Gene Rearrangement and Expression of PRKACA and PRKACB Govern Morphobiology of Pancreatobiliary Oncocytic Neoplasms.

Intraductal oncocytic papillary neoplasms (IOPNs) are distinct from intraductal papillary mucinous neoplasms based on characteristic morphologic and genetic features represented by fusion genes involving PRKACA or PRKACB (PRKACA/B). However, pancreatic and biliary tumors with partial oncocytic features are often encountered clinically, and their molecular features are yet to be clarified. This study included 80 intraductal papillary neoplasms: 32 tumors with mature IOPN morphology (typical), 28 with partial or subclonal oncocytic features (atypical), and 20 without oncocytic features (control). We analyzed PRKACA/B fusion genes, including ATP1B1::PRKACA, DNAJB1::PRKACA, and ATP1B1::PRKACB, by reverse-transcription PCR; mRNA expression of fusion genes and nonrearranged PRKACA/B genes by quantitative reverse-transcription PCR; mutations in KRAS, BRAF, and GNAS by targeted sequencing or droplet digital PCR; and the expression of cyclic adenosine monophosphate (cAMP)-dependent protein kinase catalytic subunits α (PRKACA) and ß (PRKACB), phosphorylated cAMP response element-binding protein, and aberrations of p16, p53, SMAD4, STK11, and ß-catenin by immunohistochemistry. PRKACA/B fusion genes were detected in 100% (32/32) of typical, 46% (13/28) of atypical, and 0% (0/20) of control (P < .05). Expression of PRKACA, PRKACB, and phosphorylated cAMP response element-binding protein was upregulated in neoplasms with PRKACA/B fusion genes (P < .05). mRNA expression of the PRKACA/B fusion genes and protein expression of PRKACA or PRKACB tended to be higher in typical than in atypical cases (mRNA, P = .002; protein expression, P = .054). In some atypical neoplasms with mixed subtypes, PRKACA/B fusion genes were superimposed exclusively on oncocytic components. Typical IOPNs harbored fewer KRAS and GNAS mutations than control samples and fewer alterations in p53 and STK11 than atypical samples (P < .05). In conclusion, PRKACA/B fusion genes not only are the characteristic drivers of IOPNs but also play a crucial role in the development of subclonal oncocytic neoplasms. Moreover, oncocytic morphology is strongly associated with upregulation of PRKACA/B, which may provide clues for potential therapeutic options.

Current status and therapeutic strategy of acute acalculous cholecystitis: Japanese nationwide survey in the era of the Tokyo guidelines.

PURPOSE: This study aimed to clarify the incidence, therapeutic modality, and prognosis of acute acalculous cholecystitis and to reveal its optimal treatment strategy. METHODS: As a project study of the Japanese Society for Abdominal Emergency Medicine, we performed a questionnaire survey of demographic data and perioperative outcomes of acute acalculous cholecystitis treated between January 2018 and December 2020 from 42 institutions. RESULTS: In this study, 432 patients of acute acalculous cholecystitis, which accounts for 7.04% of acute cholecystitis, were collected. According to the Tokyo guidelines severity grade, 167 (38.6%), 202 (46.8%), and 63 (14.6%) cases were classified as Grade I, II, and III, respectively. A total of 11 (2.5%) patients died and myocardial infarction/congestive heart failure was the only independent risk factor for in-hospital death. Cholecystectomy, especially the laparoscopic approach, had more preferable outcomes compared to their counterparts. The Tokyo guidelines flow charts were useful for Grade I and II severity, but in the cases with Grade III, upfront cholecystectomy could be suitable in some patients. CONCLUSIONS: The proportions of severity grade and mortality of acute acalculous cholecystitis were found to be similar to those of acute cholecystitis, and laparoscopic cholecystectomy is recommended as an effective treatment option. (UMIN000047631).

Reduced expression of phosphorylated ataxia-telangiectasia mutated gene is related to poor prognosis and gemcitabine chemoresistance in pancreatic cancer.

