Association of C-reactive protein with efficacy of avelumab plus axitinib in advanced renal cell carcinoma: long-term follow-up results from JAVELIN Renal 101.

BACKGROUND: C-reactive protein (CRP) is an important prognostic and predictive factor in advanced renal cell carcinoma (aRCC). We report the association of CRP levels at baseline and early after treatment with efficacy of avelumab plus axitinib or sunitinib from the phase III JAVELIN Renal 101 trial. PATIENTS AND METHODS: Patients were categorized into normal (baseline CRP <10 mg/l), normalized (baseline CRP ≥10 mg/l and ≥1 CRP value decreased to <10 mg/l during 6-week treatment), and non-normalized (CRP ≥10 mg/l at baseline and during 6-week treatment) CRP groups. Progression-free survival and best overall response from the second interim analysis and overall survival (OS) from the third interim analysis were assessed. RESULTS: In the avelumab plus axitinib and sunitinib arms, respectively, 234, 51, and 108 patients and 232, 36, and 128 patients were categorized into normal, normalized, and non-normalized CRP groups. In respective CRP groups, objective response rates [95% confidence interval (CI)] were 56.0% (49.4% to 62.4%), 66.7% (52.1% to 79.2%), and 45.4% (35.8% to 55.2%) with avelumab plus axitinib and 30.6% (24.7% to 37.0%), 41.7% (25.5% to 59.2%), and 19.5% (13.1% to 27.5%) with sunitinib; complete response rates were 3.8%, 11.8%, and 0.9% and 3.0%, 0%, and 1.6%, respectively. Median progression-free survival (95% CI) was 15.2 months (12.5-21.0 months), not reached (NR) [11.1 months-not estimable (NE)], and 7.0 months (5.6-9.9 months) with avelumab plus axitinib and 11.2 months (8.4-13.9 months), 11.2 months (6.7-13.8 months), and 4.2 months (2.8-5.6 months) with sunitinib; median OS (95% CI) was NR (42.2 months-NE), NR (30.4 months-NE), and 23.0 months (18.4-33.1 months) and NR (39.0 months-NE), 39.8 months (21.7-NE), and 19.1 months (16.3-25.3 months), respectively. Multivariate analyses demonstrated that normalized or non-normalized CRP levels were independent factors for the prediction of objective response rate or OS, respectively, with avelumab plus axitinib. CONCLUSIONS: In patients with aRCC, CRP levels at baseline and early after treatment may predict efficacy with avelumab plus axitinib.

ATLAS trial of adjuvant axitinib in patients with renal cell carcinoma: subgroup analyses with focus on axitinib dosing and racial groups.

BACKGROUND: The ATLAS trial, investigating adjuvant axitinib versus placebo in renal cell carcinoma (RCC), was stopped for futility at a preplanned interim analysis. We report subgroup outcome analyses by ethnicity, time on treatment, dose modification and toxicity. PATIENTS AND METHODS: Patient demographics, baseline characteristics, treatment duration and exposure and safety were analysed for Asian versus non-Asian patients treated with axitinib versus placebo. Disease-free survival (DFS) was analysed by ethnicity, treatment duration (≥1 versus <1 year), dose modification and adverse event (AE) grade. RESULTS: No DFS benefit was observed for Asian {hazard ratio (HR) 0.883 [95% confidence interval (CI) 0.638-1.220]} or non-Asian [HR 0.828 (95% CI 0.490-1.400)] patients treated with axitinib or placebo. Fewer Asian versus non-Asian patients were in the highest-risk group in axitinib (51.9% versus 72.3%) or placebo (51.5% versus 66.0%) arm. Highest-risk patients in both subgroups had no DFS benefit with either treatment. More axitinib-treated Asian versus non-Asian patients had dose reductions due to AEs (58.8% versus 46.0%; P = 0.028). Asian patients experienced more nasopharyngitis but less fatigue or asthenia than non-Asians. Among Asian patients, proteinuria, hypothyroidism, nasopharyngitis, and hypertension were more common in Japanese patients than Korean patients and more common in Korean patients than Chinese patients. Patients receiving axitinib >1 year versus ≤1 year did not have different DFS: HR 0.572 (95% CI 0.247-1.327); P = 0.1874. Compared with patients on stable axitinib dose, DFS was longer in patients with dose reduction [HR 0.458 (95% CI 0.305-0.687); P = 0.0001], whereas DFS was not different in those with dose escalation [HR 1.936 (95% CI 0.937-3.997); P = 0.0685]. DFS was not different in patients experiencing grade ≥2 versus <2 AEs within 6 months of initiating axitinib: HR 0.885 (95% CI 0.419-1.869); P = 0.7488. CONCLUSIONS: Asian versus non-Asian subgroup analysis revealed differences in AE experience and drug exposure. There were no DFS differences based on ethnicity or treatment duration, but axitinib dose reduction led to longer DFS.

