Triglyceride/low-density-lipoprotein cholesterol ratio is the most valuable predictor for increased small, dense LDL in type 2 diabetes patients.

BACKGROUND: Small, dense low-density lipoprotein (sd-LDL) increases in type 2 diabetes patients and causes arteriosclerosis. Non-high-density-lipoprotein cholesterol (non-HDL-C) is thought to be useful for predicting arteriosclerosis and sd-LDL elevation; however, there are no data about whether the triglyceride /low-density-lipoprotein cholesterol (TG/LDL-C) ratio is a valuable predictor for sd-LDL. METHODS: A total of 110 type 2 diabetes patients with hypertriglyceridemia were analyzed. No patients were treated with fibrates, but 47 patients were treated with statins. LDL-C was measured by the direct method. LDL-migration index (LDL-MI) using electrophoresis (polyacrylamide gel, PAG) was calculated, and a value ≥0.400 was determined to indicate an increase in sd-LDL. Simple regression analyses were carried out between LDL-MI and lipid markers. Receiver operating characteristic curves of lipid markers for predicting high LDL-MI were applied to determine the area under the curve (AUC), sensitivity, specificity, and cut-off point. RESULTS: LDL-MI correlated negatively with LDL-C (P = 0.0027) and PAG LDL fraction (P < 0.0001) and correlated positively with TGs, non-HDL-C, TG/LDL-C ratio, TG/HDL-C ratio, and non-HDL-C/HDL-C ratio among all study patients. Similar results were obtained for patients analyzed according to statin treatment. The AUCs (95% confidence interval) were 0.945 (0.884-1.000) for TG/LDL-C ratio and 0.614 (0.463-0.765) for non-HDL-C in patients without statins (P = 0.0002). The AUCs were 0.697 (0.507-0.887) for TG/LDL-C and 0.682 (0.500-0.863) for non-HDL-C in patients treated with statins. The optimal cut-off point for TG/LDL-C ratio for increased LDL-MI was 1.1 (molar ratio) regardless of statin treatment. The sensitivity and specificity of the TG/LDL-C ratio (90.0 and 93.9%, respectively) were higher than those of non-HDL-C (56.7 and 78.8%, respectively) in patients without statins. CONCLUSIONS: The TG/LDL-C ratio is a reliable surrogate lipid marker of sd-LDL and superior to non-HDL-C in type 2 diabetes patients not treated with statins.

Differences in the efficacy and safety of eribulin in patients with soft tissue sarcoma by histological subtype and treatment line.

Clinical evidence regarding eribulin treatment for patients with soft tissue sarcoma (STS) is limited to those with L-sarcoma (leiomyosarcoma and liposarcoma) who have completed at least two chemotherapies. Whether histological subtypes and treatment lines affect the efficacy and safety of eribulin for patients with STS has yet to be elucidated. The current study retrospectively reviewed patients with STS receiving eribulin at the Cancer Institute Hospital of JFCR and evaluated the prognostic factors affecting its efficacy and safety by histological diagnoses and treatment lines. A total of 41 patients with STS, including 26 with L-sarcoma, underwent eribulin treatment. Additionally, a total of and 14 patients, including 12 with L-sarcoma, received eribulin as a second-line treatment. The results revealed that patients with L-sarcoma demonstrated longer progression-free survival (PFS) rates compared with patients without L-sarcoma (4.5 vs. 2.3 months; P=0.005). Furthermore, differences in treatment line significantly affected PFS (4.5 months in second-line treatment vs. 2.4 months in later lines; P=0.037). A high number of patients with L-sarcoma received eribulin as a second-line treatment. Regarding safety, several adverse events were reported, such as neutropenia, which were more frequently observed in patients with L-sarcoma or other patients receiving eribulin as a second-line treatment. However, most adverse events were tolerable. The clinical efficacy of eribulin was increased in patients with L-sarcoma, which was similar to previous clinical trials. However, treatment lines could also affect its efficacy. When evaluating the clinical value of eribulin to STS, it is important to consider treatment lines.

