Conversion to complete resection with mFOLFOX6 with bevacizumab or cetuximab based on K-RAS status for unresectable colorectal liver metastasis (BECK study): Long-term results of survival.

BACKGROUND/PURPOSE: To investigate the long-term outcome and entire treatment course of patients with technically unresectable CRLM who underwent conversion hepatectomy and to examine factors associated with conversion to hepatectomy. METHODS: Recurrence and survival data with long-term follow-up were analyzed in the cohort of a multi-institutional phase II trial for technically unresectable colorectal liver metastases (the BECK study). RESULTS: A total of 22/12 patients with K-RAS wild-type/mutant tumors were treated with mFOLFOX6 + cetuximab/bevacizumab. The conversion R0/1 hepatectomy rate was significantly higher in left-sided primary tumors than in right-sided tumors (75.0% vs 30.0%, P = .022). The median follow-up was 72.6 months. The 5-year overall survival (OS) rate in the entire cohort was 48.1%. In patients who underwent R0/1 hepatectomy (n = 21), the 5-year RFS rate and OS rate were 19.1% and 66.3%, respectively. At the final follow-up, seven patients had no evidence of disease, five were alive with disease, and 20 had died from their original cancer. All 16 patients who achieved 5-year survival underwent conversion hepatectomy, and 11 of them underwent further resection for other recurrences (median: 2, range: 1-4). CONCLUSIONS: Conversion hepatectomy achieved a similar long-term survival to the results of previous studies in initially resectable patients, although many of them experienced several post-hepatectomy recurrences. Left-sided primary was found to be the predictor for conversion hepatectomy.

Postoperative Biliary Leak Treated with Chemical Bile Duct Ablation Using Absolute Ethanol: A Report of Two Cases.

BACKGROUND Postoperative bile duct leak following hepatobiliary and pancreatic surgery can be intractable, and the postoperative course can be prolonged. However, if the site of the leak is in the distal bile duct in the main biliary tract, the therapeutic options may be limited. Injection of absolute ethanol into the bile duct requires correct identification of the bile duct, and balloon occlusion is useful to avoid damage to the surrounding tissues, even in cases with non-communicating biliary fistula and bile leak. CASE REPORT Two cases of non-communicating biliary fistula and bile leak are presented; one case following pancreaticoduodenectomy (Whipple's procedure), and one case following laparoscopic cholecystectomy. Both cases were successfully managed by chemical bile duct ablation with absolute ethanol. In the first case, the biliary leak occurred from a fistula of the right posterior biliary tract following pancreaticoduodenectomy. Cannulation of the leaking bile duct and balloon occlusion were achieved via a percutaneous route, and seven ablation sessions using absolute ethanol were required. In the second case, perforation of the bile duct branch draining hepatic segment V occurred following laparoscopic cholecystectomy. Cannulation of the bile duct and balloon occlusion were achieved via a transhepatic route, and seven ablation sessions using absolute ethanol were required. CONCLUSIONS Chemical ablation of the bile duct using absolute ethanol is an effective treatment for biliary leak following hepatobiliary and pancreatic surgery, even in cases with non-communicating biliary fistula. Identification of the bile duct leak is required before ethanol injection to avoid damage to the surrounding tissues.

Solitary Metastasis to a Distant Lymph Node in the Descending Mesocolon After Primary Resection for Hepatocellular Carcinoma: Is Surgical Resection Valid?

