Search

Pancreatic cancer has the poorest prognosis among digestive cancers. During the 1990s, the 5-year survival rate of surgical patients with pancreatic cancer was 14% in Japan. However, survival rates have increased to 40% in the 2020s due to the refinement of surgical procedures and the introduction of perioperative chemotherapy. Several pivotal randomized controlled trials have played an indispensable role to establish each standard treatment strategy. Resectability of pancreatic cancer can be classified into resectable, borderline resectable, and unresectable based on the anatomic configuration, and multidisciplinary treatment strategies for each classification have been revised rapidly. Investigation of superior perioperative adjuvant treatments for resectable and borderline resectable pancreatic cancer and the establishment of optimal conversion surgery for unresectable pancreatic cancer are the progressive subjects.

Although the physiologic significance of lysine methylation of histones is well known, whether lysine methylation plays a role in the regulation of nonhistone proteins has not yet been examined. The histone lysine methyltransferase SETD8 is overexpressed in various types of cancer and seems to play a crucial role in S-phase progression. Here, we show that SETD8 regulates the function of proliferating cell nuclear antigen (PCNA) protein through lysine methylation. We found that SETD8 methylated PCNA on lysine 248, and either depletion of SETD8 or substitution of lysine 248 destabilized PCNA expression. Mechanistically, lysine methylation significantly enhanced the interaction between PCNA and the flap endonuclease FEN1. Loss of PCNA methylation retarded the maturation of Okazaki fragments, slowed DNA replication, and induced DNA damage, and cells expressing a methylation-inactive PCNA mutant were more susceptible to DNA damage. An increase of methylated PCNA was found in cancer cells, and the expression levels of SETD8 and PCNA were correlated in cancer tissue samples. Together, our findings reveal a function for lysine methylation on a nonhistone protein and suggest that aberrant lysine methylation of PCNA may play a role in human carcinogenesis. Cancer Res; 72(13); 3217–27. ©2012 AACR.

PDF file - 69K, Table S1. Primer sequences for quantitative RT-PCR. Table S2. siRNA sequences. Table S3. Sequences of oligonucleotides for Okazaki fragment maturation assay. Table S4. Statistical analysis of SETD8 expression levels in clinical bladder tissues. Table S5. Gene expression profile of SETD8 in cancer tissues analyzed by cDNA microarray. Table S6. Correlation of SETD8 and PCNA expressions at the protein level.

PDF file - 293K, Figure S1. SETD8 is overexpressed in bladder cancer. Figure S2. SETD8 is overexpressed in CML, HCC and pancreatic cancer. Figure S3. SETD8 expression in various types of cell lines. Figure S4. PIP box in SETD8 and amino acid sequence alignment of PCNA. Figure S5. Chromatogram of amino acids obtained after acid hydrolysis of PCNA. Figure S6. An in vivo methylation of PCNA by SETD8. Figure S7. Validation of the anti-mono-methylated K248 PCNA antibody. Figure S8. Validation of methylation status of endogenous PCNA using a specific antibody. Figure S9. SW780 cells were pre-treated with siEGFP and siSETD8 for 24 hours and then, cells were treated with 100 �g/ml of cycloheximide (CHX) for 0, 4 and 8 hours. Figure S10. Methylated PCNA enhances the interaction with FEN1. Figure S11 Effects of PCNA methylation on the sensitivity to H2O2 stress. Figure S12. A knockdown effect of endogenous PCNA in HeLa cells was confirmed by quantitative real-time PCR. Figure S13. Expression levels of SETD8 in 78 normal tissues.

