Determinants of bone health in elderly Japanese men: study design and key findings of the Fujiwara-kyo Osteoporosis Risk in Men (FORMEN) cohort study.

BACKGROUND: The Fujiwara-kyo Osteoporosis Risk in Men (FORMEN) study was launched to investigate risk factors for osteoporotic fractures, interactions of osteoporosis with other non-communicable chronic diseases, and effects of fracture on QOL and mortality. METHODS: FORMEN baseline study participants (in 2007 and 2008) included 2012 community-dwelling men (aged 65-93 years) in Nara prefecture, Japan. Clinical follow-up surveys were conducted 5 and 10 years after the baseline survey, and 1539 and 906 men completed them, respectively. Supplemental mail, telephone, and visit surveys were conducted with non-participants to obtain outcome information. Survival and fracture outcomes were determined for 2006 men, with 566 deaths identified and 1233 men remaining in the cohort at 10-year follow-up. COMMENTS: The baseline survey covered a wide range of bone health-related indices including bone mineral density, trabecular microarchitecture assessment, vertebral imaging for detecting vertebral fractures, and biochemical markers of bone turnover, as well as comprehensive geriatric assessment items. Follow-up surveys were conducted to obtain outcomes including osteoporotic fracture, cardiovascular diseases, initiation of long-term care, and mortality. A complete list of publications relating to the FORMEN study can be found at https://www.med.kindai.ac.jp/pubheal/FORMEN/Publications.html .

Association between frailty and bone loss in patients undergoing maintenance hemodialysis.

Frailty is significantly associated with bone loss in the general population. However, it is unclear whether this association also exists in patients undergoing hemodialysis who have chronic kidney disease-mineral and bone disorder (CKD-MBD). This study aimed to assess the association between frailty and bone loss in patients undergoing hemodialysis. This cross-sectional study included 214 (90 women, 124 men) Japanese outpatients undergoing maintenance hemodialysis three times per week, with a mean age of 67.1 years (women) and 66.8 years (men). Frailty was defined based on criteria set forth by the Cardiovascular Health Study (CHS)-19 (21.1%) women and 47 (37.9%) men were robust, 41 (45.6%) women and 43 (34.7%) men were pre-frail, and 30 (33.3%) women and 34 (27.4%) men were frail. For bone mass, quantitative ultrasound (QUS) parameters (speed of sound, broadband ultrasound attenuation, stiffness index) of the calcaneus were measured. The association between frailty and QUS parameters was determined separately for women and men using multivariate analysis of covariance (ANCOVA), with adjustments for clinical characteristics including age, body mass index, hemodialysis vintage, diabetes, current smoking, serum albumin, phosphate, corrected calcium, intact parathyroid hormone, and medication for CKD-MBD (vitamin D receptor activator, calcimimetics). ANCOVA revealed that all QUS parameters declined significantly with increasing levels of frailty in both sexes (P < 0.05). In conclusion, frailty (as defined by CHS criteria) should be considered a risk factor for bone loss in patients undergoing hemodialysis.

Muscle strength is associated with bone health independently of muscle mass in postmenopausal women: the Japanese population-based osteoporosis study.

There are conflicting reports on whether muscle strength is associated with bone mineral density (BMD) independently of muscle mass. Here, we examined the association between muscle strength and BMD in a representative population of Japanese women. Cross-sectional data from 680 postmenopausal women, who were participants in the 15th-year follow-up survey of the Japanese Population-based Osteoporosis cohort study, were analyzed. Areal BMD (aBMD) at the femoral neck and lumbar spine, whole-body bone mineral density, and appendicular skeletal muscle mass (ASM, kg) were measured by dual-energy X-ray absorptiometry. The ASM index (ASMI, kg/m2) was calculated as ASM divided by height squared (m2). Grip strength (kg) was measured as an indicator of muscle strength. Grip strength showed significantly (P < 0.05) positive relationships with aBMDs at several skeletal sites after adjusting for ASMI and age (standardized partial regression coefficient (ß) = 0.102 at femoral neck, ß = 0.126 at lumbar spine). Adjusted means of aBMD at the femoral neck and lumbar spine showed significant increasing trends from the lowest to highest tertile of grip strength. Our findings indicate that muscle strength is associated with aBMD at several sites independently of muscle mass in Japanese postmenopausal women. Thus, postmenopausal women with strong muscle strength tend to have a healthy bone status regardless of muscle size.

