Phase III study of bilayer sustained-release tramadol tablets in patients with cancer pain: a double-blind parallel-group, non-inferiority study with immediate-release tramadol capsules as an active comparator.

PURPOSE: We investigated whether twice-daily administration of a bilayer tablet formulation of tramadol (35% immediate-release [IR] and 65% sustained-release) is as effective as four-times-daily IR tramadol capsules for managing cancer pain. METHODS: This randomized, double-blind, double-dummy, active-comparator, non-inferiority study enrolled opioid-naïve patients using non-steroidal anti-inflammatory drugs or acetaminophen (paracetamol) to manage cancer pain and self-reported pain (mean value over 3 days ≥ 25 mm on a 100-mm visual analog scale [VAS]). Patients were randomized to either bilayer tablets or IR capsules for 14 days. The starting dose was 100 mg/day and could be escalated to 300 mg/day. The primary endpoint was the change in VAS (averaged over 3 days) for pain at rest from baseline to end of treatment/discontinuation. RESULTS: Overall, 251 patients were randomized. The baseline mean VAS at rest was 47.67 mm (range: 25.6-82.7 mm). In the full analysis set, the adjusted mean change in VAS was - 22.07 and - 19.08 mm in the bilayer tablet (n = 124) and IR capsule (n = 120) groups, respectively. The adjusted mean difference was - 2.99 mm (95% confidence interval [CI] - 7.96 to 1.99 mm). The upper 95% CI was less than the predefined non-inferiority margin of 7.5 mm. Other efficacy outcomes were similar in both groups. Adverse events were reported for 97/126 (77.0%) and 101/125 (80.8%) patients in the bilayer tablet and IR capsule groups, respectively. CONCLUSION: Twice-daily administration of bilayer tramadol tablets was as effective as four-times-daily administration of IR capsules regarding the improvement in pain VAS, with comparable safety outcomes. CLINICAL TRIAL REGISTRATION: JapicCTI-184143/jRCT2080224082 (October 5, 2018).

Veliparib with frontline chemotherapy and as maintenance in Japanese women with ovarian cancer: a subanalysis of efficacy, safety, and antiemetic use in the phase 3 VELIA trial.

BACKGROUND: The phase 3 VELIA trial evaluated veliparib with carboplatin/paclitaxel and as maintenance in patients with high-grade serous ovarian carcinoma. METHODS: Patients with previously untreated stage III-IV high-grade serous ovarian carcinoma were randomized 1:1:1 to control (placebo with carboplatin/paclitaxel and placebo maintenance), veliparib-combination-only (veliparib with carboplatin/paclitaxel and placebo maintenance), or veliparib-throughout (veliparib with carboplatin/paclitaxel and veliparib maintenance). Randomization stratification factors included geographic region (Japan versus North America or rest of the world). Primary end point was investigator-assessed median progression-free survival. Efficacy, safety, and pharmacokinetics were evaluated in a subgroup of Japanese patients. RESULTS: Seventy-eight Japanese patients were randomized to control (n = 23), veliparib-combination-only (n = 30), and veliparib-throughout (n = 25) arms. In the Japanese subgroup, median progression-free survival for veliparib-throughout versus control was 27.4 and 19.1 months (hazard ratio, 0.46; 95% confidence interval, 0.18-1.16; p = 0.1 [not significant]). In the veliparib-throughout arm, grade 3/4 leukopenia, neutropenia, and thrombocytopenia rates were higher for Japanese (32%/88%/32%) versus non-Japanese (17%/56%/28%) patients. Grade 3/4 anemia rates were higher in non-Japanese (65%) versus Japanese (48%) patients. Early introduction of olanzapine during veliparib monotherapy maintenance phase may help prevent premature discontinuation of veliparib, via its potent antiemetic efficacy. CONCLUSIONS: Median progression-free survival was numerically longer in Japanese patients in the veliparib-throughout versus control arm, consistent with results in the overall study population. Pharmacokinetics were comparable between Japanese and non-Japanese patients. Data for the subgroup of Japanese patients were not powered to show statistical significance but to guide further investigation.

Incidence of fistula occurrence in patients with cervical cancer treated with bevacizumab: data from real-world clinical practice.