PDF file - 65K

Predictive factors for intrahepatic cholangiocarcinoma in long-term follow-up of hepatolithiasis are unknown. We thus conducted a cohort study to investigate the predictive factors for developing intrahepatic cholangiocarcinoma in hepatolithiasis.This cohort is comprised of 401 patients registered in a nationwide survey of hepatolithiasis for 18 years of follow-up. Cox regression analysis was used to elucidate predictive factors for developing intrahepatic cholangiocarcinoma.The median follow-up period of patients was 134 months. Twenty-two patients developed intrahepatic cholangiocarcinoma and all died. Identified independent significant factors were as follows: age 63 years or older (hazard ratio [HR] 3.344), residual stones at the end of treatment (HR 2.445), and biliary stricture during follow-up (HR 4.350). The incidence of intrahepatic cholangiocarcinoma in patients with three factors was significantly higher than that in patients with one or two factors. The incidence in the groups with one or two predictive factors was not different. In 88.9% of patients with both biliary stricture and intrahepatic cholangiocarcinoma, the duration between the diagnoses of biliary stricture and intrahepatic cholangiocarcinoma was ≥ 5 years. However, once intrahepatic cholangiocarcinoma developed, 77.8% of patients died within 1 year. Of 24 patients with no symptoms, no previous choledocoenterostomy, no signs of malignancy, no biliary stricture, and no treatment for hepatolithiasis during follow-up, only one developed intrahepatic cholangiocarcinoma.Regarding carcinogenesis, complete stone clearance and releasing biliary stricture can prevent the development of intrahepatic cholangiocarcinoma and improve the prognosis of hepatolithiasis.

Objectives Neoadjuvant therapy followed by radical resection improves the borderline-resectable pancreatic cancer (BRPC) prognosis; however, the optimal therapeutic regimen remains unclear. Gemcitabine plus nab-paclitaxel (GnP) showed a high anti-tumor effect in primary lesions in a prospective study for metastatic disease. However, evidence concerning its feasibility is still lacking in patients with BRPC. We therefore evaluated the tolerability of neoadjuvant GnP (NAC-GnP) for BRPC. Patients and Methods This single-center prospective study evaluated 10 patients with BRPC who were treated with two cycles of NAC-GnP. The primary endpoint was feasibility for NAC-GnP. Treatment feasibility was defined as a successful outcome in at least eight patients. Results Ten patients who had BRPC in contact with the celiac artery (n = 5), superior mesenteric artery (n = 3), or hepatic artery (n = 2) were enrolled. The median age was 75 (range, 40-82) years old. Grade 3 anorexia and grade 2 pneumonia occurred in one patient each, so treatment was feasible in eight patients. The median primary tumor reduction and response rates were 33% (range, 0%-68%) and 60%, respectively. Six of eight patients who had abnormal CA19-9 levels at the time of enrolment showed a decrease in CA19-9 levels, with a median decrease of 72%. Five patients underwent radical resection, including R0 resection in four. Postoperative grade IIIa Clavien-Dindo complications occurred in one patient (upper gastrointestinal bleeding and pancreatic fistula). Conclusion Two-cycle NAC-GnP is a feasible treatment for patients with BRPC. Further studies on NAC-GnP in patients with BRPC are warranted.

Major hepatectomy in patients with insufficient future liver remnant (FLR) volume and impaired liver functional reserve has considerable risks for posthepatectomy liver failure (PHLF). The patient was a male in his 70s with an intrahepatic cholangiocarcinoma in left hemiliver, involving the middle hepatic vein (MHV). Although FLR volume after left hemihepatectomy was estimated to be 64.4% of the total liver volume, an indocyanine green retention rate at 15 min (ICG-R15) value was 24.2%, thus the patient underwent left portal vein embolization. The FLR volume increased to 71.3%; however, the noncongestive FLR volume was re-estimated as 45.8% after resection of the MHV, the ICG-R15 value was 29.0%, and ICG-Krem was calculated as 0.037. We performed partial rescue Associating Liver Partition and Portal vein occlusion for Staged hepatectomy (ALPPS) for left hemihepatectomy with the MHV reconstruction. On the first stage, partial liver partition was done along Rex-Cantlie’s line, preserving the MHV and sacrificing the remaining branches to segment 8. The FLR volume increased to 77.4% on day 14. The ICG-R15 value was 29.6%, but ICG-Krem after MHV reconstruction was estimated to be 0.059. The second-stage operation on day 21 was left hemihepatectomy with the MHV reconstruction using the left superficial femoral vein graft. The usage of rescue partial ALPPS may contribute to preventing PHLF by introducing occlusion of the portal and/or venous branches in the left hemiliver before curative hepatectomy.

