Efficacy and Safety of Monthly Minodronate Therapy in Postmenopausal Breast Cancer Patients Receiving Aromatase Inhibitors.

BACKGROUND/AIM: Post-menopausal breast cancer (BC) patients who receive adjuvant aromatase inhibitor (AI) therapy may be at increased risk of bone loss, osteoporosis, and bone fracture. We aimed to evaluate the efficacy and safety of oral bisphosphonate minodronate in preventing bone loss complications. PATIENTS AND METHODS: Patients receiving AI and 80% of those with suboptimal bone mineral density (BMD) were prescribed monthly oral minodronate 50 mg every 4 weeks for 72 weeks. BMD, bone metabolism markers, incidence of bone fractures, medication compliance, and other adverse events (AE) were examined every 24 weeks following administration. RESULTS: Fifty postmenopausal BC patients with a median age of 64.0 years were enrolled. The mean value of lumbar spine BMD was higher than that of the value before the minodronate administration at each observation point. Before and after the treatment, the median serum values of Tartrate-resistant Acid Phosphatase 5b (TRACP-5b) (mU/dl) and serum type I collagen cross-linked N-telopeptide (NTX) (nmolBCE/l) were decreased from 535.7 and 18.5 to 230.1 and 11.9, respectively. No adverse grade 2 or higher event was observed throughout this study. CONCLUSION: The combined administration of minodronate and AIs was safe and effective in preventing bone loss complications in postmenopausal BC patients.

Randomized phase II study comparing the efficacy and safety of SOX versus mFOLFOX6 as neoadjuvant chemotherapy without radiotherapy for locally advanced rectal cancer (KSCC1301).

BACKGROUND: Preoperative chemoradiotherapy (CRT), the current standard of care for locally advanced rectal cancer (LARC), is associated with many radiotherapy (RT)-related side effects. We aimed to evaluate whether S-1 and oxaliplatin (SOX) or folinic acid, 5-FU, and oxaliplatin (mFOLFOX6) can be as effective as neoadjuvant chemotherapy (NAC) regimens for LARC without RT. METHODS: Patients with untreated resectable LARC were randomly assigned to receive SOX or mFOLFOX6. The NAC protocol period was 3 months. The primary endpoint was 3-year disease-free survival (DFS), and the secondary endpoints included pathological effects, surgical completion rate, 3-year survival, and safety. RESULTS: From September 2013 to October 2015, 56 and 54 patients were enrolled in the SOX and mFOLFOX6 arms, respectively. The 3-year DFS rates were 69.4% (95% confidence interval [CI] 54.9-83.6) and 73.4% (95% CI 58.7-83.6) in the SOX and mFOLFOX6 arms, respectively; no significant differences were found between the arms (log-rank test; P = 0.5315, hazard ratio: 0.808, 95% CI 0.414-1.578). The 3-year survival rates were 92.3 and 91.8% in the SOX and mFOLFOX6 arms, respectively. The surgical completion rate was 98.1% overall, 100% in the SOX arm, and 96.0% in the mFOLFOX6 arm. The incidences of pathological response rates ≥grade 1b were 41.5 and 43.8% in the SOX and mFOLFOX6 arms, respectively. Both treatments were manageable and tolerable. CONCLUSION: We demonstrated the effectiveness and safety of SOX and mFOLFOX6, both of which may be new neoadjuvant treatment candidates in previously untreated LARC cases. TRIAL REGISTRATION: Date of enrolment of the first participant to the trial: 3rd Oct 2013; This study was registered in the UMIN clinical trials registry on 14th Aug, 2013. (Prospectively registered, UMIN-CTR number UMIN000011486). https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr.cgi?function=brows&recptno=R000013441&language=J.

Randomized phase II study of 5-fluorouracil hepatic arterial infusion with or without antineoplastons as an adjuvant therapy after hepatectomy for liver metastases from colorectal cancer.