An extragonadal germ cell tumor with dermatomyositis: A case report and literature review.

The risk of malignancy in inflammatory myopathy patients is well recognized. However, the incidence of germ cell tumor (GCT) with inflammatory myopathy is low, and most reported cases of GCT also exhibit testicular tumors. Therefore, a case of extragonadal GCT with dermatomyositis (DM) is reported in the current study to better understand this paraneoplastic syndrome. A 53-year-old man presented with bilateral cervical lymph node enlargement. A lymph node biopsy showed embryonal carcinoma, and computed tomography showed multiple lymph node and lung metastases. A period of one month after bleomycin, etoposide and cisplatin (BEP) chemotherapy, this patient developed an erythematous eruption over the extensor surfaces of bilateral fingers, or Gottron's sign and facial erythema. The patient was diagnosed with DM with a positive anti-TIF-1γ-antibody result. High-dose prednisolone was effective, and there has been no evidence of cancer recurrence for over one year. The literature review identified 17 cases of GCT with inflammatory myopathy that have been reported so far, and it was indicated that this is the first case of extragonadal GCT with DM following chemotherapy. This case highlights the importance of monitoring after the completion of cancer treatment, as distinctive dermal and muscular symptoms should cause us to consider the possibility of paraneoplastic inflammatory myopathy.

Retrospective Analysis of Trabectedin Therapy for Soft Tissue Sarcoma.

BACKGROUND/AIM: Trabectedin is a synthetic antineoplastic agent approved for advanced soft tissue sarcoma (STS) in Japan. The aim of this study was to evaluate the efficacy and safety of the Japan-approved dose of trabectedin for advanced STS. PATIENTS AND METHODS: We retrospectively reviewed 38 patients with advanced STS who received salvage chemotherapy with trabectedin. RESULTS: The overall response and disease control rates were 16% (5 patients) and 67% (20 patients), respectively. The median progression-free and overall survival were 7.3 and 17.8 months, respectively. There were no significant differences between patients with liposarcoma or leiomyosarcoma and those without, or between patients with TRS and those without. The most common grade 3-4 AEs were elevated transaminases and neutropenia. CONCLUSION: Trabectedin 1.2 mg/m2, as the approved dose in Japan, showed similar efficacy to the dose of 1.5 mg/m2 used in Western countries. Trabectedin could be an option for advanced STS in Japan, regardless of histological subtype.

Efficacy of denosumab for restoring normal bone mineral density in women receiving adjuvant aromatase inhibitors for early breast cancer.

BACKGROUND: Osteoporosis is a major side effect of aromatase inhibitors (AIs), which are greatly effective in the treatment of breast cancer. However, there are no satisfactory measures against osteoporosis. In this multicenter, randomized, comparative study, we evaluate the efficacy of denosumab for preventing loss of bone mineral density (BMD) induced by adjuvant therapy with AI s in breast cancer patients with normal BMD. PATIENTS AND METHODS: The bone loss-suppressing effect of denosumab will be comparatively evaluated in postmenopausal patients scheduled to receive letrozole or anastrozole as a postoperative endocrine therapy for stage I-IIIA hormone-sensitive breast cancer and a control group. Patients will be administered letrozole 2.5 mg or anastrozole 1 mg once a day, and the treatment will be continued for 5 years unless recurrence, secondary cancer, or unacceptable toxicity develops. Patients in the denosumab group will receive a subcutaneous injection of 60 mg of denosumab every 6 months. The primary endpoint is the rate of change in the lumbar spine (L1-L4) BMD, as determined by dual-energy X-ray absorptiometry (DXA), 12 months after the start of the injection. The secondary endpoints were ETHICS AND DISSEMINATION:: The protocol was approved by the institutional review boards of Kyoto Prefectural University of Medicine and all the participating faculties. Written informed consent was obtained from all patients before registration, in accordance with the Declaration of Helsinki. Results of the study will be disseminated via publications in peer-reviewed journals. TRIAL REGISTRATION: Clinical Trials.gov Identifier: NCT03324932, Japan Registry of Clinical Trial (jRCT): CRB5180001.