Background To clarify whether double-volume peritoneal lavage can decrease the risk of clinically relevant postoperative pancreatic fistula after pancreaticoduodenectomy. Materials and Methods Forty-nine patients who underwent pancreaticoduodenectomy and intraoperative peritoneal lavage using 6000 mL of saline before abdominal closure were studied retrospectively. Bacterial cultures of the lavage fluid were taken twice, after irrigation using 3000 mL of saline and then after an additional 3000 mL of saline. Bacterial culture of the drainage fluid was taken on day 1, and the relationship between the results of bacterial cultures and clinically relevant postoperative pancreatic fistula was examined. Results Double amount of peritoneal lavage significantly decreased the incidence of positive bacterial cultures than single amount of peritoneal lavage (45% vs. 29%, P < .05). Multivariate analysis showed that positive bacterial culture of drainage fluid on day 1 and main pancreatic duct size (Discussion A positive bacterial culture on day 1 is an independent risk factor for clinically relevant postoperative pancreatic fistula during pancreaticoduodenectomy. Double-volume intraperitoneal lavage may be effective for reducing the incidence of clinically relevant postoperative pancreatic fistula.

Pancreatic cancer is known to have the poorest prognosis among digestive cancers. With the development of new chemotherapeutic agents and introduction of multidisciplinary therapy, however, the treatment outcomes for pancreatic cancer have dramatically improved over the past two decades. The keys to successful treatment will be accurate assessment of resectability [resectable (R), borderline resectable (BR) or unresectable (UR)] at the time of diagnosis and prompt adoption of an appropriate multidisciplinary treatment strategy. Prep-02/JSAP-05 trial which is an RCT of upfront surgery versus neoadjuvant chemotherapy using GEM and S-1 (GS) and subsequent surgery for R-PDAC in Japan indicated neoadjuvant chemotherapy had a longer overall survival (OS) than those undergoing upfront surgery (36.7M vs. 26.6M, p = 0.015). In a retrospective multicenter study in Japan reported that in BR-PDAC, median survival time (MST) in the pretreatment group was significantly better than that in the upfront surgery group (25.7 months vs. 19.0 months, p = 0.015) according to a propensity score matching analysis. Another retrospective multicenter study with UR-LA PDAC in Japan reported that conversion surgery was more beneficial for patients with more than 8 months of preoperative therapy than those with less than 8 months of that therapy. Various clinical trials on pancreatic cancer are ongoing, and the results of trials on chemotherapeutic regimens and multidisciplinary treatments will be of further interest.

Repeat hepatectomy for recurrent colorectal liver metastases (CRLM) for the remnant hemiliver is sometimes challenging due to the insufficient future liver remnant (FLR) volume. We present an aggressive strategy for resection of the recurrent CRLM involving bisegmentectomy of the remnant right hemiliver with the aid of portal vein embolization (PVE) and venous reconstruction. The patient was a 50‐year‐old woman who had undergone left hemihepatectomy for a CRLM 10 months ago. Three metastatic tumors were found in the remnant segments 7 and 8 (S7&8) of the liver, and one of them involved the right hepatic vein (RHV). Conducting bisegmentectomy of S7&8 with resection of the RHV, the non‐congestive FLR volume was calculated as 34.9% of the remnant total liver volume, which was deemed insufficient considering the mild liver damage after repeated chemotherapy. After trans‐ileocecal PVE of the portal branches in S7&8 in a hybrid angio room, the non‐congestive FLR volume increased to 42.3%, which could be further advanced to 58.0% if the RHV was reconstructed. Segmentectomies of S7&8 with resection and reconstruction of the RHV using the right superficial femoral vein graft was performed. The patient was discharged without any complications, and the postoperative computed tomography (CT) scan showed the good patency of the reconstructed venous graft. Aggressive segmentectomies and venous reconstruction of the remnant hemiliver after PVE might be a new strategy to overcome the insufficient FLR volume., Bisegmentectomy for recurrent colorectal liver metastases (CRLM) is sometimes challenging due to the insufficient future liver remnant volume in patients undergoing hemihepatectomy for initial CRLM. Segmentectomy combined with venous reconstruction after portal vein embolization for the remnant hemiliver could be a new strategy.

