Examination of Prognostic Factors Affecting Long-Term Survival of Patients with Stage 3/4 Gallbladder Cancer without Distant Metastasis.

In advanced gallbladder cancer (GBC) radical resection, if multiple prognostic factors are present, the outcome may be poor; however, the details remain unclear. To investigate the poor prognostic factors affecting long-term surgical outcome, we examined 157 cases of resected stage 3/4 GBC without distant metastasis between 1985 and 2017. Poor prognostic factors for overall survival and treatment outcomes of a number of predictable preoperative poor prognostic factors were evaluated. The surgical mortality was 4.5%. In multivariate analysis, blood loss, poor histology, liver invasion, and ≥4 regional lymph node metastases (LNMs) were independent prognostic factors for poor surgical outcomes; invasion of the left margin or the entire area of the hepatoduodenal ligament and a Clavien-Dindo classification ≥3 were marginal factors. The analysis identified outcomes of patients with factors that could be predicted preoperatively, such as liver invasion ≥5 mm, invasion of the left margin or the entire area of the hepatoduodenal ligament, and ≥4 regional LNMs. Thus, the five-year overall survival was 54% for zero factors, 34% for one factor, and 4% for two factors (p < 0.05). A poor surgical outcome was likely when two or more factors were predicted preoperatively; therefore, new treatment strategies are required for such patients.

Dramatic response of FOLFIRINOX regimen in a collision pancreatic adenocarcinoma patient with a germline BRCA2 mutation: a case report.

Germline BRCA1 and BRCA2 mutations are the most common gene mutations in familial pancreatic adenocarcinoma. Several reports have demonstrated the utility of platinum-based chemotherapy for treating cancer patients who harbour a BRCA mutation. Here we discuss a 47-year-old Japanese female with no relevant past history who presented with epigastralgia and fever in September 2016. A computed tomography scan revealed a low-density, low-enhanced tumour 15 mm in diameter in the head of the pancreas. The pathological diagnosis was a ductal pancreatic carcinoma. A 6 mm low-enhanced metastatic tumour was also detected in segment 4 of the liver. Because she had early onset of the disease and a family history-her mother died of pancreatic adenocarcinoma at age 48-we considered a diagnosis of familial pancreatic adenocarcinoma. She received modified FOLFIRINOX. Two months after starting chemotherapy, she was diagnosed with an invasive ductal carcinoma in the right breast. FOLFIRINOX was continued for 8 cycles (4 months); the primary pancreatic adenocarcinoma shrank and the liver metastatic foci disappeared, but the size of the breast tumour increased. Total right breast excision and sentinel lymph node dissection were performed. FOLFIRINOX was continued and after 12 cycles (6 months), both her pancreatic adenocarcinoma and liver metastasis were no longer visible using imaging. Pancreatoduodenectomy was performed and the primary tumour had shrunk to 2.5 mm. Genetic testing revealed a germline BRCA2 mutation. The FOLFIRINOX regimen showed dramatic effects on the collision pancreatic but not on the breast cancer.

Amphiregulin/epiregulin mRNA Expression and Primary Tumor Location in Colorectal Cancer.

BACKGROUND/AIM: Amphiregulin (AREG) and epiregulin (EREG) mRNA expression levels are predictors of response to anti-EGFR antibody therapy. Left-sided colon cancer is more sensitive to anti-EGFR antibodies than right-sided, although the mechanism is unclear. The aim of this study was to determine the relationship between AREG, EREG mRNA expression levels and tumor location as well as the efficacy of anti-EGFR antibody agents. MATERIALS AND METHODS: Real-time PCR was used to assess AREG and EREG mRNA expression in metastatic colorectal cancer (CRC) samples from 153 patients. RESULTS: Among KRASwt samples, high AREG expression (AREGHigh) was significantly more common in left-sided tumors than in right-sided. Among patients who received anti-EGFR antibody, response rates were significantly higher in AREGHigh than in AREGLow In the left-sided tumor group, overall survival was significantly longer in patients with high EREG levels than with low levels, whereas the right-sided tumor group showed no survival difference between them. CONCLUSION: AREG and EREG mRNA expression levels in left-sided CRC were higher than in right-sided tumors. This may help explain why left-sided CRC is more responsive to anti-EGFR antibodies.

