Spinal Cord Injury in Middle-aged and Older Adults Who Had Undergone Active Rehabilitation Treatment at a Remote Hospital: A Case Series.

Background: Middle-aged and older individuals with spinal cord injury (SCI) often require long-term care even after receiving rehabilitation treatment, making it difficult for them to return home. We retrospectively investigated our active rehabilitation treatment for patients with SCI. Case: Included in this case series were ten patients with SCI who were admitted to our general hospital (located in the southern part of Wakayama Prefecture) and who underwent active rehabilitation treatment. The participants were investigated retrospectively by access to electronic medical records. The Barthel index scores for discharged patients were determined at an outpatient clinic, and the community phase of rehabilitation management was recorded. The average age of the 10 patients was 67.4 ± 13.4 years, and the average period from onset to transfer to our hospital was 102.6 ± 69.9 days. The Barthel index scores significantly improved from 39.0 ± 30.9 at admission to 65.0 ± 28.2 at discharge (P<0.05). Among the seven patients who were discharged to their homes, six had cervical SCI. Some patients with American Spinal Injury Association impairment scale grades A and B at admission could be discharged home, and their Barthel index scores were maintained after discharge. Discussion: : Even in a remote rural hospital, the activities of daily living of patients with SCI improved, and seven of the ten patients were discharged home. The activities of daily living of the discharged patients were maintained. To achieve these results, active rehabilitation treatment conducted by rehabilitation specialists is important.

A Novel Formulation of Cisplatin with γ-Polyglutamic Acid and Chitosan Reduces Its Adverse Renal Effects: An In Vitro and In Vivo Animal Study.

Cisplatin (cis-diamminedichloroplatinum (II); CDDP) is a key chemotherapeutic agent but causes renal damage and other off-target effects. Here, we describe the pharmacological and biochemical characteristics of a novel formulation of CDDP complexed with γ-polyglutamic acid (γ-PGA) and chitosan (CS), γ-PGA/CDDP-CS, developed by complexing CDDP with γ-PGA, then adding CS (15 kDa; 10 mol%/γ-PGA). We analyzed tumor cytotoxicity in vitro, as well as blood kinetics, acute toxicity, and antitumor efficacy in vivo in BALB/cAJcl mice. γ-PGA/CDDP-CS showed pH-dependent release in vitro over 12 days (9.1% CDDP released at pH 7.4; 49.9% at pH 5.5). It showed in vitro cytotoxicity in a dose-dependent manner similar to that of uncomplexed CDDP. In a mesothelioma-bearing mouse model, a 15 mg/kg dose of CDDP inhibited tumor growth regardless of the type of formulation, complexed or uncomplexed; however, all mice in the uncomplexed CDDP group died within 13 days. γ-PGA/CDDP-CS was as effective as free CDDP in vivo but much less toxic.

The effect of denosumab in breast cancer patients receiving adjuvant aromatase inhibitors: 36-month results.

INTRODUCTION: Aromatase inhibitor (AI)-associated bone loss increases the risk of bone fracture and reduces patients' quality of life, making it a critical issue worldwide. We conducted a prospective non-randomized clinical trial (UMIN-CTR, UMIN 000016173) to assess the effect of denosumab on bone loss in patients treated with adjuvant AI and have previously reported the results at 12 and 24 months. This study aimed to present the results at 36 months of treatment with denosumab for osteopenia in breast cancer patients who were undergoing treatment with adjuvant AI; 36 months is the longest denosumab treatment period reported so far. MATERIALS AND METHODS: Patients received 60-mg denosumab subcutaneously every 6 months. Daily supplements containing 500-mg elemental calcium and at least 400 international units of vitamin D were highly recommended throughout the study period. The levels of bone mineral density (BMD) and bone turnover markers, serum tartrate-resistant acid phosphatase isoform 5b, and bone alkaline phosphatase were determined at baseline and 6, 12, 18, 24, and 36 months. RESULTS: At 36 months, the bone mineral density of the lumbar spine, right femoral neck, and left femoral neck were found to increase by 8.8% (95% confidence interval CI 7.6-10.1), 4.3% (95% CI 3.0-5.5), and 3.1% (95% CI 2.1-4.1), respectively. No non-traumatic clinical fractures occurred in patients receiving AI and denosumab. CONCLUSION: Twice-yearly administration of denosumab to the breast cancer patients treated with adjuvant AI, regardless of the skeletal site, resulted in consistent increases in BMD without severe adverse events at 36 months.