Axitinib versus placebo as an adjuvant treatment of renal cell carcinoma: results from the phase III, randomized ATLAS trial.

Background: The ATLAS trial compared axitinib versus placebo in patients with locoregional renal cell carcinoma (RCC) at risk of recurrence after nephrectomy. Patients and methods: In a phase III, randomized, double-blind trial, patients had >50% clear-cell RCC, had undergone nephrectomy, and had no evidence of macroscopic residual or metastatic disease [independent review committee (IRC) confirmed]. The intent-to-treat population included all randomized patients [≥pT2 and/or N+, any Fuhrman grade (FG), Eastern Cooperative Oncology Group status 0/1]. Patients (stratified by risk group/country) received (1 : 1) oral twice-daily axitinib 5 mg or placebo for ≤3 years, with a 1-year minimum unless recurrence, occurrence of second primary malignancy, significant toxicity, or consent withdrawal. The primary end point was disease-free survival (DFS) per IRC. A prespecified DFS analysis in the highest-risk subpopulation (pT3, FG ≥ 3 or pT4 and/or N+, any T, any FG) was conducted. Results: A total of 724 patients (363 versus 361, axitinib versus placebo) were randomized from 8 May 2012, to 1 July 2016. The trial was stopped due to futility at a preplanned interim analysis at 203 DFS events. There was no significant difference in DFS per IRC [hazard ratio (HR) = 0.870; 95% confidence interval (CI) : 0.660-1.147; P = 0.3211). In the highest-risk subpopulation, a 36% and 27% reduction in risk of a DFS event (HR; 95% CI) was observed per investigator (0.641; 0.468-0.879; P = 0.0051), and by IRC (0.735; 0.525-1.028; P = 0.0704), respectively. Overall survival data were not mature. Similar adverse events (AEs; 99% versus 92%) and serious AEs (19% versus 14%), but more grade 3/4 AEs (61% versus 30%) were reported for axitinib versus placebo. Conclusions: ATLAS did not meet its primary end point; however, improvement in DFS per investigator was seen in the highest-risk subpopulation. No new safety signals were reported. Trial registration number: NCT01599754.

Overall survival and oncological outcomes after partial nephrectomy and radical nephrectomy for cT2a renal tumors: A collaborative international study from the French kidney cancer research network UroCCR.

BACKGROUND: Partial nephrectomy (PN) is recommended as first-line treatment for cT1 stage kidney tumors because of a better renal function and probably a better overall survival than radical nephrectomy (RN). For larger tumors, PN has a controversial position due to lack of evidence showing good cancer control. The aim of this study was to compare the results of PN and RN in cT2a stage on overall survival and oncological results. METHOD: A retrospective international multicenter study was conducted in the frame of the French kidney cancer research network (UroCCR). We considered all patients aged≥18 years who underwent surgical treatment for localized renal cell carcinoma (RCC) stage cT2a (7.1-10cm) between 2000 and 2014. Cox and Fine-Gray models were performed to analyze overall survival (OS), cancer specific survival (CSS) and cancer-free survival (CFS). Comparison between PN and RN was realized after an adjustment by propensity score considering predefined confounding factors: age, sex, tumor size, pT stage of the TNM classification, histological type, ISUP grade, ASA score. RESULTS: A total of 267 patients were included. OS at 3 and 5 years was 93.6% and 78.7% after PN and 88.0% and 76.2% after RN, respectively. CSS at 3 and 5 years was 95.4% and 80.2% after PN and 91.0% and 85.0% after RN. No significant difference between groups was found after propensity score adjustment for OS (HR 0.87, 95% CI: 0.37-2.05, P=0.75), CSS (HR 0.52, 95% CI: 0.18-1.54, P=0.24) and CFS (HR 1.02, 95% CI: 0.50-2.09, P=0.96). CONCLUSION: PN seems equivalent to RN for OS, CSS and CFS in cT2a stage kidney tumors. The risk of recurrence is probably more related to prognostic factors than the surgical technique. The decision to perform a PN should depend on technical feasibility rather than tumor size, both to imperative and elective situation. LEVEL OF EVIDENCE: 4.

