Hepatectomy Followed by Adjuvant Chemotherapy with 3-Month Capecitabine Plus Oxaliplatin for Colorectal Cancer Liver Metastases.

LESSONS LEARNED: Three-month adjuvant capecitabine plus oxaliplatin in combination (CAPOX) appeared to reduce recurrence, with mild toxicity in postcurative resection of colorectal cancer liver metastases (CLM). Recurrence in patients who underwent the 3-month adjuvant CAPOX after resection of CLM was most commonly at extrahepatic sites. BACKGROUND: The role of neoadjuvant and adjuvant chemotherapy in the management of initially resectable colorectal cancer liver metastases (CLM) is still unclear. We evaluated the feasibility of 3-month adjuvant treatment with capecitabine plus oxaliplatin in combination (CAPOX) for postcurative resection of CLM. METHODS: Patients received one cycle of capecitabine followed by four cycles of CAPOX as adjuvant chemotherapy after curative resection of CLM. Oral capecitabine was given as 1,000 mg/m2 twice daily for 2 weeks in a 3-week cycle, and CAPOX consisted of oral capecitabine plus oxaliplatin 130 mg/m2 on day 1 in a 3-week cycle. Primary endpoint was the completion rate of adjuvant chemotherapy. Secondary endpoints included recurrence-free survival (RFS), overall survival (OS), dose intensity, and safety. RESULTS: Twenty-eight patients were enrolled. Median age was 69.5 years, 54% of patients had synchronous metastases, and 29% were bilobar. Mean number of lesions resected was two, and mean size of the largest lesion was 31 mm. Among patients, 20 (71.4%; 95% confidence interval, 53.6%-89.3%) completed the protocol treatment and met its primary endpoint. The most common grade 3 or higher toxicity was neutropenia (29%). Five-year recurrence-free survival and overall survival were 65.2% and 87.2%, respectively. CONCLUSION: Three-month adjuvant treatment with CAPOX is tolerable and might be a promising strategy for postcurative resection of CLM.

A novel challenge of nondestructive analysis on OGATA Koan's sealed medicine by muonic X-ray analysis.

OGATA Koan (1810-63) was a physician and the director of Tekijuku, and he contributed to Western medicine in the late Edo period. Osaka University preserves two of his medicine chests. One of the chests, which was used in his last years (the second chest) contained 22 glass bottles and 6 wooden cylinders. These bottles and cylinders contained formulated medicines; however, about half cannot be opened because of the long-term storage. It is necessary to comprehend the physical property of both the containers and their contents for investigation of this adequate preservation method; however, destructive analysis is not allowed. To analyze the medicines sealed in the glass bottles, we focused on muonic X-ray analysis, which has high transmittance. First, we certified the analytical methods using a historical medicinal specimen preserved in Osaka University. Thereafter, we applied the method on the bottles stored in the second chest. X-ray fluorescence identified the glass of those bottles to be lead potash glass. Among these bottles, we chose the bottle with the label "," which contains white powdered medication, for muonic X-ray analysis. We identified the contents of the medication in the glass to be Hg2Cl2. Through this study, we first applied muonic X-ray analysis on the medical inheritances and succeeded to detect the elements contained both in the container and in the contents of the sealed bottle. This would be a new method for nondestructive analysis of such cultural properties.

Phase III trial comparing UFT + PSK to UFT + LV in stage IIB, III colorectal cancer (MCSGO-CCTG).