BACKGROUND: This study aimed to determine the incidence of pelvic fistulas in cervical cancer patients treated with bevacizumab in Japanese clinical practice. METHODS: A post-marketing surveillance (PMS) study was conducted between June 2016 and February 2018 to survey physicians who treated advanced or recurrent cervical cancer patients with bevacizumab (according to the product label). The clinical/treatment status of patients with pelvic fistulas was assessed in an additional retrospective case series study. RESULTS: 142 patients were included in the PMS study (median age 51 years; 66.9% squamous cell carcinoma; 66.2% recurrent cervical cancer; 64.1% previous radiotherapy). Patients received a median of seven bevacizumab doses. Six patients, all of whom had a history of pelvic irradiation, developed seven fistulas (4.2%; 95% confidence interval, 1.56-8.96), and five patients had also undergone pelvic surgery. The case series study of the patients who developed fistulas indicated that three patients had high cumulative bladder and rectal doses of radiation, and two of them had undergone salvage re-irradiation for pelvic recurrence. The other three patients underwent both radical hysterectomy and adjuvant radiotherapy, but did not receive an excessive radiation dose to the bladder or rectum. CONCLUSIONS: This study found that the upper limit of the 95% confidence interval for pelvic fistula incidence did not exceed the incidence reported in the GOG 240 study. To ensure an adequate benefit-risk assessment of bevacizumab in cervical cancer patients, a comprehensive evaluation of prior treatment is essential and the possibility of unexpected fistulas, even after careful evaluation, should be considered.

4-step, 2-h carboplatin desensitization in Japanese patients with ovarian cancer: a prospective study.

BACKGROUND: Carboplatin is a key drug for ovarian cancer. However, it sometimes induces hypersensitivity reactions (HSRs) that result in the discontinuation of the treatment. Although various desensitization protocols have been reported in previous retrospective studies, a limited number of prospective studies have analyzed these protocols. METHODS: Patients with platinum-sensitive relapsed ovarian cancer who experienced carboplatin-induced HSRs were treated with diluted solutions of 1/1000, 1/100, 1/10 and an undiluted solution of carboplatin over a 1-h period. If no HSRs occurred within the first two cycles, a short protocol regimen over a 30-min period per solution was followed. The primary endpoint was treatment completion rate. RESULTS: Between May 2015 and September 2018, 21 patients were enrolled from two institutions. One patient experienced platinum-sensitive recurrence after the desensitization protocol; thus, 22 sessions were analyzed. Epinephrine use, treatment-related death, and intensive care unit (ICU) admissions did not occur. The median number of desensitization cycles was 6 (range 1-6). Two sessions were discontinued early because of grade 2 dysgeusia and grade 2 malaise. Treatment in two (9.1%) patients was discontinued because of HSR development. The treatment completion rate was 90.9%. Six (27.3%) sessions met the criteria for transition to the short protocol regimen. In 14 (63.6%) sessions, HSRs were observed during infusion of the undiluted solution. The median progression-free survival and overall survival were 14.8 and 23.8 months, respectively. CONCLUSION: This 4-step, 2-h carboplatin desensitization protocol is safe and feasible. Patients require careful monitoring with a rapid response to HSRs, especially during the administration of undiluted solutions.

[Clinical Guidelines for Cancer Chemotherapy under COVID-19 in the World].

A risk of COVID-19 infection for cancer patients is reported slightly high compared with general citizens. Among patients with cancer and COVID-19, severe illness and mortality is slightly high and associated with general risk factors and risk factors unique to patients with cancer. Cancer therapy should not be stopped or postponed under COVID-19 because cancer will be fatal disease if delaying or stopping cancer treatment. Clinical guidelines for cancer chemotherapy is discussed under COVID-19 in this article.

Efficacy and safety of nivolumab in Japanese patients with uterine cervical cancer, uterine corpus cancer, or soft tissue sarcoma: Multicenter, open-label phase 2 trial.

