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Invasive intraductal papillary mucinous carcinoma (IPMC) has a high malignant potential, with surgical resection being the only potentially curative treatment. However, even after surgical resection, recurrence occurs frequently and the prognosis is poor once recurrence develops. While retrospective studies aiming to achieve long‐term survival in invasive IPMC patients have been reported, the rarity of invasive IPMC has resulted in small‐scale datasets, leading to low levels of evidence. Consequently, the utility of adjuvant therapy after surgery, neoadjuvant therapy (NAT) before surgery, and treatments for postoperative recurrence in invasive IPMC remains unclear, with treatment strategies varying by institution—ranging from surgical resection alone to approaches based on conventional pancreatic cancer treatment. Recently, several large‐scale multicenter studies on invasive IPMC have been reported. These studies suggested that while adjuvant therapy after surgery may not be beneficial for all invasive IPMC patients, it could potentially extend survival in cases with advanced‐stage disease. Regarding NAT before surgery for invasive IPMC, the number of reported cases is extremely limited, and no definitive evidence has been established. For postoperative recurrence of invasive IPMC, some studies have indicated that administering treatment may prolong survival. Although these large‐scale studies have gradually clarified certain characteristics of invasive IPMC, they are all retrospective in nature, resulting in a low level of evidence. To achieve long‐term survival for invasive IPMC patients, large‐scale prospective multicenter studies are needed in the future.

BackgroundAlthough there are numerous reports focusing on surgical indication for intraductal papillary mucinous neoplasm (IPMN), the recurrence patterns following surgery are less widely reported. To ascertain optimal treatment and postoperative surveillance for IPMN patients, we analyzed patterns and risk factors for recurrence after surgery for IPMN.MethodsThis study is a retrospective, multi-institutional, observational study, including 1074 patients undergoing surgery for IPMN at 11 academic institutions. We analyzed the risk factors for recurrence after classifying postoperative recurrences into metachronous high-risk lesions (malignant progression of IPMN and/or metachronous pancreatic ductal adenocarcinoma) in the remnant pancreas and extra-pancreatic recurrence.ResultsOf 1074 patients undergoing surgery for IPMN, 155 patients (14.4%) developed postoperative recurrence. We found that 34.3% of 70 high-risk lesions in the remnant pancreas occurred over 5 years after surgery, and survival of 36 patients undergoing second operation for high-risk lesions was better than that of 34 patients who did not (P = 0.04). We found four independent risk factors for metachronous high-risk lesions in remnant pancreas: symptoms [P = 0.005, hazard ratio (HR) 1.988], location of pancreatic body/tail (P < 0.001, HR 3.876), main duct size ≥ 10 mm (P = 0.021, HR 1.900), and high-grade dysplasia/invasive intraductal papillary mucinous carcinoma (IPMC) (P < 0.001, HR 3.204). Although six patients (0.7%) with low- or high-grade dysplasia IPMN developed extra-pancreatic recurrence, invasive IPMC was the strongest risk factor for extra-pancreatic recurrence (P < 0.001, HR 39.667).ConclusionWe suggest that life-time continuous surveillance might be necessary for IPMN patients. Second surgery for metachronous high-risk lesions in remnant pancreas should be considered to improve survival.

BackgroundCirculating tumor DNA (ctDNA) might be a promising biomarker for pancreatic cancer in liquid biopsy. This study aimed to evaluate the usefulness of liquid biopsy for patients with borderline-resectable pancreatic cancer (BR-PC).MethodsPatients with BR-PC according to the National Comprehensive Cancer Network guidelines (2017) and eligible for neoadjuvant chemotherapy (NAC) followed by pancreatectomy were recruited at Wakayama Medical University Hospital (UMIN000026647) between March 2017 and April 2020. The study enrolled 55 patients with locally advanced PC, and each patient consented to inclusion in the study. The study investigated the relationship between KRAS status in ctDNA and clinicopathologic features, analyzing ctDNA at three time points: pretreatment, post-NAC, and post-operation.ResultsOf the 55 enrolled patients with a diagnosis of BR-PC, 34 were scheduled to undergo pancreatectomy. From 27 patients with resected BR-PC, 81 blood samples were analyzed in triplicate for ctDNA. The patients with positive pretreatment and post-NAC ctDNA status had no significant decrease in median relapse-free survival (RFS) or overall survival (OS). However, the patients with positive postoperation ctDNA status had a significantly shorter median OS (723 days) than the patients with negative ctDNA results (not reached; P = 0.0148). A combined analysis of postoperative ctDNA and CA19-9 values showed the cumulative effect on both RFS (P = 0.0066) and OS (P = 0.0046). The adjusted hazard ratio for risk of survival computed for the patients carrying risk factors (either detectable ctDNA or CA19-9 > 37 U/ml) increased from 4.13-fold to 17.71-fold (both P = 0.0055) compared with the patients who had no risk factors.ConclusionPositive ctDNA predicts poor survival for patients with BR-PC who undergo NAC followed by pancreatectomy.