Effect of denosumab on low bone mineral density in postmenopausal Japanese women receiving adjuvant aromatase inhibitors for non-metastatic breast cancer: 24-month results.

BACKGROUND: Aromatase inhibitors (AI) have been established as the gold-standard therapy for postmenopausal patients. Worldwide, adjuvant denosumab at a dose of 60 mg twice per year reduces the risk of clinical fractures in postmenopausal patients with breast cancer who received AI. However, the efficacy of denosumab in the treatment of AI-associated bone loss had not been prospectively evaluated in Japan. Previously, we reported the 12-month effect of denosumab in Japanese patients for the first time; the primary endpoint was the change in the percentage of bone mineral density (BMD) of the lumbar spine from baseline to 12 months. METHODS: This secondary follow-up study prospectively evaluated the change in the percentage of BMD of the lumbar spine from baseline to 24 months. Postmenopausal women with early-stage, histologically confirmed, hormone receptor-positive, invasive breast cancer who were receiving or scheduled to receive AI were included. Denosumab was administered subcutaneously on day 1 of the study and then 6, 12, 18, and 24 months. The lumbar spine and bilateral femoral neck BMD was measured at baseline and 6, 12, 18, and 24 months. RESULTS: At 18 and 24 months, the lumbar spine BMD increased by 5.9 and 7.0%, respectively. The femoral neck BMD also increased. Grade ≥ 2 hypocalcemia, osteonecrosis of the jaw, and atypical femoral fractures did not occur. CONCLUSIONS: Our prospective study showed that semiannual treatment with denosumab was associated with continuously increased BMD in Japanese women receiving adjuvant AI therapy for up to 24 months, regardless of prior AI treatment.

Outcome for Advanced or Metastatic Soft Tissue Sarcoma of Nonextremities Treated with Doxorubicin-Based Chemotherapy: A Retrospective Study from a Single Cancer Institution.

BACKGROUND: Doxorubicin is the key drug for treatment of advanced soft tissue sarcoma (STS). The appropriate dosage of doxorubicin, regarding monotherapy or the role of combination therapy, is unclear. METHODS: We retrospectively reviewed patients with advanced or metastatic STS of nonextremities who were treated with doxorubicin-based chemotherapies in our institution. Time to treatment failure (TTF), overall survival (OS), overall response, and prognostic factors for OS were evaluated. RESULTS: Seventy-five patients were enrolled. The median TTF was 4.7 months, and the median OS was 20.1 months. The overall response rate was 20%. Doses of doxorubicin monotherapy did not show significant difference either in TTF or in OS. There were no significant differences in OS between combination therapy and monotherapy, but the TTF with combination therapy was better than monotherapy. The overall response for combination therapy indicated a better response rate. Less number of involved organs, no bulky mass, and a normal CRP level were independent favorable prognostic factors for OS. CONCLUSIONS: Combination therapy showed better response and TTF than monotherapy but did not show better OS. Possible prognostic factors for OS were indicated. This retrospective study was approved by the institutional review board. This trial is registered with UMIN000028787.

A comparison of weekly paclitaxel and cetuximab with the EXTREME regimen in the treatment of recurrent/metastatic squamous cell head and neck carcinoma.