Predictive factors for the efficacy of denosumab in postmenopausal Japanese women with non-metastatic breast cancer receiving adjuvant aromatase inhibitors: a combined analysis of two prospective clinical trials.

Aromatase inhibitors (AIs) are the gold standard therapy for breast cancer in postmenopausal women. AI suppresses the conversion of androgens to estrogens; however, this results in osteopenia, osteoporosis, and bone fracture, thus reducing the patient's quality of life. The use of adjuvant denosumab reduces the risk of clinical fractures in postmenopausal patients with breast cancer receiving AI. However, the efficacy of denosumab in the treatment of AI-associated bone loss has not been prospectively evaluated in Japan. In this study, we aimed to investigate the predictive factors for the efficacy of denosumab in postmenopausal patients with breast cancer treated with AI by analyzing the results of two prospective trials. The patients received 60 mg denosumab subcutaneously every 6 months. The primary endpoint was percentage change in lumbar spine bone mineral density (BMD) from baseline to month 12 in lumbar spine. Post hoc analysis and T tests were performed. A total of 205 patients were enrolled. At 12 and 24 months, the lumbar spine BMD increased by 5.6% [95% confidence interval (CI) 4.9-6.3] and 8.3% (95% CI 7.5-9.1), respectively. Subgroup analysis was conducted according to the time of AI therapy initiation, type of AI therapy, age, time since menopause, baseline body mass index, and BMD. The results showed that baseline lumbar and left femoral BMD was significantly associated with a percentage change in these sites, respectively. In addition, baseline left femoral BMD was also associated with a change in lumbar BMD. In conclusion, the baseline BMD in the lumbar spine was a predictive indicator for the efficacy of denosumab in this site and the baseline BMD in left femoral neck was a predictive indicator in lumbar spine and left femur.

[A Case of Breast Cancer with Parenchymal and Meningeal Central Nervous System Metastases Treated with Multimodality Therapy].

A 64-year-old woman who received neo-adjuvant chemotherapy and human epidermal growth factor receptor 2(HER2)- targeted therapy underwent modified radical mastectomy and axillary lymph node resection for HER2-positiveright breast cancer. After the surgery, chemotherapy, post-mastectomy radiation therapy, and HER2-targeted therapy were administered as adjuvant therapies. Two years and 6 months postoperatively, she complained of headaches and nausea. Magnetic resonance imaging showed brain metastasis, which was treated with gamma knife surgery. Two weeks later, she was urgently admitted to the hospital because of impaired consciousness. Based on cerebrospinal fluid cytology, she was diagnosed with meningeal metastasis of breast cancer. She developed hydrocephalus; thus, external ventricular drainage was performed, and a ventriculoperitoneal shunt was inserted. She was treated with whole-brain irradiation(30 Gy)and trastuzumab emtansine (T-DM1)as systemic therapy. Treatment of the patient was possible without recurrence continuously for over 12 months and with the maintenance of daily activities. The prognosis of patients with meningeal metastasis of breast cancer is extremely poor, and effective pharmacotherapy has not yet been established. T-DM1 may improvepatie nts' quality of lifeand the clinical outcomes of meningeal metastasis.

Sonodynamic Therapeutic Effects of Sonosensitizers with Different Intracellular Distribution Delivered by Hollow Nanocapsules Exhibiting Cytosol Specific Release.

Sonodynamic therapy (SDT) is a novel promising noninvasive therapy involving utilization of low-intensity ultrasound and sonosensitizer, which can generate reactive oxygen species (ROS) by sonication. In SDT, a high therapeutic effect is achieved by intracellular delivery and accumulation at the target sites of sonosensitizer followed by oxidative damage of produced ROS by sonication. Here, pH- and redox-responsive hollow nanocapsules are prepared through the introduction of disulfide cross-linkages to self-assembled polymer vesicles formed from polyamidoamine dendron-poly(l-lysine) for the efficient delivery of sonosensitizer. As sonosensitizer, doxorubicin (DOX), an anticancer drug accumulating into cell nucleus, is selected. Also, the conjugate of DOX and triphenylphosphonium (TPP-DOX) is synthesized as sonosensitizer with mitochondrial targeting ability. DOX and TPP-DOX are delivered to nucleus and mitochondria by nanocapsules. Furthermore, DOX- or TPP-DOX-loaded nanocapsules exhibit in vitro sonodynamic therapeutic effect to HeLa cells with sonication, which might be through oxidative damage to nucleus and mitochondria.