BACKGROUND: Loss of expression of the gene ataxia-telangiectasia mutated (ATM), occurring in patients with multiple primary malignancies, including pancreatic cancer, is associated with poor prognosis. In this study, we investigated the detailed molecular mechanism through which ATM expression affects the prognosis of patients with pancreatic cancer. METHODS: The levels of expression of ATM and phosphorylated ATM in patients with pancreatic cancer who had undergone surgical resection were analyzed using immunohistochemistry staining. RNA sequencing was performed on ATM-knockdown pancreatic-cancer cells to elucidate the mechanism underlying the invlovement of ATM in pancreatic cancer. RESULTS: Immunohistochemical analysis showed that 15.3% and 27.8% of clinical samples had low levels of ATM and phosphorylated ATM, respectively. Low expression of phosphorylated ATM substantially reduced overall and disease-free survival in patients with pancreatic cancer. In the pancreatic cancer cell lines with ATM low expression, resistance to gemcitabine was demonstrated. The RNA sequence demonstrated that ATM knockdown induced the expression of MET and NTN1. In ATM knockdown cells, it was also revealed that the protein expression levels of HIF-1α and antiapoptotic BCL-2/BAD were upregulated. CONCLUSIONS: These findings demonstrate that loss of ATM expression increases tumor development, suppresses apoptosis, and reduces gemcitabine sensitivity. Additionally, loss of phosphorylated ATM is associated with a poor prognosis in patients with pancreatic cancer. Thus, phosphorylated ATM could be a possible target for pancreatic cancer treatment as well as a molecular marker to track patient prognosis.

Chronic Glucocorticoid Use is a Potential Risk Factor for Delayed Pancreatic Fistula after Laparoscopic Distal Pancreatectomy: A Retrospective Analysis.

Pancreatic fistula is a potentially morbid complication after distal pancreatectomy. Chronic glucocorticoid use is one of the risk factors for pancreatic fistula in pancreaticoduodenectomy, though it has not been reported in distal pancreatectomy. We explored whether chronic glucocorticoid use can be a risk factor for pancreatic fistula in distal pancreatectomy. We reviewed 408 consecutive patients who underwent elective distal pancreatectomy from 2011 to 2021. We evaluated two kinds of pancreatic fistula (postoperative pancreatic fistula and delayed pancreatic fistula). We defined delayed pancreatic fistula as a patient who was re-admitted for pancreatic fistula after the first discharge from the hospital. Preoperative characteristics and postoperative outcomes were analyzed. Two hundred sixty-seven patients underwent open distal pancreatectomy, while 141 patients had laparoscopic distal pancreatectomy. A comparison of patient with and without chronic glucocorticoid use showed that only patients with chronic glucocorticoid use developed delayed pancreatic fistula (0% vs. 16.7%; p < 0.001). In addition, delayed pancreatic fistula occurred in only laparoscopic distal pancreatectomy patients with chronic glucocorticoid use (0% vs. 25.0%; p < 0.001). Although sample size is small, it is reasonable to presume that chronic glucocorticoid use is a potential risk factor for delayed pancreatic fistula in laparoscopic distal pancreatectomy.

GATA6 and CK5 Stratify the Survival of Patients With Pancreatic Cancer Undergoing Neoadjuvant Chemotherapy.