BACKGROUND Lymph node metastasis of hepatocellular carcinoma is rare, and lymph nodes located on hepatic hilar and hepatoduodenal ligaments are primary targets. Metastasis to a mesocolic lymph node has not been reported previously. CASE REPORT A 65-year-old woman with liver cirrhosis underwent primary resection of hepatocellular carcinoma. Two and a half years later, tumor marker levels increased remarkably and imaging revealed a mesocolic mass. The tumor measured 27 mm in diameter and showed characteristic findings consistent with hepatocellular carcinoma in dynamic computed tomographic images, although the tumor was negative in fluorine-18-fluorodeoxyglucose positron emission tomographic images. A preoperative diagnosis of solitary metastasis to a mesocolic lymph node was made, and we elected to perform surgical resection, although therapeutic strategies for rare solitary extrahepatic metastasis are controversial. The tumor was located in the mesocolon nearly at the wall of the descending colon. Curative resection was performed and histopathological analysis confirmed metastatic hepatocellular carcinoma to a mesocolic lymph node. Tumor marker levels normalized immediately postoperatively. To date, the patient remains free from recurrence without adjuvant therapy. CONCLUSIONS This is the first known case of solitary hepatocellular carcinoma metastasis to a distant mesocolic lymph node, successfully treated. Diagnosing solitary hepatocellular carcinoma metastases to distant lymph nodes can be difficult. Although the ideal therapeutic approach has not be defined, surgical resection of solitary metastatic lymph nodes may be beneficial in carefully selected cases.

Hepatectomy Based on Future Liver Remnant Plasma Clearance Rate of Indocyanine Green.

Background. Hepatectomy, an important treatment modality for liver malignancies, has high perioperative morbidity and mortality rates. Safe, comprehensive criteria for selecting patients for hepatectomy are needed. Since June 2011, we have used a cut-off value of ≧ 0.05 for future liver remnant plasma clearance rate of indocyanine green as a criterion for hepatectomy. The aim of this study was to verify the validity of this criterion. Methods. From June 2011 to December 2015, 212 hepatectomies were performed in Tenri Yorozu Hospital. Of these 212 patients, 107 who underwent preoperative computed tomography imaging volumetry, indocyanine green clearance test, and hepatectomy (excluding partial resection or enucleation) were retrospectively analyzed. Results. There was no postoperative mortality. Posthepatectomy liver failure occurred in 59 patients (55.1%) (International Study Group of Liver Surgery Grade A: 43 cases (40.2%), Grade B: 16 cases (15.0%), and Grade C: no cases). Operative morbidity greater than Clavien-Dindo Grade 3 occurred in 23 patients (21.5%). A low future liver remnant plasma clearance rate of indocyanine green was a good predictor for Grade B cases (area under curve = 0.804; 95% confidence interval, 0.712-0.895). Conclusion. Liver remnant plasma clearance rate of indocyanine green is a valid criterion for hepatectomy.

Preventive Measures for Postoperative Bile Leakage After Central Hepatectomy: A Multicenter, Prospective, Observational Study of 101 Patients.

BACKGROUND: There are no conclusive measures for preventing postoperative bile leakage (POBL). METHODS: First, 310 patients who underwent hepatectomy were analyzed retrospectively to clarify risk factors for POBL. Then, focusing on operations at high risk of POBL, patients who underwent central hepatectomy were recruited prospectively among 18 institutions, to evaluate various preventive measures for avoiding POBL. The primary endpoint was the frequency of POBL. RESULTS: The retrospective analysis revealed central hepatectomy and repeated hepatectomy to be independent risk factors for POBL. One hundred and one patients undergoing central hepatectomy were enrolled in the prospective study. POBL developed in 13 patients (12.9 %). Intraoperative bile leakage was recognized in 42 of the 101 patients (41.6 %), and 10 of the 42 patients developed POBL (23.8 %). Primary closure of the site of bile leakage and/or biliary drainage tube placement was preferable for preventing POBL in the patients with intraoperative bile leakage. Although 59 patients (58.4 %) did not show intraoperative bile leakage, three patients (5.1 %) developed POBL. In the group without intraoperative bile leakage, treatment with fibrin glue with a polyglycolic acid (PGA) sheet or collagen sheet coated with a fibrinogen and thrombin layer (CSFT) had good results. CONCLUSIONS: Primary closure of the site of bile leakage and/or placement of biliary drainage tubes may be recommended in cases involving intraoperative bile leakage. Treatment with fibrin glue with a PGA sheet and/or CSFT might have preventive effects in patients without intraoperative bile leakage.