Effects of denosumab on bone mineral density in Japanese women with osteoporosis treated with aromatase inhibitors for breast cancer.

Adjuvant aromatase inhibitor (AI) therapy, for hormone receptor-positive breast cancer, in postmenopausal women is associated with bone loss, leading to an increased risk of fractures. Denosumab, an antibody raised against the receptor activator of nuclear factor-κB ligand, has been proven to protect against AI-induced bone loss. Hence, we aimed to determine whether denosumab is effective in postmenopausal Japanese women with osteoporosis, treated with AI. We prospectively evaluated the bone mineral density (BMD) in the lumbar spine and the bilateral femoral neck in 102 postmenopausal women with clinical hormone receptor-positive breast cancer, stages I-IIIA, during a postoperative period of 12 months. The other inclusion criteria for this study were: women that should receive AIs as adjuvant therapy and those with evidence of osteoporosis (lumbar spine or bilateral femoral neck BMD, equivalent to T-score classification of ≤ - 2.5) upon enrollment. The patients received supplemental calcium, vitamin D, and 60 mg of subcutaneous denosumab every 6 months. The BMD of the lumber spine increased by 4.9 and 6.6% at 6 and 12 months, respectively. An increase in BMD was observed at the femoral neck, bilaterally. Hypocalcemia ≥ grade 2, osteonecrosis of the jaw, and non-traumatic clinical fracture were not observed in this study. Our findings revealed that biannual treatment with denosumab is associated with a great increase of BMD in Japanese women receiving adjuvant AI therapy, irrespective of their previous history of AI therapy.

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.

Phase II Clinical Trial of First-line Eribulin Plus Trastuzumab for Advanced or Recurrent HER2-positive Breast Cancer.

BACKGROUND/AIM: Eribulin mesylate has been approved for advanced or metastatic breast cancers subjected to at least two previous chemotherapy regimens. The present multicenter, phase II, single-arm study assessed the efficacy and safety of a first-line regimen of eribulin plus trastuzumab for untreated advanced or metastatic HER2-positive breast cancer. PATIENTS AND METHODS: Enrolled patients received eribulin (1.4 mg/m2 intravenously; I.V.) on days 1 and 8 of each 21-day cycle, an initial trastuzumab dose (8 mg/kg I.V.) on day 1, and 6 mg/kg of trastuzumab on day 1 of each subsequent cycle. The primary endpoint was the response rate (RR). The secondary endpoints were progression-free survival (PFS), overall survival (OS), duration of response (DOR), and safety. Twenty-eight patients (median age: 62.5 years) received a median of 12 (range: 2-53) cycles of eribulin plus trastuzumab. RESULTS: The RR was 53.6% [complete response (CR), 4; partial response (PR), 11] with a median PFS of 344 days. The clinical benefit rate was 64.0%. Grade 3/4 adverse events were observed in 12 (42.9%) patients. For details, neutropenia in 8 (28.6%) patients, peripheral neuropathy in 2 (7.1%) patients, interstitial pneumonia in 1 (3.6%) patient, ALT elevation in 1 (3.6%) patient, osteonecrosis of the jaw in 1 (3.6%) patient, and fatigue in 1 (3.6%) patient. The patient with osteonecrosis received denosumab, too. No symptomatic congestive heart failure was observed. CONCLUSION: Combination therapy of eribulin plus trastuzumab is acceptable in efficacy and safety, and a capable option for first-line advanced or recurrent HER2-positive breast cancer.

Effect of denosumab on bone mineral density in Japanese women with osteopenia treated with aromatase inhibitors for breast cancer: subgroup analyses of a Phase II study.