Nivolumab is a human monoclonal antibody against the immune checkpoint receptor programmed death-1, inhibiting binding to programmed death-ligand 1 or 2 (PD-L1 or PD-L2). This phase 2 study evaluated the efficacy and safety of nivolumab in patients with advanced/recurrent uterine cervical cancer, uterine corpus cancer, or soft tissue sarcoma (STS). Patients received nivolumab 240 mg at 2-week intervals. Primary endpoint was objective response rate; secondary endpoints included overall survival, progression-free survival, and safety. PD-L1 expression and microsatellite-instability (MSI) status were analyzed as potential efficacy biomarkers. Objective response rate was 25%, 23%, and 0% in patients with cervical cancer (n = 20), corpus cancer (n = 22), and STS (n = 21), respectively. The lower 80% confidence intervals of objective response rates in patients with cervical or corpus cancer exceeded the threshold rate (5%); the primary endpoint was met in cervical and corpus cancer, but not in STS. Median progression-free survival was 5.6, 3.4, and 1.4 months, and 6-month overall survival was 84%, 73%, and 86% in cervical cancer, corpus cancer, and STS, respectively. The objective response rate was higher in patients with cervical cancer with PD-L1-positive (n = 5/15; 33%) versus PD-L1-negative (n = 0/5; 0%) tumors. The two patients with corpus cancer classified as MSI-high responded; the six patients classified as microsatellite stable did not respond. Overall, nivolumab showed acceptable toxicity in all cohorts, with evidence of clinical activity in uterine cervical or corpus cancer, but not in STS. PD-L1 expression in cervical cancer and MSI-high in corpus cancer may predict clinical activity of nivolumab in these cancers.

Phase III study of cisplatin with or without S-1 in patients with stage IVB, recurrent, or persistent cervical cancer.

BACKGROUND: This open-label phase III trial evaluated efficacy and safety of S-1 plus cisplatin vs. cisplatin alone as first-line chemotherapy in patients with stage IVB, recurrent, or persistent cervical cancer. METHODS: Patients were randomised (1:1) to S-1 plus cisplatin (study group) or cisplatin alone (control group). In each cycle, cisplatin 50 mg/m2 was administered on Day 1 in both groups. S-1 was administered orally at 80-120 mg daily on Days 1-14 of a 21-day cycle in the study group. The primary endpoint was overall survival (OS). RESULTS: A total of 375 patients were enrolled, of whom 364 (188, study group; 176, control group) received treatment. Median OS was 21.9 and 19.5 months in the study and control groups, respectively (log-rank P = 0.125; hazard ratio [HR] 0.84, 95% confidence interval [CI] 0.67-1.05). Median progression-free survival (PFS) was 7.3 and 4.9 months in the study and control groups, respectively (HR 0.62, 95% CI 0.48-0.80, P < 0.001). The adverse event (AE) rate increased in the study group despite the absence of any unexpected AEs. CONCLUSIONS: S-1 plus cisplatin did not show superiority over cisplatin alone in OS but significantly increased PFS in patients with stage IVB, recurrent, or persistent cervical cancer. Since the standard therapy has changed in the course of this study, further studies are warranted to confirm the clinical positioning of S-1 combined with cisplatin for this population.

Standardization of Growth Hormone and Insulin-like Growth Factor-I Measurement.

Determination of serum levels of GH and IGF-I is crucial for the diagnosis and treatment of GH deficiency and disorders related to GH excess such as acromegaly and pituitary gigantism. However, significant discrepancies in measured GH values among the methods were observed around the world. In Japan, the Study Committee for GH and Its Related Factors of The Foundation for Growth Science standardized GH values measured with various commercially available GH assay kits by creating formulas to adjust them to their averages. The committee also established reference values for IGF-I in Japanese subjects at all ages from childhood to adulthood. Internationally, collaborators have been working on the harmonization of GH measurements.

Providing written information increases patient satisfaction: a web-based questionnaire survey of Japanese cancer survivors.

PURPOSE: The Institute of Medicine (IOM) of the United States recommends that all cancer survivors be provided with a survivorship care plan (SCP), which includes a patient treatment summary and a follow-up care plan. However, SCPs have not been widely adopted in Japan. To provide basic data necessary for implementing SCPs in Japan, we aimed to investigate the forms of clinical and survivorship-related information that Japanese cancer survivors receive from their healthcare providers, and to examine whether written information increases their satisfaction. METHODS: We performed a cross-sectional online survey of cancer survivors who underwent acute cancer treatment and had at least one follow-up with a physician in the past year. Cancer survivors provided the elements and forms (verbally and/or written) of information they received, as well as the degree of satisfaction with the information provided. RESULTS: Responses were obtained from 545 cancer survivors. Information elements such as surgical procedure (98.3%), surgical outcome (98.1%), and names of administered chemotherapy agents (97.8%) were commonly provided, whereas mental care resources and providers (29.7%), effects on marital relationship and sexual health (35.7%), and effects on fertility (43.4%) were less common. A large proportion of cancer survivors received verbal information only. For 18 of 20 elements, except for effects on fertility and duration of hormonal therapy, satisfaction was significantly higher when both forms of information were provided (P < 0.05). CONCLUSIONS: Providing written and verbal explanations of clinical and survivorship-related information can better meet the needs of Japanese cancer survivors.