Protocol for laparoscopic cholecystectomy: Is it rocket science?

Laparoscopic cholecystectomy (LC) does not require advanced techniques, and its performance has therefore rapidly spread worldwide. However, the rate of biliary injuries has not decreased. The concept of the critical view of safety (CVS) was first documented two decades ago. Unexpected injuries are principally due to misidentification of human factors. The surgeon's assumption is a major cause of misidentification, and a high level of experience alone is not sufficient for successful LC. We herein describe tips and pitfalls of LC in detail and discuss various technical considerations. Finally, based on a review of important papers and our own experience, we summarize the following mandatory protocol for safe LC: (1) consideration that a high level of experience alone is not enough; (2) recognition of the plateau involving the common hepatic duct and hepatic hilum; (3) blunt dissection until CVS exposure; (4) Calot's triangle clearance in the overhead view; (5) Calot's triangle clearance in the view from underneath; (6) dissection of the posterior right side of Calot's triangle; (7) removal of the gallbladder body; and (8) positive CVS exposure. We believe that adherence to this protocol will ensure successful and beneficial LC worldwide, even in patients with inflammatory changes and rare anatomies.

Conversion to complete resection with mFOLFOX6 with bevacizumab or cetuximab based on K-ras status for unresectable colorectal liver metastasis (BECK study).

BACKGROUND: Patients with colorectal liver metastasis (CRLM) might be down-staged by chemotherapy from an initially unresectable stage to a resectable stage. Because the tumor response to preoperative chemotherapy has been correlated with resection rate, the improved efficacy from the concept that only the patients without K-ras mutations receive an anti-EGFR antibody might be expected to increase the conversion rate. The purpose of this study is to evaluate the conversion rate from unresectable CRLM to complete resection. METHODS: We conducted a multi-institutional phase II trial for unresectable CRLM. Patients received mFOLFOX6 with either bevacizumab (bev) or cetuximab (cet) based on K-ras status (UMIN000004310). Planned treatment was for six cycles during which tumors were assessed for resectability every three cycles. Patients whose disease was unresectable after six cycles switched their chemotherapy regimen from mFOLFOX6 to FOLFIRI. The primary endpoint was R0 resection rate. RESULTS: Thirty-five patients with unresectable CRLM were enrolled. A total of 22/12 patients with K-ras wild-type/mutant (wt/mt) were treated with mFOLFOX6 plus cet/bev, respectively. The overall response rate was 64.7% (wt/mt; 77.3%/41.7%, P = 0.04). In 20 patients (58.8%), hepatectomy was performed according to protocol treatment, and the conversion rate was 72.7%/33.3% in wt/mt patients, respectively (P = 0.03). Finally, 23 patients (67.6%) underwent hepatectomy, and the conversion rate was 77.2%/50.0% in wt/mt patients (P = 0.09). The overall R0 resection rate was 47.1% (wt/mt; 50.0%/41.7%, P = 0.36). CONCLUSIONS: This prospective study showed that combined chemotherapy based on K-ras status can facilitate conversion to resection in patients with unresectable CRLM.

Indication for neoadjuvant chemotherapy in patients with colorectal liver metastases based on a nomogram that predicts disease-free survival.

BACKGROUND: The purpose of this study was to validate the Beppu nomogram, which predicts disease-free survival (DFS) after resection of colorectal liver metastases, and to investigate the efficacy of neoadjuvant chemotherapy based on the nomogram-predicted recurrence risk. METHODS: We retrospectively analyzed 234 patients with colorectal liver metastases who underwent a hepatic resection at eight hospitals between 2005 and 2010. RESULTS: The nomogram c-index of all the patients was 0.59. The observed and the predicted 3-year DFS showed good agreement. When the patients were divided into two groups who received or did not receive pre-hepatectomy chemotherapy (PHC), the c-index of the patients who received PHC was inferior to that of the patients who did not (0.56 and 0.61, respectively). In patients who received PHC, DFS among the quintiles clustered by the nomogram score indicated no significant differences (P = 0.25), unlike in patients who did not receive PHC (P < 0.0001). Surprisingly, in patients with no risk factors for recurrence, neoadjuvant chemotherapy provided significantly lower DFS than no neoadjuvant chemotherapy (3-year DFS: 42.9% vs. 80.0%, P = 0.03). CONCLUSIONS: The nomogram validation was shown to be moderately predictive. PHC decreased the performance of the nomogram and might produce no DFS benefit in patients with low recurrent risk.