BACKGROUND: The aim of the study was to conduct subgroup analyses of therapeutic effects of 12-month denosumab therapy on the percentage change in bone mineral density (BMD) from baseline in the lumber spine and femoral neck. MATERIALS AND METHODS: We prospectively evaluated the BMD of the lumbar spine and femoral neck of 100 hormone receptor-positive, clinical stage I-IIIA postoperative postmenopausal breast cancer patients, for whom treatment with aromatase inhibitors (AIs) as adjuvant endocrine therapy was scheduled. The primary endpoint was the percent change in lumbar spine BMD from baseline to 12 months. Patient subgroups were analyzed according to baseline variables that are known risk factors for bone loss, including previous AI therapy, age, time since menopause, baseline body mass index (BMI), and baseline BMD T-score. RESULTS: At 12 months, lumbar spine BMD increased by 4.7%; the patients who were administered AI therapy prior to denosumab (n=70) demonstrated a 4.7% increase in BMD, and the patients who received denosumab at the start of AI therapy (n=30) demonstrated a 4.5% increase in BMD (p=0.8385). Additionally, 2.4% and 1.4% increases in BMD of the right and left femoral neck, respectively, were observed. Initiation of AI (with denosumab, before denosumab), type of AI (non-steroidal, steroidal), age (<65, ≥65 years), time since menopause (≤5, >5 years), BMI (<25, ≥25 kg/m2), and T-score (≤-1.0, >-1.0) of the right femoral neck were as follows: (2.2%, 2.5%, p=0.7773), (2.6%, 0.9%, p=0.1726), (2.5%, 2.3%, p=0.7594), (2.1%, 2.4%, p=0.2034), (2.1%, 2.9%, p=0.2034), and (2.3%, 2.7%, p=0.6823), respectively. Initiation of AI (with denosumab, before denosumab), type of AI (non-steroidal, steroidal), age (<65, ≥65 years), time since menopause (≤5, >5 years), BMI (<25, ≥25 kg/m2), and T-score (≤-1.0, >-1.0) of the left femoral neck were as follows: (1.0%, 1.5%, p=0.1972), (1.2%, 2.7%, p=0.2931), (1.4%, 1.3%, p=0.8817), (-0.1%, 1.6%, p=0.1766), (1.3%, 1.9%, p=0.6465), and (1.5%, 1.1%, p=0.6573), respectively. CONCLUSION: Twice-yearly treatment with denosumab was associated with increased BMD among Japanese women receiving adjuvant AI therapy, regardless of the baseline characteristics or skeletal site.

Effect of denosumab administration on low bone mineral density (T-score -1.0 to -2.5) in postmenopausal Japanese women receiving adjuvant aromatase inhibitors for non-metastatic breast cancer.

Although adjuvant aromatase inhibitor (AI) therapy is widely used in postmenopausal women with hormone receptor-positive breast cancer, it is known to be associated with bone loss and increased fracture risk. Denosumab, a fully human monoclonal antibody against the receptor activator of nuclear factor-κB ligand, has been shown to protect against AI-induced bone loss. However, the efficacy of denosumab in the treatment of AI-associated bone loss has not been prospectively evaluated in Japan. We prospectively monitored bone mineral density (BMD) of the lumbar spine and bilateral femoral necks in 100 postmenopausal women with hormone receptor-positive postoperative breast cancer of clinical stage I-IIIA in whom treatment with AI as adjuvant endocrine therapy was planned or had been ongoing. Study participants received supplemental calcium and vitamin D every day and denosumab (60 mg) subcutaneously every 6 months. At enrollment, patients were required to have evidence of low bone mass without meeting the criteria for osteoporosis. The primary endpoint was percentage change from baseline in lumbar spine BMD at month 12. At 6 and 12 months, lumbar spine BMD increased by 3.3 and 4.7%, respectively. BMD of the femoral necks also increased. Hypocalcemia of grade ≥2, osteonecrosis of the jaw, and non-traumatic clinical fracture did not occur. In conclusion, semi-annual treatment with denosumab was associated with increased BMD in Japanese women receiving adjuvant AI therapy, regardless of prior AI treatment.

Docetaxel and cyclophosphamide as neoadjuvant chemotherapy in HER2-negative primary breast cancer.