Standardization of Growth Hormone and Insulin-like Growth Factor-I Measurements.

Measurement of the levels of growth hormone (GH) and its related factor insulin-like growth factor I (IGF-I) is essential for the diagnosis and treatment of GH deficiency (GHD) and conditions related to excess GH such as acromegaly and pituitary gigantism. Measurement of GH levels is also used as an indicator of hypothalamic-pituitary function. Because of the marked variability in GH measurements among kits, the Study Committee for GH and Its Related Factors of The Foundation for Growth Science, Japan standardized GH values measured with various commercially available GH assay kits in Japan. The committee also established IGF-I reference values for Japanese subjects of all ages, from childhood to adulthood. Hopefully, international harmonization of GH measurements will be achieved in the future.

Extra-adrenal induction of Cyp21a1 ameliorates systemic steroid metabolism in a mouse model of congenital adrenal hyperplasia.

Congenital adrenal hyperplasia (CAH) due to steroid 21-hydroxylase (21-OH) deficiency (21-OHD) is an autosomal recessive disorder, in which CYP21A2 mutations or deletions result in underproduction of glucocorticoid and mineralocorticoid, and overproduction of androgens. Patients with CAH are treated with oral steroid supplementation, but optimal control of blood steroid levels remains difficult. Thus, new therapeutic approaches are still needed. Previously, adenovirus-mediated administration of human CYP21A2 to adrenal glands rescued the phenotype of a mouse model of 21-OHD. In this study, we examined whether transduction of murine Cyp21a1 in extra-adrenal tissues could rescue steroid metabolism in 21-OHD mice. We transduced primary fibroblasts obtained from 21-OHD mice with a retroviral vector containing Cyp21a1. In vitro assays demonstrated that Cyp21a1-expressing fibroblasts can uptake progesterone from the culture media, convert it to deoxycorticosterone (DOC), and subsequently release DOC back into the media. Autotransplantation of Cyp21a1-expressing fibroblasts into the subcutaneous tissues of the back resulted in a significant reduction in the serum progesterone/DOC ratio in four of six 21-OHD mice at 4 weeks after injection. We also directly injected an adeno-associated viral vector containing Cyp21a1 into the thigh muscles of 21-OHD mice. Serum progesterone/DOC ratios were markedly reduced in all four animals at 4 weeks after injection. These results indicate that extra-adrenal induction of Cyp21a1 ameliorates steroid metabolism in 21-OHD mice. This study suggests a novel therapeutic strategy for congenital adrenal hyperplasia, which warrants further investigations.

Continuing efforts to standardize measured serum growth hormone values in Japan.

Determination of serum growth hormone (GH) levels is mandatory for diagnosis of GH deficiency and excess. In the present study, we, the Study Committee for GH and Its Related Factors, The Foundation for Growth Science, Japan measured GH values in serum samples using all the commercially available kits in Japan. Significant discrepancies in the GH values were observed among the kits in spite of using the unified recombinant human GH-based standards. To deal with the discrepancies, we established a formula using a linear structural relationship model and were able to standardize the GH values. We propose to use the formula to diagnose GH deficiency and excess in Japan.

[Acute Hyperuricemia and Kidney Injury after Three Cycles of Dose-Dense Chemotherapy for Retroperitoneal Choriocarcinoma -- A Case Report].

CASE: A 32 year-old man was diagnosed with retroperitoneal choriocarcinoma with metastasis to the lungs and liver. One cycle of modified BEP regimen did not sufficiently decrease the hCG. Therefore, we chose the GETUG 13 protocol of dose dense chemotherapy. After 6 days of cisplatin administration(3 cycles), he was diagnosed with acute hyperuricemia and kidney injury. He was treated with intravenous hydration and rasburicase. The hyperuricemia improved after a few days.