Comparative outcomes of elderly and non-elderly patients receiving first-line palliative chemotherapy for advanced biliary tract cancer.

BACKGROUND AND AIM: Few studies have reported the efficacy and safety of palliative chemotherapy in elderly patients with advanced biliary tract cancer. We aimed to investigate the clinical outcomes of palliative chemotherapy for advanced biliary tract cancer in elderly patients. METHODS: We retrospectively evaluated 403 consecutive patients who received palliative chemotherapy between April 2006 and March 2009 for pathologically confirmed unresectable or recurrent biliary tract cancer. Clinical outcomes of the elderly group (≥ 75 years old; n = 94) were compared with those of the non-elderly group (< 75 years old; n = 309). RESULTS: Except for the extent of disease, patient baseline characteristics were well balanced between both groups. The median overall survival was 10.4 months in the elderly group and 11.5 months in the non-elderly group (hazard ratio, 1.14; 95% confidence interval, 0.89-1.45; P = 0.31). Although the frequency of adverse events between both groups was similar, interstitial pneumonitis was significantly more frequent in the elderly group than in the non-elderly group (4.3% vs 0%, P < 0.01). CONCLUSIONS: In advanced biliary tract cancer, overall survival of elderly patients receiving palliative chemotherapy is comparable with that of non-elderly patients. To our knowledge, this is one of the largest studies that have reported the clinical outcomes of elderly patients following palliative chemotherapy.

Patients with recurrent biliary tract cancer have a better prognosis than those with unresectable disease: retrospective analysis of a multi-institutional experience with patients of advanced biliary tract cancer who received palliative chemotherapy.

BACKGROUND: Prognostic factors for patients with advanced biliary tract cancer (BTC) who received palliative chemotherapy have not been fully established. Especially, the status of unresectable/recurrent disease has not been well studied because of a small number of patients with recurrent BTC in previous studies. METHODS: This multicenter retrospective study was conducted in 18 institutions in Japan. We retrospectively reviewed data regarding 403 patients with pathologically proven BTC who received palliative chemotherapy between April 2006 and March 2009. One hundred and ninety-two patients with recurrent BTC were included. Univariate and multivariate analyses were performed to identify prognostic factors. RESULTS: The median overall survival was significantly longer in the recurrent BTC patients than in the unresectable BTC patients (398 days vs. 323 days, P = 0.004). After adjustment using multivariate analysis, the status of recurrent/unresectable disease remained an independent prognostic factor (hazard ratio 1.33, 95% confidence interval 1.04-1.70, P = 0.022) in addition to performance status, extent of disease, carbohydrate antigen 19-9 levels, and carcinoembryonic antigen levels. CONCLUSIONS: The status of unresectable/recurrent disease was shown as an independent prognostic factor in the BTC patients. This result may help to predict life expectancy of BTC patients and design future clinical trials evaluating palliative chemotherapy in BTC.

[A case of stage IV rectal cancer successfully resected after chemotherapy (mFOLFOX6 plus panitumumab)].