Effects of forced deep breathing on blood flow velocity in the femoral vein: Developing a new physical prophylaxis for deep vein thrombosis in patients with plaster cast immobilization of the lower limb.

INTRODUCTION: Patients with plaster cast immobilization of the lower limb have an estimated symptomatic venous thromboembolism rate of 5.5%. However, there is currently no practical physical prophylaxis for deep-vein thrombosis (DVT). The objective of this study was to examine the effects of forced deep breathing on peak blood velocity in the superficial femoral vein (PBVFV), which is a surrogate measure of the efficacy of thromboprophylaxis against DVT, in patients with plaster cast immobilization of the lower limb. MATERIALS AND METHODS: Nine young males and 18 elderly males were recruited. We immobilized the right lower limb of each subject with a plaster splint and measured PBVFV during forced deep breathing in supine and sitting positions. RESULTS: In all subjects, PBVFV during forced deep breathing in both positions was significantly higher than at rest. There was no significant difference in the PBVFV change ratio for three breathing rates in the sitting position for the young subjects (15breaths/min: 415%, 5breaths/min: 475%, 3breaths/min: 483%), whereas that for the elderly subjects at 3breaths/min (449%) was significantly higher than that at 15breaths/min (284%). CONCLUSIONS: Forced deep breathing significantly increased PBVFV in patients with plaster cast immobilization of the lower limb in both supine and sitting positions. Testing the efficacy and adherence in clinical contexts, and following up with the incidence rate of DVT in future studies, is necessary for the development of a new physical prophylaxis for DVT.

Intense Triceps Surae Contraction Increases Lower Extremity Venous Blood Flow.

OBJECTIVE: Venous thromboembolism can be prevented by physical prophylaxis, such as active ankle exercise (AAE), in addition to pharmacological treatment. However, the relationship between the intensity of triceps surae (TS) exercise and venous flow is unclear, and physical thromboprophylaxis has not been established for patients with leg cast immobilization. The goals of the current study were to clarify the degree of intensity of TS isotonic contraction required to increase peak blood velocity (PV) in the superficial femoral vein to higher than that at no resistance and to determine if TS isometric contraction can increase PV. METHODS: A prospective, nonrandomized, controlled trial was performed in 20 healthy young adult men. PVs at rest and during one TS isotonic or isometric contraction were measured using Doppler ultrasonography. Isotonic contraction intensity was defined as no resistance with contraction of maximum effort and 25%, 50%, 75%, and 100% of one repetition maximum (1RM). Isometric contraction intensity was defined as 15-35%, 40-60%, 65-85%, and 90-100% of the maximal voluntary contraction. RESULTS: Isotonic contraction at 75% 1RM (51.4 cm/s [95% CI, 40.1-62.6]) and 100% 1RM (54.9 cm/s [95% CI, 43.1-66.7]) significantly increased PV compared to that with no resistance (41.0 cm/s [95% CI, 32.2-49.8]) (P=0.005, 0.001, respectively). Isometric contraction increased PV significantly at all intensities (all P≤0.002). CONCLUSIONS: Applying resistance at ≥75% 1RM increases venous flow and enhances the effect of AAE with TS isotonic contraction. TS isometric contraction may serve as thromboprophylaxis for patients undergoing leg cast immobilization.

Effects of intermittent pneumatic compression of the thigh on blood flow velocity in the femoral and popliteal veins: developing a new physical prophylaxis for deep vein thrombosis in patients with plaster-cast immobilization of the leg.