Relevant protein expression of GATA6, CK5, vimentin, and mucins using immunohistochemistry was assessed for predicting the prognosis of and chemotherapy efficacy in patients with pancreatic cancers (PCs). The protein expression was examined in 159 PCs resected after neoadjuvant chemotherapy (NAC-PCs) and compared with that of 120 matched biopsy specimens taken before NAC. KRAS mutations were assessed by digital PCR. NAC-PCs were classified by GATA6 expression initially and CK5 expression subsequently into 4 types: classical-type (n = 22) with GATA6-high (≥50%)/CK5-low (<10%) PCs; hybrid-type (n = 45) with GATA6-high/CK5-high (≥10%) PCs; basal-like-type (n = 53) with GATA6-low (<50%)/CK5-high (≥30%) PCs; and null-type (n = 39) with GATA6-low/CK5-low (<30%) PCs, which resulted in clear stratification of patient prognosis. The classical-type was associated with the most favorable prognosis, whereas the null-type was associated with the worst prognosis (multivariate hazard ratio: 3.56; 95% CI, 1.63-7.77; P = .0015). The hybrid and basal-like types correlated with in-between levels of prognosis. The risk of hepatic recurrence was lower in the classical-type than in null (multivariate odds ratio [mOR]: 0.18; 95% CI, 0.04-0.96; P = .0449) and basal-like (mOR: 0.24; 95% CI, 0.05-1.16; P =.0750) types. By contrast, the risk of locoregional recurrence was higher in the classical-type than in the basal-like-type (mOR: 5.03; 95% CI, 1.20-21.1; P = .0272). The hybrid-type was subclassified into transition and coexpression patterns with different gastric mucin expression levels. High levels of vimentin (≥10%, n = 30) in pre-NAC-PC tissues was associated with poor prognosis (P = .0256). Phenotypic transitions between pre-NAC and post-NAC-PCs were common (73/120; 61%). PCs with NAC regression grades 2 and 3 showed a transition to poorer prognostic phenotypes (P = .0497). KRAS mutations were not associated with these phenotypes. In conclusion, GATA6 and CK5 immunohistochemical expression phenotypes may stratify the survival of patients with NAC-PCs and reflect post-NAC phenotypic transitions associated with poor prognosis. Prompt evaluation of immunohistochemical phenotypes may contribute to designing a precision therapeutic strategy for patients with PCs.

The Possibility of IPC to Prevent Ischemic-Reperfusion Injury in Skeletal Muscle in a Rat.

Blood removal with air tourniquets for a long time induces muscle damage after reperfusion. Ischemic preconditioning (IPC) has a protective effect against ischemia-reperfusion injury in striated muscle and myocardium. However, the mechanism of action of IPC on skeletal muscle injury is unclear. Thus, this study aimed to investigate the effect of IPC in reducing skeletal muscle damage caused by ischemia-reperfusion injury. The hindlimbs of 6-month-old rats were wounded with air tourniquets at a carminative blood pressure of 300 mmHg on the thighs. Rats were divided into the IPC (-) group and the IPC (+) group. The vascular endothelial growth factor (VEGF), 8-hydroxyguanosine (8-OHdG), and cyclooxygenase 2 (COX-2) were investigated by protein levels. Quantitative analysis of apoptosis was performed using the TUNEL method. Compared with the IPC (-) group, the IPC (+) group retained the VEGF expression, and the COX-2 and 8-OHdG expressions were suppressed. The proportion of apoptosis cells decreased in the IPC (+) group compared with the IPC (-) group. IPC in skeletal muscles proliferated VEGF and suppressed inflammatory response and oxidative DNA damage. IPC has the potential to reduce muscle damage after ischemia-reperfusion.

[A Case of an Elderly Patient Who Underwent Conversion Resection for Pancreatic Cancer with Positive Peritoneal Cytology].

We report a case of an elderly patient, 82 years-old, with initially-unresectable pancreatic head cancer, who successfully underwent complete resection of the primary lesion after systemic chemotherapy for 6 months. The patient had a history of pancreatic body-tail resection for intraductal papillary mucinous carcinoma in 2005. In 2020, a routine examination revealed an increased CA19-9 value of 1,958 U/mL and showed a pancreatic head tumor of 35 mm on CT images. Finally, the tumor was pathologically diagnosed as pancreatic cancer by a biopsied sample. Although CT images showed no distant metastasis, peritoneal lavage cytology was indicated as positivity(H0P0CY1)in the staging laparoscopy. We implanted a peritoneal port and introduced systemic chemotherapy of gemcitabine and nab-paclitaxel combination therapy. This treatment for 6 months induced tumor shrinkage to 30 mm on the CT image, normalized CA19-9 value to 22.6 U/mL, and negative cytology in the collected lavage fluid from the peritoneal port. The patient's general condition was maintained even after the chemotherapy and the lavage cytology was pathologically diagnosed as negative(H0P0CY0)in the repeated staging laparoscopy, therefore we decided to perform pancreaticoduodenectomy as a conversion surgery. The patient was discharged on the 21st postoperative day with an uneventful course and underwent adjuvant chemotherapy of S-1 for 6 months. No recurrence was found in 8 months after the surgery. In such a case of the selected elderly patient with a maintained general condition, it is feasible to undergo multimodal treatments including conversion surgery for an initially-unresectable pancreatic cancer with positive peritoneal cytology.

