Multicenter randomized phase II study on S-1 and oxaliplatin therapy as an adjuvant after hepatectomy for colorectal liver metastases (YCOG1001).

PURPOSE: The high recurrence rate of colorectal cancer liver metastasis (CRCLM) after surgery remains a crucial problem. However, adjuvant chemotherapy after hepatectomy for CRCLM has not yet been established. This study evaluated the efficacy of adjuvant therapy with S-1 and oxaliplatin (SOX). METHODS: In a multicenter, randomized, phase II study, patients undergoing curative resection of CRCLM were randomly enrolled in a 1:1 ratio to either the low- or high-dose group. S-1 and oxaliplatin were administered from days 1 to 14 of a 3-week cycle as a 2-h infusion every 3 weeks. The dose of S-1 was fixed at 80 mg/m2. The doses in the low- and high-dose oxaliplatin groups were 100 mg/m2 (low-dose group) and 130 mg/m2 (high-dose group), respectively. This treatment was repeated eight times. The primary endpoint was the rate of discontinuation owing to toxicity. The secondary endpoints were the relapse-free survival (RFS) and frequency of adverse events (AEs). RESULTS: Between August 2010 and March 2015, 44 patients (low-dose group: 31 patients and high-dose group: 13 patients) were enrolled in the study. Of these, one patient was excluded from the efficacy analysis. In the high-dose group, five of nine patients were unable to continue the study due to toxicity in February 2013. At that time, recruitment to the high-dose group was stopped from the protocol. The relative dose intensity (RDI) for S-1 in the low- and high-dose groups were 49.8 and 48.7% (p = 0.712), and that for oxaliplatin was 75.9 and 73.0% (p = 0.528), respectively. The rates of discontinuation due to toxicity were 60 and 53.8% in the low- and high-dose groups, respectively, with no marked difference noted between the groups (p = 0.747). The frequency of grade ≥ 3 common adverse events was neutropenia (23.3%/23.1%), diarrhea (13.3%/15.4%), and peripheral sensory neuropathy (6.7%/7.7%). The disease-free survival (DFS) at 3 years was 52.9% in the low-dose group, which was not significantly different from that in the high-dose group (46.2%; p = 0.705). CONCLUSIONS: SOX regimens as adjuvant therapy after hepatectomy for CRCLM had high rates of discontinuation due to toxicity in both groups. In particular, the RDI of S-1 was < 50%. Therefore, the SOX regimen is not recommended as adjuvant chemotherapy after hepatectomy for CRCLM.

Incidental Gallbladder Cancer on Cholecystectomy: Strategy for Re-resection of Presumed Benign Diseases from a Retrospective Multicenter Study by the Yokohama Clinical Oncology Group.

BACKGROUND/AIM: Current expert consensus recommends re-resection for incidental gallbladder cancer (IGBC) of pT1b-3. This study examined whether this consensus was reasonably applicable to patients with IGBC in one Japanese region. PATIENTS AND METHODS: This was a multicenter, retrospective analysis of cholecystectomies for presumed benign diseases between January 2000 and December 2009. RESULTS: IGBC was diagnosed in 70 (1.0%) out of 6,775 patients undergoing cholecystectomy. Five-year disease-specific cumulative survival was 100% in 19 patients with pT1a, 80.0% in five with pT1b, 49.5% in 33 with pT2, and 23.1% in 13 with pT3. Re-resection was not performed for the 24 patients with pT1a/1b disease, whereas 24 out of 46 patients with pT2/3 underwent re-resection. Regardless of re-resection, independent factors associated with a poor prognosis on multivariate analysis were grade 2 or poorer disease and bile spillage at prior cholecystectomy. In the 24 patients with pT2/3 re-resection, 11 patients without either of these two factors had significantly better 5-year disease-specific cumulative survival than the 13 patients with one or two independent factors associated with a poor prognosis (72.7% vs. 30.8%, p=0.009). CONCLUSION: This Japanese regional study suggests that indication of re-resection for IGBC should not be determined by pT-factor alone and that much more attention should be paid to pathological and intraoperative findings at prior cholecystectomy.

High-Mobility Group Box 1 expression predicts survival of patients after resection of adenocarcinoma of the ampulla of Vater.

