCA1/2 carriers for a yield of 18.9%. Six patients carried Ashkenazi Jewish founder mutations (3 with BRCA1 and 3 with BRCA2), and 1 patient was found to have a BRCA2 mutation on comprehensive testing. Thirty-two patients with PDAC underwent BRCA1/2 genetic testing. Five patients had Ashkenazi Jewish founder mutations (2 with BRCA1 and 3 with BRCA2), and 2 patients were found to have BRCA2 mutations on comprehensive testing. The diagnostic yield was 7 of 32 patients (21.9%). CONCLUSIONS: BRCA1/2 testing is useful in PDAC risk stratification and alters risk assignment and screening recommendations for mutation-positive patients and their families. Clinical BRCA1/2 testing should be considered in patients of Ashkenazi Jewish descent with a personal history or family history of PDAC, even in the absence of a family history of breast and ovarian cancer.

Uptake and patterns of use of gemcitabine for metastatic pancreatic cancer: a population-based study.

Gemcitabine was approved for advanced pancreatic cancer in 1996. We investigated uptake and predictors of its use. We identified 3,231 individuals > 65 years in the SEER-Medicare database with stage IV pancreatic adenocarcinoma, diagnosed between 1998-2005, who survived > 30 days. Of these, 54% received chemotherapy, 93% with gemcitabine. Gemcitabine nonreceipt was associated with advanced age and unmarried (OR: 0.65, 95% CI: 0.55-0.76). Diagnosis in 2004-2005 versus 1998-2000 was more likely to receive gemcitabine (OR: 1.51, 95% CI: 1.23-1.84) as were higher SES patients (highest versus lowest quintile, OR: 2.14, 95% CI: 1.60-2.85). Gemcitabine was rapidly adopted among elderly advanced pancreatic cancer patients; several factors are associated with use.