A phase I/II study of cancer peptide vaccine S-288310 in patients with advanced urothelial carcinoma of the bladder.

Background: S-288310, a cancer peptide vaccine composed of two HLA-A*24:02-restricted peptides derived from two oncoantigens, DEP domain-containing 1 (DEPDC1) and M-phase phosphoprotein 1 (MPHOSPH1), was investigated in urothelial carcinoma (UC) of the bladder. Patients and methods: Thirty eight HLA-A*24:02-positive patients with progressive UC were enrolled in this study. In the phase I part of the study, three patients each were treated with S-288310 at 1 mg or 2 mg/peptide subcutaneously once a week to evaluate safety and tolerability. In the phase II, 32 patients were randomized to receive either 1 mg or 2 mg to evaluate the difference in cytotoxic T lymphocytes (CTL) induction and safety. Results: S-288310 was safe and well tolerated in the phase I. Of 27 patients evaluable for immune responses in the phase II, there was no difference in CTL induction rate between the 1 mg (100%) and 2 mg (80.0%) groups. Of 32 patients receiving S-288310 in the phase II, the most frequent drug-related AE was the injection site reaction that was observed in 29 patients (90.6%), but none of the patients discontinued administration due to these reactions and no dose relationship in the frequency and severity was observed. The objective response rate of the 32 patients was 6.3% and the disease control rate was 56.3%. The median overall survival (OS) rates for patients vaccinated with S-288310 after one regimen of chemotherapy, 2 regimens, or 3 or more were 14.4, 9.1 and 3.7 months, respectively, and 32.2% of patients post first-line treatment were alive at 2 years. OS of patients who showed CTL induction to both peptides was longer than that of those with CTL induction to no or one peptide. Conclusion: S-288310 was well-tolerated and effectively induced peptide-specific CTLs, which were correlated with longer survival for patients with UC of the bladder. Trial registration ID: JapicCTI-090980.

Gene polymorphisms in antioxidant enzymes correlate with the efficacy of androgen-deprivation therapy for prostate cancer with implications of oxidative stress.

Background: Oxidative stress mitigated by antioxidant enzymes is thought to be involved in the progression to castration-resistant prostate cancer (CRPC) during androgen-deprivation therapy (ADT). This study investigated the association between genetic variations in antioxidant enzymes and the efficacy of ADT as well as its biological background. Patients and methods: The non-synonymous or promoter-locating polymorphisms of antioxidant enzymes were examined as well as the time to CRPC progression and overall survival in 104 and 92 patients treated with ADT for metastatic and non-metastatic prostate cancer, respectively. In addition, intracellular reactive oxygen species and expression levels of antioxidant enzymes were examined in castration-resistant and enzalutamide-resistant cells. Results: In metastatic prostate cancer, the AG/GG allele in GSTM3 rs7483 and CT/TT allele in CAT rs564250 were associated with a significantly lower risk of progression to CRPC and all-cause death compared with homozygotes of the major AA allele (hazard ratio [HR]; [95% confidence interval (CI)], 0.55 [0.34-0.86], P = 0.0086) and CC allele (HR; [95% CI], 0.48 [0.24-0.88], P = 0.016), respectively. On multivariate analyses, only GSTM3 rs7483 was associated with significant progression risk (AG/GG versus AA; HR; [95% CI], 0.45 [0.25-0.79], P = 0.0047) even after Bonferroni adjustment. In non-metastatic prostate cancer, the AG/GG allele in GSTM3 rs7483 was associated with a significantly lower risk of progression to CRPC (HR; [95% CI], 0.35 [0.10-0.93], P = 0.034) and all-cause death (HR; [95% CI], 0.26 [0.041-0.96], P = 0.043) compared with the AA allele. Intracellular reactive oxygen species levels were increased, accompanied with augmented GSTM3 expression in both castration-resistant and enzalutamide-resistant cells. Conclusions: Differential activity of antioxidant enzymes caused by the polymorphism in GSTM3 may contribute to resistance to hormonal therapy through oxidative stress. The GSTM3 rs7483 polymorphism may be a promising biomarker for prostate cancer patients treated with ADT.