PURPOSE: Oral adjuvant uracil and tegafur plus leucovorin (UFT/LV) is not inferior to standard weekly fluorouracil and folinate for stage II/III colon cancer. However, protein-bound polysaccharide K (PSK) has been evaluated as postoperative adjuvant therapy for colorectal cancer. This report is the first of MCSGO-CCTG, which compared UFT/LV to UFT/PSK as adjuvant chemotherapy for stage IIB or III colorectal cancer in patients who had undergone Japanese D2/D3 lymph node dissection. METHODS: The primary endpoint was the 3-year disease-free survival (DFS). A randomized non-inferiority study compared UFT/LV to UFT/PSK. The overall survival, adverse events, compliance, and quality of life were also investigated as the secondary endpoints. RESULTS: Between March 2006 and December 2010, 357 patients were randomized to UFT/PSK (n = 178) or UFT/LV (n = 179) (median age 65 years, colon/rectum 67.4/32.6%, stage IIB/IIIA/IIIB/IIIC 11.1/15.7/55.0/18.2%). The 3-year DFS rate was 82.3% in those receiving UFT/LV and 72.1% in those receiving UFT/PSK. The non-inferiority of UFT/PSK adjuvant therapy to UFT/LV therapy was not verified (-9.06%, 90% confidence interval -17.06 to -1.06%). The 3-year overall survival rate was 95.4% in those receiving UFT/LV and 90.7% in those receiving UFT/PSK. CONCLUSIONS: As adjuvant chemotherapy for stage IIB and III colorectal cancer patients, UFT/PSK adjuvant therapy was not non-inferior to UFT/LV therapy with respect to the DFS.

Micrometastasis Volume in Lymph Nodes Determines Disease Recurrence Rate of Stage II Colorectal Cancer: A Prospective Multicenter Trial.

PURPOSE: We reported in a retrospective study that the presence of micrometastasis in lymph nodes, when assessed by carcinoembryonic antigen (CEA)-specific RT-PCR, is a significant prognostic factor in stage II colorectal cancer. The aim of this study was to clarify the clinical value of micrometastasis in a prospective multicenter trial. EXPERIMENTAL DESIGN: From November 2001 to December 2005, a total of 419 colorectal cancer cases were preoperatively registered at a central data center. Of them, 315 node-negative stage II colorectal cancer cases were enrolled. After RNA quality check, 304 colorectal cancer cases were analyzed for CEA mRNA in lymph nodes by both conventional RT-PCR (a band method) and quantitative RT-PCR. Long-term prognosis of the patients was determined by each method. RESULTS: A positive band for CEA mRNA was detected in 73 (24.0%) of 304 patients. Postoperative adjuvant chemotherapy was applied in 31 CEA band-positive cases with an oral 5-fluorouracil derivative HCFU (1-hexylcarbamoyl-5-fluorouracil) for 1 year, whereas chemotherapy was not administered to CEA band-negative group. Multivariate Cox regression analyses revealed that a high micrometastasis volume (high MMV, n = 95) was an independent poor prognostic factor for 5-year disease-free survival (DFS; P = 0.001) and 5-year overall survival (OS; P = 0.016). CONCLUSIONS: This prospective clinical trial demonstrates that micrometastasis volume is a useful marker in identifying patients who are at high or low risk for recurrence of stage II colorectal cancer. Clin Cancer Res; 22(13); 3201-8. ©2016 AACR.

Preventive effect of Goshajinkigan on peripheral neurotoxicity of FOLFOX therapy (GENIUS trial): a placebo-controlled, double-blind, randomized phase III study.

BACKGROUND: Peripheral sensory neurotoxicity is a frequent adverse effect of oxaliplatin therapy. Calcium and magnesium (Ca/Mg) infusions are frequently used as preventatives, but a recent phase III trial failed to show that they prevent neurotoxicity. We therefore conducted a multicenter randomized phase III trial to compare fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) with and without Goshajinkigan (GJG), a traditional Japanese herbal medicine (Kampo), to determine GJG's potential for reducing peripheral neuropathy in patients with colorectal cancer. METHODS: Patients with colon cancer who were undergoing adjuvant therapy with infusional mFOLFOX6 were randomly assigned to GJG (7.5 mg three times daily) or placebo in a double-blind manner. The primary endpoint was the time to grade 2 or greater neuropathy, which was determined at any point during or after oxaliplatin-based therapy using version 3 of the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE). FINDINGS: An interim analysis was performed when 142 of the planned 310 patients had been enrolled and the safety assessment committee recommended that the study be discontinued. One hundred eighty-two patients were evaluable for response. They included 89 patients in the GJG group and 93 patients in the placebo group. The incidence of grade 2 or greater neurotoxicity was 50.6 % in the GJG group and 31.2 % in the placebo group. A Cox proportional hazards analysis indicated that the use of GJG was significantly associated with the incidence of neuropathy (hazard ratio, 1.908; p = 0.007). CONCLUSION: Goshajinkigan did not prevent oxaliplatin-associated peripheral neuropathy in this clinical trial. The clinical study was therefore terminated.