Negative prognostic impact of sarcopenia before and after neoadjuvant chemotherapy for pancreatic cancer.

OBJECTIVES: To elucidate the prognostic impact of sarcopenia before and after neoadjuvant chemotherapy (NAC) for pancreatic cancer (PC). METHODS: We retrospectively studied 75 consecutive PC patients who underwent neoadjuvant gemcitabine plus S-1 combination therapy followed by pancreatectomy between 2008 and 2016. According to the skeletal muscle volume index (SMI), the patients were divided into the muscle attenuation group (MAG) and normal group (NG) before or after NAC. Prognostic factors for overall survival (OS) were analyzed by Cox proportional hazards models. RESULTS: The MAG showed significantly poorer OS than the NG before and after NAC. Pre-NAC, median OS was 20.0 months in the MAG versus 49.0 months in the NG (p = 0.006). Post-NAC, median OS was 21.3 months in the MAG versus 48.8 months in the NG (p = 0.014). Multivariate analysis, excluding muscle attenuation after NAC because of confounding factors and lower hazard ratio (2.08, 95% confidence interval: 1.14-3.78, p = 0.016) than that before NAC (2.14, 1.23-3.70, p = 0.007) by univariate analysis, revealed the following independent prognostic factors: muscle attenuation pre-NAC (2.25, 1.26-4.05, p = 0.007); borderline resectability (1.96, 1.04-3.69, p = 0.038); operative blood loss (2.60, 1.38-4.88, p = 0.003); and distant metastasis (3.31, 1.40-7.82, p = 0.006). CONCLUSIONS: Sarcopenia before and after NAC for PC is suggested to be a poor prognostic factor, with a stronger impact before than after NAC.

Serine/Threonine Kinase 11 Plays a Canonical Role in Malignant Progression of KRAS -Mutant and GNAS -Wild-Type Intraductal Papillary Mucinous Neoplasms of the Pancreas.

OBJECTIVE: We aimed to elucidate the clinicopathobiological significance of Serine/Threonine Kinase 11 (STK11) in pancreatic intraductal papillary mucinous neoplasms (IPMNs). BACKGROUND: STK11 is a tumor suppressor involved in certain IPMNs; however, its significance is not well known. METHODS: In 184 IPMNs without Peutz-Jeghers syndrome, we analyzed expression of STK11 and phosphorylated-AMPKa in all cases, and p16, p53, SMAD4, and ß-catenin in 140 cases by immunohistochemistry; and we analyzed mutations in 37 genes, including whole coding exons of STK11, CDKN2A, TP53, and SMAD4, and hotspots of KRAS, BRAF, and GNAS in 64 cases by targeted sequencing. KRAS and GNAS were additionally analyzed in 86 STK11-normal IPMNs using digital-PCR. RESULTS: Consistent loss or reduction of STK11 expression was observed in 26 of 184 (14%) IPMNs. These STK11-aberrant IPMNs were 17 of 45 (38%) pancreatobiliary, 8 of 27 (30%) oncocytic, 1 of 54 (2%) gastric, and 0 of 58 (0%) intestinal subtypes ( P = 8.5E-11), and 20 of 66 (30%) invasive, 6 of 74 (8%) high-grade, and 0 of 44 (0%) low-grade ( P = 3.9E-06). Sixteen somatic STK11 mutations (5 frameshift, 6 nonsense, 1 splicing, and 4 missense) were detected in 15/26 STK11-aberrant IPMNs ( P = 4.1E-06). All STK11-aberrantIPMNs were GNAS -wild-type and 96% of them were KRAS or BRAF -mutant.Morphologically, STK11-aberrant IPMNs presented "fern-like" arborizing papillae with thin fibrovascular core. Phosphorylated-AMPKa was down-regulated in STK11-aberrant IPMNs (92%, P = 6.8E-11). Patients with STK11-aberrant IPMNs showed poorer survival than patients with STK11-normal IPMNs ( P = 3.6E-04 overall; P = 6.1E-04 disease-free). CONCLUSION: STK11 may play a canonical role in malignant progression and poor survival of patients with IPMNs. Aberrant STK11-driven phosphorylated AMPK downregulation may provide therapeutic opportunities with mTOR inhibitors/AMPK activators.