BACKGROUND: The effectiveness of the combination chemotherapy of weekly paclitaxel and cetuximab has not yet been compared to that of the current standard regimen, EXTREME (combination of 5-fluorouracil, cisplatin and cetuximab). METHODS: We retrospectively reviewed the clinical records of R/M SCCHN patients who received cetuximab-containing chemotherapy as a first-line therapy; from these, patients receiving a weekly paclitaxel and cetuximab regimen (cohort A) and the EXTREME regimen (cohort B) were extracted. The responses, prognoses and adverse events of these two cohorts were evaluated. RESULTS: A total of 86 patients were included (cohort A, 49; cohort B, 36). Patients with histories of platinum-based chemotherapy were more frequently given the cohort A treatment. Though the response rates were similar in the two cohorts (45% in cohort A and 51% in cohort B; p=0.83), the progression-free survival (PFS) was significantly more favorable in cohort A by the log-rank test (6.0monthsvs 5.0months; p=0.027). In the Cox-regression hazard analyses, male gender (hazard ratio [HR]=2.1, p=0.010), older age (≥ 70 yo) (HR=5.0, p=0.018), PS 0 (HR=2.2, p=0.027), no history of platinum chemotherapy (HR=3.2, p=0.003) and the presence of a tracheostomy (HR=2.3, p=0.039) were favorable factors within cohort A. CONCLUSION: In selected R/M SCCHN patients, the combination of weekly paclitaxel and cetuximab could be the better treatment option than the EXTREME regimen.

Effects of the brown rice diet on visceral obesity and endothelial function: the BRAVO study.

Brown rice (BR) and white rice (WR) produce different glycaemic responses and their consumption may affect the dietary management of obesity. In the present study, the effects of BR and WR on abdominal fat distribution, metabolic parameters and endothelial function were evaluated in subjects with the metabolic syndrome in a randomised cross-over fashion. In study 1, acute postprandial metabolic parameters and flow- and nitroglycerine-mediated dilation (FMD and NMD) of the brachial artery were determined in male volunteers with or without the metabolic syndrome after ingestion of either BR or WR. The increases in glucose and insulin AUC were lower after ingestion of BR than after ingestion of WR (P= 0·041 and P= 0·045, respectively). FMD values were decreased 60 min after ingestion of WR (P= 0·037 v. baseline), but the decrease was protected after ingestion of BR. In study 2, a separate cohort of male volunteers (n 27) with the metabolic syndrome was randomised into two groups with different BR and WR consumption patterns. The values of weight-based parameters were decreased after consumption of BR for 8 weeks, but returned to baseline values after a WR consumption period. Insulin resistance and total cholesterol and LDL-cholesterol levels were reduced after consumption of BR. In conclusion, consumption of BR may be beneficial, partly owing to the lowering of glycaemic response, and may protect postprandial endothelial function in subjects with the metabolic syndrome. Long-term beneficial effects of BR on metabolic parameters and endothelial function were also observed.

Lipid deposition in various sites of the skeletal muscles and liver exhibits a positive correlation with visceral fat accumulation in middle-aged Japanese men with metabolic syndrome.

Objective In addition to excess visceral fat, lipid deposition in the liver and skeletal muscle has been implicated in the pathophysiology of type 2 diabetes and metabolic syndrome. This study was designed to explore the relationship between hepatic and muscular lipid deposition and visceral fat accumulation in 105 middle-aged men with metabolic syndrome. Methods Abdominal computed tomography (CT) was used to simultaneously evaluate the visceral fat area (VFA) and CT Hounsfield unit (HU) values of three different portions of skeletal muscle and the liver. Results A significant inverse correlation was observed between the VFA and the CT HU values of the iliopsoas muscle, back muscle, rectus abdominis muscle and liver. Three types of interventions, i.e., lifestyle modification and treatment with antidiabetic drugs, such as Pioglitazone or Miglitol, caused significant decreases in visceral fat accumulation. The extent of lipid deposition in the liver was strongly correlated with the levels of glucose-lipid metabolic markers, which decreased significantly following Pioglitazone treatment. On the other hand, the amount of lipid deposition in the three skeletal muscles and the liver did not decrease after Miglitol treatment. Conclusion Visceral fat accumulation is accompanied by excess lipid deposition in skeletal muscle and the liver in patients with metabolic syndrome. The CT-based simultaneous, concise evaluations of ectopic lipid deposition and visceral fat mass used in the present study may provide unique information for assessing cardiometabolic risks and the therapeutic impact in patients with diabetes-obesity syndrome.

Ectopic fat deposition and global cardiometabolic risk: new paradigm in cardiovascular medicine.