Background Perioperative atrial fibrillation (POAF) in noncardiac surgeries is common. However, it is unclear whether such atrial fibrillation (AF) recurs in the long term. Methods This study was a prospective, single-center, observational study that included patients who underwent noncardiac surgeries for malignancies. Patients were followed up for 1 year to evaluate the incidence of AF, ischemic stroke, and mortality. An event-triggered recorder was used in patients with POAF. The incidences were compared according to the presence of POAF. Results Of 752 consecutive patients, 77 (10.2%) developed POAF and wore an event recorder for 19 (12-30) days. AF and ischemic stroke at 1 year were observed in 24 patients (31.1%) and 2 patients (2.6%) with POAF and 4 patients (0.6%) and 3 patients (0.4%) without POAF, respectively. Of the 24 patients with POAF and AF recurrence, 22 (92%) were asymptomatic. Anticoagulation was prescribed in 67 patients (87%) with POAF. Multivariate Cox regression analysis demonstrated that a higher AF recurrence rate in patients with POAF was associated with hypertension (hazard ratio, 2.79; 95% confidence interval, 1.06-7.38) and serum creatinine level (hazard ratio for 20 μmol/L increase, 2.32; 95% confidence interval, 1.16-4.62). Conclusions AF recurs in approximately 30% of patients with POAF with malignancy in the subsequent year; most recurrences are asymptomatic.

Recent developments in systemic chemotherapy for advanced hepatocellular carcinoma have been outstanding. However, reports on conversion surgery after lenvatinib therapy are scarce. We present the first case of advanced hepatocellular carcinoma with tumor thrombus in the suprahepatic vena cava close to the right atrium, which shrank after 12 weeks’ administration of lenvatinib, thereby leading to successful conversion surgery without using total vascular exclusion or extracorporeal circulation. The treatment strategy for hepatocellular carcinoma with macroscopic hepatic vein tumor thrombus is controversial, however, from a Japanese nationwide survey, surgical resection has been accepted as one of the treatment options for advanced hepatocellular carcinoma with hepatic vein tumor thrombus in Japan. However, the survival rate after resection of hepatocellular carcinoma having inferior vena cava tumor thrombus with extracorporeal circulation was reported to be worse than without extracorporeal circulation, and some preoperative down-sizing therapy for inferior vena cava tumor thrombus was advocated. Preoperative lenvatinib therapy might be a promising option among the multidisciplinary treatments for hepatocellular carcinoma with macroscopic tumor thrombus in the hepatic veins.

Resection of liver cancer involving the paracaval portion (PC) of the caudate lobe is challenging because the PC is located deepest in the liver. This study aimed to elucidate the utility of two parenchymal-sparing approaches of limited resection and central hepatectomy for resecting tumors located in the PC. In 2018 and 2020, 12 out of 143 patients underwent hepatectomy for tumors located in the PC of the liver. In six patients, limited resection (LR) of the PC after full mobilization of the liver off the inferior vena cava (IVC) was performed for tumors excluding the hilar plate or large hepatic veins (large HVs), including major hepatic veins or thick short hepatic veins. In six patients, central hepatectomy (CH) using liver tunnel was performed for tumors involving or close to the hilar plate and/or large HVs. During CH, the surgical view of the cranial side of the hilar plate was wide enough to perform combined resection of the large HVs in front of the IVC. Five of the six CHs were performed with resection of the LHVs. No LRs were accompanied with resection of the LHVs. The CH was associated with longer Pringle’s time (76 min vs. 29.5 min, p = 0.015) and blood loss (1104 ml vs. 370 ml, p = 0.041). The preserved liver parenchyma volumes were 82% and 95% of the total liver volume after CH and LR, respectively. Our parenchymal-sparing approach for resection of liver cancer located in the PC is feasible for curative resection.

Hepatocellular carcinoma (HCC) is the fifth leading cause of cancer deaths in Japan, and it has gradually decreased in the last quarter century. The reason for the decrease in HCC patients is the decrease of patients with hepatitis C virus due to avoiding unnecessary blood transfusions and development of direct-acting antiviral agents (DAAs), which have been available since 2014, along with interferon and oral antiviral agents in Japan. On the other hand, the numbers of HCC patients with non-alcoholic steatohepatitis (NASH) and non-alcoholic fatty liver disease (NAFLD) are increasing. In the treatment strategy for HCC in the Japanese guideline, the algorithm involves five clinicopathological factors: liver function (assessed using the Child-Pugh classification, liver damage score, and the ICG-R15 value), presence of extrahepatic metastases, presence of vascular invasion, number of tumors (within 3 or more than 4), and tumor size (within 3 cm or over 3 cm). Surgical resection is sometimes indicated for extrahepatic metastases in patients with well-controlled intrahepatic HCC, and for advanced HCC with vascular invasion, hepatectomy is also recommended as one of the treatment options according to the results of a nationwide survey in Japan. In the latest Japanese guideline, the recommended chemotherapy for advanced HCC is lenvatinib or sorafenib as first-line and regorafenib as second-line therapy. Currently, based on the results of various clinical trials for advanced HCC, the therapeutic options for advanced HCC have increased, such as combination therapy of atezolizumab and bevacizumab, ramucirumab, and cabozantinib. Reports of conversion surgery after chemotherapy have also increased, and the development of multidisciplinary treatment for advanced HCC will be of further interest in the future.