Phase II study of bevacizumab and irinotecan as second-line therapy for patients with metastatic colorectal cancer previously treated with fluoropyrimidines, oxaliplatin, and bevacizumab.

PURPOSE: Fluorouracil and folinic acid with irinotecan (FOLFIRI) plus bevacizumab (BV) is widely used as second-line chemotherapy for patients with metastatic colorectal cancer (mCRC) previously treated with fluoropyrimidines, oxaliplatin, and BV. FOLFIRI requires a CV catheter and an infusion pump, which are inconvenient for patients. Sufficient data are not available for characterizing the effectiveness of fluoropyrimidines beyond first disease progression. In this study, we evaluated the efficacy and safety of irinotecan (CPT-11) plus BV as second-line therapy. METHODS: Patients with mCRC previously treated with at least four courses of a fluoropyrimidine, oxaliplatin, and BV were designated to receive 150 mg/m2 of CPT-11 and 10 mg/kg of BV every 2 weeks as second-line therapy. The primary endpoint was progression-free survival (PFS), and secondary endpoints included response rate (RR), overall survival (OS), and adverse events. RESULTS: Thirty patients from six institutes were enrolled from March 2011 to January 2014. The median PFS was 5.7 months (95% CI 4.2-7.3 months), and the RR was 6.7% (range 0.8-22.1%). Grades 3-4 adverse events included leucopenia (36.7%), neutropenia (50%), thrombocytopenia (26.7%), anemia (30%), diarrhea (3.3%), anorexia (6.7%), and hypertension (3.3%). Relative dose intensities were 94.5 and 96.3% for CPT-11 and BV, respectively. The median OS was 11.8 months (6.3 months-not reached). CONCLUSIONS: Administration of CPT-11 plus BV to patients with mCRC achieved comparable efficacies with relatively lower toxicities compared with the results of previous studies using FOLFIRI plus BV as second-line therapy. The dose intensity of CPT-11 was judged as satisfactory. CLINICAL TRIAL INFORMATION: UMIN000005228.

PTEN mRNA expression is less pronounced in left- than right-sided colon cancer: a retrospective observational study.

BACKGROUND: Several recent studies have reported that patients with metastatic colorectal cancer (CRC) whose primary tumor is located in left side of the colon have more favorable responses to anti-epidermal growth factor receptor (EGFR) antibody therapy than those with right-sided tumors. However, the mechanism for this phenomenon is unknown. METHODS: Fifty-two cases of primary CRC with liver metastases were analyzed in this retrospective study. The mRNA levels of 19 signal transduction genes in both primary tumor and liver metastases were measured by real-time reverse transcription polymerase chain reaction. The purposes of this study were (1) to determine the correspondence between signal transduction gene expressions in primary tumors and corresponding liver metastases, and (2) to determine whether expression levels of these genes differ by primary tumor location. RESULTS: mRNA expression levels of 14 of 19 signal transduction genes, including PTEN, ERBB2, MET, HGF, AREG, and EREG, showed significant correlations between the primary tumor and corresponding liver metastases. When the mRNA levels of the primary tumors were compared by tumor location, only PTEN mRNA expression differed significantly between left and right-sided CRC (median PTEN expression: left 1.00 vs. right 1.68; p = 0.017). When rectal cancers were separated from left-sided colon cancers, PTEN mRNA levels increased progressively from rectum to right-sided colon (median; rectum 0.84, left colon 1.23, right colon 1.68, p = 0.013). PTEN mRNA expression in liver metastases also differed significantly according to primary tumor location (median; left 0.92 vs. right 1.27, p = 0.048). There was no difference in overall survival between patients with high versus low levels of PTEN mRNA (p = 0.59). CONCLUSIONS: Our data suggest that the PIK3/AKT/mTOR pathway is more active in left- than right-sided CRC, which provides a possible explanation for the fact that efficacy of anti-EGFR therapy differs by location of primary tumor.

Improved surgical outcomes for hilar cholangiocarcinoma: changes in surgical procedures and related outcomes based on 40 years of experience at a single institution.