The obesity epidemic is a global public health concern that increases the likelihood of morbidity and mortality of metabolic and cardiovascular disease (CVD) and threatens to reduce life expectancy around the world. The concept of the metabolic syndrome (MetS) takes into account that visceral fat plays an essential role in the development of metabolic and cardiovascular diseases. However, MetS cannot be used to assess global CVD risk but is at best one more modifiable CVD risk factor. Thus, global cardiometabolic risk (the global risk of cardiovascular disease resulting from traditional risk factors combined with the additional contribution of the metabolic syndrome and/or insulin resistance) should be considered individually. There is solid evidence supporting the notion that excess abdominal fat is predictive of insulin resistance and the presence of related metabolic abnormalities currently referred to as MetS. Despite the fact that abdominal obesity is a highly prevalent feature of MetS, the mechanisms by which abdominal obesity is causally related to MetS are not fully elucidated. Besides visceral fat accumulation, ectopic lipid deposition, especially in liver and skeletal muscle, has been implicated in the pathophysiology of diabetes, insulin resistance and obesity-related disorders. Also, ectopic fat deposition could be deteriorated in the heart components such as (1) circulatory and locally recruited fat, (2) intra- and extra-myocellular fat, (3) perivascular fat, and (4) pericardial fat. In this review, the contribution of ectopic lipid deposition to global cardiometabolic risk is reviewed and also discussed are potential underlying mechanisms including adipocytokine, insulin resistance and lipotoxicity.

Brown rice and its component, γ-oryzanol, attenuate the preference for high-fat diet by decreasing hypothalamic endoplasmic reticulum stress in mice.

Brown rice is known to improve glucose intolerance and prevent the onset of diabetes. However, the underlying mechanisms remain obscure. In the current study, we investigated the effect of brown rice and its major component, γ-oryzanol (Orz), on feeding behavior and fuel homeostasis in mice. When mice were allowed free access to a brown rice-containing chow diet (CD) and a high-fat diet (HFD), they significantly preferred CD to HFD. To reduce hypothalamic endoplasmic reticulum (ER) stress on an HFD, mice were administered with 4-phenylbutyric acid, a chemical chaperone, which caused them to prefer the CD. Notably, oral administration of Orz, a mixture of major bioactive components in brown rice, also improved glucose intolerance and attenuated hypothalamic ER stress in mice fed the HFD. In murine primary neuronal cells, Orz attenuated the tunicamycin-induced ER stress. In luciferase reporter assays in human embryonic kidney 293 cells, Orz suppressed the activation of ER stress-responsive cis-acting elements and unfolded protein response element, suggesting that Orz acts as a chemical chaperone in viable cells. Collectively, the current study is the first demonstration that brown rice and Orz improve glucose metabolism, reduce hypothalamic ER stress, and, consequently, attenuate the preference for dietary fat in mice fed an HFD.

Detection of circulating tumor cells in peripheral blood of heavily treated metastatic breast cancer patients.

BACKGROUND: Circulating tumor cells (CTCs) are detected in peripheral blood of breast cancer patients, and they may play an important role as a prognostic and predictive marker. We conducted this study to determine the presence of CTCs with the CellSearch System™ and the clinical significance in treatment of metastatic breast cancer (MBC). METHOD: Twenty-eight MBC patients were enrolled. These patients were followed by assessing CTCs, imaging studies, and serum tumor markers. Blood samples were collected before starting a new treatment and at the treatment evaluation period (2-3 months after starting chemotherapy). The cutoff for CTC level was 5. RESULTS: At baseline, 9 of 28 patients (32%) had ≥5 CTCs per 7.5 mL of blood. At the evaluation period, 5 of 23 patients (22%) had ≥5 CTCs. The baseline CTC number did not contribute to determine their overall survival (OS); however, CTCs at the evaluation period were available to predict their OS (p < 0.001). In two cases, both CTCs and tumor markers were available as predictors of treatment efficacy. In two other cases, although alterations of tumor markers might not reflect disease condition, CTC alteration corresponded to their condition. One patient who had multiple skeletal metastasis only, experienced a decrease in her CTCs in spite of tumor marker alteration. CONCLUSIONS: We suggest that monitoring the number of CTCs may be helpful in predicting the efficacy of the treatment and the prognosis. CTCs might be especially useful with patients whose lesions are difficult to assess.