BACKGROUND: Expression of High-Mobility Group Box 1 (HMGB1), a multifunctional protein involved in DNA function as well as cell proliferation, inflammation, and the immune response, has been reported to be prognostic in several types of malignancies. However, the prognostic value of HMGB1 in ampullary cancer has not been studied. METHODS: Patients with adenocarcinoma of the ampulla of Vater who underwent R0 resection with pancreaticoduodenectomy between 2001 and 2011 were included in the present multi-institutional study. The degree of HMGB1 expression was examined in each resected specimen by immunohistochemical staining. RESULTS: A total of 101 patients were enrolled of which, 79 patients were eligible. High expression of HMGB1 was observed in 31 (39%) patients. Blood loss, transfusion, tumor stage, nodal status, and HMGB1 expression were identified as predictors with univariate analysis. Multivariate analysis showed that transfusion, lymph-node metastasis, and high HMGB1 expression were independent predictors of poor overall survival. Subgroup analysis showed that high HMGB1 expression was predictive, especially in patients who did not receive adjuvant chemotherapy. CONCLUSIONS: High HMGB1 expression is an independent predictor of poor prognosis in patients with adenocarcinoma of the ampulla of Vater not treated with adjuvant chemotherapy.

Predictive factors for bile leakage after hepatectomy for hepatic tumors: a retrospective multicenter study with 631 cases at Yokohama Clinical Oncology Group (YCOG).

BACKGROUND: International Study Group of Liver Surgery (ISGLS) proposed the standardized definition for bile leakage (BL) after hepatectomy (Hx) at 2011 to precisely perceive incidence and predictive factors of this critical condition. METHODS: We conducted a multicenter retrospective study using the ISGLS definition of BL after Hx. RESULTS: Perioperative data regarding 631 patients undergoing elective Hx for hepatic tumors without biliary reconstruction performed between January 2009 and December 2011 were analyzed. BL was observed in 30 patients (4.8%). (Grade A, 8 (1.3%); B, 21(3.3%); C, 1 (0.2%)). Five independent predictors (diagnosis of liver metastases, prolonged operation, high risk procedures defined as Hx with broad exposure of the hilar Glissonean sheath, low platelet count and high serum total bilirubin on postoperative day 1) for grade B/C BL were elucidated by the multivariate analysis. When the study cohorts were divided into groups by number of accompanying these predictors, the more the accompanying independent predictors, the higher the incidence of BL. Notably, incidence of BL exceeded 40% in patients with four or more of these predictors. CONCLUSIONS: Risk stratification for BL after Hx can be achievable using independent predictors clarified in this study. However, proper management for high risk patients remains to be elucidated.

[A case report of bi-weekly docetaxel and S-1 combination chemotherapy for gastric cancer with carcinomatous lymphangitis of the lung].

A 38-year-old man with complaints of nausea, epigastralgia, cough, and decrease body weight was given a diagnosis of advanced gastric cancer (type 4) with carcinomatous lymphangitis of the lung (UM-circ cT3, N3, H0, P0, M1, stage IV, por2). He was treated with combination of docetaxel (DOC) 40 mg/m(2)/day (days 1, 15) and S-1 orally 80 mg/m(2)/day (days 1-7, 15-21), 1 week administered 1 week rest. After 2 courses of treatment, the patient achieved a partial response in the carcinomatous lymphangitis of the lung. Tumor markers decreased and symptoms improved. He experienced grade 2 peripheral neuropathy but with no grade 3 adverse events. Although the prognosis of gastric cancer with carcinomatous lymphangitis is poor. These results indicate that bi-weekly DOC and S-1 combination chemotherapy might be effective for gastric cancer with carcinomatous lymphangitis of the lung.

[A case report of bi-weekly docetaxel and S-1 combination chemotherapy for gastric cancer with multiple liver metastases and esophageal invasion].

A 61-year-old man with the chief complaint of pressure with swallowing was referred to our hospital with type 3 cardiac gastric cancer. Gastrofiberscope showed type 3 cardiac cancer with esophageal invasion. On the abdominal computed tomography, there was evidence of lymph node swelling in the lesser curvature and multiple liver metastases. Blood tumor markers were elevated: CEA 200 ng/mL, CA19-9 2,490 U/mL. He was diagnosed as unresectable advanced gastric cancer UE-circ, type-3, c-T3N2H1P0M1, Stage IV. A biopsy revealed adenocarcinoma (tub2-por1). We started bi-weekly docetaxel and S-1 combination chemotherapy(DOC 40 mg/m2 day 1, 14, S-180 mg/m2 day 1-7, 14-21). After completion of the first course of this combination therapy, his feeling of pressure was relieved and CT showed reduction of multiple liver lesions and lymph node metastases, indicating partial response. No regrowth was seen for 7 courses of the therapy. Regarding toxicity, grade 2 nausea and grade 1 nail pain were observed. After 7 courses, because of serum CEA elevation, bi-weekly CPT-11/CDDP therapy (CPT-11 60 mg/m2, CDDP 30 mg/m2) was administered followed by weekly PTX therapy (65 mg/m2 day 1, 7, 14; total of 4 weeks). To date, 17 months after administration of chemotherapy, he has been treated on an outpatient basis. Biweekly DOC/S-1 therapy can be novel antitumor therapy which can be conducted safely in an outpatient setting for advanced gastric cancer.