Patients with plaster-cast immobilization of the lower limb have an estimated venous thromboembolism rate of 2.5 % without prophylaxis, which includes many fatal cases. However, there is no practical physical prophylaxis for deep-vein thrombosis (DVT) in these patients. The aim of this study was to examine the effects of intermittent pneumatic compression on the thigh alone (IPC to the thigh) on peak blood velocity (PBV) in the legs and to consider the possibility that IPC of the thigh could be used as physical prophylaxis for DVT in patients with plaster-cast immobilization of the lower leg. Nine healthy male volunteers and eighteen elderly males were recruited. We immobilized each subject's right lower leg and ankle with a plaster splint, and applied the ActiveCare+S.F.T.(®) (Medical Compression Systems, Inc.) device to each subject's right thigh. The PBV in the superficial femoral vein (PBVFV) and the popliteal vein (PBVPV) were measured using duplex Doppler ultrasonography. IPC to the thigh resulted in a 2.3-fold increase in PBVFV and a 3.0-fold increase in PBVPV compared with resting at supine in the elderly group. Although IPC to the thigh also increased PBVFV and PBVPV significantly in the sitting position, the change ratios of PBV in the supine and sitting positions were equal (2.6-fold increase in PBVFV and 2.9-fold increase in PBVPV). IPC to the thigh in supine and sitting positions significantly increased PBVFV and PBVPV, and could be a useful prophylaxis for DVT in patients with plaster-cast immobilization of the lower leg.

Pre- and post-accident (129)I and (137)Cs levels, and (129)I/(137)Cs ratios in soil near the Fukushima Dai-ichi Nuclear Power Plant, Japan.

To evaluate the deposition density and extent of subsurface infiltration of (129)I and (137)Cs in the restricted area that was highly contaminated by the accident of Fukushima Dai-ichi Nuclear Power Plant, cumulative inventories of (129)I and (137)Cs, concentrations of (129)I and (137)Cs, and (129)I/(137)Cs ratio in 30-cm-long soil columns were compared with pre-accident levels from the same area. The cores were collected before and after the accident from locations of S-1 (4 km west of FDNPP) and S-2 (8 km west of FDNPP). Deposition densities of (129)I and (137)Cs in the soil following the accident were 0.90-2.33 Bq m(-2) and 0.80-4.04 MBq m(-2), respectively, which were 14-39 and 320-510 times larger than the pre-accident levels of (129)I (59.3-63.3 mBq m(-2)) and (137)Cs (2.51-7.88 kBq m(-2)), respectively. Approximately 90% of accident-derived (129)I and (137)Cs deposited in the 30-cm soil cores was concentrated in the surface layer from 0 to 44-95 kg m(-2) of mass depth (0-4.3-6.2 cm depth) and from 0 to 16-25 kg m(-2) of mass depth (0-1.0-3.1 cm depth), respectively. The relaxation mass depths (h0) of 10.8-11.2 kg m(-2) for (129)I estimated in the previous study were larger than those of 8.1-10.6 kg m(-2) for (137)Cs at both sites, owing to the larger infiltration depth of radioiodine mainly by the gravitational water penetration in the surface soil in our study sites. Approximately 7-9% of the accident-derived (129)I was present in the lower layer from 44 to 100 kg m(-2) (4.3-8.6 cm depth) at S-1, and from 95 to 160 kg m(-2) (6.2-10.2 cm depth) at S-2. Approximately 1% of (137)Cs seems to infiltrate deeper than (129)I in the lower layer at each site in contrast to the surface layer.

Cohort Profile: The Japanese Population-based Osteoporosis (JPOS) Cohort Study.

The Japanese Population-based Osteoporosis (JPOS) Cohort Study was launched in 1996 to produce a reference database of areal bone mineral density (aBMD) by dual energy X-ray absorptiometry (DXA) and bone turnover markers in the Japanese female population and to determine risk factors for osteoporotic fractures. At baseline, 3984 women aged 15 to 79 years were randomly selected to provide representative bone status data and aBMD values for the diagnosis of osteoporosis. Follow-up surveys were conducted in 1999, 2002, 2006 and 2011/12 to determine changes in aBMD and identify incident morphometry-confirmed vertebral fractures and clinical fractures. These outcomes were obtained from 2174 women who participated in at least one follow-up survey. JPOS is a unique resource of individual-level bone health information with radiological and biological archives that include DXA images, and serum, plasma and DNA for future analyses with emerging radiological and biological techniques. The JPOS dataset is not freely available, but new collaborations are encouraged. Potential collaborators are invited to contact the Secretary General (M.I.) at the administrative office of the JPOS Study Group.