Multicenter phase II study of second-line cetuximab plus folinic acid/5-fluorouracil/irinotecan (FOLFIRI) in KRAS wild-type metastatic colorectal cancer: the FLIER study.

BACKGROUND: This study was the first multicenter phase II study of cetuximab plus folinic acid/5-fluorouracil/irinotecan (FOLFIRI) in KRAS wild-type mCRC as a second-line treatment in Japan including BRAF and PIK3CA genotyping. PATIENTS AND METHODS: Tumors of 112 pre-registered patients were genotyped for KRAS, BRAF, and PIK3CA. The primary study end-point was response rate, and secondary end-points were progression-free survival (PFS), overall survival (OS), and safety. RESULTS: Sixty-seven patients (59.8%) were EGFR-positive and KRAS wild-type. The mean age of the enrolled patients (n=60) was 62.6 years (range=37-82 years). The response rate was 31.7% and stable disease was observed in 53.3%. No objective response was observed in patients with BRAF or PIK3CA mutations. The median PFS and OS were 7.4 and 18.2 months, respectively. Grade-3/4 adverse events were leucopenia (26.7%), neutropenia (43.3%), paronychia (10.0%), fissure (10.0%) and acne-like rash (5.0%). CONCLUSION: Second-line cetuximab plus FOLFIRI was effective and well-tolerated.

[Fluoropyrimidines with oxaliplatin(L-OHP) as an adjuvant chemotherapy for Stage III colon cancer].

As an adjuvant treatment for Dukes B2 and C colon cancer, adding oxaliplatin (L-OHP) to a regimen of fluorouracil and Leucovorin improved disease-free survival in Western countries. In Japan, however, adjuvant chemotherapy with L-OHP is not commonly used to treat Stage III colon cancer. We report the present condition of adjuvant treatment for colon cancer in our hospital. Between September 2009 and December 2011, 66 patients with Stage III colon cancer were enrolled after curative surgery. The details of adjuvant therapy with fluoropyrimidines with and without L-OHP were explained to the patients. After the explanation, 33.3% of the patients(IIIa: 18.9%, IIIb: 55.5%) selected L-OHP chemotherapy. Regardless of the side effects, adjuvant chemotherapy including L-OHP is expected to protect against cancer recurrence in patients with Stage IIIb colon cancer.

Hydrogen-rich water prevents progression of nonalcoholic steatohepatitis and accompanying hepatocarcinogenesis in mice.