Prognostic impact of postoperative circulating tumor DNA as a molecular minimal residual disease marker in patients with pancreatic cancer undergoing surgical resection.

PURPOSE: We aimed to clarify the prognostic impact of postoperative circulating tumor DNA (ctDNA) shortly after pancreatectomy in patients with pancreatic ductal adenocarcinoma (PDAC). METHODS: Preoperative and paired postoperative blood samples were obtained from 66 patients in patients with PDAC. Cell-free DNA was extracted from the plasma, and KRAS mutations, as a benchmark of ctDNA, were examined using droplet digital PCR. Disease-free survival (DFS) and overall survival (OS) were compared between patients with presence and absence of ctDNA. RESULTS: In univariate analysis, patients with detectable postoperative ctDNA showed worse survival than those with undetectable in both DFS (P = .034) and OS (P = .022). Multivariate analysis also revealed that the presence of postoperative ctDNA was an independent risk factor for recurrence (hazard ratio: 2.677, P = .011). In contrast, preoperative ctDNA detection did not affect long-term outcomes. These trends persisted in 34 patients with resectable PDAC who underwent resection after neoadjuvant chemotherapy. Patients with detectable postoperative ctDNA were more prone to developing hepatic recurrence than those with undetectable postoperative ctDNA (P = .039). CONCLUSION: Postoperative ctDNA, as a minimal residual marker, can be useful for predicting the risk of recurrence in patients with PDAC even after curative resection.

Levels of tumor markers CEA/CA 19-9 in serum and peritoneal lavage predict postoperative recurrence in patients with pancreatic cancer.

Aim: This study aimed to clarify the usefulness of tumor markers from peritoneal lavage in selecting patients with a high risk of recurrence and predicting site-specific recurrence in patients with pancreatic cancer. Methods: The levels of serum carcinoembryonic antigen (CEA) and carbohydrate antigen (CA) 19-9 (sCEA/sCA 19-9) and paired peritoneal lavage CEA and CA 19-9 (pCEA/pCA 19-9) were measured in 90 patients with pancreatic cancer who underwent surgery. Using the cutoff values determined by maximally selected rank statistics for disease-free survival (DFS), the risk of recurrence and its patterns were evaluated in combination with different markers and different test specimens. Results: In univariate and multivariate analysis, an elevated pCA 19-9 level (>1.3 U/mL) was an independent prognostic marker for both DFS (hazard ratio [HR], 2.391; P = .018) and overall survival (HR, 3.194; P = .033). Combination analyses contributed to further stratification of a very high risk of recurrence. Of the 58 patients with resectable pancreatic cancer who underwent curative resection, elevated pCA19-9 was also associated with inferior DFS and overall survival (OS). Patients with elevated pCA 19-9 levels were more likely to have an earlier onset of peritoneal recurrence than those with normal pCA 19-9 levels (P = .048, Gehan-Breslow-Wilcoxon test). Conclusion: pCA 19-9 is a reliable marker for predicting postoperative recurrence in patients with pancreatic cancer after surgery. Further risk stratification can be achieved by using combination assays. The combination of pCA 19-9 and sCA19-9 also serves as a predictor of recurrence site-specific recurrence.

Dependence of Molecular Diode Behaviors on Aromaticity.

A molecule-scale diode is an essential component for the concept of molecular electronics. Here we report on heterogeneous contact-mediated rectifying behavior in single-molecule junctions. We performed massive current versus voltage characteristics measurements of metal-molecule-metal structures under stretching by a mechanical break junction method. In-situ deformations of the molecular bridges were revealed to induce stochastic switching of the rectifying direction to varying rectification ratio derived from the induced asymmetry in the contact motifs at the molecule termini. Aromatic molecules were found to enable stronger rectifications via the more pronounced Fermi pinning effect to shift the molecular orbital levels by the applied voltage. Dissimilar anchoring groups also served to stabilize the single-molecule diode properties by bestowing a chemically defined difference in the electronic coupling strengths at the electrode-molecule links. The present findings provide a guide to design diodes with the smallest and simplest structures.