A phase II study of rituximab combined with pirarubicin-cyclophosphamide, vincristine and prednisolone regimen as first-line therapy for patients with indolent B-cell lymphoma.

The anthracycline drug pirarubicin (tetrahydropyranyl-adriamycin [THP]) apparently has been reported to show fewer cardiotoxic effects than doxorubicin. We have previously described the effectiveness of the R-THP-COP regimen comprising rituximab, cyclophosphamide, pirarubicin, vincristine and prednisolone in patients with diffuse large B-cell lymphoma. We conducted a phase II study to determine the effectiveness of a regimen incorporating rituximab (R-THP-COP) for patients with previously untreated advanced-stage indolent CD20-positive B-cell lymphoma according to the Working Formulation and World Health Organization classification. Four to six courses of the regimen were administered every 3 weeks in 50 patients. The complete remission rate was 57%, while the 3-year overall survival rate was 92%. Regimen-related death was not observed. The R-THP-COP regimen appears very effective for patients with previously untreated advanced-stage indolent CD20-positive B-cell lymphoma. The present results indicate the need for randomized trials of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone) and R-THP-COP among patients with CD20-positive indolent lymphoma.

Assessment of individual radionuclide distributions from the Fukushima nuclear accident covering central-east Japan.

A tremendous amount of radioactivity was discharged because of the damage to cooling systems of nuclear reactors in the Fukushima No. 1 nuclear power plant in March 2011. Fukushima and its adjacent prefectures were contaminated with fission products from the accident. Here, we show a geographical distribution of radioactive iodine, tellurium, and cesium in the surface soils of central-east Japan as determined by gamma-ray spectrometry. Especially in Fukushima prefecture, contaminated area spreads around Iitate and Naka-Dori for all the radionuclides we measured. Distributions of the radionuclides were affected by the physical state of each nuclide as well as geographical features. Considering meteorological conditions, it is concluded that the radioactive material transported on March 15 was the major contributor to contamination in Fukushima prefecture, whereas the radioactive material transported on March 21 was the major source in Ibaraki, Tochigi, Saitama, and Chiba prefectures and in Tokyo.

Phase II study of the tetrahydropyranyl adriamycin-cyclophosphamide, vincristine, and prednisolone regimen combined with rituximab as first-line treatment for elderly patients with diffuse large B-cell lymphoma.

The anthracycline drug pirarubicin (tetrahydropyranyl adriamycin; THP) apparently has fewer cardiotoxic effects than doxorubicin. We previously described the benefit of the THP-COP regimen comprising cyclophosphamide, THP, vincristine, and prednisolone for elderly patients with diffuse large B-cell lymphoma (DLBCL). However, that study was completed before rituximab (R) was introduced into clinical practice. Here we report a phase II study of the THP-COP regimen combined with R (R-THP-COP) every 3 weeks. The complete response and 3-year overall survival rates was 63% and 53%, respectively, and no deaths were related to the regimen. We conclude that the R-THP-COP regimen is safe and effective for patients with DLBCL. Based on these results, a randomized controlled trial of rituximab-cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) and R-THP-COP as a phase III study is ongoing.

Long-term survival of a patient with splenic angiosarcoma after resection, high-dose chemotherapy, and autologous peripheral blood stem cell transplantation.

A 48-year-old woman was admitted to our hospital in 2003, complaining of weight loss. Complete blood cell count revealed thrombocytopenia. Abdominal CT demonstrated marked splenomegaly. FDG-PET revealed a hot spot in the whole spleen. A splenectomy was performed. Histological examination was typical for angiosarcoma. Adjuvant chemotherapy was given, and high-dose chemotherapy with autologous peripheral blood stem cell transplantation was performed. Thrombocytopenia developed again in 2008. CT scan showed a hepatic tumor. A fine-needle biopsy of the liver revealed the first relapse. Despite hepatic lobectomy, radiofrequency ablations and administration of recombinant interleukin-2, she died from respiratory failure in 2009.