UNLABELLED: Oxidative stress is a strong contributor to the progression from simple fatty liver to nonalcoholic steatohepatitis (NASH). Molecular hydrogen is an effective antioxidant that reduces cytotoxic reactive oxygen species. In this study, we investigated the effects of hydrogen-rich water and the drug pioglitazone on the progression of NASH in mouse models. A methionine-choline-deficient (MCD) diet mouse model was prepared. Mice were divided into three experimental groups and fed for 8 weeks as follows: (1) MCD diet + control water (CW group); (2) MCD diet + hydrogen-rich water (HW group); and (3) MCD diet mixed with pioglitazone (PGZ group). Plasma alanine aminotransferase levels, hepatic expression of tumor necrosis factor-α, interleukin-6, fatty acid synthesis-related genes, oxidative stress biomarker 8-hydroxydeoxyguanosine (8-OHdG), and apoptosis marker terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL)-positive cells in the liver were decreased in the HW and PGZ groups. The HW group showed a smaller decrease in hepatic cholesterol; however, stronger antioxidative effects in serum and lower peroxisome proliferator-activated receptor-α expression in the liver were seen in comparison with the PGZ group. We then investigated the effects of hydrogen in the prevention of hepatocarcinogenesis in STAM mice, known as the NASH-related hepatocarcinogenesis model. Eight-week-old male STAM mice were divided into three experimental groups as follows: (1) control water (CW-STAM); (2) hydrogen-rich water (HW-STAM); and (3) pioglitazone (PGZ-STAM). After 8 weeks, hepatic tumors were evaluated. The number of tumors was significantly lower in the HW-STAM and PGZ-STAM groups than in the CW-STAM group. The maximum tumor size was smaller in the HW-STAM group than in the other groups. CONCLUSION: Consumption of hydrogen-rich water may be an effective treatment for NASH by reducing hepatic oxidative stress, apoptosis, inflammation, and hepatocarcinogenesis.

Risk factors for recurrence after transarterial chemoembolization for early-stage hepatocellular carcinoma.

BACKGROUND: Radiofrequency ablation (RFA) is a standard therapy for the treatment of hepatocellular carcinoma (HCC) with 3 or fewer tumors of up to 3 cm (early-stage HCC); when RFA is unsuccessful or unfeasible, transcatheter arterial chemoembolization (TACE) has often been performed. However, little information about the outcome of TACE for early-stage HCC has been reported and it is hard to decide whether to perform additional treatment following TACE in these difficult conditions. The aim of this study was to determine the risk factors for local or intrahepatic distant recurrence after TACE in early-stage HCC. METHODS: Among 1,560 newly diagnosed HCC patients who were admitted to Okayama University Hospital, 43 patients with early-stage HCC who received only TACE in at least one nodule were enrolled in this study. We analyzed the risk factors for local and distant recurrence by the Cox proportional hazard model. RESULTS: The local recurrence rates and intrahepatic distant recurrence rates at 3 months, 6 months, and 1 year were 18.6, 33.4, and 61.8%, and 2.8, 2.8, and 34.3%, [corrected] respectively.Among 12 parameters examined as possible risk factors for recurrence, heterogeneous Lipiodol uptake (risk ratio 3.38; 95% confidence interval 1.14-10.60) and high serum des-gamma-carboxy prothrombin (DCP) (2.58; 1.03-7.14) were significantly correlated with local recurrence, and the presence of multiple tumors (10.64; 1.76-93.75) was significantly correlated with intrahepatic distant recurrence. CONCLUSIONS: Heterogeneous Lipiodol uptake, high serum DCP, and multiple tumors are risk factors for recurrence in patients with early-stage HCC who have undergone palliative TACE.

Predicting the treatment effect of sorafenib using serum angiogenesis markers in patients with hepatocellular carcinoma.

BACKGROUND AND AIM: Sorafenib, the first agent demonstrated to have efficacy to improve the survival of patients with advanced hepatocellular carcinoma (HCC), is an active multikinase inhibitor affecting angiogenesis and tumor proliferation. We analyzed cytokines related to angiogenesis or cell proliferation, and tried to determine their utility as biomarkers of sorafenib treatment effect for HCC. METHODS: Nine serum cytokines (angiopoietin-2 [Ang-2], follistatin, granulocyte colony-stimulating factor [G-CSF], hepatocyte growth factor [HGF], interleukin-8 [IL-8], leptin, platelet-derived growth factor-BB, platelet endothelial cell adhesion molecule-1, and vascular endothelial growth factor) were measured in 30 HCC patients treated with sorafenib, and the effects of treatment were compared using modified Response Evaluation Criteria in Solid Tumors. RESULTS: All but IL-8 were significantly higher at baseline in patients with progressive disease. Progression-free survival was significantly shorter in patients with high levels of Ang-2, G-CSF, HGF, and leptin, and the hazard ratios were 2.51, 6.89, 2.55, and 4.14, respectively. As the number of cytokines at a high level increased, the treatment response deteriorated. Disease progression was seen in three of 12 (25.0%) patients with zero to two high biomarkers, two of six (33.3%) patients with 3-5 high biomarkers, and 10 of 12 (83.3%) patients with six to eight high biomarkers (P=0.008). The prognosis of all patients with eight high biomarkers was progressive disease. CONCLUSION: High levels of serum cytokines at baseline were correlated with poor effects of sorafenib treatment in patients with HCC.