A phase I study of farletuzumab, a humanized anti-folate receptor α monoclonal antibody, in patients with solid tumors.

Farletuzumab is a humanized monoclonal antibody against folate receptor α (FRA). The purpose of the study is to assess safety and tolerability, the pharmacokinetic (PK) profile, and preliminary antitumor effect. Patients with ovarian cancer (OC) or FRA-expressing solid tumors who are resistant to standard treatments were eligible for the study. After single-dose administration for PK assessment, farletuzumab was administered by intravenous injection, repeating every week until disease progression. Dose-limiting toxicities (DLTs) were defined as grade 4 hematological and grade 3/4 nonhematological toxicities. Dose escalation was planned in 4 cohorts (50, 100, 200, and 400 mg/m(2)). Fourteen patients with OC and two patients with gastric cancer (GC) received farletuzumab infusion. Neither DLTs nor grade 3/4 toxicities were reported in all cohorts. Major adverse events, including grade 1/2 infusion related reaction (15 patients, 93.8%), headache (seven patients, 43.8%), and nausea and decreased appetite (five patients each, 31.3%), were observed and medically managed. AUC and Cmax increased dose-dependently and linear PK profiles were observed. No tumor shrinkage was recorded, but long-term disease stabilization for 25 and 20 months was observed in one patient with clear cell OC (100 mg/m(2)) and one patient with GC (400 mg/m(2)), respectively. No cumulative toxicity occurred in any patient. Farletuzumab was well tolerated in Japanese patients with a similar PK profile as compared with the US population. Long-term disease stabilization was observed in a subpopulation of clear cell OC and GC; both of them were resistant and progressive after standard chemotherapies (ClinicalTrials.gov Identifier: NCT01049061).

Attitudes and practice patterns for maintaining relative dose intensity of chemotherapy in outpatient clinics: results of a Japanese web-based survey.

BACKGROUND: This analysis was undertaken to evaluate the practice patterns of Japanese physicians regarding curative-intent chemotherapy, especially in outpatient settings, and to define factors negatively affecting the maintenance of relative dose intensity (RDI). METHODS: We performed a web-based questionnaire survey of Japanese physicians involved in malignant lymphoma chemotherapy (Group ML) or in breast cancer chemotherapy (Group BC). The questionnaire inquired how they manage low-risk febrile neutropenia (FN) caused by initial chemotherapy for diffuse large B-cell lymphoma(DLBCL) or by adjuvant chemotherapy for breast cancer in an outpatient setting. RESULTS: Valid responses were obtained from 185 physicians in Group ML and 160 in Group BC. In Group ML, 76 % (n = 141) of the physicians were board-certified hematologists, while 82 % (n = 131) of the physicians in Group BC were board-certified surgeons. A significantly higher proportion of physicians in Group ML responded that "dose reduction is not required for the subsequent course of chemotherapy after the first episode of FN" than in Group BC (ML versus BC; 77 % versus 31 %; P < 0.001). Significantly higher proportions of physicians in Group ML were more likely to prophylactically administer antibiotics or granulocyte-colony stimulating factor (G-CSF; ML versus BC; antibiotics: 36 % versus 26 %, P = 0.049; G-CSF: 25 % versus 16 %, P = 0.047). Eighty six percent (n = 159) of Group ML and 70 % (n = 112) of Group BC responded that "emergency outpatient unit is open at all hours". CONCLUSIONS: Japanese physicians are more likely to administer reduced doses of chemotherapy to patients with breast cancer than to patients with malignant lymphoma. Supportive infrastructures should be improved to ensure the provision of adequate chemotherapy to all cancer patients.

Phase II trial of oral etoposide plus intravenous irinotecan in patients with platinum-resistant and taxane-pretreated ovarian cancer (JCOG0503).