PURPOSE Splenic vein (SV) ligation combined with portal vein (PV)/superior mesenteric vein (SMV) confluence resection during pancreaticoduodenectomy (PD) is reported to cause left-side portal hypertension (LPH). The purpose of this study was to present our technique of the SV reconstruction and to evaluate the surgical outcomes with/without SV ligation during PD. METHODS Twenty-four patients undergoing PD with PV and/or SMV resection and being followed over 4 months after surgery between March 2013 and December 2019 in our hospital were evaluated. Resection of the PV/SMV confluence were performed in 14, and SV reconstruction was successfully performed in 3. Presence of LPH was assessed by examining changes in splenic volume, newly venous collateral formation, and platelet counts before and 4-8 months after PD. Surgical technique is the direct anastomosis between SV and PV. RESULTS Splenic volume ratio was significantly higher in the SV ligation group (n = 11) than in the SV preservation group (n = 13) (median (range) 1.11 (0.57-1.62) vs. 1.68 (1.05-2.22), p < 0.01), but no significant differences were found in the incidence of newly formed venous collaterals or platelet counts between groups. CONCLUSION SV ligation may represent the cause of LPH after PD combined with resection of PV/SMV confluence. Our simple procedure may help decrease the incidence of LPH.

Mesopancreas excision in pancreatoduodenectomy is technically complicated because of the anatomical complexity of the mesopancreas with the inferior peripancreatic blood vessels which is caused by intestinal rotation in fetal life. We have developed a novel artery-first approach (the intestinal derotation procedure) for facilitating mesopancreas excision. The aim of this study was to clarify the vascular anatomy of the mesopancreas after derotation. The right-sided colon and small intestine are mobilized from the retroperitoneum, and the intestinal loop is then derotated. In 136 cases of pancreatoduodenectomy employing the derotation procedure, we analyzed the vascular anatomy of the mesopancreas. After derotation, the anatomy was simplified. The mesopancreas extended from the right aspect of the superior mesenteric artery (SMA), forming a horizontal plane. The first jejunal trunk (FJT) was situated in parallel with the second jejunal artery and was anterior (91%) or posterior (9%) to the SMA. The inferior pancreaticoduodenal vein (IPDV) entered the right side of the FJT (83%) or the superior mesenteric vein (17%). Besides the IPDV, 1–4 tributaries entered the right wall of the FJT, in 89% of cases. The inferior pancreaticoduodenal artery was observed to originate from the right wall of the SMA, sharing a common stem with the first jejunal artery (70%) or branching directly from the SMA (29%). Intestinal derotation simplifies the mesopancreas anatomy and reveals the anatomical details of the inferior peripancreatic blood vessels in pancreatoduodenectomy.

Excision of the mesopancreas with lymphadenectomy is an important component of pancreatoduodenectomy. However, the optimal extent of lymphadenectomy remains unclear. Furthermore, accurate description of the mesopancreatic lymphatic pathways is difficult, probably because of the complex anatomy. Intestinal derotation simplifies the anatomy and facilitates both examination of lymphatic flow and the surgical procedure. The aim of this study was to evaluate lymphatic flow in the mesopancreas using indocyanine green fluorescence imaging with an intestinal derotation technique, and to clarify the optimal extent of mesopancreas excision and lymphadenectomy in pancreatoduodenectomy. Indocyanine green solution (2.5 × 10−3 mg) was injected into the pancreatic head parenchyma. After intestinal derotation, the spread of indocyanine green was observed using near-infrared imaging. Participants comprised 10 patients who underwent pancreatoduodenectomy for periampullary neoplasms. With indocyanine green fluorescence imaging, 9 of the 10 patients showed lymphatic flow from the pancreatic head to the superior mesenteric artery via the inferior pancreaticoduodenal artery and first jejunal artery (but not via the second and more distant arteries), with eventual drainage into the paraaortic region. Lymphatic pathways from the pancreatic head were connected to the superior mesenteric artery via the inferior pancreaticoduodenal artery and first jejunal artery. Excision of the mesopancreas with the inferior pancreaticoduodenal artery and first jejunal artery while preserving the second or more distant arteries appears optimal in pancreatoduodenectomy for periampullary malignancies.