A 6 6-year-old woman with hematochezia was admitted to our hospital. A colonoscopy detected KRAS wild-type rectal cancer. An abdominal computed tomography (CT) scan revealed a liver metastasis, and invasion to the uterus was suspected. The patient underwent a laparotomy, and intraoperative cytology and peritoneal dissemination proved positive. The tumor had invaded the uterus. We administered chemotherapy consisting of 5-fluorouracil, Leucovorin, and oxaliplatin(mFOL FOX6)plus panitumumab. A CT scan and colonoscopy performed after 10 courses of chemotherapy indicated remarkable tumor regression. An abdominal CT scan did not detect any liver metastases, and we performed a laparoscopic low anterior resection. In the second operation, peritoneal dissemination and washing cytology were negative. The pathological diagnosis of the surgically resected specimen was ypStageII. The patient is recurrence-free 7 months after surgery.

[A case of resection for a huge pancreatic acinar cell carcinoma with tumor thrombus in the portal vein].

A 6 3-year-old man with a huge pancreatic tumor was referred to our hospital. Abdominal computed tomography revealed a heterogeneously enhanced encapsulated mass, 14 cm in diameter, in the pancreas head. The tumor thrombus extended to the bifurcation of the portal vein. The tumor, which had invaded the descending duodenum, was diagnosed as a probable case of acinar cell carcinoma, based on the biopsy results. Prior to resection, we prepared an ileocecal vein-umbilical vein bypass. Initially, we planned to perform a pancreatoduodenectomy, however, a total pancreatectomy had to be performed due to the atrophy of the residual pancreas tail. Since the tumor thrombus was visible, floating up from the portal vein wall at the upper level of pancreas, we dissected the portal vein at this level. The thrombus was extracted after securing the main tract and both (right and left) branches of the portal vein with vessel tape. About 5 cm of portal vein was resected and reconstructed. Since patients who undergo resection of acinar cell carcinoma have a better prognosis and long-term survival is often reported for cases of resected tumor thrombus of the portal vein, it is advisable to resect acinar cell carcinomas even in cases as advanced as reported here.

[Curative resection for Stage IV advanced gastric cancer that responded to combination chemotherapy with docetaxel, cisplatin, and S-1].

A 50-year-old man was diagnosed with advanced gastric cancer(Borrmann type 3)accompanied with N3.Staging laparoscopy revealed invasion to the transverse mesocolon and positive cytology from peritoneal washing (CY1). After the patient underwent gastrojejunostomy, we administered DCS combination chemotherapy consisting of docetaxel (40 mg/m² intravenously on day 1), cisplatin(60 mg/m² intravenously on day 1), and S-1 (orally 80 mg/m² on days 1 to 14).Four courses of this treatment were provided every 4 weeks, and it resulted in a partial response (PR).We performed curative distal gastrectomy with transverse mesocolon resection and D2 plus 14v lymph node dissection. Cytological analysis of the samples obtained after peritoneal washing showed negative results.Histopathologically, no variable cancer cells remained in the primary lesion, but a few degenerated cancer cells remained in one of the lymph nodes.Pathological features were classified as Grade 3 for the primary lesion and Grade 2 for the lymph node lesions.S -1 and S-1/cisplatin were administered as adjuvant chemotherapy.One year and 6 months after surgery, the patient is alive and free of disease.

[A case of advanced gastric cancer successfully treated with trastuzumab, capecitabine, and Cisplatin therapy followed by curative resection].

We report a case of human epidermal growth factor receptor 2(HER2)-positive advanced gastric cancer successfully treated with combination therapy of trastuzumab, capecitabine, and cisplatin, followed by a curative resection. A 23-year-old woman was diagnosed with advanced type 3 gastric cancer, and the clinical findings were T3N0M0, StageIIA. A laparoscopic exploration revealed that it was a CY1 unresectable StageIV cancer. Initially, docetaxel, cisplatin, and S-1 therapy was chosen. However, the patient's HER2 status proved to be positive (IHC 3+), and so trastuzumab, capecitabine and cisplatin therapy was administered. After four cycles, the tumor significantly decreased in size, suggesting a partial response(PR). A further laparoscopic exam showed no apparent dissemination or metastatic cancer cells. We performed a curative resection consisting of a laparoscopic distal gastrectomy and D2 lymphadenectomy. The patient's postoperative course has been uneventful. She has been alive for 4 months and is receiving adjuvant chemotherapy comprising trastuzumab and S-1.