BACKGROUND: Docetaxel plus cyclophosphamide (TC) has recently been established as a standard adjuvant chemotherapy regimen for HER2-negative (HER2-) operable breast cancer. However, the efficacy and tolerability of TC as neoadjuvant chemotherapy (NAC) remain unclear. We, therefore, conducted a prospective study to evaluate the efficacy of TC NAC in HER2- primary breast cancer. METHODS: Patients who were diagnosed with HER2-, N0-N1, invasive breast cancer between July 2011 and February 2014 and had tumors measuring 1-7 cm were eligible. The subtypes were classified using a core-needle or vacuum-assisted breast biopsy. The efficacy and safety of NAC comprising TC (75 mg/m2 docetaxel and 600 mg/m2 cyclophosphamide, four cycles every 3 weeks) were investigated in a prospective study in patients with HER2- breast cancer. RESULTS: Fifty-two patients were enrolled. Of these, 94.2 % (49/52) completed four cycles of TC. The overall pCR rate was 16.3 % (8/49). The pCR rates for patients with luminal A-like breast cancer [estrogen receptor-positive (ER+), Ki67 index of <20 %, and HER2-], luminal B-like breast cancer (ER+, Ki67 index of >20 %, and HER2-), and triple-negative breast cancer [ER-negative (ER-) and HER2-] were 0 % (0/12), 4.3 % (1/23), and 50.0 % (7/14), respectively. Almost all pCRs occurred in triple-negative breast cancer patients. CONCLUSIONS: The pCR rate of TC NAC was not very high despite the high completion rate. TC NAC was effective against the triple-negative subtype, resulting in a higher pCR rate. Therefore, our results indicated that TC NAC showed limited efficacy in luminal subtype breast cancer with the exception of the triple-negative subtype.

Docetaxel, cyclophosphamide, and trastuzumab as neoadjuvant chemotherapy for HER2-positive primary breast cancer.

BACKGROUND: The standard primary systemic therapy for human epidermal growth factor receptor 2-positive (HER2+) breast cancer is anthracyclines and/or taxanes combined with trastuzumab, which demonstrates a high pathological complete response (pCR). A pCR is a predictive marker of prognosis. However, results slightly differ, depending on the hormone receptor status. The efficacy and tolerability of docetaxel, cyclophosphamide, and trastuzumab (HER-TC) as neoadjuvant chemotherapy (NAC) remain unclear. We performed a prospective multicenter study of HER-TC NAC for HER2+ primary breast cancer. METHODS: Eligible patients had a clinical diagnosis of HER2+ invasive breast cancer greater than 1 cm but less than 7 cm and a tumor stage of N0 or N1. T hey were diagnosed between July 2011 and February 2014. For NAC, four cycles of HER-TC (6 mg/kg loading dose, 8 mg/kg, 75, and 600 mg/m2) were administered intravenously every 3 weeks. We investigated the pCR of the primary breast tumors. A pCR was defined as no histological evidence of invasive carcinoma or the appearance of only ductal carcinoma in situ. RESULTS: We enrolled 42 patients. The completion rate for four cycles of HER-TC was 97.6 % (41/42 patients). The overall pCR rate was 43.9 % (18/41 patients). The pCR rate for patients with the luminal HER2 subtype [estrogen receptor (ER)-positive+, HER2+] and the HER2-enriched subtype (ER-, HER2+) was 40.0 % (8/20 patients) and 47.6 % (10/21 patients), respectively. A pCR was achieved with nearly the same probability for each subtype. CONCLUSIONS: Four cycles of HER-TC may be a NAC option for HER2-positive breast cancer.

[A Case of Luminal-HER2 Advanced Breast Cancer with Liver Metastasis Showed Pathological Complete Response to the Therapy with Pertuzumab plus Trastuzumab plus Docetaxel].