Hepatolithiasis frequently results in severe complications. We conducted a cohort study to identify prognostic factors and to establish a hepatolithiasis severity classification system. The study cohort comprised 396 patients who were identified through a 1998 nationwide survey and followed up for 18 years or until death. Cox regression analysis was used to identify prognostic factors. Median survival time of the patients was 308 (range 0–462) months. Of the 396 patients enrolled in the study, 118 (29.8%) died, most frequently from intrahepatic cholangiocarcinoma (25 patients, 21.2%). Age of ≥ 65 years at the time of initial diagnosis [hazard ratio (HR) 3.410], jaundice for ≥ 1 week during follow-up (HR 2.442), intrahepatic cholangiocarcinoma (HR 3.674), and liver cirrhosis (HR 5.061) were shown to be significant risk factors for death from any therapeutic course. The data led to a 3-grade disease severity classification system that incorporates intrahepatic cholangiocarcinoma and liver cirrhosis as major factors and age of ≥ 65 years and jaundice for ≥ 1 week during follow-up as minor factors. Survival rates differed significantly between grades. The proposed hepatolithiasis severity classification system can be used to assess prognosis and thereby improve patient outcomes.

OBJECTIVE A simple system is needed to determine whether surgery is indicated in cases of intraductal papillary mucinous neoplasm (IPMN). METHODS We conducted a retrospective study to identify factors predictive of malignant IPMN and thus simplify the treatment decision-making process. Ninety-six consecutive patients treated surgically for IPMN at Kyorin University Hospital (Tokyo, Japan) between 1994 and 2014 were included. Univariate and multivariate analyses were used to identify preoperative factors predictive of malignancy. A simple scoring formula was derived from the regression equation. RESULTS Twenty-two (23%) of the IPMNs were malignant, and 74 (77%) were benign. Pancreatic head tumor, cyst diameter of 47 mm or greater, and mural nodule diameter of 9 mm or greater were identified as significant predictors of malignant IPMN. The following scoring formula was developed: 4 × tumor location (pancreatic head, 1; pancreatic body or tail, 0) + 3 × cyst diameter (≥47 mm, 1

Duct-to-mucosa pancreatojejunostomy after pancreatoduodenectomy can be technically difficult, particularly in cases with a non-dilated pancreatic duct. We devised a novel procedure employing a pancreatic duct holder and mucosa squeeze-out technique facilitating duct-to-mucosa anastomosis. We compared the perioperative outcomes of pancreatoduodenectomy with duct-to-mucosa pancreatojejunostomy between the novel and conventional procedures. Our pancreatic holder has a cone-shaped tip with a slit. The holder can expand the pancreatic duct and provides a good surgical field for anastomosis. A small incision for anastomosis is made on the jejunum, while the jejunum is grasped around the incision. Then, the jejunal mucosa becomes squeezed-out and everted. This mucosa squeeze-out technique facilitates suturing the full thickness of the jejunum. Propensity score matching yielded 113 cases each undergoing the novel and the conventional procedure, among 308 cases receiving pancreatoduodenectomy with duct-to-mucosa pancreatojejunostomy. The overall morbidity rate was significantly lower in the novel procedure group. The pancreatic fistula (ISGPF grade B/C) rate was significantly lower in the novel (5 %) than in the conventional (13 %) procedure group. For cases with a non-dilated pancreatic duct (≤3 mm), the rate was significantly lower in the novel (10 %) than in the conventional procedure group (24 %). Multivariate analysis identified a non-dilated pancreatic duct, soft pancreas, and the conventional procedure as factors independently predicting the complication of pancreatic fistula formation. Our novel procedure facilitates duct-to-mucosa pancreatojejunostomy and decreases the pancreatic fistula rate. This procedure is simple, rational, and useful for achieving anastomosis, particularly in cases with a non-dilated pancreatic duct.