BACKGROUND: Antineoplastons are naturally occurring peptides and amino acid derivatives found in human blood and urine. Antineoplaston A10 and AS2-1 reportedly control neoplastic growth and do not significantly inhibit normal cell growth. Antineoplastons contain 3-phenylacetylamino-2, 6-piperidinedione (A10), phenylacetylglutamine plus phenylacetylisoglutamine (A10-I), and phenylacetylglutamine plus phenylacetate (AS2-1). This open label, non- blinded randomized phase II study compared the efficacy of hepatic arterial infusion (HAI) with 5-fluorouracil,with or without antineoplastons as a postoperative therapy for colorectal metastasis to the liver. METHODS: Sixty-five patients with histologically confirmed metastatic colon adenocarcinoma in liver, who had undergone hepatectomy, and/or thermal ablation for liver metastases were enrolled between 1998- 2004 in Kurume University Hospital. Patients were randomly assigned to receive systemic antineoplastons (A10-I infusion followed by per-oral AS2-1) plus HAI (AN arm) or HAI alone (control arm) based on the number of metastases and presence/ absence of extra-hepatic metastasis at the time of surgery. Primary endpoint was cancer-specific survival (CSS); secondary endpoints were relapse-free survival (RFS), status and extent of recurrence, salvage surgery (rate) and toxicity. FINDINGS: Overall survival was not statistically improved (p=0.105) in the AN arm (n=32). RFS was not significant (p=0.343). Nevertheless, the CSS rate was significantly higher in the AN arm versus the control arm (n=33) with a median survival time 67 months (95%CI 43-not calculated) versus 39 months (95%CI 28-47) (p=0.037) and 5 year CSS rate 60% versus 32% respectively. Cancer recurred more often in a single organ than in multiple organs in the AN arm versus the control arm. The limited extent of recurrent tumours in the AN arm meant more patients remained eligible for salvage surgery. Major adverse effects of antineoplastons were fullness of the stomach and phlebitis. No serious toxicity, including bone marrow suppression, liver or renal dysfunction, were found in the AN arm. INTERPRETATION: Antineoplastons (A10 Injection and AS2-1) might be useful as adjunctive therapy in addition to HAI after hepatectomy in colorectal metastases to the liver. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov UMIN000012099.

Hyperthermia in the treatment of recurrent abdominal desmoid tumor.

The most suitable management of recurrent abdominal desmoid tumor is still unclear. A case of recurrent huge abdominal desmoid tumor successfully treated by hyperthermia therapy is described. A 63-year-old man was operated upon for desmoid tumor in the retroperitoneum involving pancreas, posterior wall of the stomach and transverse mesocolon in 2007. In 2008, the tumor recurred and could not be resected because of the patient refused the operation. Several therapies using tamoxifen, anastrozole, imatinib mesylate and radiotherapy were all ineffective. The tumor grew bigger and bigger during a treatment period. Finally, hyperthermia treatment was applied to the tumor. The size of the recurrent desmoid tumor reduced 75% by hyperthermia treatment for 46-month. Base on this experience, we recommend hyperthermia as the treatment for patients with recurrent abdominal desmoid tumor that several therapeutic strategies did not achieve a remarkable response.

Heat-shock pre-treatment reduces liver injury and aids liver recovery after partial hepatectomy in mice.

