The benefit of pancreatic cancer surveillance in carriers of germline BRCA1/2 pathogenic variants.

BACKGROUND: Surveillance of high-risk individuals for pancreatic ductal adenocarcinoma (PDAC) is recommended. This study aimed to determine the prevalence and outcomes of PDAC and its precursor lesions in BRCA1/2 pathogenic variants (PVs) carriers undergoing pancreatic surveillance. METHODS: A retrospective multicenter cohort study of pancreatic surveillance outcomes in Israeli BRCA1/2 carriers preferably with a family history of PDAC. RESULTS: A total of 180 asymptomatic carriers participated in the screening programs, including 57 (31.7%) with BRCA1 PVs, 121 (67.2%) with BRCA2 PVs, and 12 (6.6%) with PVs in BRCA1/2 and other genes, for a median follow-up period of 4 years. Ninety-one individuals (50.5%) fulfilled the International Cancer of the Pancreas Screening (CAPS) criteria for surveillance whereas 116 (64.4%) fulfilled the American College of Gastroenterology (ACG) criteria. There were four cases of adenocarcinoma and four cases of grade 1-neuroendocrine tumor (G1-NET). All were BRCA2 carriers, and two had no family history of PDAC. Three cancer patients were at resectable stages (IA, IIA, IIB) whereas one had a stage IIIB tumor. Of the G1-NET cases, one had surgery and the others were only followed. Success rate for detection of confined pancreatic carcinoma was thus 1.6% (three of 180) in the whole cohort, 1.6% (two of 116) among individuals who fulfilled ACG criteria and 2.2% (two of 91) in those fulfilling CAPS criteria for surveillance. CONCLUSIONS: Despite the low detection rate of PDAC and its' high-risk neoplastic precursor lesions among BRCA1/2 carriers undergoing pancreatic surveillance, 75% of cancer cases were detected at a resectable stage.

Endoscopic Ultrasound-Guided Radiofrequency Ablation: A New Therapeutic Approach for Pancreatic Neuroendocrine Tumors.

CONTEXT: Endoscopic ultrasound-guided radiofrequency ablation (EUS-RFA) is rapidly emerging as feasible therapy for patients with pancreatic neuroendocrine tumors (pNETs) in selected cases, as a result of its favorable safety profile. OBJECTIVE: To assess the feasibility, safety, and efficacy of EUS-RFA in a cohort of patients with functional and nonfunctional pNETs (NF-pNETs). DESIGN: Data on pNET patients treated with EUS-RFA between March 2017 and October 2018 at two tertiary centers was retrospectively analyzed. RESULTS: The cohort included 18 adults (eight women, 10 men), aged 60.4 ± 14.4 years (mean ± SD), seven insulinoma patients, and 11 patients with NF-pNETs. Twenty-seven lesions with a mean diameter of 14.3 ± 7.3 mm (range 4.5 to 30) were treated. Technical success defined as typical postablative changes on a surveillance imaging was achieved in 26 out of 27 lesions. Clinical response with normalization of glucose levels was observed in all (seven of seven) insulinoma cases within 24 hours of treatment. Overall, there were no major complications 48 hours postprocedure. No clinically significant recurrences were observed during mean follow-up of 8.7 ± 4.6 months (range 2 to 21 months). CONCLUSIONS: EUS-guided RFA of pNETs is a minimally invasive, safe, and technically feasible procedure for selected patients.

RNAi therapy targeting KRAS in combination with chemotherapy for locally advanced pancreatic cancer patients.

PURPOSE: The miniature biodegradable implant siG12D-LODER™ was inserted into a tumor and released a siRNA drug against KRAS(G12D) along four months. This novel siRNA based drug was studied, in combination with chemotherapy, as targeted therapy for Locally Advanced Pancreatic Cancer (LAPC). METHODS: An open-label Phase 1/2a study in the first-line setting of patients with non-operable LAPC was initiated. In this study patients were assigned to receive a single dose of siG12D-LODERs, in three escalating dose cohorts (0.025mg, 0.75mg and 3.0mg). Gemcitabine was given on a weekly basis, following the siG12D-LODERTM insertion, until disease progression. The recommended dose was further examined with modified FOLFIRINOX. The follow up period was eight weeks and survival until death. RESULTS: Fifteen patients with LAPC were enrolled. Among the 15 treated patients, the most frequent adverse events observed were grade 1or 2 in severity (89%); five patients experienced serious adverse events (SAEs). In 12 patients analyzed by CT scans, none showed tumor progression, the majority (10/12) demonstrated stable disease and two showed partial response. Decrease in tumor marker CA19-9 was observed in 70% (7/10) of patients. Median overall survival was 15.12 months; 18 month survival was 38.5%. CONCLUSIONS: The combination of siG12D-LODER™ and chemotherapy is well tolerated, safe and demonstrated a potential efficacy in patients with LAPC. NCT01188785.