[A case of a 14-month survival patient on advanced esophageal cancer with uncontrolled brain metastasis completely responding to nedaplatin, adriamycin, plus 5-FU (NAF) therapy].

This case was a male patient, about 50 years old. He received a curative operation for advanced esophageal carcinoma [poorly differentiated squamous cell carcinoma type, Lt, pT3 (pAd) pN3, pstage III] in March 2005. He also received adjuvant chemotherapy of 5-FU plus cisplatin (CDDP). Fourteen months later (May 2006) from surgery, metastases to the left lung and left subclavian lymph nodes were diagnosed, so he received first-line triplet combination chemotherapy (NAF regimen; nedaplatin 60 mg/m2: day 1, adriamycin 50 mg/m2: day 1, 5-FU 700 mg/m2: day 1-5). According to the 9 courses of treatment of this regimen, complete response for these metastases was observed and first-line chemotherapy was finished. However, a severe headache appeared 3 months later, and he had a diagnosis of solitary 5 cm brain metastasis by MRI. Excision of the metastasis was performed with sequential whole-brain radiation therapy (30 Gy). Five months later, diffuse and multiple brain metastases relapsed, and second-line chemotherapy did not respond well, and finally he was died 3 months after palliative care. But, completely controlled metastases (lung and lymph node) by first-line chemotherapy did not relapse again in all his clinical period. If an anticancer therapy goes in complete response in an advanced esophageal carcinoma patient, we should consider about a rare brain metastasis in order to find out as small and solitary state.

[Three-case reports--a program of strength training for home health care on frail elderly patients with protein rich supplement just after the training].

We have a program of strength training for home health care with protein rich supplement just after the training on frail elderly patients. Three cases (80-90 years old) received a new good taste protein rich supplement. They were also frail patients after acute clinical treatments, and were able to go home directly against their physical moving problems for daily life. We performed cardio-pulmonary and swallowing function, energy intake, parameters of muscle strength and the status for daily life before and after the training. Practical results were very different among the patients. But, the status for daily life of all was better than before. It was not clear that the new supplement was effective for the parameters of muscle strength, or not. But a trial for programs with thus foods should be an option for promoting to home health care after hospitalization in frail elderly.

[A long term survival case of advanced colon cancer with adjacent organ involvement and multiple liver metastases].

We report a long-term survival case of advanced colon cancer with adjacent organ involvement and multiple liver metastases. A 50-year-old man was admitted to our hospital because of occult bloody feces. An advanced colon cancer of the cecum was found with a colonoscopy. Histopathologically, it was a moderately differentiated adenocarcinoma with a biopsy examination. Abdominal CT showed advanced colon cancer with adjacent organ involvement and multiple liver metastases. He received right hemi-colon resection and right hepatic lobectomy. The patient was followed by 8 courses of adjuvant chemotherapy with 5-FU. He has been doing well without any recurrence for five years and six months after the operation. Usually the prognoses of Stage IV colorectal cancer patients are very unpleasant. Even thougn a few patients with Stage IV colorectal cancer can be a long-term survivor after multiple operations, we need to consider carefully the indication of the operation and QOL for a Stage IV colorectal cancer patient.