The prognostic impact of serum testosterone during androgen-deprivation therapy in patients with metastatic prostate cancer and the SRD5A2 polymorphism.

BACKGROUND: Although testosterone suppression during androgen-deprivation therapy (ADT) and obesity have been reported to affect ADT efficacy, there are few comprehensive analyses on the impact on ADT outcome. Recently, we demonstrated that the SRD5A2 polymorphism was associated with metastatic prostate cancer prognosis. Therefore, in this study, we investigated the relationship between ADT serum testosterone levels or body mass index (BMI) and the prognosis among men treated with primary ADT for metastatic prostate cancer. In addition, we examined the association of serum testosterone levels during ADT with the SRD5A2 polymorphism. METHODS: This study included 96 Japanese patients with metastatic prostate cancer. The relationship between clinicopathological parameters, including serum testosterone levels during ADT and BMI, and progression-free survival, overall survival and survival from progression following primary ADT treatment for metastatic prostate cancer was examined. Additionally, the association between the SRD5A2 gene polymorphism (rs523349) and serum testosterone levels during ADT was examined in 86 cases. RESULTS: Among clinicopathological parameters, the lowest quartile of serum testosterone levels during ADT was a significant predictor of better overall survival as well as survival from castration resistance. However, BMI was not associated with prognosis. The CC allele in the SRD5A2 gene (rs523349), encoding the less active 5α-reductase, was associated with lower serum testosterone levels during ADT. CONCLUSIONS: Taken together, these findings revealed a dramatic suppression of serum testosterone by ADT was associated with better survival among men with metastatic prostate cancer that have undergone primary ADT, which may be affected by the SRD5A2 gene polymorphism.

Phase I/II study of S-1 in combination with sorafenib for metastatic renal cell carcinoma.

BACKGROUND: The potential of S-1 for the treatment of metastatic renal cell carcinoma (mRCC) has been shown in two phase II studies. We aimed to assess the safety, tolerance, pharmacokinetics and clinical activity of S-1 combined with sorafenib in patients with mRCC. PATIENTS AND METHODS: In this multicenter, single-arm, open-label, phase I/II study of S-1 plus sorafenib, we recruited patients with clear-cell or papillary renal cell carcinoma who had received a maximum of one prior cytokine-based regimen. The phase I primary end points were the maximum tolerated dose (MTD) and recommended dose (RD). S-1 was administered orally at 60, 80, 100 or 120 mg/day on days 1-28 of a 42-day cycle in combination with sorafenib (400 or 800 mg/day), given daily with dose adjustment. In phase II, the primary end point was to assess the overall response rate (ORR) at the RD. RESULTS: Nine patients were enrolled into phase I and 21 (including 6 patients who received the RD in the phase I portion) were enrolled into phase II. In the phase I portion, the MTD could not be determined, and the RD was defined as S-1 80 mg/m(2)/day on days 1-28 + sorafenib 800 mg/day on days 1-42. In the phase II portion, 21 patients were fully assessable for efficacy and safety. The confirmed ORR was 52% [95% confidence interval (CI) 29.8-74.3], including one complete response (5%) and 10 partial responses (48%). The median progression-free survival was 9.9 (95% CI 6.5-17.1) months. The most frequently reported treatment-related adverse event for all grades was hand-foot skin reaction (100%). The major reasons for dose reduction were hand-foot skin reaction (38%) and rash (14%). CONCLUSION: Combination therapy with S-1 plus sorafenib is effective and tolerable for patients with mRCC. However, skin events management is important in S-1 plus sorafenib combination therapy.

Randomised phase III study of neoadjuvant chemotherapy with methotrexate, doxorubicin, vinblastine and cisplatin followed by radical cystectomy compared with radical cystectomy alone for muscle-invasive bladder cancer: Japan Clinical Oncology Group Study JCOG0209.