A 56-year-old woman noticed a mass on her left breast and visited our hospital. An irregular mass of 3 cm with associated axillary lymphadenopathy was detected under the nipple of the left breast. After further evaluations, the diagnosis was an invasive ductal carcinoma(scirrhous carcinoma)ofLuminal -HER2 type with liver metastases(cT4bN1M1, Stage IV). Treatment was initiated with a combination ofpertuzumab, trastuzumab, and docetaxel(PTD). The primary tumor showed a clinical complete response, and the liver metastases and the axillary lymph node metastases showed a partial response. Docetaxel was excluded after the 8th cycle because the patient experienced severe edema. After 15 cycles of therapy, the primary tumor was resected, and pathological examination revealed a pathological complete response ofthe primary lesion. Thus, PTD combination therapy is effective for Stage IV metastatic breast cancer ofthe Luminal-HER2 type.

Discovery of a 2-hydroxyacetophenone derivative as an outstanding linker to enhance potency and ß-selectivity of liver X receptor agonist.

Our research found that the 2-hydroxyacetophenone derivative is an outstanding linker between the 1,1-bistrifluoromethylcarbinol moiety and the imidazolidine-2,4-dione moiety to enhance the potency and ß-selectivity of liver X receptor (LXR) agonist in our head-to-tail molecular design. The incorporation of this linker is 20-fold more potent than our previous compound (2) for LXR ß agonistic activity (EC50) in a GAL-4 luciferase assay. Furthermore, we also identified 5-[5-(1-methylethoxy)pyridyl-2-yl]-5-methylimidazoline-2,4-dione (54), which lowers the lipophilicity of 2-hydroxyacetophenone derivative. We revealed that a combination of our newly developed linker and hydantoin (54) plays a pivotal role in improving the potency and selectivity of LXRß. The optically separated (-)-56 increases high-density lipoprotein cholesterol levels without elevating plasma triglyceride levels and results in a decrease of the lipid accumulation area in the aortic arch in a high-fat- and cholesterol-fed low-density lipoprotein receptor knock-out mice. In this manuscript, we report that (-)-56 is a highly potent and ß-selective LXR agonist for use in the treatment of atherosclerosis.

Design, synthesis and pharmacology of 1,1-bistrifluoromethylcarbinol derivatives as liver X receptor ß-selective agonists.

A novel series of 1,3-bistrifluoromethylcarbinol derivatives that act as liver X receptor (LXR) ß-selective agonists was discovered. Structure-activity relationship studies led to the identification of molecule 62, which was more effective (Emax) and selective toward LXRß than T0901317 and GW3965. Furthermore, 62 decreased LDL-C without elevating the plasma TG level and significantly suppressed the lipid-accumulation area in the aortic arch in a Bio F1B hamster fed a diet high in fat and cholesterol. We demonstrated that our LXRß agonist would be potentially useful as a hypolipidemic and anti-atherosclerotic agent. In this manuscript, we report the design, synthesis and pharmacology of 1,3-bistrifluoromethylcarbinol derivatives.

Design and discovery of 2-oxochromene derivatives as liver X receptor ß-selective agonists.

In an attempt to molecularly design liver X receptor (LXR) ß-selective agonists, we discovered that the combination of the 2-oxochromene moiety (head) and the imidazoline-2,4-dione moiety (tail) plays an important role in the expression potency and selectivity toward LXRß. We synthesized a series of 2-oxochromene derivatives and identified 43 as a LXRß-selective agonist that increased the HDL-C level without significantly elevating the TG level and resulted in a decreased lipid-accumulation area in the aortic arch in a high-fat-and-cholesterol-fed Bio F1B hamster. In this manuscript, we report the design, synthesis and pharmacology of these 2-oxochromene derivatives.

Laparoscopic Diagnosis and Laparoscopic Hyperthermic Intraoperative Intraperitoneal Chemotherapy for Pseudomyxoma Peritonei Detected by CT Examination.