PURPOSE: This study aimed to examine the changes in procedures for hilar cholangiocarcinoma (HC) surgery and patient survival following HC surgery over a 40-year period. METHODS: Between 1974 and 2014, 239 consecutive patients underwent surgery for HC. The changes in perioperative therapy and short- and long-term surgical outcomes were evaluated. RESULTS: The rates of major hepatectomy (in particular, right hepatectomy) and R0 resection significantly increased. Blood loss, transfusion rate, morbidity, and surgical mortality all significantly decreased. The 5-year disease-specific survival was 9.29 % (n = 38) in 1974-1988, 41.1 % (n = 88) in 1989-2003 and 55.6 % (n = 57) in 2004-2008 (p = 0.0001: 1974-1988 vs 1989-2003, p < 0.0001:1974-1988 vs 2004-2008, p = 0.076: 1989-2003 vs 2004-2008). According to a multivariate analysis, Bismuth classification IV (HR vs I, 2.86), period 1989-2003 (HR vs 1974-1988, 0.31), 2004-2008 (HR vs 1974-1988, 0.26), and R1 or R2 resection (HR vs R0, 2.22) were independent prognostic factors. CONCLUSION: The surgical outcomes for HC over the 40-year period clearly improved as a result of aggressive surgery and progress in surgical techniques, perioperative management, and diagnostic tools.

Surgical approaches to advanced gallbladder cancer : a 40-year single-institution study of prognostic factors and resectability.

PURPOSE: The aim was to evaluate prognostic factors and factors associated with the resectability of advanced gallbladder cancer (GBC). METHODS: This was a single-institution retrospective review of 274 consecutive surgically-treated cases of advanced GBC (excluding incidental GBC and early GBC). Univariate and multivariate analysis were performed to assess prognostic variables. R0 resection and survival rates were investigated for each local extension factor. RESULTS: Long-term survival was uncommon among patients with multiple liver metastases (H2-3: n = 22; 2-year survival, 0 %), dissemination (P1-3: n = 16; 3-year survival, 0 %), invasion through the hepatoduodenal ligament (Binf3: n = 45; 5-year survival, 4.6 %), or group 3 lymph node (LN) metastasis including of the para-aortic LN (N3: n = 52; 13.7 %). Long-term survival rates did not differ significantly between patients who did and did not undergo bile duct resection or pancreaticoduodenectomy. Survival did not differ significantly according to the type of hepatectomy performed. CONCLUSION: Surgery may not be indicated for patients with multiple liver metastasis, dissemination, Binf3, or visible para-aortic LN metastasis. Furthermore, it is important to achieve R0 surgery in cases of GBC.

Clinical features of pancreaticobiliary maljunction: update analysis of 2nd Japan-nationwide survey.

INTRODUCTION: Pancreaticobiliary maljunction (PBM) is a congenital anomaly, which can be defined as a union of the pancreatic and biliary ducts located outside off the duodenal wall. We herein investigate clinical features of PBM including as the 2nd report of a Japanese nationwide survey. PATIENTS AND METHODS: During a period of 18 years (from 1990 to 2007), 2,561 patients with PBM were registered at 141 medical institutions in Japan. Among them, eligible patients (n = 2,529) were divided into two groups: adult (n = 1,511) and pediatric patients (n = 1,018). Comparisons of clinical features including associated biliary cancers were performed according to the biliary dilatation (BD), age factor, and time era. RESULTS: Only one case in pediatric patients with BD combined with a bile duct cancer (0.1 %). In adult patients, the bile duct cancer and the gallbladder cancer was seen in 6.9 and 13.4 % patients with BD and in 3.1 and 37.4 % patients without BD, respectively. In adult patients with BD, the occurrence rates of biliary cancers were increased in latter period (00'-07') compared with former period (90'-99'). The ratio of biliary cancer localization was changed between former and latter period, and the bile duct cancer was increased in latter period (from 5.5 to 9.3 %). CONCLUSIONS: The largest series of PBM were evaluated to clarify the clinical features including the associated biliary cancer in this Japan-nationwide survey. This report could be widely used in the future as a reference data for diagnosis and treatment of PBM.

Successful treatment of pseudoaneurysm rupture after pylorus preserving pancreaticoduodenectomy by covered stent placement.