Phase II study of Rituximab combined with THP-COP as first-line therapy for patients younger than 70 years with diffuse large B cell lymphoma.

INTRODUCTION: We previously described the effectiveness of the THP-COP regimen comprising cyclophosphamide, pirarubicin (tetrahydropyranyl adriamycin; THP), vincristine and prednisolone in patients with diffuse large B-cell lymphoma (DLBCL). The anthracycline drug THP was apparently less cardiotoxic than doxorubicin. However, that study was completed before rituximab was introduced into clinical practice. We conducted a phase II study to determine the effectiveness of a regimen incorporating rituximab (R-THP-COP) against DLBCL. PATIENTS: Six to 8 courses of the regimen were administered every 2 weeks in 48 patients who were younger than 70 years. RESULTS: The complete remission rate was 92%, the 3-year overall survival rate was 83% and 3-year progression free survival rate was 74%. No deaths were associated with the treatment regimen. CONCLUSION: We conclude that R-THP-COP regimen is very effective against DLBCL. The results of our study urge randomized trials of R-CHOP and R-THP-COP among patients with CD20+ DLBCL.

Serum soluble Fas level determines clinical outcome of patients with diffuse large B-cell lymphoma treated with CHOP and R-CHOP.

INTRODUCTION: We previously reported that serum concentrations of soluble Fas (sFas) predict the clinical outcome of patients with diffuse large B cell lymphoma (DLBCL) after treatment with CHOP but without rituximab (R). Here, we investigated whether the role of sFas as a prognostic factor remains valid in the R-CHOP era. PATIENTS: We treated 132 patients with DLBCL between October 1995 and September 2002 (group A: without rituximab), and 75 between December 2002 and March 2007 (group B: with rituximab). The patients received eight cycles of CHOP or THP (tetrahydropyranyl-adriamycin)-COP before September 2002, and R-CHOP or R-THP-COP after October 2002. The distribution of patients according to the International Prognostic Index did not significantly differ between the groups. RESULTS: The 5-year overall survival (OS) rates for patients with sFas levels of > or = 3.0 and <3.0 ng/ml in group A were 19.8 and 61.9% (P < 0.0001), whereas the 3-year OS rates in group B were 54.7 and 92.2% (P < 0.01), respectively. Multivariate analysis using the proportional hazards model revealed that sFas most significantly correlated with overall survival (P < 0.05). CONCLUSION: Serum sFas is thus a useful tool for selecting the appropriate therapeutic strategy for DLBCL.

Serum-soluble interleukin-2 receptor (sIL-2R) is an extremely strong prognostic factor for patients with peripheral T-cell lymphoma, unspecified (PTCL-U).

PURPOSE: The aim of this study was to assess the prognostic factors of peripheral T-cell lymphoma, unspecified (PTCL-U). PATIENTS AND METHODS: We retrospectively analyzed 30 cases fulfilling the criteria of PTCL-U defined by the World Health Organization classification. The patients were treated with 6-8 cycles of a CHOP or THP (pirarubicin)-COP regimen. RESULTS: A high serum sIL-2R level (> or =2,000 U/ml) at onset was associated with a low complete remission rate. Patients with high sIL-2R had significantly lower survival rates (5 year, 15.1%) than those with low sIL-2R (<2,000 U/ml) (100%) (P < 0.005). Factors associated with worse overall survival in a univariate analysis were high sIL-2R (P < 0.005), high age (>60 years) (P < 0.05), poor performance status (P < 0.01) and poor international prognostic index (P < 0.05). No correlation was observed between sIL-2R and other markers. Multivariate analysis showed that only sIL-2R was a prognostic factor for overall survival (P < 0.01). CONCLUSION: The results suggest that a high serum sIL-2R level predicts a poor prognosis in PTCL-U.