Macrocystic pancreatic cystadenoma: The role of EUS and cyst fluid analysis in distinguishing mucinous and serous lesions.

BACKGROUND: Benign pancreatic serous cystadenoma usually is morphologically distinguishable from mucinous cystadenomas, which require resection because of their malignant potential. A macrocystic variant of serous cystadenoma recently has been described, rendering this important distinction more difficult. The aim of this study was to determine the EUS and tumor marker characteristics of mucinous cystadenoma compared with macrocystic serous cystadenomas. METHODS: Medical records for consecutive patients seen between 1995 and 2002, with a histopathologic diagnosis of mucinous cystadenoma or macrocystic serous cystadenoma after surgery, who had undergone a detailed EUS examination, including EUS-guided FNA, were retrospectively reviewed. RESULTS: A resection specimen was available for 32 mucinous cystadenomas and 9 macrocystic serous cystadenomas. No significant differences were observed with regard to clinical data (age, gender, presence of symptoms), lesion size, and location within the pancreas. All mucinous cystadenomas had a discernible cyst wall (thickened, 66%; focal parietal nodules, 25%) compared with 56% of macrocystic serous cystadenomas (p<0.0001). A thick echo content also was more frequent in mucinous cystadenoma (56% vs. 11%; p=0.04; statistical significance removed by the Bonferroni correction). Microcysts were only observed in macrocystic serous cystadenomas (44%; p=0.0008). The combination of a cyst wall that is thickened and the absence of microcysts had a sensitivity of 100% and specificity of 78% for the diagnosis of mucinous cystadenoma compared with macrocystic serous cystadenoma. Although intracystic carbohydrate-associated antigen 72-4 and mucins M1 were non-discriminatory, low carcinoembryonic antigen (<5 ng/mL) and carbohydrate-associated antigen 19-9 (<50,000 U/mL) values were found in macrocystic serous lesions (respectively, 100% and 100%; p=0.0002 and p=0.0002). CONCLUSIONS: Although there is considerable overlap, helpful EUS characteristics that differentiate mucinous cystadenoma from macrocystic serous cystadenoma include a thick cyst wall and microcysts. These features, coupled with analysis of aspirated fluid for tumor markers (especially carcinoembryonic antigen), should help to confirm the diagnosis.

Intraductal papillary mucinous tumors of the pancreas: the preoperative value of cytologic and histopathologic diagnosis.

BACKGROUND: The preoperative diagnosis of intraductal papillary mucinous tumors of the pancreas must be as certain as possible because removal of a large portion of the pancreas or even total pancreatectomy may be necessary. The value of cytologic and histopathologic analysis of specimens obtained by preoperative endoscopic investigations is unknown. The aim of this study was to assess the value of such analyses of specimens obtained by EUS-guided FNA and/or biopsy, or transpapillary biopsy specimens obtained during endoscopic retrograde pancreatography for the diagnosis of intraductal papillary mucinous tumors of the pancreas and for the detection of malignancy. METHODS: Between 1992 and 2001, 42 patients (22 men, 20 women; median age 64 years) underwent surgical resection for intraductal papillary mucinous tumors of the pancreas and had preoperative pancreatic tissue sampling. In the case of isolated dilatation of pancreatic ducts, pancreatic juice was obtained by EUS-guided FNA for cytologic analysis. In the presence of a solid lesion or main pancreatic duct stenosis, biopsy specimens were obtained by EUS-guided FNA biopsy or endoscopic retrograde pancreatography, which permitted histopathologic assessment. The accuracy of cytology and histopathology was evaluated for the following: (1) positive diagnosis of intraductal papillary mucinous tumors of the pancreas and (2) assessment of malignancy, by comparison with histopathologic examination of surgical resection specimens. RESULTS: Cytologic analysis was performed in 19 patients; it was positive in 4 (21%) and noninformative in 15 (79%). Histopathologic analysis was performed in 23 patients; it was positive in 21 (91%) and negative in 2 (9%). Histopathologic analysis yielded a positive result in 83% of patients who did not have extrusion of mucus from a patulous papilla. The sensitivity, specificity, and positive and negative predictive values of histopathologic analysis for the diagnosis of malignancy were, respectively, 44%, 100%, 100%, and 33%. When histopathologic analysis was positive, the tumor grade was similar to that determined by final histopathologic examination in 38% of patients, whereas the grade was underestimated in 62%. No complication occurred as a result of tissue sampling. CONCLUSIONS: The sensitivity of histopathologic analysis of EUS-guided FNA biopsy specimens or transpapillary biopsy specimens is 91% for the positive diagnosis of intraductal papillary mucinous tumors of the pancreas with a solid component, which is of particular interest as extrusion mucus from the papilla was absent in most patients. Histopathologic analysis of biopsy specimens of malignant intraductal papillary mucinous tumors of the pancreas often underestimates tumor grade. The result for cytologic analysis of juice obtained from dilated pancreatic ducts is disappointing.