The appropriate surgical stump closure after distal pancreatectomy (DP) is still controversial. This study investigated the benefits and risks of stapler closure during DP. The risk factors of pancreatic fistulas were investigated in 122 DPs among 3 types of stump closure: hand-sewn suture (n = 32), bipolar scissors (n = 45), and stapler closure (n = 45). There was no significant difference in the incidence of pancreatic fistula between the 3 types of stump closure (hand-sewn suture [44%] vs bipolar scissors [37.7%] vs stapler closure [35.5%]). By using receiver operating characteristics curves, 12 mm was the best cutoff value of the thickness of the pancreas for pancreatic fistulas after DP using stapler closure. Three factors (ie, male sex, body mass index >25 kg/m2, and stapler closure) were independent risk factors of pancreatic fistulas after DP with a pancreas thicker than 12 mm. A pancreas thicker than 12 mm significantly increased the incidence of pancreatic fistulas after DP using stapler closure.

Background Although the standard therapy for advanced-stage hepatocellular carcinoma (HCC) is systemic chemotherapy, the combination of atezolizumab and bevacizumab (atezo + bev) with a high objective response rate may lead to conversion to resection in patients with initially unresectable HCC. This study aims to evaluate the efficacy of atezo + bev in achieving conversion surgery and prolonged progression-free survival (PFS) for initially unresectable HCC. Methods The RACB study is a prospective, single-arm, multicenter, phase II trial evaluating the efficacy of combination therapy with atezo + bev for conversion surgery in patients with technically and/or oncologically unresectable HCC. The main eligibility criteria are as follows: (1) unresectable HCC without a history of systemic chemotherapy, (2) at least one target lesion based on RECIST ver. 1.1, and (3) a Child‒Pugh score of 5–6. The definition of unresectable tumors in this study includes macroscopic vascular invasion and/or extrahepatic metastasis and massive distribution of intrahepatic tumors. Patients will be treated with atezolizumab (1200 mg/body weight) and bevacizumab (15 mg/kg) every 3 weeks. If the patient is considered resectable on radiological assessment 12 weeks after initial chemotherapy, the patient will be treated with atezolizumab monotherapy 3 weeks after combination chemotherapy followed by surgery 3 weeks after atezolizumab monotherapy. If the patient is considered unresectable, the patient will continue with atezo + bev and undergo a radiological assessment every 9 weeks until resectable or until disease progression. The primary endpoint is PFS, and the secondary endpoints are the overall response rate, overall survival, resection rate, curative resection rate, on-protocol resection rate, and ICG retention rate at 15 min after atezo + bev therapy. The assessments of safety and quality of life during the treatment course will also be evaluated. The number of patients has been set at 50 based on the threshold and the expected PFS rate at 6 months after enrollment of 40% and 60%, respectively, with a one-sided alpha error of 0.05 and power of 0.80. The enrollment and follow-up periods will be 2 and 1.5 years, respectively. Discussion This study will elucidate the efficacy of conversion surgery with atezo + bev for initially unresectable HCC. In addition, the conversion rate, safety and quality of life during the treatment course will also be demonstrated. Trial registration This study is registered in the Japan Registry of Clinical Trials (jRCTs051210148, January 7, 2022).

PurposeThe prognostic impact of radiographic splenic vessel involvement in pancreatic cancer remains unclear. We evaluate its oncological significance in resectable pancreatic body/tail cancer.Patients and MethodsWe retrospectively review 102 cases of resectable pancreatic cancer and 51 of borderline resectable pancreatic cancer (BRPC) who underwent pancreatectomy for pancreatic body/tail cancer. Resectable pancreatic body/tail cancer was classified into one of three categories based on radiographic splenic vessel involvement.ResultsAmong 102 cases of resectable pancreatic cancer, 37 (36.3%), 35 (34.3%), and 30 cases (29.4%) were classified as no splenic vessel involvement (Rnone), splenic vein involvement (RV), and splenic artery involvement (RA), respectively. Disease-free survival (DFS) among patients with Rnone, RV, RA, and BRPC was 58.5, 18.4, 10.8, and 9.2 months, respectively. Patients with RV and RA had significantly poorer DFS than patients with Rnone (P = 0.010, P < 0.001, respectively). Median survival among Rnone, RV, RA, and BRPC was 80.6, 23.4, 15.1, and 21.3 months, respectively. Patients with RV and RA had significantly poorer survival than patients with Rnone (P = 0.001, P < 0.001, respectively) and had short survival similar to that of those with BRPC. Multivariate Cox proportional hazard analysis detected preoperative CA19-9 ≥ 37 IU/L, radiologic splenic vein involvement, radiologic splenic artery involvement, intraoperative bleeding ≥ 500 ml, transfusion, positive washing cytology, and noncompletion of adjuvant therapy as independent prognostic factors.ConclusionsRadiographic splenic artery involvement is a poor prognostic factor in resectable pancreatic body/tail cancer and may have a role in stratification of treatment strategy.

