Long-term survival with sorafenib-based multidisciplinary treatment for Vp4 hepatocellular carcinoma: a case report.

The prognosis of highly advanced unresectable hepatocellular carcinoma (HCC) with a portal vein tumor thrombus (PVTT) is poor. There are currently no reports of long-term survival for up to 5 years in patients with advanced HCC who were treated with sorafenib. We describe a patient with Vp4 HCC who was treated with a sorafenib-based multidisciplinary treatment and experienced long-term survival, which may be the longest survival to date. A man in his late 60 s presented with general fatigue. Eight years previously, he received interferon monotherapy for chronic hepatitis C for 48 weeks and achieved a sustained virological response. He was diagnosed with a PVTT (Vp4) with diffuse-type HCC in the S6 lobe of the liver. He received hepatic arterial infusion of chemotherapy using 5-fluorouracil and cisplatin. Because of the occurrence of adverse effects, he was placed on sorafenib treatment. The treatment was effective and the HCC reduced. However, after 3 years of treatment, a 2-cm HCC was observed in the S5 lobe, and the patient underwent laparoscopic partial hepatectomy. After the operation, he continued to receive sorafenib, with no obvious recurrence, and survived for over 108 months after the first treatment. There are currently no reported cases of long-term progression-free survival by sorafenib for five years in patients of Vp4 HCC. In conclusion, we report a case of longest survival of a patient with Vp4 HCC treated with sorafenib-based multidisciplinary treatment.

Effect of Oral Nutritional Supplementation on the Prognostic Nutritional Index in Gastric Cancer Patients.

This prospective study was undertaken to investigate whether preoperative oral nutritional supplementation (ONS) would increase the prognostic nutritional index (PNI) in gastric cancer patients undergoing gastrectomy. Before surgery for resectable gastric cancer, Racol® NF (Otsuka Pharmaceutical Factory, Japan) was administered orally at a recommended dose of 600 kcal/600 ml per day to patients with a PNI of <48. The primary endpoint was the change in the PNI, which was calculated as 10 × serum albumin (g/dl) + 0.005 × total lymphocyte count (per mm3). Forty-six patients received Racol® NF. The mean PNI at baseline and before surgery was 44 ± 3.9 and 43 ± 4.4, respectively (p = 0.049). The mean serum albumin level was significantly decreased after the administration of Racol® NF (p = 0.001), while the mean total lymphocyte count (p = 0.001) and body weight (p = 0.004) were significantly increased. The mean daily intake and duration of Racol® NF administration were 340 ml and 22.6 day, respectively. Adverse events during the administration of Racol® NF were observed in 12 (26.1%) patients. The present study indicated that preoperative ONS did not increase the PNI in gastric cancer patients with low PNI values.

No Significant Effect of Daikenchuto (TJ-100) on Peritoneal IL-9 and IFN-γ Levels After Pancreaticoduodenectomy.

AIM AND BACKGROUND: TJ-100 is a traditional Japanese medicine that affects inflammation and gastrointestinal motility, and is used as a preventive and treatment for paralytic ileus. This study aims at determining the effect of TJ-100 on the peritoneal levels of IFN-γ/IL-9, cytokines related to ileus, after pancreaticoduodenectomy (PD) in a clinical setting. METHODS: This was a subsidiary study of the clinical trial investigating the effect of TJ-100 on postoperative bowel function. Ascites was collected from 180 patients using an abdominal drainage tube on postoperative day 1 and 3 after PD (POD 1 or POD 3) and used to measure 27 cytokines. We performed univariate and multivariate analyses using several perioperative variables and administration of TJ-100/placebo to determine the effect of TJ-100 on the levels of IFN-γ and IL-9. RESULTS: Peritoneal levels of IL-9 and IFN-γ decreased between POD 1 and 3 (Wilcoxon signed-rank test p<0.001). Multivariate analysis was performed after univariate analysis to select the variables and patients with a body mass index of ≥22 kg/m2, older age, use of epidural anesthesia, and longer surgery correlated with the levels of IL-9 and IFN-γ. However, we could not detect a correlation between the use of TJ-100 and cytokine levels in ascites either on POD 1 or 3. CONCLUSION: TJ-100 did not affect peritoneal IL-9 and IFN-γ levels after PD. This was in accordance with published clinical findings showing no improvement in bowel function after PD and TJ-100 treatment.

Selective TACE with irinotecan-loaded 40 µm microspheres and FOLFIRI for colorectal liver metastases: phase I dose escalation pharmacokinetic study.