BACKGROUND: This study aimed to determine the clinical benefit of neoadjuvant methotrexate, doxorubicin, vinblastine, and cisplatin (MVAC) in patients with muscle-invasive bladder cancer (MIBC) treated with radical cystectomy. PATIENTS AND METHODS: Patients with MIBC (T2-4aN0M0) were randomised to receive two cycles of neoadjuvant MVAC followed by radical cystectomy (NAC arm) or radical cystectomy alone (RC arm). The primary end point was overall survival (OS). Secondary end points were progression-free survival, surgery-related complications, adverse events during chemotherapy, proportion with no residual tumour in the cystectomy specimens, and quality of life. To detect an improvement in 5-year OS from 45% in the RC arm to 57% in the NAC arm with 80% power, 176 events were required per arm. RESULTS: Patients (N = 130) were randomly assigned to the RC arm (N = 66) and the NAC arm (N = 64). The patient registration was terminated before reaching the initially planned number of patients because of slow accrual. At the second interim analysis just after the early stoppage of patient accrual, the Data and Safety Monitoring Committee recommended early publication of the results because the trial did not have enough power to draw a confirmatory conclusion. OS of the NAC arm was better than that of the RC arm, although the difference was not statistically significant [hazard ratio 0.65, multiplicity adjusted 99.99% confidence interval 0.19-2.18, one-sided P = 0.07]. In the NAC arm and the RC arm, 34% and 9% of the patients had pT0, respectively (P < 0.01). In subgroup analyses, OS in almost all subgroups was in favour of NAC. CONCLUSIONS: This trial showed a significantly increased pT0 proportion and favourable OS of patients who received neoadjuvant MVAC. NAC with MVAC can still be considered promising as a standard treatment. UMIN CLINICAL TRIALS REGISTRY IDENTIFIER: C000000093.

A randomized multicenter phase II trial on the efficacy of a hydrocolloid dressing containing ceramide with a low-friction external surface for hand-foot skin reaction caused by sorafenib in patients with renal cell carcinoma.

BACKGROUND: The purpose of this study was to investigate the usefulness of a hydrocolloid dressing containing ceramide for hand-foot skin reaction (HFSR) on the soles of the feet in metastatic renal cell carcinoma (RCC) patients treated with sorafenib. PATIENTS AND METHODS: Patients with grade 1 HFSR on the soles of the feet were randomly assigned in to two groups. One group received a hydrocolloid dressing containing ceramide (arm A) and the other received 10% urea cream (arm B). Patients in both groups applied treatment to the affected sites on the soles of the feet, but not to the hands. The primary end point was the incidence of grade 2 or 3 HFSR on the soles of the feet in the first 4 weeks. RESULTS: Thirty-three patients were assessed (17 in arm A and 16 in arm B), and there were no significant differences in baseline characteristics between the two groups. During the observation period of this study, grade 2 or 3 HFSR on the soles of the feet was found in 29% of patients in arm A and was significantly less than the 69% in arm B (P=0.03). The incidence of HFSR on the hands, however, was similar in both arms. The median time to grade 2 or 3 HFSR on the soles of the feet was also significantly longer in arm A than in arm B (P=0.03). CONCLUSIONS: These results indicate that a hydrocolloid dressing containing ceramide prevented the worsening of HFSR caused by sorafenib in metastatic RCC patients. CLINICAL TRIAL REGISTRATION NUMBER: UMIN000002016.

Human heterochromatin protein 1 isoform HP1beta enhances androgen receptor activity and is implicated in prostate cancer growth.