A 72-year-old woman with advanced ascending colon cancer and an intraductal papillary mucinous neoplasm (IPMN) of the pancreatic head was treated by right hemicolectomy (RHC) and pylorus-preserving pancreaticoduodenectomy (PpPD). Adjuvant chemotherapy was not administered. Multimodal examinations at 5 months after surgery detected a solitary metastatic liver tumor derived from cancer of the ascending colon. Liver resection proceeded at 7 months after the first surgery. A pathological study of a surgical specimen of the liver identified a necrotic nodule that did not contain viable tumor cells. However, an immunohistological study of the hepatic mass indicated metastasis derived from cancer of the ascending colon. These findings were consistent with total necrosis of a liver metastasis of colorectal cancer. The mechanism of spontaneous regression of tumors remains unexplained. In our case, pancreaticoduodenectomy was performed at the same time as right hemicolectomy, which involved a risk of continuous biliary infection after biliary tract reconstruction. A host immune response to chronic biliary tract infection might have been involved in the spontaneous regression of liver metastasis. Spontaneous regression of colorectal liver metastasis is rare, and the mechanism remains unknown. This needs to be investigated in more tissues from patients who have experienced this phenomenon.

BackgroundPerioperative atrial fibrillation (POAF) is one of the common arrhythmias in the setting of non-cardiac surgeries for malignancy. As POAF may cause subsequent adverse events, it is important to confirm its characteristics and risk factors.Materials and methodsThe prospective cohort study of surveillance for perioperative atrial fibrillation recurrence (PREDICT AF RECURRENCE) is an ongoing prospective, single-center, observational study that aims to illustrate the clinical impact of POAF in major non-cardiac surgery for malignancy. Patients who planned to undergo non-cardiac surgery for definitive/suspected malignancy were registered. Those with a history of AF and atrial flutter were excluded. Any 30-day complications included acute myocardial infarction, congestive heart failure, bleeding, thrombosis, any infection, and acute kidney injury. The primary endpoint was an incidence of POAF.ResultsThe present study included 799 patients (age, 68 ± 11; male, 62%). Of these, 80 patients (10.0%) developed POAF. Notably, 66 patients (83%) had no symptoms. Any 30-day complications occurred in 180 patients (23%) (with POAF: 34 (43%); without POAF: 146 (20%); p < 0.001). POAF in 17 patients (50%) was preceded by the development of complications. No patient developed cardiogenic shock and/or acute heart failure. The association between 30-day complications and POAF development were analyzed using the multivariate adjusted model (odds ratio: 2.84; 95% confidence interval: 1.74-4.62; p < 0.001).ConclusionTen percent of patients who underwent non-cardiac surgery for malignancy developed POAF, which was strongly associated with perioperative complications. As a majority were asymptomatic, careful observation using electrocardiography monitoring is important to avoid oversights.Clinical trial registrationUMIN ID: UMIN000016146.

Background In pancreatoduodenectomy (PD), mesopancreas excision with division of the inferior pancreatoduodenal artery (IPDA) is technically difficult because of the complex anatomy resulting from intestinal rotation occurring during embryological development. We have developed an intestinal derotation procedure for facilitating mesopancreas excision. The perioperative factors of PD were retrospectively compared between our derotation and the conventional procedure. Methods The entire small intestine and right colon are mobilized from the retroperitoneum, and intestinal rotation is reduced. This procedure simplifies the anatomic situation, in which (1) the mesopancreas stretches from the right side of the superior mesenteric artery (SMA) in a horizontal plane, (2) the IPDA arises from the right wall of the SMA, and (3) the SMA is situated at the right-posterior side of the superior mesenteric vein. In 232 cases undergoing PD, perioperative factors were compared retrospectively between the derotation ( n = 117) and conventional ( n = 115) procedure groups. Results The derotation procedure significantly decreased operative time (434 vs 516 minutes) and blood loss (521 vs 908 mL), and tended to increase the rate of R0 resection (90% vs 78%), compared with the conventional procedure. The derotation group had a significantly higher incidence of early, that is, before division of the drainage vein, IPDA division. Postoperative complication rates did not differ, between the 2 groups. Conclusion The derotation procedure is a simple but useful technique that facilitates mesopancreas excision and early IPDA division during PD.