A pitfall of the diagnostic process of differentiating bile peritonitis from acute appendicitis.

BACKGROUND/AIMS: We often encounter patients with bile peritonitis expressing right hypogastralgia who have been easily misdiagnosed as acute appendicitis. The aim of this study is to clarify why patients with bile peritonitis express right hypogastralgia and to recommend a way in which to prevent misdiagnosis of patients with bile peritonitis with right hypogastralgia as acute appendicitis. METHODOLOGY: Subjects were 12 patients with bile peritonitis who underwent laparotomy in Yokohama City Nambu Hospital or Critical Care and Emergency Center of Yokohama Citizen Medical Center Hospital. The spread of bile and inflammatory peritoneal fluid confirmed during laparotomy was compared with the preoperative abdominal findings. RESULTS: Five of the 12 cases (42%) showed signs of peritoneal irritation only in the epigastric and right hypochondral region; 6 (50%) in the right lateral and hypogastric region; and 1 (8%) in the diffuse abdomen. Four of the 12 cases (33%) showed widespread inflammation and accumulation of fluid in the whole peritoneal cavity (generalized peritonitis). Five cases (42%) showed limited peritoneal inflammation with green coating, leaked bile, and accumulation of inflammatory fluid within the hepatoduodenal ligament, Morison's pouch, right paracolic gutter, and right ileac pouch. Three of these 5 cases and 3 of the 4 generalized peritonitis cases showed signs of peritoneal irritation in the right hypogastric region. US of these cases showed signs of cholecystitis. Three of the 6 cases underwent emergency operation by right hypogastric incision under the diagnosis of acute appendicitis. One of these 3 cases underwent neither US nor CT; the second of these cases showed ileocecal inflammation by US but did not undergo CT; and the last of these cases expressed peritoneal irritation most strongly in the right hypogastric quadrant despite of signs of cholecystitis by US and CT. CONCLUSIONS: If patients who complain of right hypogastralgia like acute appendicitis also complain of right epigastralgia or right hypochondralgia, we should suspect biliary peritonitis due to gangrenous or perforated cholecystitis and should perform upper abdominal scanning, especially around the gallbladder, by US and CT.

Changes in the response of neutrophils to endotoxin priming following major abdominal surgery.

Endotoxin (ETX) primes polymorphonuclear cells (PMNs) for the subsequent release of reactive oxygen species (ROS) in response to various stimulants such as phorbol myristate acetate (PMA). Although PMNs contribute to oxidative stress after stimulation by standard stimulants and after priming by many humoral factors, it is unknown whether the PMNs from patients at different postoperative times exhibit the same response to the same standard stimulant. We examined the response of PMA-induced production of ROS from PMNs at various intervals after major abdominal surgery in response to ETX priming. This study was a prospective clinical and laboratory study conducted over a 7-day period that involved 25 patients who were referred for elective major abdominal surgery (8 for gastric cancer, 9 for colonic cancer, 8 for rectal cancer). Blood was sampled on the day before operation and on postoperative days (PODs) 1, 3, and 7. For each sample we measured luminol-dependent chemiluminescence (CL), the time to peak counts (Tmax) of PMNs stimulated by PMA, and the serum ETX level. We studied the correlation between CL and ETX in samples from PODs 1 and 3. We also studied the CL of PMNs on PODs 1 and 3 preincubated (primed) with various concentrations of ETX (0, 20, 40, 60, and 100 pg/ml). We found that CL decreased on POD 1 compared with the preoperative level (p <0.05) because of the decreased Tmax. The level of CL per 1 ml of whole blood, however, was higher on PODs 1 and 3 than preoperatively. During this time, leukocytosis should compensate for the impaired production of ROS by an individual PMN. The serum ETX level was increased on POD 1 (p <0.05). There was a negative correlation between CL and ETX on POD 1 (correlation coefficient ?0.62, p < 0.01) and a positive correlation on POD 3 (0.61, p <0.01). CL on POD 3 was accelerated by ETX priming, but the CL on POD 1 was depressed by the priming using a low concentration of ETX. The mode of the response of PMNs to ETX priming differed between PODs 1 and 3. On POD 1 the responses of PMNs to environmental stimulants is suppressed, but by POD 3 these responses had increased.