Pancreaticoduodenectomy for pancreatic head cancer with cavernous transformation of the portal vein: a case report.

BACKGROUND: Cavernous transformation of the portal vein (CTPV) due to extrahepatic portal vein obstruction is a rare vascular anomaly. Since its symptoms usually appear in childhood, most of the adult cases are detected unexpectedly with other diseases. Only a few reports have described surgical difficulties in patients with CTPV. We report a case of pancreatic head cancer with CTPV in a patient who underwent pancreaticoduodenectomy. CASE PRESENTATION: A 77-year-old man with epigastric and back pain was referred to our hospital. Computed tomography revealed a tumor in the pancreatic head and a CTPV near the hepatic hilum. CTPV consisted of two main collateral vessels connected by multiple surrounding small vessels. Also, portal vein obstruction was observed near the hepatic hilum, which was far from the pancreatic head tumor. After confirming that there was no distant metastasis by a thorough whole-body search, we performed a pancreaticoduodenectomy following neoadjuvant chemotherapy. During the operation, we carefully manipulated the area of the CTPV and omitted lymph node dissection in the hepatoduodenal ligament to prevent massive venous bleeding and intestinal congestion. Pancreaticoduodenectomy was performed without any intraoperative complications and the postoperative course was uneventful. Complete tumor resection was histologically confirmed. CONCLUSION: Although pancreaticoduodenectomy for patients with CTPV involves many surgical difficulties, we successfully performed it by determining specific treatment strategies tailored to the patient and following careful and delicate surgical procedures.

Laparoscopic and robot-assisted surgery for adult congenital biliary dilatation achieves favorable short-term outcomes without increasing the risk of late complications.

PURPOSE: Minimally invasive surgery (MIS) is the optimal treatment for congenital biliary dilatation (CBD), but few studies on adults have been reported. We compared the postoperative outcomes of MIS with those of open surgery (OS) in adult patients with CBD. METHODS: The subjects of this retrospective study were 36 adult patients who underwent surgery for CBD. We compared the postoperative outcomes of 20 patients who underwent laparoscopic (n = 15) or robotic (n = 5) surgery with those of 16 patients who underwent OS. RESULTS: MIS was associated with a significantly higher rate of type I (p < 0.001), significantly less blood loss (p < 0.001), a significantly lower rate of internal stents (p = 0.048), significantly longer operation times (p = 0.009), and a significantly shorter postoperative hospital stay (p = 0.007) than OS. The postoperative outcomes of MIS for type I CBD were similar to those of the whole cohort. There were no significant differences in late complications between the groups. The robotic procedure had a significantly shorter operative time than laparoscopic surgery for hepaticojejunostomy (HJ; p = 0.029). CONCLUSIONS: MIS achieved favorable short-term outcomes without compromising mid-term outcomes compared to OS and is appropriate for adult patients with CBD. Robotic HJ may be more ideal than its laparoscopic counterpart.

What is the impact of zinc deficiency for pancreatectomies in patients with pancreatic ductal adenocarcinoma?