BACKGROUND: Efficacy of treatments for colorectal liver metastases after failure of first-line chemotherapy is limited. The aim of this study was to prospectively evaluate the feasibility, tolerability, and pharmacokinetics of selective transarterial chemoembolization (TACE) with irinotecan-loaded 40 µm microspheres combined with systemic FOLFIRI for colorectal liver metastases refractory to oxaliplatin regimen. METHODS: The dose escalation study was conducted in three patient groups with different amounts of irinotecan loaded (50, 75 and 100 mg per mL-microspheres). Selective catheterization was performed to embolize subsegments or segments of located tumors using TACE navigation system. FOLFIRI was administrated 7 days after TACE. Plasma concentration was measured before and time points after administration. RESULTS: Nine patients successfully underwent a total of 22 TACE procedures. Dose-limiting toxicity did not appear at any level. The overall response rate was 55.6%. The median progression free and overall survival were 8.1 and 18.2 months, respectively. The AUC and Cmax of plasma SN-38 per 1 mg injected irinotecan dose were significantly higher in irinotecan-loaded microspheres compared with FOLFIRI (P = 0.009 and P <  0.001, respectively). CONCLUSION: Selective TACE using 40 µm irinotecan-loaded microspheres combined with systemic FOLFIRI was feasible and safe even when a high dose of irinotecan was loaded. Irinotecan-loaded microspheres resulted in a higher plasma concentration and AUC of SN-38 than treatment with FOLFIRI. Further large scale trials to evaluate the efficacy are mandatory. TRIAL REGISTRATION: University Hospital Medical Information Network (UMIN) Clinical Trials Registry, Registration number; UMIN000015367 ; Registered date; 08,10,2014.

Transition of serum cytokines following pancreaticoduodenectomy: A subsidiary study of JAPAN-PD.

Our previous study aimed to examine the effect of TJ-100, a widely used herbal medicine, on intestinal function following pancreaticoduodenectomy (PD) in a multicenter, randomized, double-blinded, placebo-controlled manner (JAPAN-PD study). This concomitant study investigated the effect of TJ-100 on serum cytokine levels in patients who underwent PD. Due to the fact that several clinical variables can affect the absolute values of baseline serum cytokine levels, the ratios of the cytokine levels on postoperative day (POD)3 to those on POD1 were also used for analysis. The present study enrolled 180/224 randomized patients, of whom 91 received TJ-100 and 89 received placebo. As the main findings of the analysis, Wilcoxon signed-rank test revealed no significant difference in the levels of serum cytokines between the groups; however, patients in the TJ-100 group without severe inflammatory complications exhibited significantly higher ratios of interleukin (IL)-4 (n=123), IL-9 (n=72), IL-10 (n=97), PDGF-BB (n=143) and tumor necrosis factor-α (n=135), compared with patients in the Placebo Group (P<0.05). According to the results of the present study, TJ-100 has an effect on the change in serum cytokine levels from POD1 to POD3 following PD. However, the role of different transition pattern of cytokines in postoperative recovery following PD has to be investigated by further mechanical studies focusing on these extracted cytokines (ClinicalTrials.gov; no. NCT01607307; May 30, 2012).

Usefulness of computed tomography density of a tumor in predicting the response of advanced esophageal cancer to preoperative chemotherapy.

BACKGROUND: In Japan, preoperative chemotherapy is considered essential for resectable stage II or III esophageal cancers. It is important to identify nonresponders for preoperative chemotherapy because continuing ineffective chemotherapy is not beneficial for them. We investigated the correlation between the computed tomography number of tumor and the effect of preoperative chemotherapy in patients with esophageal cancer. METHODS: This retrospective study included 50 patients receiving preoperative chemotherapy with docetaxel, cisplatin, and 5-fluorouracil for stage II or III esophageal cancer. The computed tomography number of tumor was measured as the mean of Hounsfield Units of the primary lesion on a plain computed tomography measured within a freehand region of interest drawn around the tumor border. For analysis, the patients were classified into responders and nonresponders to chemotherapy, with the pathologic response evaluated using the Japanese and Mandard classification. We analyzed the associations between the computed tomography number of tumor and clinical factors; histopathologic features, including the tumor size, depth of tumor invasion, capillary invasion, Ki-67, p53, and CK5/6 expression; the pathologic response to chemotherapy and prognosis. RESULTS: There was a significant association between the computed tomography number of tumor and the response to chemotherapy. The cut-off value of the computed tomography number of tumor in predicting responders to chemotherapy was 40 Hounsfield Units (area under the receiver operating characteristic curve = 0.73, P = .009); patients with computed tomography number of tumor greater than this value significantly responded to chemotherapy (P = .02 in the Japanese and P = .009 in the Mandard classification) with good postoperative prognosis (P = .04). Only Ki-67 expression among the histopathogic features were associated with the computed tomography number of tumor in histopathologic features (P = .01). CONCLUSION: The computed tomography number of tumor may be useful to predict the efficacy of preoperative chemotherapy and subsequent prognosis for patients with advanced esophageal cancer.