[A case of recurrent colon cancer developed thrombosis in superior mesenteric vein after chemotherapy].

A 48-year-old man was administered bevacizumab+FOLFOX for lymph node recurrence of colon cancer in the abdominal cavity, and developed serious thrombosis of the portal system after 6 courses of the chemotherapy. We discontinued it promptly and anticoagulant therapy with urokinase was started immediately, but a complete dissolution was not achieved. Preservation therapy using anticoagulants for a long duration was effective for controling the of clinical symptom of thrombosis. The result of 6 courses of chemotherapy was CR, and the effect continues today, without further treatment 2 years later.

Preoperative evaluation of malignancy in intraductal papillary mucinous neoplasms of the pancreas, especially in relation to dysplastic epithelial changes.

BACKGROUND/AIMS: Intraductal papillary mucinous neoplasms have a better prognosis than ductal adenocarcinomas of the pancreas. The aim of this study was to evaluate the malignant potential of IPMNs by their preoperative images. METHODOLOGY: Forty-three intraductal papillary mucinous neoplasms were divided into 3 duct ectatic types using preoperative images (the main duct type, the branch duct type, and the mixed type), and into 2 groups using resected specimens (the malignant group including severe dysplasia based on the WHO classification and the benign group). The diameters of the tumor, main pancreatic duct and mural nodule were measured on the images. RESULTS: Two thirds of main duct type cases were in the malignant group. For the branch duct and mixed types, the diameters of the tumor and detectable mural nodules were larger in the malignant group than in the benign group. A tumor diameter larger than 3.5cm and a mural nodule diameter larger than 6mm were risk factors for malignancy (p < 0.05). CONCLUSIONS: The main duct type, a tumor larger than 3.5cm of the branch duct or mixed type, and a mural nodule larger than 6mm were all indicators of malignancy risk.

Simultaneous transfer of vascular endothelial growth factor and hepatocyte growth factor genes effectively promotes liver regeneration after hepatectomy in cirrhotic rats.

BACKGROUND/AIMS: Liver regeneration in a cirrhotic liver is unsatisfactory. In the course of liver regeneration, non-parenchymal cells such as sinusoidal endothelial cells as well as hepatocytes increase in number while the liver structure and physiological functions are maintained. The aim of this study was to examine whether sufficient liver regeneration could be obtained by the simultaneous, preoperative injection of recombinant adenoviral vectors encoding human vascular endothelial growth factor (VEGF), a potent mitogen for sinusoidal endothelial cells, (pAxCAVEGF) and rat hepatocyte growth factor (HGF), a potent mitogen for hepatocytes, (pAxCAHGF) in 70% hepatectomized cirrhotic rats. METHODOLOGY: Forty-eight hours before 70% hepatectomy, dimethylnitrosamine-induced cirrhotic rats were infused intravenously with pAxCAVEGF or with pAxCAVEGF and pAxCAHGF, or with a control virus encoding Escherichia coli beta-galactosidase (pAxCALacZ). RESULTS: Strong VEGF mRNA expressions were shown in the livers of VEGF and VEGF/HGF-treated animals. The plasma HGF concentrations in the VEGF/HGF-treated rats were elevated compared with the other groups. Proliferating cell nuclear antigen immunostaining showed increased labeling indices of hepatocytes in the VEGF/HGF-treated rats at 24 and 48 h after hepatectomy. PCNA labeling indices of SECs were increased in the VEGF and VEGF/HGF-treated rats compared with the control animals at 24 and 48 h after hepatectomy. Moreover, the hepatic regeneration rate after hepatectomy was significantly augmented by the VEGF and VEGF/HGF treatment. CONCLUSIONS: Simultaneous preoperative injection of recombinant adenoviral vectors encoding VEGF and HGF effectively stimulates liver regeneration in cirrhotic rats.