BACKGROUND: and purpose: Zinc is an essential element for human health and plays an important role in metabolic, immunological and other biological processes. The present study was conducted to investigate the association between zinc deficiency (ZD) and the perioperative clinical course in patients with pancreatic ductal adenocarcinoma (PDAC). METHODS: Of 216 patients with PDAC who underwent elective pancreatectomy between 2013 and 2017 at our institution, 206 patients with sufficient clinical data were retrospectively reviewed. The perioperative variables were compared and the risk factors associated with infectious complications were identified. RESULTS: ZD was preoperatively present in 36 (17.5%) of 206 patients with PDAC. In the patients of the ZD group, a higher proportion of males, higher preoperative modified Glasgow prognostic scores, a higher neutrophil-to-lymphocyte ratio, and a higher occurrence of postoperative infectious complications after pancreatectomy were observed, compared to the non-ZD group. By a univariate analysis, three risk factors were significantly associated with infectious complications after pancreatectomy: ZD (vs non-ZD: p = 0.002), serum albumin <3.5 g/dl (vs ≥ 3.5 g/dl: p = 0.005), and the procedure of pancreaticoduodenectomy (vs others: p = 0.013). By multivariate logistic regression analysis, the occurrence of infectious complications was significantly associated with ZD (OR 3.430, 95%CI 1.570 to 7.490, p = 0.002) and the procedure of pancreaticoduodenectomy (OR 2.030, 95%CI 1.090 to 3.770, p = 0.025). CONCLUSIONS: The current study newly demonstrated that ZD could serve as a preoperative predictor of infectious complications after pancreatectomies in the patients with PDAC.

Impact of Tumor-Derived DNA Testing in Peritoneal Lavage of Pancreatic Cancer Patients with and Without Occult Intra-Abdominal Metastases.

BACKGROUND: The fractional abundance of tumor-derived DNA in body fluids depends on the metastatic sites and the degree of expansion. We aimed to assess the clinical significance of tumor-derived DNA testing in the peritoneal lavage of patients with pancreatic cancer. METHODS: The prevalence and abundance of tumor-derived DNA was assessed in 204 subjects with ascites by peritoneal lavage (AS) and the evaluable paired plasma (PL) from 149 pancreatic cancer patients undergoing abdominal exploration. Genetic profiles were evaluated by next-generation sequencing, and prognostic impact was assessed using Cox proportional hazard models. RESULTS: Of 204 subjects, AS samples from patients with peritoneal dissemination (PER+) and positive cytology (CY+) showed significantly higher prevalence and abundance of tumor-derived DNA than those with negative counterparts. Tumor-derived DNA prevalence and abundance in AS were more likely to be higher than in paired PL in a subgroup of patients with PER+ and CY+, respectively. Next-generation sequencing revealed concordant or discrepant mutational patterns between the AS and PL samples. Multivariate analysis showed that both tumor-derived DNA in AS (hazard ratio [HR] 3.940, p = 0.009) and PL (HR 2.936, p = 0.026) were independently associated with poor survival in treatment-naïve patients. In patients who underwent resection, tumor-derived DNA positivity in the AS was more predictive of early recurrence than in PL. CONCLUSIONS: Tumor-derived DNA in AS can serve as characterizing the genetic profiles of tumor cells attributable to the development of PER+ and predicting the minimal residual disease and early recurrence in patients with pancreatic cancer.

[Successful R0 Resection of Two Metachronous Krukenberg Tumors from Gastric Cancer-A Case Report].

A 50s woman with a stomachache was referred to our hospital with diagnosed gastric cancer. Upper endoscopy showed a type 3 tumor in the lower gastric body, and CT demonstrated a pelvic tumor 10 cm in size. Laparoscopic surgery was performed; since the pelvic tumor was found to derive from the left ovary, left oophorectomy and total gastrectomy were performed. Pathological examination revealed that the ovarian tumor was a gastric cancer metastasis. Adjuvant chemotherapy with S-1 monotherapy was introduced. Four months after the operation, metastasis was suspected due to right ovary tumor edema. Due to the possibility of obtaining R0 resection and adverse events of chemotherapy, we chose right oophorectomy. Pathological examination demonstrated signet-ring cell cancer. Fourteen months after the first operation, the patient is alive with no recurrence or metastasis.

[A Case of Multiple Gastric GIST with Lymph Nodes Metastases in a Young Woman].

A 21-year-old woman with bloody stool was referred to our hospital with multiple submucosal tumors at the posterior and anterior wall of the gastric angle under upper gastrointestinal endoscopy. Both of the tumors were diagnosed with gastric gastrointestinal stromal tumor(GIST)by EUS-FNA, then laparoscopic distal gastrectomy with D1 lymph node dissection was performed. The size of those tumors were 47 mm and 15 mm respectively, and pathological examination revealed multiple lymph nodes metastases. Neither KIT nor PDGFRA mutation was found. She had received postoperative adjuvant chemotherapy with imatinib mesylate for 3 years. No sign of recurrence has been confirmed thereafter. GISTs in young adults are rare and their oncological features are considered to be different from common type of GIST.