Evaluation of the efficacy of daikenchuto (TJ -100) for the prevention of paralytic ileus after pancreaticoduodenectomy: A multicenter, double-blind, randomized, placebo-controlled trial.

BACKGROUND: We assessed the efficacy of TJ-100 taken perioperatively to recovery among patients with periampullary tumor or tumor of the head of the pancreas who underwent pancreaticoduodenectomy (PD). PATIENTS AND METHODS: In this multicenter, randomized, double-blinded, placebo-controlled, phase II trial (JAPAN-PD Study), patients were assigned randomly in a 1:1 ratio to receive TJ-100 or placebo. The coprimary endpoints were (1) incidence of postoperative paralytic ileus lasting >72 hours after surgery and (2) time to occurrence of postoperative paralytic ileus. This trial is registered at the UMIN Clinical Trials Registry (000007975) and at ClinicalTrials.gov (NCT01607307). RESULTS: From August 2012 through July 2013, we assessed 273 patients for eligibility, and 224 underwent randomization; 112 patients received TJ-100, and 112 patients received placebo. The population for analysis consisted of 104 patients who received TJ-100 and 103 who received placebo. Paralytic ileus occurred 35 (33.7%) in the TJ-100 group and 38 (36.9%) in the placebo group (P = .626). Time to first flatus was 2.25 (2.00-2.50) days in the TJ-100 group and 2.50 (1.50-2.50) days in the placebo group (P = .343). Among 23 patients who underwent a pylorus ring-preserving PD, time to first flatus was lower in the TJ-100 group than in the placebo group: 0.50 (0.50-1.00) days versus 1.50 (0.50-3.00) days (P = .034). CONCLUSION: Our findings suggest that use of TJ-100 did not improve recovery from paralytic ileus after PD, and may preclude the routine use of TJ-100 in clinical practice after PD operation.

[A Case of Advanced Hepatocellular Carcinoma, Its Disease Progression Could Be Controlled by Multimodal Treatment].

The patient was a 73-year-old man, diagnosed with advanced huge hepatocellular carcinoma with a tumor thrombus extending into the inferior vena cava and extrahepatic metastases. Radiation therapy(50 Gy)was applied for the bone metastases, primary tumor, and tumor thrombus, and the patient received a cisplatin transcatheter arterial infusion(100mg/ body, 5 courses). Sorafenib was administered orally once the local lesion was under control. The tumor showed a partial response according to the RECIST criteria, but the tumor thrombus in the inferior vena cava almost disappeared. The presence of a tumor thrombus in the inferior vena cava must be regarded as an oncologic emergency. Acisplatin transcatheter arterial infusion and radiation therapy may be treatment options for unresectable cases.

Proposed preoperative risk factors for early recurrence in patients with resectable pancreatic ductal adenocarcinoma after surgical resection: A multi-center retrospective study.

BACKGROUND/OBJECTIVE: Although surgical resection remains the only chance for cure in patients with pancreatic ductal adenocarcinoma (PDAC), postoperative early recurrence (ER) is frequently encountered. The purpose of this study is to determine the preoperative predictive factors for ER after upfront surgical resection. METHODS: Between 2001 and 2012, 968 patients who underwent upfront surgery with R0 or R1 resection for PDAC at seven high-volume centers in Japan were retrospectively reviewed. ER was defined as relapse within 6 months after surgery. Study analysis stratified by resectable (R) and borderline resectable (BR) PDACs was conducted according to the National Comprehensive Cancer Network guidelines. RESULTS: ER occurred in 239 patients (25%) with a median survival time (MST) of 8.8 months. Modified Glasgow prognostic score = 2 (odds ratio (OR) 2.06, 95% confidence interval (CI) 1.05-3.95; P = 0.044), preoperative CA19-9 ≥300 U/ml (OR 1.94, 1.29-2.90; P = 0.003), and tumor size ≥30 mm (OR 1.72, 1.16-2.56; P = 0.006), were identified as preoperative independent predictive risk factors for ER in patients with R-PDAC. In the R-PDAC patients, MST was 35.5, 26.3, and 15.9 months in patients with 0, 1 and ≥2 risk factors, respectively. There were significant differences in overall survival between the three groups (P < 0.001). No preoperative risk factors were identified in BR-PDAC patients with a high rate of ER (39%). CONCLUSIONS: There is a high-risk subset for ER even in patients with R-PDAC and a simple risk scoring system is useful for prediction of ER.