Intraductal approach to the detection of intraductal lesions of the breast.

Bloody nipple discharge is a clue in the detection of ductal carcinoma of the breast that do not display a mass. Since sensitivity of discharge cytology is not sufficiently high and mammary ductendoscopy (MS) contributes to the diagnosis of intraductal lesions. We set out to determine whether the intraductal approach is effective for detection of ductal carcinoma. We performed 445 MS procedure in 323 patients who had nipple discharge but no overt mass. The diagnostic accuracy rates of discharge cytology and intraductal breast biopsy (IDBB) were studied in detecting malignancy. The therapeutic value of IDBB for intraductal papillomas was studied in 73 patients. Out of 323 patients, 80 had breast cancer and 155 had intraductal papilloma. MS detected intraductal tumors in 47 cases (58.8%). IDBB was performed in 35 of these 47 cases. The sensitivity was 37.1% by touch cytology, 68.6% by IDBB, and 82.8% by directed ductal lavage cytology. Of the 73 intraductal papilloma patients who were followed for more than 3 years, the therapeutic effectiveness of IDBB was recognized in 57 (78.1%). Directed ductal lavage cytology was the most sensitive method in detecting malignancy. MS and IDBB were benefit in the treatment of intraductal papilloma.

Influence of bacterial superantigen TSST-1 against the anti-proliferative efficacy of immunosuppressive drugs and interleukin 2 production in peripheral blood mononuclear cells of hemodialysis patients and healthy subjects.

We investigated the influence of bacterial superantigen on the efficacies of immunosuppressive drugs on the blastogenesis of peripheral-blood mononuclear cells of 27 hemodialysis patients awaiting renal transplantation. The IC(50) values for prednisolone, methylprednisolone, cyclosporine, and tacrolimus evaluated in the superantigen-stimulated cells were significantly higher than those evaluated in concanavalin A-stimulated cells (p = 0.0002-0.018). Interleukin-2 amounts produced from superantigen-stimulated cells were significantly larger than those from concanavalin A-stimulated cells (p = 0.0363). These results suggest that superantigen attenuates the suppressive efficacies of glucocorticoids and calcineurin inhibitors by stimulating lymphocytes of hemodialysis patients awaiting transplantation to overproduce interleukin-2.

Evidence of different pharmacokinetics including relationship among AUC, peak, and trough levels between cyclosporine and tacrolimus in renal transplant recipients using new pharmacokinetic parameter--why cyclosporine is monitored by C(2) level and tacrolimus by trough level--.

The clinical efficacy of calcineurin inhibitors administered to renal transplant patients is considered to be a strong function of the area under the concentration time curve (AUC). Interestingly, monitoring timings of blood concentrations for two similar calcineurin inhibitors, cyclosporine (CYA; Neoral) and tacrolimus (TAC; Prograf) are different. Namely, CYA blood concentration is usually monitored at 2 h after administration (C(2)) substituted for peak concentration (C(p)) and TAC at trough concentration (C(t)). In the literature, data describing such characteristics of CYA and TAC have been presented in the past. However, each of these patient groups had different backgrounds. We have attempted to examine the behavior of blood concentration curves simultaneously for both CYA and TAC by establishing controlled groups of renal transplant patients with similar clinical backgrounds. Furthermore, we have analyzed the correlation with C(p) and C(t) versus AUC implementing area under the trough level (AUTL), or area above the trough level (AATL) as new pharmacokinetic parameters, such that C(2) for CYA and C(t) for TAC have been verified using controlled clinical data. We have also found distinct differences in the pharmacokinetics between CYA and TAC with the relationships between AUC, C(p), and C(t).