OBJECTIVE: To assess the safety and efficacy of the combination of oral etoposide and intravenous irinotecan in patients with platinum-resistant and taxane-pretreated ovarian cancer. METHODS: Eligible patients (age, 20-75years; platinum-free interval, ≤28weeks) with an adequate organ function received oral etoposide (50mg/m(2) once a day) from day 1 to day 21 and intravenous irinotecan (70mg/m(2)) on days 1 and 15. The regimen was repeated every 28days up to 6cycles. The primary endpoint was the response rate (RR) with a threshold of 20%. The response was evaluated according to RECIST 1.0 and Gynecologic Cancer Intergroup CA-125 Response Definition, and toxicities were evaluated according to CTCAE version 3.0. This trial was registered at UMIN-CTR as UMIN000001837. RESULTS: Between April 1, 2009 and January 20, 2012, 61 patients were enrolled. Sixty patients were eligible. 1 CR and 12 PRs were confirmed; RR was 21.7% (p=0.42, the exact binomial test). PFS and OS were 4.1 and 11.9months, respectively. Major toxicities of ≥grade 3 were neutropenia (60%), anemia (36.7%), thrombocytopenia (11.7%), febrile neutropenia (18.3%), fatigue (13.3%), anorexia (11.7%), and nausea (11.7%). Three patients died from treatment related death (interstitial pneumonia, a pulmonary embolism, and DIC due to infection). Two of these patients were aged ≥65years. CONCLUSIONS: Oral etoposide and intravenous irinotecan had a moderate RR but did not meet the primary endpoint. Because of toxicity, we do not recommend this regimen outside of clinical trials. In particular, when considering this regimen for elderly patients, extreme caution is advised.

Dose-dense approaches to ovarian cancer treatment.

OPINION STATEMENT: Currently, paclitaxel and carboplatin are administered every 3 weeks as the standard agents for the first-line treatment of advanced ovarian cancer. The concept of "dose-dense therapy" is based on the Norton-Simon hypothesis that a shorter interval between the doses of cytotoxic agents is more effective in reducing tumor burden than dose escalation. The results of phase III clinical trials demonstrating the superiority of weekly paclitaxel administration, compared with a 3-week schedule in breast cancer in both the metastatic and adjuvant settings support the hypothesis. The Japanese Gynecologic Oncology Group reported the results from a phase III study comparing the conventional paclitaxel and carboplatin every 3-week administration vs dose-dense weekly administration of paclitaxel combined with the every 3-week administration of carboplatin in advanced epithelial ovarian cancer, Fallopian tube, or primary peritoneal cancer. The median progression-free survival (PFS), the primary endpoint of this study, was substantially improved in the dose-dense treatment group (28 vs 17.2 months, hazard ratio [HR]: 0.71, 95% CI: 0.58-0.88, P = 0.0015), and the overall survival (OS) at 3 years was also higher in the dose-dense treatment group (72 · 1%) than in the conventional treatment group (65.1%; HR 0.75, 0.57-0.98; P = 0 · 03). The long-term outcomes at a median follow-up period of 76.8 months were reported. The median PFS was significantly longer in the dose-dense regimen than in the conventional regimen (28.2 vs 17.5 months; hazard ratio [HR], 0.76; 95% CI, 0.62-0.91; P = 0.0037), and the median OS was 100.5 months (95% CI 65.2-∞) in the dose-dense regimen and 62.2 months (52.1-82.6) in the conventional regimen (HR, 0.79; 95% CI, 0.63-0.99; P = 0.039; log-rank test). Dose-dense treatment offers a potential new standard of care for first-line chemotherapy for patients with advanced epithelial ovarian cancer. Ongoing studies will clarify the best dose, schedule, and route of administration.

Two novel HSD3B2 missense mutations with diverse residual enzymatic activities for Δ5-steroids.