National Comprehensive Cancer Network Resectability Status for Pancreatic Carcinoma Predicts Overall Survival.

BACKGROUND: The aim of this study was to evaluate the validity of preoperative resectability status, as defined by the National Comprehensive Cancer Network (NCCN), from the viewpoint of overall survival. METHODS: A total of consecutive 704 patients with pancreatic head carcinoma who underwent pancreatoduodenectomy with upfront surgery at seven Japanese hospitals between 2001 and 2012 were evaluated retrospectively. According to the NCCN definition of preoperative resectability status, tumors were divided into resectable tumors without vascular contact (R group), resectable tumors with portal or superior mesenteric vein (PV/SMV) contact of ≦180° (R-PV group), borderline resectable(BR) tumors with PV/SMV contact of >180° (BR-PV group), and BR tumors with arterial contact (BR-A group). The relationship between the NCCN definition of preoperative resectability status and overall survival was analyzed. RESULTS: Of the 704 patients, 389, 114, 145, and 56 were classified into the R group, the R-PV group, the BR-PV group, and the BR-A group, respectively. Overall survival of the BR-PV and BR-A groups was significantly worse than that of the R group and R-PV groups (P < 0.05), although there was no significant difference in overall survival between the R group and the R-PV group (P = 0.310). Multivariate analysis revealed that PV/SMV contact of >180° (P = 0.008) and arterial contact (P < 0.001) were independent prognostic factors of overall survival. CONCLUSION: From the viewpoint of overall survival, the NCCN definition of preoperative resectability status was valid.

Randomized phase III study of gemcitabine plus S-1, S-1 alone, or gemcitabine alone in patients with locally advanced and metastatic pancreatic cancer in Japan and Taiwan: GEST study.

PURPOSE: The present phase III study was designed to investigate the noninferiority of S-1 alone and superiority of gemcitabine plus S-1 compared with gemcitabine alone with respect to overall survival. PATIENTS AND METHODS: The participants were chemotherapy-naive patients with locally advanced or metastatic pancreatic cancer. Patients were randomly assigned to receive only gemcitabine (1,000 mg/m(2) on days 1, 8, and 15 of a 28-day cycle), only S-1 (80, 100, or 120 mg/d according to body-surface area on days 1 through 28 of a 42-day cycle), or gemcitabine plus S-1 (gemcitabine 1,000 mg/m(2) on days 1 and 8 plus S-1 60, 80, or 100 mg/d according to body-surface area on days 1 through 14 of a 21-day cycle). RESULTS: In the total of 834 enrolled patients, median overall survival was 8.8 months in the gemcitabine group, 9.7 months in the S-1 group, and 10.1 months in the gemcitabine plus S-1 group. The noninferiority of S-1 to gemcitabine was demonstrated (hazard ratio, 0.96; 97.5% CI, 0.78 to 1.18; P < .001 for noninferiority), whereas the superiority of gemcitabine plus S-1 was not (hazard ratio, 0.88; 97.5% CI, 0.71 to 1.08; P = .15). All treatments were generally well tolerated, although hematologic and GI toxicities were more severe in the gemcitabine plus S-1 group than in the gemcitabine group. CONCLUSION: Monotherapy with S-1 demonstrated noninferiority to gemcitabine in overall survival with good tolerability and presents a convenient oral alternative for locally advanced and metastatic pancreatic cancer.

[Resection of the remnant pancreas for recurrent pancreatic cancer after distal pancreatectomy-a case report].