There are currently few successful therapies for castration-resistant prostate cancer (CRPC). CRPC is thought to result from augmented activation of the androgen/androgen receptor (AR) signaling pathway, which could be enhanced by AR cofactors. In this study, heterochromatin protein 1beta (HP1beta), but not HP1alpha or HP1gamma was found to be an AR cofactor. HP1beta interacted with the AR, and enhanced the DNA-binding ability of AR to androgen-responsive element in the prostate-specific antigen enhancer and promoter regions, and to increase the transcription of AR target genes. In prostate cancer (PCa) tissues, HP1beta expressions correlated with Gleason score and tri-methylation levels of histone H3 lysine 9. Silencing of HP1beta suppressed the growth of AR-expressing PCa cells by inducing cell-cycle arrest at the G(1) phase, similar to inhibition of androgen/AR signaling. Furthermore, HP1beta was overexpressed in castration-resistant LNCaP derivative CxR cells, and HP1beta knockdown also suppressed the cell growth in CxR cells. These findings indicate that HP1beta is involved in the proliferation of AR-expressing PCa cells and progression to CRPC as an AR coactivator. Modulation of HP1beta expression or function might be a useful strategy for developing novel therapeutics for PCa, even in CRPC.

Castration resistance of prostate cancer cells caused by castration-induced oxidative stress through Twist1 and androgen receptor overexpression.

There are few successful therapies for castration-resistant prostate cancer (CRPC). Recently, CRPC has been thought to result from augmented androgen/androgen receptor (AR) signaling pathway, for most of which AR overexpression has been observed. In this study, Twist1, a member of basic helix-loop-helix transcription factors as well as AR was upregulated in response to hydrogen peroxide, and the response to which was abolished by an addition of N-acetyl-L-cysteine and Twist1 knockdown. In addition, castration-resistant LNCaP derivatives and hydrogen peroxide-resistant LNCaP derivatives exhibited a similar phenotype to each other. Then, both castration and AR knockdown increased intracellular reactive oxygen species level. Moreover, Twist1 was shown to regulate AR expression through binding to E-boxes in AR promoter region. Silencing of Twist1 suppressed cell growth of AR-expressing LNCaP cells as well as castration-resistant LNCaP derivatives by inducing cell-cycle arrest at G1 phase and cellular apoptosis. These findings indicated that castration-induced oxidative stress may promote AR overexpression through Twist1 overexpression, which could result in a gain of castration resistance. Modulation of castration-induced oxidative stress or Twist1/AR signaling might be a useful strategy for developing a novel therapeutics in prostate cancer, even in CRPC, which remains dependent on AR signaling by overexpressing AR.

Sirt1 inhibitor, Sirtinol, induces senescence-like growth arrest with attenuated Ras-MAPK signaling in human cancer cells.

The induction of senescence-like growth arrest has emerged as a putative contributor to the anticancer effects of chemotherapeutic agents. Clinical trials are underway to evaluate the efficacy of inhibitors for class I and II histone deacetylases to treat malignancies. However, a potential antiproliferative effect of inhibitor for Sirt1, which is an NAD(+)-dependent deacetylase and belongs to class III histone deacetylases, has not yet been explored. Here, we show that Sirt1 inhibitor, Sirtinol, induced senescence-like growth arrest characterized by induction of senescence-associated beta-galactosidase activity and increased expression of plasminogen activator inhibitor 1 in human breast cancer MCF-7 cells and lung cancer H1299 cells. Sirtinol-induced senescence-like growth arrest was accompanied by impaired activation of mitogen-activated protein kinase (MAPK) pathways, namely, extracellular-regulated protein kinase, c-jun N-terminal kinase and p38 MAPK, in response to epidermal growth factor (EGF) and insulin-like growth factor-I (IGF-I). Active Ras was reduced in Sirtinol-treated senescent cells compared with untreated cells. However, tyrosine phosphorylation of the receptors for EGF and IGF-I and Akt/PKB activation were unaltered by Sirtinol treatment. These results suggest that inhibitors for Sirt1 may have anticancer potential, and that impaired activation of Ras-MAPK pathway might take part in a senescence-like growth arrest program induced by Sirtinol.

Impact of adiposity and plasma adipocytokines on diabetic angiopathies in Japanese Type 2 diabetic subjects.

