Impact of renal transplantation on glucose tolerance in Japanese recipients with impaired glucose tolerance.

AIMS: To investigate changes in glucose tolerance, insulin secretion and insulin sensitivity in Japanese recipients before and 1 year after renal transplantation. METHODS: We conducted a study of Japanese recipients without diabetes who underwent renal transplantation at Hokkaido University Hospital. A 75-g oral glucose tolerance test was performed before and 1 year after renal transplantation in these recipients. Insulin sensitivity was estimated using the Matsuda index and homeostasis model assessment of insulin resistance (HOMA-IR). Insulin secretion was evaluated based on the insulin secretion sensitivity index-2 (ISSI-2). RESULTS: Of the 62 renal transplant recipients, 31 were diagnosed as having impaired glucose tolerance before transplantation. Among these 31 recipients, after 1 year, four had developed new-onset diabetes after transplantation, and nine had impaired glucose tolerance. Unexpectedly, 18 changed from impaired to normal glucose tolerance. When these recipients with impaired glucose tolerance were classified into a non-amelioration group and an amelioration group, the ISSI-2 was significantly reduced, with no significant changes in the Matsuda index or HOMA-IR, in the non-amelioration group 1 year after renal transplantation. By contrast, ISSI-2 and Matsuda index values were significantly increased, with no significant changes in HOMA-IR values in the amelioration group. CONCLUSIONS: More than half of Japanese renal transplant recipients with impaired glucose tolerance had normal glucose tolerance 1 year after renal transplantation. These results suggest that an increase in insulin secretion and whole insulin sensitivity was associated with improvement in glucose tolerance in these recipients.

Molecular Biomarker Study in a Randomised Phase III Trial of Irinotecan Plus S-1 versus S-1 for Advanced Gastric Cancer (GC0301/TOP-002).

AIMS: Gastric cancer is a common and heterogeneous disease; however, global standard and biomarkers for selecting chemotherapy regimens have not been established. This study was designed retrospectively to identify molecular biomarkers for irinotecan plus S-1 (IRI-S) and S-1 therapy from subset analyses in GC0301/TOP-002, a randomised phase III trial for advanced gastric cancer. MATERIALS AND METHODS: Paraffin-embedded primary tumour specimens were collected from 126 of 326 randomised patients in GC0301/TOP-002. The mRNA was measured for thymidylate synthase, dihydropyrimidine dehydrogenase, topoisomerase I, excision repair cross-complementing gene 1 (ERCC1) and thymidine phosphorylase; categorised into low and high to analyse their association with efficacy end points. RESULTS: There was no significant difference in each mRNA between S-1 and IRI-S groups, whereas there were differences among some clinical characteristics. Multivariate analyses for overall survival showed that mRNA levels were not correlated with prognosis. By comparison, between IRI-S and S-1 arms, low thymidylate synthase, low ERCC1 and high thymidine phosphorylase were associated with better prognosis for IRI-S versus S-1 (hazard ratio = 0.653, 0.702 and 0.709, respectively; P < 0.15 for each interaction). CONCLUSION: Low thymidylate synthase, low ERCC1 and high thymidine phosphorylase are candidates for predictive biomarkers for first-line treatment in advanced gastric cancer by IRI-S. Further study is warranted to confirm these results in other clinical trials and cohort studies.

Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS): short-term outcome, functional changes in the future liver remnant, and tumor growth activity.

BACKGROUND: We compared clinical outcomes of associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) against those of classical 2-stage hepatectomy in treating metastatic liver disease. METHODS: Short-term outcomes, serial changes in volume of the future liver remnant (FLR), functional FLR volume, and tumor growth activity during the treatment period, were compared between our first 11 consecutive patients treated with ALPPS and 54 patients treated with classical 2-stage hepatectomy. RESULTS: Mortality in the ALPPS group (9%) tended to be higher than in the classical 2-stage group (2%, P = 0.341). The FLR hypertrophy ratio (FLR volume after vs. before the procedure) 1 week after the first operation in the ALPPS group (1.54 ± 0.18) exceeded that in the classical 2-stage group (1.19 ± 0.29, P = 0.005), being similar to the ratio at 3 weeks after the first procedure in the classical 2-stage group (1.40 ± 0.43). However, functional volume of the FLR in the ALPPS group 1 week after the first procedure (52.1%) tended to be smaller than that in the classical group 3 weeks after the first procedure (59.2%). CONCLUSIONS: ALPPS should be used with extreme caution, giving special attention to postoperative complications and grade of functional liver regeneration.

Impact of underlying diabetes and presence of lung cavities on treatment outcomes in patients with pulmonary tuberculosis.