Serious complications after pancreaticoduodenectomy (PD) include pseudoaneurysm formation andABSTRACT rupture accompanying pancreatic fistula, and pancreatojejunostomy leakage, which is commonly associated with mortality or liver failure. We report a case of the successful treatment of pseudoaneurysm rupture after pylorus-preserving pancreaticoduodenectomy (PPPD) by covered stent placement. A 70-year-old man underwent PPPD for ampullary carcinoma. After the procedure, a pancreatic fistula was detected, and suction drainage was continued. The patient was discharged on the twenty-first post-operative day. On the same day, arterial bleeding was detected from the pancreatojejunostomy drain, and emergency abdominal angiography showed a pseudoaneurysm of 3-cm diameter at the proper hepatic artery (PHA). Multiple embolization coils were placed in a pseudoaneurysm. However, bleeding still continued, so hemostasis with coils was considered unfeasible. The next strategy was to place a covered stent, but the PHA was thick; thus, a biliary covered stent was implanted. Angiographic examination subsequently revealed that hepatic arterial flow was maintained, and there were no aneurysms. However, a few days later, a coil that had migrated into a peripheral branch of the right hepatic artery caused multiple hepatic abscesses, and percutaneous transhepatic abscess drainage was performed before the patient was discharged. Although coils were initially sufficient for hemostasis, repeatedly recurrent bleeding led to the consideration of a covered stent.

Proposed new simple scoring system to identify indications for urgent ERCP in acute cholangitis based on the Tokyo Guidelines.

BACKGROUND/PURPOSE: The Tokyo Guidelines (TG) have enabled more accurate diagnosis of acute cholangitis (AC). This study was undertaken to develop a new prognostic scoring system to predict the need for urgent endoscopic retrograde cholangiopancreatography (ERCP) based on the clinical findings on admission. METHODS: We prospectively reviewed 40 consecutive cases of AC and divided them into an urgent-ERCP group and an elective-ERCP group. RESULTS: Univariate analysis identified four factors that predicted the need for urgent ERCP: serum albumin level below 3.0 g/dl, blood urea nitrogen level above 20 mg/dl, platelet count below 120,000/µl, and the presence of systemic inflammatory response syndrome. These four predictors plus four predictors of organ dysfunction in the TG: shock, consciousness disturbance, respiratory failure, and prothrombin time/international normalized ratio >1.5, were used to devise a scoring system in which 1 point was assigned for the first four predictors and 2 points were assigned for the latter four predictors (maximum score possible: 12 points). The receiver-operator characteristic curve of the scores showed good test performance for predicting the need for urgent ERCP and for predicting a positive blood culture, and the areas under the concentration curves (AUCs) were 0.96 and 0.97, respectively. The optimal cut-off value for urgent ERCP was 2 points. CONCLUSIONS: This new simple scoring system allows identification of high-risk AC patients soon after admission to hospital.

Gastrectomy and chemotherapy with S-1 for gastric cancer in a patient with acquired immunodeficiency syndrome.

Total gastrectomy and chemotherapy with S-1 after surgery were performed in a 50-year-old woman with gastric cancer associated with acquired immunodeficiency syndrome (AIDS). She was given a diagnosis of gastric cancer at the lesser curvature of the body of the stomach, and distal gastrectomy was performed in December 2004. The postoperative course was eventful, with persistent high fever of unknown origin after surgery and infiltrative shadows in the bilateral lung fields showing on CT scan. Polymerase chain reaction (PCR) for pneumocystis carinii on bronchoscopy was positive, serum HIV antibody was positive, HIV-RNA was 2.2 × 10(5) copies/ml, and the serum CD4 lymphocyte level was 25/mm(3) on postoperative day 28. She was given a diagnosis of pneumocystis carinii with AIDS. Pneumocystis carinii and fever improved immediately when ST mixture and highly active antiretroviral therapy (HAART) were performed. After 3 months, the serum CD4 lymphocyte level was elevated to 125/mm(3), and she underwent total gastrectomy because cancer cells at the cut end of the resected stomach were positive microscopically. The postoperative course was uneventful, and she underwent adjuvant chemotherapy with S-1 because the serum CD4 lymphocyte level was 568/mm(3). S-1 therapy was continued for 2 years (each course consisting of 2 weeks of administration followed by 2 weeks off) while performing HAART and monitoring CD4 lymphocyte levels. No side effects such as decreases in white blood cell counts or CD4 lymphocyte levels were seen during S-1 therapy. She is alive and well without recurrence of gastric cancer 5 years after initial gastrectomy.