Background. Patients with early stage of pseudomyxoma peritonei (PMP) are sometimes difficult to diagnose the primary sites and intraperitoneal spread of tumor and to perform a cytological study. Methods. Patients without a definitive diagnosis and with unknown extent of peritoneal spread of tumor underwent laparoscopy. Hyperthermic intraoperative intraperitoneal chemotherapy (HIPEC) was administered as part of the same intervention. The results of treatment were evaluated at the time of second-look laparotomy (SLL) as a subsequent intervention. Results. Eleven patients were managed by diagnostic laparoscopy followed by laparoscopic HIPEC (LHIPEC). The operation time of laparoscopic examination and LHIPEC was 177 ± 26 min (range 124-261 min). No intraoperative complication was experienced. The peritoneal carcinomatosis index (PCI) score by laparoscopic observation was 16.5 ± 6.4 (range 0-30). One patient with localized pseudomyxoma peritonei (PMP) mucocele did not received LHIPEC; the other 10 patients with peritoneal metastases (PM) were treated with LHIPEC. After LHIPEC, ascites disappeared in 2 cases and decreased in the amount in the other 8 cases. Nine patients underwent SLL and cytoreductive surgery (CRS) combined with HIPEC. The duration between LHIPEC and SLL ranged from 40 to 207 days (97 ± 40 days). The PCI at the SLL ranged from 4 to 27 (12.9 ± 7.1). The PCI at the time of SLL decreased as compared to PCI at the time of diagnostic laparotomy in 7 of 9 patients. Median follow-up period is 22 months (range 7-35). All 11 patients are alive. Conclusion. The early results suggest that laparoscopic diagnosis combined with LHIPEC is useful to determine the surgical treatment plan and reduce the tumor burden before definitive CRS at SLL.

Morbidity and mortality outcomes of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy at a single institution in Japan.

Background. Even though cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) are associated with a high morbidity and mortality rates, it has been reported that CRS and HIPEC improved survival of selected patients with peritoneal carcinomatosis. We aimed to report morbidity and mortality results of CRS and HIPEC from a single institution in Japan. Methods and Results. Total of 284 procedures of CRS were performed on patients with pseudomyxoma peritonei, peritoneal carcinomatosis (PC) from colon cancer and gastric cancer between 2007 and 2011 in our institution. The morbidity rate was 49% of all procedure, and grades I/II and grades III/IV complications were 28% and 17%, respectively. Most frequent complication was surgical site infections including intraabdominal abscess. The mortality rate was 3.5%, and reoperation was needed in 11% of all procedures. Univariate and multivariate analysis showed peritoneal carcinomatosis index (PCI) greater than 20 was the only significant factor for occurrence of postoperative complications (P < 0.01). In contrast, HIPEC significantly reduced postoperative complications (P < 0.05). Conclusions. The morbidity and mortality rates of our institution are comparable with previous reports that are in acceptable rates. Optimal patient selection such as patients with PCI less than 20 seems to be of paramount importance to CRS and HIPEC.

Historical review on development of environmental quality standards and guideline values for air pollutants in Japan.

Environmental quality standards (EQSs) have been established as desirable levels to be maintained for protection of human health and the conservation of the living environment by Basic Environment Law. EQSs in ambient air had been set for 10 substances (sulfur dioxide (SO(2)), carbon monoxide (CO), suspended particulate matter (SPM), nitrogen dioxide (NO(2)) and photochemical oxidants (Ox), benzene, tetrachloroethylene, trichloroethylene, dioxins and dichloromethane) and guideline values for 7 (acrylonitorile, vinyl chloride monomer, mercury, nickel compounds, 1,3-butadiene, chloroform and 1,2-dichloromethane) in Japan by 2009. EQSs for the classical (or traditional) air pollutants, SO(2), CO, SPM, NO(2) and Ox, were set according to the minimal requirement to protect human health, based on evidence from epidemiological studies conducted before the 1970s. In 1996, the Central Environment Council designated substances which may be hazardous air pollutants and substances requiring priority action, and adopted the concept of risk assessment to set EQSs and guideline values. A life-long risk level (virtually safe dose) of 10(-5) was used to set EQS for benzene, and guideline values for vinyl chloride monomer, nickel compounds, and 1,3-butadiene. EQSs for trichloroethylene, tetrachloroethylene and dichloromethane, and guideline values for acrylonitorile and mercury were set using uncertain factors and lowest observed adverse effect (LOAEL)/no observed adverse effect level (NOAEL). The results of animal experiments were utilized to set guideline values for chloroform and 1,2-dichloroethane. The benchmark approach and human equivalent concentration (HEC) were adopted for 1,2-dichloroethane. The history of setting EQSs and guideline values for hazardous air pollutants is one of adopting new concepts into risk assessment.