AIMS: Adipocytokines, products from adipose tissue, have biological activities on the vascular system, and may affect diabetic angiopathy. In this study, we assessed the relationship between adiposity and plasma adipocytokine levels, and investigated the clinical significance of adiposity and plasma adipocytokine levels on diabetic micro- and macroangiopathy in Type 2 diabetic subjects. METHODS: We studied 231 Japanese Type 2 diabetic subjects (135 men and 96 women, aged 60.4 +/- 12.3 years, body mass index 24.8 +/- 5.2 kg/m2). We measured adipocytokine [adiponectin, leptin, resistin, and tumour necrosis factor (TNF)-alpha] levels, lipid profiles and urine albumin excretion. We also performed optic fundus examination and measured carotid intramedia thickness (IMT) using B-mode ultrasonography, and the localization of fat with abdominal computed tomography. A group of 93 subjects with microalbuminuria or overt proteinuria was compared with the other 148 to assess the effect on nephropathy. A group of 191 eyes with simple retinopathy or more advanced changes was compared with 263 eyes without retinal changes to assess the effect on retinopathy. RESULTS: Plasma adiponectin level was negatively correlated with both visceral (r = -0.37, P < 0.01) and subcutaneous (r = -0.25, P < 0.01) fat areas. Resistin concentration was positively related with visceral fat area (r = 0.15, P < 0.05). Adiponectin concentration was positively correlated with age (r = 0.26, P < 0.01). TNF-alpha was correlated with IMT (r = 0.16, P < 0.05) after correction for age. Logistic regression analysis indicates a 4085 times greater chance of having retinopathy with a one unit increase in TNF-alpha (pmol/l) and a 30.64 times greater chance of having nephropathy with one unit increase in leptin (nmol/l). CONCLUSIONS: The present observations suggest that visceral and subcutaneous fat has an impact on microangiopathy as well as macroangiopathy, possibly through different adipocytokines.

Bone mass and lifestyle related factors: a comparative study between Japanese and Inner Mongolian young premenopausal women.

The purpose of this study was to evaluate the ethnic difference in bone mass between Japanese and Inner Mongolian young premenopausal women and to assess the contribution of lifestyle related and anthropometric factors to bone mass. We studied 33 Japanese and 44 Inner Mongolian healthy young women, aged 20-34 years, in urban area. Speed of sound (SOS), broadband ultrasound attenuation (BUA) and stiffness index (SI) were measured at the calcaneus using quantitative ultrasound (QUS) analysis. Age at menarche, regularity of menstruation and lifestyle related factors were estimated by a self-reported questionnaire. There were no differences between the two groups in age, height, weight, BMI, regularity of menstruation, frequency of meat intake, frequency of yellow-green vegetable intake and exercise habit. Japanese women had significantly lower age at menarche and higher proportion of milk consumption habit at junior high school, senior school and present. Before adjustment, Japanese women had significantly higher SOS and SI than Inner Mongolian women. However, after adjustment for age at menarche and milk consumption habit at junior high school, both of which were significantly different between groups, no group-differences remained in either SOS or SI. These results suggest that the differences in age at menarche and milk consumption habit at junior high school, which relate to hormonal and nutritional status during puberty, may account for the differences in bone mass between Japanese and Inner Mongolian young women.

Type III hyperlipoproteinema with apolipoprotein E2/2 genotype in Japan.

Limited information is available concerning type III hyperlipoproteinemia (HLP) in the Asian population. Therefore, clinical and biochemical characteristics of type III HLP were examined in 16 Japanese patients. Mean plasma triglyceride (TG) and total cholesterol (chol) levels were 381 mg/dl and 253 mg/dl, respectively, and the mean very low density lipoprotein (VLDL)-chol/plasma TG ratio was 0.27, which were lower than those reported in Western countries. Eighty percent of the patients had high plasma remnant-like particles (RLP)-chol levels above 50 mg/dl and a high RLP-chol/plasma TG ratio above 0.1. Twelve patients (75.0%) were obese. Seven patients (43.8%) had type 2 diabetes mellitus and four patients (25.0%) had impaired glucose tolerance. Six patients (37.5%) had coronary heart disease (CHD), but none had peripheral vascular disease or xanthomas. TG-rich lipoproteins from type III HLP patients with diabetes mellitus stimulated cholesteryl ester synthesis by human macrophages significantly (p < 0.001) more than those from type III HLP patients without diabetes mellitus. In conclusion, the Japanese type III HLP patients had lower plasma TG and total chol levels and a lower VLDL-chol/plasma TG ratio, but CHD was more common. The patients were characterized by a high frequency of obesity and/or glucose intolerance. The TG-rich lipoproteins from type III HLP patients with diabetes mellitus were more atherogenic.