CONTEXT: Classical 3ß-hydroxysteroid dehydrogenase (3ß-HSD) deficiency (3ß-HSDD) is caused by loss-of-function mutations in the HSD3B2 gene encoding type II 3ß-HSD, which has a key role in steroid biosynthesis, converting Δ5-steroids to Δ4-steroids in adrenal glands and gonads. PATIENT: A patient (46, XX) was found to have elevated 17-hydroxyprogesterone (17-OHP) [203 nmol/l (normal range: 2·94 ± 0·9 nmol/l)] by newborn screening. Endocrinological examination revealed dramatically increased Δ5-steroids [e.g. 17-OH pregnenolone: 910 nmol/l (normal range: 12·6 ± 10·5 nmol/l)]. The patient had virilization of external genitalia with labial fusion, suggesting classical 3ß-HSDD. METHODS AND RESULTS: Consistent with the endocrinological data, the patient was a compound heterozygote for two novel missense mutations (p.Y190C and p.S218P) that were identified in HSD3B2. Both Y190 and S218 are conserved among mammals. The mutant proteins had severely impaired residual enzymatic activity in vitro, although both mutants retained higher activity for 17-OH pregnenolone than for the other Δ5-steroids. In a three-dimensional model of the enzyme based on the known structures of similar proteins, both mutations were located extremely close to the predicted substrate-binding pocket. This suggests that the mutations can cause a local conformational change in the substrate-binding pocket, leading to alterations of the binding affinities for Δ5-steroids. CONCLUSIONS: We identified two novel missense mutations of HSD3B2 that resulted in unbalanced residual enzymatic activities for Δ5-steroids. As a potential novel mechanism, we propose that the mutations, which differently affect the activity towards different substrates, the effects of these mutations provide novel insights into the pathophysiology of 3ß-HSDD.

Human glutathione S-transferase A (GSTA) family genes are regulated by steroidogenic factor 1 (SF-1) and are involved in steroidogenesis.

Steroidogenic factor 1 (SF-1) is a master regulator for steroidogenesis. In this study, we identified novel SF-1 target genes using a genome-wide promoter tiling array and a DNA microarray. SF-1 was found to regulate human glutathione S-transferase A (GSTA) family genes (hGSTA1-hGSTA4), a superfamily of detoxification enzymes clustered on chromosome 6p12. All hGSTA genes were up-regulated by transduction of SF-1 into human mesenchymal stem cells, while knockdown of endogenous SF-1 in H295R cells down-regulated all hGSTA genes. Chromatin immunoprecipitation assays, however, revealed that SF-1 bound directly to the promoters of hGSTA3 and weakly of hGSTA4. Chromosome conformation capture assays revealed that the coordinated expression of the genes was based on changes in higher-order chromatin structure triggered by SF-1, which enables the formation of long-range interactions, at least between hGSTA1 and hGSTA3 gene promoters. In steroidogenesis, dehydrogenation of the 3-hydroxy group and subsequent Δ(5)-Δ(4) isomerization are thought to be enzymatic properties of 3ß-hydroxysteroid dehydrogenase (3ß-HSD). Here, we demonstrated that, in steroidogenic cells, the hGSTA1 and hGSTA3 gene products catalyze Δ(5)-Δ(4) isomerization in a coordinated fashion with 3ß-HSD II to produce progesterone or Δ(4)-androstenedione from their Δ(5)-precursors. Thus, hGSTA1 and hGSTA3 gene products are new members of steroidogenesis working as Δ(5)-Δ(4) isomerases.

Satisfying the needs of Japanese cancer patients: a comparative study of detailed and standard informed consent documents.

BACKGROUND: Simplified informed consent forms have been successful in improving patient satisfaction and decreasing patient anxiety. However, unsolved problems remain about whether these documents improve comprehension and satisfaction of patients with standard literacy skills. PURPOSE: s To investigate whether a detailed consent form explaining the key elements of informed consent, in comparison to a standard consent form, would increase the comprehension and satisfaction of adult cancer patients. METHODS: Patients who were eligible for the National Surgical Adjuvant Study of Breast Cancer (protocol 01(N-SAS/BC-01)) were randomly selected to receive one of the following four versions: detailed document with graphics, detailed document without graphics, standard document with graphics, and standard document without graphics. The forms were written in plain language from the patients' point of view. A total of 85 patients were administered questionnaires via interview to assess levels of comprehension, satisfaction, and anxiety. RESULTS: Patients demonstrated a strong understanding of information regarding treatment and research. Patient comprehension did not differ significantly between the detailed document arms and the standard document arms. Patient satisfaction level increased according to the amount of information presented in the consent form; most patients preferred the detailed document with graphics. Anxiety and accrual rates in the parent study were not affected by informed consent procedures. LIMITATIONS: Findings were limited to adults who had standard literacy skills and may not be generalizable to a population with lower literacy. CONCLUSION: Informed consent can be a significant experience for a population with standard literacy skills, as long as the document is easily comprehensible. Such information should be provided in a format that corresponds with patient needs, education levels, and preferences.