INTRODUCTION: Acinar cell carcinoma (ACC) is a rare malignant tumor arising from pancreatic exocrine cells. While it typically originates in the pancreas, ectopic occurrences, especially in the duodenum, are extremely uncommon. Few reports exist of duodenal ACC, particularly those presenting as large tumors.CASE PRESENTATION: An 83-year-old man presented with melena. Endoscopy and imaging revealed a large mass, approximately 7 cm in size, extending from the duodenal bulb to the descending portion of the duodenum. Contrast-enhanced CT showed no evidence of extramural invasion or distant metastasis. Although biopsy confirmed malignancy, a definitive diagnosis could not be established preoperatively. The patient underwent pancreaticoduodenectomy. Postoperative histopathological examination, including immunohistochemical staining positive for trypsin, confirmed the diagnosis of pancreatic-type ACC, likely arising from ectopic pancreatic tissue in the duodenum.CONCLUSIONS: We report a rare case of a giant pancreatic-type ACC of the duodenum, which was strongly suspected to have arisen from ectopic pancreatic tissue. This case highlights the diagnostic challenges associated with pancreatic-type ACC of the duodenum and adds valuable information to the limited literature on this rare entity.

The invasion process is a crucial step for pancreatic ductal adenocarcinoma (PDAC); however, the genes related to invasion remain unclear. To identify specific genes for the invasion process, we compared microarray data for infiltrating cancer and PanIN‐3, which were harvested from an individual PDAC patient by microdissection. Furthermore, immunohistochemical, coimmunoprecipitation and invasion analyses were performed to confirm the biologic significance of molecules identified by expression profile. In the present study, we focused on MUC16 and mesothelin among 87 genes that were significantly upregulated in infiltrating components compared to PanIN‐3 in all PDAC patients, because MUC16 was the most differently expressed between two regions, and mesothelin was reported as the receptor for MUC16. Immunohistochemical analysis revealed that MUC16 and mesothelin were expressed simultaneously only in infiltrating components and increased at the invasion front, and binding of MUC16 and mesothelin was found in PDAC by immunoprecipitation assay. The downregulation of MUC16 by shRNA and the blockage of MUC16 binding to mesothelin by antibody inhibited both invasion and migration of pancreatic cancer cell line. MUC16 high/mesothelin high expression was an independent prognostic factor for poor survival in PDAC patients. In conclusion, we identified two specific genes, MUC16 and mesothelin, associated with the invasion process in patients with PDAC. (Cancer Sci 2012; 103: 739–746)

BackgroundTo accomplish laparoscopic anatomical liver resection, intraoperative liver segmentation is necessary. Tattooing method or Glissonian approach will be used in a similar way to that in open liver resection. Moreover, in liver segment detection, the fluorescence of indocyanine green (ICG) means it has been recognized as a useful dye. In laparoscopy, however, there are technical difficulties in performing these conventional methods, so development of new techniques is necessary for liver segment identification. We report a pilot study using interventional radiology technique for laparoscopic intraoperative liver segmentation.MethodsJust prior to liver parenchymal resection, angiography was performed using a hybrid operation room. A catheter was inserted from the right femoral artery into the targeted arterial branch. After confirming the perfusion area by arteriography, embolic solution containing ICG was injected, and the branch was embolized. ICG fluorescence was observed by PINPOINT, a near-infrared imaging system.ResultsImmediately after embolic solution injection, we were able to observe ICG fluorescence on the surface of the liver to be resected. This visual effect continued during liver parenchymal resection. We were able to confirm the intra-parenchymal boundary by observing ICG fluorescence on the cut surface of the resecting side and accomplished precise anatomical liver resection.ConclusionsOur novel technique provides advances in laparoscopic anatomical liver resection performance. As two-dimensional laparoscopy lacks depth perception, additional visual information, such as ICG fluorescence imagery, is helpful as a navigation tool for precise laparoscopic anatomical liver resection.

Vascular endothelial growth factor receptor 2 (VEGFR2) is an essential factor in tumor angiogenesis and in the growth of pancreatic cancer. Immunotherapy using epitope peptide for VEGFR2 (VEGFR2‐169) that we identified previously is expected to improve the clinical outcome. Therefore, a phase I clinical trial combining of VEGFR2‐169 with gemcitabine was conducted for patients with advanced pancreatic cancer. Patients with metastatic and unresectable pancreatic cancer were eligible for the trial. Gemcitabine was administered at a dose of 1000 mg/m2 on days 1, 8, and 15 in a 28‐day cycle. The VEGFR2‐169 peptide was subcutaneously injected weekly in a dose‐escalation manner (doses of 0.5, 1, and 2 mg/body, six patients/one cohort). Safety and immunological parameters were assessed. No severe adverse effect of grade 4 or higher was observed. Of the 18 patients who completed at least one course of the treatment, 15 (83%) developed immunological reactions at the injection sites. Specific cytotoxic T lymphocytes (CTL) reacting to the VEGFR2‐169 peptide were induced in 11 (61%) of the 18 patients. The disease control rate was 67%, and the median overall survival time was 8.7 months. This combination therapy for pancreatic cancer patients was tolerable at all doses. Peptide‐specific CTL could be induced by the VEGFR2‐169 peptide vaccine at a high rate, even in combination with gemcitabine. From an immunological point of view, the optimal dose for further clinical trials might be 2 mg/body or higher. This trial was registered with ClinicalTrial.gov (no. NCT 00622622). (Cancer Sci 2009)