Prognostic relevance of ductal margins in operative resection of bile duct cancer.

BACKGROUND: The clinical relevance of the ductal margins in operative resection of bile duct carcinoma has not been well established. The purpose of this study was to assess the prognostic significance of ductal margins in patients with bile duct carcinoma. METHOD: A total of 256 patients with bile duct carcinoma were analyzed retrospectively. We compared clinicopathologic features, outcomes, and recurrences among patients who underwent curative resections with free margins (D-FRE: n = 185), noncurative resections only resulting from the involvement of ductal margins with carcinoma in situ (D-CIS: n = 13), noncurative resections only caused by the involvement of ductal margins with invasive foci of carcinoma (D-INV: n = 17), and noncurative resections resulting from any other margin state and/or distant metastases (OTH: n = 41). RESULTS: Histologic grades, node involvements, T classifications, and JSBS staging were significantly associated with the ductal margin state. The 5-year survival rate by Kaplan-Meier analysis was 54.7%, 52.4%, 17.6%, and 16.7% for patients with D-FRE, D-CIS, D-INV, and OTH, respectively. A multivariate analysis by the Cox proportional hazards model has shown that, in addition to lymph node involvement (P = 6.6 x 10(-4)) and venous invasion (P = 2 x 10(-5)), D-FRE versus D-INV and D-FRE versus OTH, but not D-FRE versus D-CIS, were independently associated with survival with P values of 8 x 10(-4) and 1.4 x 10(-5), respectively. Taken together along with the difference in the recurrence rates, patients with D-CIS seem to have outcomes similar to D-FRE but different from D-INV or OTH. CONCLUSION: Compared with free ductal margins, the ductal margins with invasive foci of carcinoma may involve a significant disadvantage in terms of patients' outcomes in surgical resection for bile duct carcinoma, unlike those with carcinoma in situ.

Should the extrahepatic bile duct be resected or preserved in R0 radical surgery for advanced gallbladder carcinoma? Results of a Japanese Society of Biliary Surgery Survey: a multicenter study.

PURPOSE: We assessed the significance of an extra bile duct resection by comparing the survival of patients with advanced gallbladder carcinoma who had resected bile ducts with those who had preserved bile ducts. A radical cholecystectomy that includes extra bile duct resections has been performed without any clear evidence of whether an extra bile duct resection is preventive or curative. METHODS: We conducted a questionnaire survey among clinicians who belonged to the 114 member institutions of the Japanese Society of Biliary Surgery. The questionnaires included questions on the preoperative diagnosis, complications, treatment, and surgical treatment, resection procedures, surgical results, pathological and histological findings, mode and site of recurrence, and the need for additional postoperative treatment. A total of 4243 patients who had gallbladder carcinoma and were treated from January 1, 1994 to December 31, 2003 were identified. The 838 R0 patients with pT2, pT3, and pT4 advanced carcinoma of the gallbladder for which there was no cancer invasion to the hepatoduodenal ligament or cystic duct in the final analysis. RESULTS: The 5-year cumulative survival, postoperative complications, postoperative lymph node metastasis, and local recurrence along the hepatoduodenal ligament were not substantially different between the resected bile duct and the preserved bile duct groups. CONCLUSIONS: Our retrospective questionnaire survey showed that an extrahepatic bile duct resection had no preventive value in some patients with advanced gallbladder carcinoma in comparison to similar patients who had no such bile duct resection. An extrahepatic bile duct resection may therefore be unnecessary in advanced gallbladder carcinoma without a direct infiltration of the hepatoduodenal ligament and the cystic duct.

Hepatic resection in 485 R0 pT2 and pT3 cases of advanced carcinoma of the gallbladder: results of a Japanese Society of Biliary Surgery survey--a multicenter study.