Associations of daily walking steps with calcaneal ultrasound parameters and a bone resorption marker in elderly Japanese women.

Quantitative ultrasound (QUS) parameters of the calcaneus and bone resorption markers predict osteoporotic fractures. High levels of physical activity have positive effects on bone health. The purpose of this cross-sectional study was to investigate the effects of daily walking activity (number of steps taken), as an outcome of physical activity, on QUS parameters of the calcaneus and urinary deoxypyridinoline (DPD) in elderly Japanese women. The subjects were 113 postmenopausal women aged 60-85 years. The speed of sound (SOS), broadband ultrasound attenuation (BUA), and the stiffness index (Stiffness) of the calcaneus were measured with A-1000 (GE-Lunar, USA). Spot urine samples were collected between 09:00 and 10:00, and the levels of urinary DPD were measured. The subjects were instructed to wear a pedometer during waking hours for 7 consecutive days. In univariate analyses, steps/day significantly decreased with aging (r=-0.306, p<0.001). Steps/day showed significant positive correlations with SOS (r=0.252, p<0.01) and Stiffness (r=0.258, p<0.01). There was a significant decrease in DPD with steps/day (r=-0.262, p<0.01). These effects of walking on QUS parameters and DPD remained significant after adjustment for confounding factors by multiple regression analyses. We conclude that high levels of walking activity may be effective in both maintaining the levels of QUS parameters and reducing bone resorption, and hence preserve bone health in elderly women.

Immunoproliferative small intestinal disease with protein loss complicated with duodenal T cell lymphoma during progression.

A 52-year-old man was admitted to our hospital in October 2001 with abdominal pain. Abdominal X-ray indicated a diagnosis of ileus. Histopathological and immunological examination resulted in a diagnosis of immunoproliferative small intestinal disease (IPSID). He was treated with THP-COP therapy (pirarubicin, cyclophosphamide, vincristine, and prednisolone), which resulted in complete remission. Outpatient follow-up revealed hypoalbuminemia in May 2003 and upper gastrointestinal endoscopy showed duodenal mucosal nodularity. He was diagnosed with relapsed IPSID and salvage chemotherapy was started. Follow-up endoscopy confirmed that the therapy was effective, but uncovered another duodenal mucosal nodularity. Immunohistochemical staining revealed T-cell lymphoma. Chemotherapy was discontinued and the patient died in December 2004.

Continuous drip infusion of low dose cytarabine and etoposide with granulocyte colony-stimulating factor for elderly patients with acute myeloid leukaemia ineligible for intensive chemotherapy.

BACKGROUNDS AND OBJECTIVES: The optimal strategy for the management of elderly patients with acute myeloid leukaemia (AML) is still controversial. We previously reported the effectiveness of low dose cytarabine (Ara-C) and etoposide (VP-16) (AV therapy) for those elderly AML patients ineligible for intensive chemotherapy. We initiated the present feasibility study to improve the efficacy by using glanulocyte-colony stimulating factor (G-CSF) with AV therapy (AVG therapy). PATIENTS AND METHODS: The eligibility for enrolment was AML patients according to the World Health Organization (WHO) criteria who were over 60 years of age and who had difficulty in tolerating intensive chemotherapy due to their poor performance status (PS) or some comorbidities. They were given continuous drip infusion of Ara-C (20 mg/body) and VP-16 (50 mg/body) for 7-14 days, and were also simultaneously administered G-CSF (150 microg/m2) once daily. RESULTS: The median age of consecutively enrolled 25 patients was 73 years. Eighteen (72%) patients achieved complete remission (CR). The 1-year overall survival (OS) and the 3-year OS rates were 69% and 22%, respectively. The 1-year disease free survival (DFS) rate in CR patients was 44%. The major regimen related toxicities of grade 3 or 4 were only febrile neutropenia in 15 patients (60%). No regimen-related mortality was observed. CONCLUSION: AVG therapy was therefore found to be an effective and well-tolerated regimen for remission induction in elderly AML patients with poor PS or comorbidity.