BACKGROUND: Heat-shock proteins (HSPs) are members of a chaperone protein family reported to modify stress responses. The aim of this study was to clarify the hypothesis of whether pre-treatment with heat shock reduces liver damage and influences liver regeneration after partial hepatectomy. MATERIALS AND METHODS: Mice (N=6) were divided into two groups: the control group underwent partial hepatectomy without heat shock pre-treatment, the heat shock (HS) group underwent partial hepatectomy 12 hours after pre-treatment with heat shock. Mice were sacrificed at different time points after hepatectomy, remnant liver and blood were collected for further analyses in blood samples and liver tissues. Aspartate aminotransferase (AST), alanine aminotransferase (ALT), interleukin-6 (IL6), and tumor necrosis factor-alpha (TNFα) were measured using enzyme-linked immunosorbent assay (ELISA). We used tissue samples for several experiments: staining by 5-bromo-2-deoxyuridine (BrdU), evaluation of cytokines, transcription factors and signal-transduction associated proteins. RESULTS: HSP70 levels in the liver were clearly increased from 6 h to 72 h after heat shock treatment. Serum ALT and AST levels were significantly reduced in the HS group compared to the control group after partial hepatectomy. Liver regeneration rate and BrdU labeling index were significantly higher in the HS group than in the control group after partial hepatectomy. IL6 and TNFα in serum and liver tissues were significantly reduced in the HS group compared to the control group after hepatectomy. We did not detect phosphorylation of signal transducer and activator of transcription-3 (STAT3) protein by western blotting. Binding activities of transcription factors: nuclear factor-interleukin-6 (NF-IL6) and nuclear factor-kappa B (NF-kB) were significantly lower in the HS group than in the control group after hepatectomy. CONCLUSION: Pre-treatment with heat shock appears to reduce liver injury and promote liver regeneration, as HSP70 can reduce the inflammatory response and up-regulate liver regeneration without IL6 STAT signaling pathway in the liver after partial hepatectomy.

Initial report of KSCC0803: feasibility study of capecitabine as adjuvant chemotherapy for stage III colon cancer in Japanese patients.

BACKGROUND: A prospective feasibility study was planned to clarify the proportion of compliance and adverse events in the administration of capecitabine as adjuvant chemotherapy for colon cancer in Japanese patients. METHODS: We aimed initially to register 92 cases of R0 stage III colon cancer. Capecitabine (2,500 mg/m(2)/day) was given orally on days 1-14 every 3 weeks for 8 cycles. The proportion of treatments completed as planned was selected as the primary endpoint. RESULTS: Ninety-seven cases were registered and treated between September 2008 and August 2009. The proportion of treatments completed in the full analysis set was 64/97 [66.0%; 95% confidence interval (CI), 55.7-75.3%] and in the per protocol set was 64/91 (70.3%; 95% CI, 59.8-79.5%). Adverse events which led to treatment discontinuation included hand-foot syndrome (HFS) (7), haematotoxicity (5) and increased hepatic damage (4). The proportions of patients with major grade 3/4 adverse events were HFS 22.7%, neutropenia 7.2%, diarrhoea 2.1%, and increased bilirubin 0.0%. CONCLUSIONS: This collaborative multi-facility study, the first of its kind in Japan, presented results of a safety confirmation experiment on capecitabine as adjuvant chemotherapy for stage III colon cancer. The results suggest that capecitabine may be administered safely to Japanese patients.

Clinical examination of the water-soluble vitamin levels in blood during peripheral parenteral nutrition.

The water-soluble vitamin (included vitamin B1, B6, B12 and C) preparations are not always replenished when peripheral parenteral nutrition (PPN) is used in Japan. We evaluated the need for administration of vitamins preparation during PPN, and involved analysis of the blood levels of water-soluble vitamins in patients receiving perioperative PPN before and after gastrectomy. Patients were examined as two set of groups as follows; 18 patients who did not receive water-soluble vitamin preparations during PPN, the Unsupplemented Group, and 22 patients who received such preparations during PPN, the Supplemented Group. Consequently, in the Unsupplemented Group, the blood vitamin B1 level during the early postoperative period was significantly lower than the preoperative level, but in the Supplemented Group, it was significantly higher than the preoperative level. In the Supplemented Group, the blood vitamin B12 level during the early postoperative period was markedly higher than the preoperative level. And in both groups, the blood vitamin C level remained below the lower limit of the criterion range throughout the perioperative period. These results suggested that administration of water-soluble vitamins during PPN was needed to avoid potential vitamin deficiencies after surgery and to prevent a potential onset of severe metabolic complications from any deficiencies.