PURPOSE: We conducted this study to evaluate the optimal hepatic resection for pT2 and pT3 advanced carcinoma of the gallbladder without invasion of the hepatoduodenal ligament. METHODS: We conducted a questionnaire survey regarding 4,243 cases of carcinoma of the gallbladder treated during the recent 10-year period at 112 institutions belonging to the Japanese Society of Biliary Surgery. The questionnaires included questions on preoperative-diagnosis, complications, treatment, and surgical treatment, procedures of resection, surgical result, path histological findings, mode, and site of recurrence, additional post-operative treatment. They included 293 pT2 and 192 pT3 R0 cases, which were negative for hepatoduodenal ligament invasion, and the cumulative survival rates and sites of postoperative recurrence in the form of liver metastasis, were retrospectively analyzed in these 485 cases. RESULT: There were no significant differences in survival rate or recurrence rates in the form of liver metastasis between the groups that underwent resection of the gallbladder bed, the group that underwent segmentectomy 4a+5, and the group that underwent hepatectomy in patients with of both pT2 or pT3 gallbladder cancers. Our results also did not show that liver metastasis to segment 4a5 alone was particularly common. CONCLUSION: For gallbladder cancer, neither with hepatoduodenal ligament invasion nor hepatic invasion, resection of the gallbladder bed is more preferable for surgical hepatic procedure. For gallbladder cancer that invades any hepatic sites, a hepatic surgical procedure that could eliminate surgical margins would be desirable.

Advanced gastric cancer associated with nodular gastritis in a young patient.

A 20-year-old female underwent an endoscopy for epigastralgia that revealed many small, elevated nodules in the antrum that were diagnosed as nodular gastritis. The endoscopy also showed an ulcerative lesion with an uneven round wall at the greater curvature of the middle corpus. Biopsy of the ulcerative lesion yielded a diagnosis of poorly differentiated adenocarcinoma. A distal gastrectomy was performed on the basis of a diagnosis of gastric cancer associated with nodular gastritis. The intraoperative findings revealed serosal invasion of the gastric cancer and the patient tested positive for peritoneal cytology. The pathological findings revealed poorly differentiated adenocarcinoma showing invasive growth with fibrosis on the corpus and large and superficial lymphoid follicles on the miliary nodules at the antrum. The patient was positive for Helicobacter pylori infection by both the serum Helicobacter pylori antibody and histopathological findings.

Indications for pancreatoduodenectomy in patients undergoing lymphadenectomy for advanced gallbladder carcinoma.

BACKGROUND/PURPOSE: Carcinoma of the gallbladder shows diverse patterns of spread. The most appropriate surgical procedures according to the depth and extent of the spread of the tumor are still controversial. METHODS: We investigated this surgical problem clinicopathologically, especially regarding the indications for pancreatoduodenectomy (PD), by retrospectively reviewing the clinical records of 216 patients who were surgically treated for advanced gallbladder carcinoma. Detailed studies of resected specimens, in our department, showed that preservation of the pancreas head carried an increased risk of residual microscopic metastases in small peripancreatic lymphatic nodes and ducts. Some patients with curative operations had shown recurrence in lymph nodes around the head of the pancreas within a few years after PD. Therefore, we performed hepatopancreato duodenectomy (HPD) in 93 patients, some of whom underwent the HPD as a prophylactic dissection of peripancreatic lymph nodes and some of whom underwent the HPD as a curative resection due to invasion to the peripancreatic lymph nodes, duodenum, and pancreas, observed macroscopically. The surgical outcome after PD was compared with that obtained after other curative resections (non-HPD). RESULTS: In patients with microscopically negative lymph node metastasis without hepatoduodenal ligament invasion, PD was not necessary for a complete resection of lymphatic metastases around the pancreas head. The 5-year survival rate of these patients who had HPD was not significantly higher than that for non-HPD resections with curative intent (73% vs 63%), and lymphatic recurrence was not marked. On the other hand, in patients with positive lymph node metastases without hepatoduodenal ligament invasion, PD was necessary for a complete resection. The 5-year survival rate after HPD in these patients was significantly improved compared to that after non-HPD resections with curative intent (87% vs 17%), because lymphatic recurrence was reduced (0% vs 80%). CONCLUSIONS: In advanced carcinomas with positive hepatoduodenal ligament invasion, although the basic operative strategy, which inevitably includes right lobectomy, should be curative, PD should not be performed for prophylactic lymphatic resection, because local recurrence in the hepatoduodenal ligament cannot be controlled by PD, and the 5-year survival rate of curative HPD was only 4% (non-HPD resection with curative intent, 18%); moreover, frequent, lethal, major postoperative complications (hepatic failure) occurred after combined right lobectomy.