The standard treatment for metastatic pancreatic cancer is chemotherapy. The effect of surgical resection for localized recurrence in the remnant pancreas after pancreatectomy for pancreatic cancer is unknown, but is reported to have a moderately good outcome in a few reports. We herein report a case of curative resection for recurrence in the remnant pancreas, 24 months after distal pancreatectomy for pancreatic cancer. A 71-year-old man was diagnosed with pancreas tail cancer. Neoadjuvant treatment with chemoradiotherapy[ weekly full-dose gemcitabine(GEM) and radiation therapy 50 Gy/25 Fr] was followed by distal pancreatectomy. Postoperative adjuvant therapy with hepatic arterial infusion of 5-FU and systemic GEM therapy was completed. Twenty-four months after surgery, follow-up computed tomography scan results showed a lesion of 15-mm diameter in the remnant pancreas. Resection of the remnant pancreas was performed. The pathological findings showed moderately differentiated adenocarcinoma, morphologically similar to the primary pancreatic cancer. Six months following surgery, there are no signs of recurrence at present.

Safety and optimal management of hepatic arterial infusion chemotherapy after pancreatectomy for pancreatobiliary cancer.

OBJECTIVE: The purpose of this study was to assess the safety of hepatic arterial infusion (HAI) chemotherapy after pancreatectomy for pancreatobiliary cancer. MATERIALS AND METHODS: The study subjects comprised 51 patients treated with HAI chemotherapy after pancreatectomy: 31 patients had undergone pancreaticoduodenectomy or total pancreatectomy and 20 patients had undergone distal pancreatectomy. HAI chemotherapy was performed for the prevention of liver metastasis in 42 patients and for the treatment of metastases in nine patients. HAI chemotherapy consisted of 5-fluorouracil administered at 1000 mg/m(2)/wk. After each cycle of chemotherapy, the patency of the hepatic artery and complications were evaluated using digital subtraction angiography and CT arteriography via the catheter-port system. RESULTS: Placement of the catheter-port system was successful in all patients. Hepatic arterial occlusion and severe asymptomatic hepatic artery stenosis were observed in one patient (2%) and 10 patients (19.6%), respectively. The hepatic arterial patency rate tended to be lower in the group who underwent pancreaticoduodenectomy or total pancreatectomy (71%) than in the group who underwent distal pancreatectomy (90%), although the difference was not significant (p = 0.107). Four asymptomatic patients with hepatic artery stenosis restarted HAI chemotherapy after a 4-week withdrawal of treatment. In three patients (5.9%), all of whom had undergone pancreaticoduodenectomy, liver abscess or biloma developed synchronously with asymptomatic hepatic artery stenosis. All three cases were cured by percutaneous abscess drainage or conservative management. The tumor response rate in the treatment of liver metastases was 44.4%. The hepatic recurrence rate with adjuvant therapy was 7.1%. CONCLUSION: Our findings suggest that HAI chemotherapy after pancreatectomy is feasible and tolerable, although caution is required particularly after pancreaticoduodenectomy or after total pancreatectomy.

[Locally advanced pancreatic cancer successfully treated by arterial infusion chemotherapy combined with stereotactic radiotherapy--a case report].

We report a 60-year-old female with locally advanced pancreatic cancer successfully treated with stereotactic radiotherapy after arterial chemoinfusion. Using the indwelling catheter-port system with the unification of the pancreatic blood supply, we initially conducted an arterial infusion of weekly high-dose 5-FU (1,000 mg/m2/qw) combined with systemic gemcitabine (1,000 mg/m2/qw). As a result, the tumor was remarkably decreased. However, a part of the tumor where the drug had not been distributed remained in no reduction. Therefore, we added the stereotactic radiotherapy (50 Gy) targeted on the limited residual tumor and combined with concurrent systemic gemcitabine (1,000 mg/m2/qw). The residual tumors have been controlled well without distant metastases, and the patient is alive today 36 months after our initial treatment.

[A case of postoperative multiple liver metastases of pancreatic cancer successfully treated by combination chemotherapy with weekly high-dose 5-FU hepatic arterial infusion plus systemic infusion of gemcitabine].

We report a case of a 65-year-old man with postoperative multiple liver metastases of pancreatic cancer successfully treated with weekly high-dose 5-FU hepatic arterial infusion chemotherapy plus systemic infusion of gemcitabine. The patient was admitted because of suffering from epigastralgia and jaundice. He underwent pancreaticoduodenectomy for pancreatic head cancer and received postoperative adjuvant chemotherapy of gemcitabine. Abdominal CT after 6 months showed multiple liver metastases. Then we started a systemic gemcitabine (1,000 mg/body) infusion and weekly high- dose 5-FU (1,500 mg/body) hepatic arterial infusion chemotherapy. After 26 times of treatment, CT indicated that the tumors completely disappeared. He survived for 34 months after surgery. It has been suggested that this combined chemotherapy might be an effective treatment to control liver metastases of pancreatic cancer.