Germline DNA damage repair gene mutations in pancreatic cancer patients with personal/family histories of pancreas/breast/ovarian/prostate cancer in a Japanese population.

AIM: Cancer patients with personal/family histories of pancreatic/breast/ovarian/prostate cancer are associated with a higher likelihood of harboring DNA damage repair (DDR)-related germline mutations. Here, we aimed to obtain a better understanding of DDR-related germline mutations in Japanese pancreatic ductal adenocarcinoma (PDAC) patients with personal and/or family histories of BRCA-related cancers of the pancreas, breast, ovary, and prostate. METHODS: We performed next-generation sequencing (NGS) and evaluated germline mutations in nine DDR-related genes (BRCA1, BRCA2, ATM, PALB2, CHEK2, MLH1, MSH2, MSH6, and PMS2) in PDAC patients with personal and/or family histories. RESULTS: Of 196 patients with PDAC, 39 (19.9%) fulfilled the criteria for at least one family history of pancreatic/breast/ovarian/prostate cancer in first-degree relatives (sibling-sibling or parent-child) or the personal history of these malignancies. Targeted NGS revealed that four (10.2%) of 39 patients with personal/family histories harbored deleterious germline mutations-two in BRCA2, one in ATM, and one in MLH1. Both the BRCA2 variants showed frameshift mutations due to short insertion/deletions. In the 39 patients undergoing NGS, a similar distribution of the clinicopathological characteristics was observed between those with deleterious mutations/variants of unknown significance (VUSs) and with benign/wild types. Patients with deleterious germline mutations/VUSs in DDR-related genes showed a significantly more favorable prognosis than those with benign mutations/wild-type genes (hazard ratio: 0.160, P = .040). CONCLUSIONS: A significant fraction of PDAC patients with personal/family histories of BRCA-related cancers harbored deleterious germline mutations in DDR-related genes. DDR-related germline gene mutations might be a favorable prognostic factor in patients with pancreatic cancer.

The role of bilio-pancreatic limb in nonalcoholic steatohepatitis improvement after duodenal-jejunal bypass in rats.

BACKGROUND: Nonalcoholic fatty liver disease, which is highly associated with obesity, includes nonalcoholic steatohepatitis. Lipopolysaccharides from the intestine would induce inflammation in the liver in nonalcoholic fatty liver disease. This study aimed to examine the role of the bilio-pancreatic limb in the effect of duodenal-jejunal bypass on nonalcoholic steatohepatitis, with respect to the gut-liver axis, using a rat model. METHODS: Nonalcoholic steatohepatitis model rats were randomly assigned into 3 groups as follows: 1 sham group and 2 duodenal-jejunal bypass groups. The 2 duodenal-jejunal bypass groups were defined according to the bilio-pancreatic limb length: 30 cm (30-DJB group) and 0 cm (0-DJB group). Pathology findings and blood biochemistry, inflammatory cytokine and lipopolysaccharides receptor mRNA in the liver and common channel, and lipopolysaccharide-binding protein level in the portal vein were assessed. RESULTS: The reduction in plasma alanine aminotransferase and nonalcoholic fatty liver disease activity score in the 30-DJB group was not observed in the 0-DJB group, similar to the sham group. In the liver tissue, mRNA of inflammatory cytokines and lipopolysaccharide receptors, the area occupied by CD68-positive macrophages, and the number of CD3-positive T-lymphocytes on immunostaining were lower in the 30-DJB group; however, these findings were not observed in the 0-DJB group, and lipopolysaccharide-binding protein levels in the portal vein and mRNA expressions of inflammation-related genes in the common channel showed similar tendencies. CONCLUSION: The bilio-pancreatic limb plays an important role in the beneficial effect of duodenal-jejunal bypass for nonalcoholic steatohepatitis. The bilio-pancreatic limb may suppress lipopolysaccharides-related cascades in the liver by reducing intestinal inflammation.