AIMS: We investigated the effects of diabetes and the presence of lung cavities on treatment outcomes in patients with pulmonary tuberculosis. METHODS: We conducted a retrospective review of the clinical records of all consecutive patients admitted to the Kanagawa Cardiovascular and Respiratory Centre with the diagnosis of pulmonary tuberculosis. The study outcomes examined were time to sputum culture conversion and percentage of patients with sputum culture conversion by the time 2 months of treatment, and these outcomes were compared between patients with and without diabetes. RESULTS: Of the 260 patients enrolled in the study, 69 were diagnosed as having diabetes mellitus, while the remaining 191 did not have diabetes. The percentage of patients with cavities was higher in the patients with diabetes (71.0%) than in those without (45.5%; P = 0.0003). The time to sputum culture conversion was significantly longer in the patients with diabetes than in those without (P = 0.0005), and the percentage of patients with a positive sputum culture at 2 months was higher in the patients with diabetes (43.5%) than in those without (18.8%; P = 0.0001). Multivariate analyses revealed that the presence/absence of lung cavities was a more important determinant of treatment outcomes than the presence/absence of diabetes. CONCLUSIONS: The presence of lung cavities was found to be a more important determinant of the treatment outcomes than that of diabetes per se in patients with pulmonary tuberculosis.

Debulking surgery followed by intraarterial 5-fluorouracil chemotherapy plus subcutaneous interferon alfa for massive hepatocellular carcinoma with multiple intrahepatic metastases: a pilot study.

BACKGROUND: The prognosis in advanced hepatocellular carcinoma (HCC) with multiple intrahepatic metastases is extremely poor. Combination therapy with subcutaneous interferon (IFN) alfa and intraarterial 5-fluorouracil was reported to be effective against such advanced HCC. We describe results of debulking surgery followed by combination therapy with IFN alfa and 5-FU for massive HCC with multiple intrahepatic metastases. METHODS: In 27 HCC patients with massive tumors and multiple intrahepatic metastases, we performed combination therapy with IFN alfa and 5-FU after maximal liver tumor resection. RESULTS: Mean patient age was 63.3 years. Including intrahepatic metastases, tumors numbered 5 or more in 17 patients (63%). Portal or hepatic vein branches were invaded in 22 (81%). The mean maximum tumor diameter was 102 mm. Among 24 patients whose results were analyzed, an objective response by residual intrahepatic metastases was observed in 13 (54%; complete response in 12, and partial response in 1). Overall 1-, 3-, and 5-year survival was 73.2%, 38.7%, and 38.7%, respectively; 1-, 3-, and 5-year progression-free rates were 38.2%, 22.3%, and 22.3%. CONCLUSIONS: Debulking surgery followed by IFN alfa and 5-FU combination chemotherapy offers possibility of long-term survival despite massive HCC with multiple intrahepatic metastases.

Homozygous c.14576G>A variant of RNF213 predicts early-onset and severe form of moyamoya disease.

OBJECTIVE: RNF213 was recently reported as a susceptibility gene for moyamoya disease (MMD). Our aim was to clarify the correlation between the RNF213 genotype and MMD phenotype. METHODS: The entire coding region of the RNF213 gene was sequenced in 204 patients with MMD, and corresponding variants were checked in 62 pairs of parents, 13 mothers and 4 fathers of the patients, and 283 normal controls. Clinical information was collected. Genotype-phenotype correlations were statistically analyzed. RESULTS: The c.14576G>A variant was identified in 95.1% of patients with familial MMD, 79.2% of patients with sporadic MMD, and 1.8% of controls, thus confirming its association with MMD, with an odds ratio of 259 and p < 0.001 for either heterozygotes or homozygotes. Homozygous c.14576G>A was observed in 15 patients but not in the controls and unaffected parents. The incidence rate for homozygotes was calculated to be >78%. Homozygotes had a significantly earlier age at onset compared with heterozygotes or wild types (median age at onset 3, 7, and 8 years, respectively). Of homozygotes, 60% were diagnosed with MMD before age 4, and all had infarctions as the first symptom. Infarctions at initial presentation and involvement of posterior cerebral arteries, both known as poor prognostic factors for MMD, were of significantly higher frequency in homozygotes than in heterozygotes and wild types. Variants other than c.14576G>A were not associated with clinical phenotypes. CONCLUSIONS: The homozygous c.14576G>A variant in RNF213 could be a good DNA biomarker for predicting the severe type of MMD, for which early medical/surgical intervention is recommended, and may provide a better monitoring and prevention strategy.

Postprogression survival for first-line chemotherapy of patients with advanced non-small-cell lung cancer.

BACKGROUND: Given the growing number of drugs available for non-small-cell lung cancer (NSCLC), an effect of first-line chemotherapy on overall survival (OS) might be confounded by subsequent therapies. We examined the relation between postprogression survival (PPS) and OS in phase III trials of first-line chemotherapy for advanced NSCLC. PATIENTS AND METHODS: A literature search identified 69 trials that were published during the past decade. We partitioned OS into progression-free survival (PFS) and PPS and evaluated the relation between OS and either PFS or PPS. We also examined whether any association might be affected by the year of completion of trial enrollment. RESULTS: The average PPS was longer in recent trials than in older trials (6.5 versus 4.4 months, P < 0.0001). For all trials, PPS was strongly associated with OS (r = 0.82), whereas PFS was moderately associated with OS (r = 0.43). The correlation between OS and PPS in recent trials was stronger than that in older trials (r = 0.89 and 0.66). CONCLUSIONS: Our findings indicate that, especially for recent trials, PPS is highly associated with OS in first-line chemotherapy for advanced NSCLC, whereas PFS is only moderately associated with OS.