Although a number of JmjC-containing histone demethylases have been identified and biochemically characterized, pathological roles of their dysfunction in human disease such as cancer have not been well elucidated. Here, we report the Jumonji domain containing 2A (JMJD2A) is integral to proliferation of cancer cells. Quantitative real-time PCR analysis revealed higher expression of JMJD2A in clinical bladder cancer tissues than in corresponding non-neoplastic tissues (P < 0.0001). Immunohistochemical analysis also showed positive staining for JMJD2A in 288 out of 403 lung cancer cases, whereas no staining was observed in lung normal tissues. Suppression of JMJD2A expression in lung and bladder cancer cells overexpressing this gene, using specific siRNAs, inhibited incorporation of BrdU and resulted in significant suppression of cell growth. Furthermore, JMJD2A appears to directly transactivate the expression of some tumor associated proteins including ADAM12 through the regulation of histone H3K9 methylation. As expression levels of JMJD2A are low in normal tissues, it may be feasible to develop specific inhibitors targeting the enzyme as anti-tumor agents which should have a minimal risk of adverse reaction.

Histone lysine methylation plays a fundamental role in chromatin organization. Although a set of histone methyltransferases have been identified and biochemically characterized, the pathological roles of their dysfunction in human cancers are still not well understood. In this study, we demonstrate important roles of WHSC1L1 in human carcinogenesis. Expression levels of WHSC1L1 transcript were significantly elevated in various human cancers including bladder carcinoma. Immunohistochemical analysis of bladder, lung, and liver cancers confirmed overexpression of WHSC1L1. WHSC1L1-specific small interfering RNAs significantly knocked down its expression and resulted in suppression of proliferation of bladder and lung cancer cell lines. WHSC1L1 knockdown induced cell cycle arrest at the G2/M phase followed by multinucleation of cancer cells. Expression profile analysis using Affymetrix GeneChip® showed that WHSC1L1 affected the expression of a number of genes including CCNG1 and NEK7, which are known to play crucial roles in the cell cycle progression at mitosis. As WHSC1L1 expression is significantly low in various normal tissues including vital organs, WHSC1L1 could be a good candidate molecule for development of novel treatment for various types of cancer. © 2012 Wiley Periodicals, Inc.

Although the physiologic significance of lysine methylation of histones is well known, whether lysine methylation plays a role in the regulation of nonhistone proteins has not yet been examined. The histone lysine methyltransferase SETD8 is overexpressed in various types of cancer and seems to play a crucial role in S-phase progression. Here, we show that SETD8 regulates the function of proliferating cell nuclear antigen (PCNA) protein through lysine methylation. We found that SETD8 methylated PCNA on lysine 248, and either depletion of SETD8 or substitution of lysine 248 destabilized PCNA expression. Mechanistically, lysine methylation significantly enhanced the interaction between PCNA and the flap endonuclease FEN1. Loss of PCNA methylation retarded the maturation of Okazaki fragments, slowed DNA replication, and induced DNA damage, and cells expressing a methylation-inactive PCNA mutant were more susceptible to DNA damage. An increase of methylated PCNA was found in cancer cells, and the expression levels of SETD8 and PCNA were correlated in cancer tissue samples. Together, our findings reveal a function for lysine methylation on a nonhistone protein and suggest that aberrant lysine methylation of PCNA may play a role in human carcinogenesis. Cancer Res; 72(13); 3217–27. ©2012 AACR.

The histone methyltransferase enhancer of zeste 2 (EZH2) is known to be a polycomb protein homologous to Drosophila enhancer of zeste and catalyzes the addition of methyl groups to histone H3 at lysine 27 (H3K27). We previously reported that EZH2 was overexpressed in various types of cancer and plays a crucial role in the cell cycle regulation of cancer cells. In the present study, we demonstrated that EZH2 has the function to monomethylate lysine 120 on histone H2B (H2BK120). EZH2-dependent H2BK120 methylation in cancer cells was confirmed with an H2BK120 methylation-specific antibody. Overexpression of EZH2 significantly attenuated the ubiquitination of H2BK120, a key posttranslational modification of histones for transcriptional regulation. Concordantly, knockdown of EZH2 increased the ubiquitination level of H2BK120, suggesting that the methylation of H2BK120 by EZH2 may competitively inhibit the ubiquitination of H2BK120. Subsequent chromatin immunoprecipitation- Seq and microarray analyses identified downstream candidate genes regulated by EZH2 through the methylation of H2BK120. This is the first report to describe a novel substrate of EZH2, H2BK120, unveiling a new aspect of EZH2 functions in human carcinogenesis.