Interstitial lung disease with prolonged fever that occurred during long-term administration of olaparib in a 74-year-old ovarian cancer patient: Radiological features and considerations for preventing delayed diagnosis.

A 74-year-old woman, who had been receiving olaparib for the treatment of ovarian cancer for more than a year, visited the emergency department complaining of a fever that had lasted for 1 month. She had been taking antipyretics and antibiotics for her fever, but without any effect. Although she had no symptoms other than fever, she had stopped taking olaparib for 1 week before her visit because she had developed anemia caused by myelosuppression from olaparib. After discontinuing olaparib, her maximum body temperature decreased. On admission, chest X-ray revealed no abnormalities, but chest CT showed diffuse ground-glass opacities. Chest CT taken 5 days later showed partial improvement; therefore, we diagnosed her with interstitial lung disease (ILD) associated with olaparib. After short-term steroid treatment, the ground-glass opacities disappeared, and the patient became afebrile. The CT scan taken for tumor evaluation 2 days before the onset of fever showed a few centrilobular nodular opacities and small patchy ground-glass opacities. These findings could indicate early lesions of ILD, but they seemed inconspicuous and nonspecific, and it might have been difficult to diagnose ILD then. To date, few cases of ILD associated with olaparib have been reported. However, based on previous reports, fever is often seen, and CT findings mainly comprise diffuse ground-glass opacities, and in some cases, centrilobular nodular shadows. Thus, in conjunction with the findings of the present case, these characteristics may be representative of olaparib-induced ILD.

Single-Exon Deletions of ZNRF3 Exon 2 Cause Congenital Adrenal Hypoplasia.

CONTEXT: Primary adrenal insufficiency (PAI) is a life-threatening condition characterized by the inability of the adrenal cortex to produce sufficient steroid hormones. E3 ubiquitin protein ligase zinc and ring finger 3 (ZNRF3) is a negative regulator of Wnt/ß-catenin signaling. R-spondin 1 (RSPO1) enhances Wnt/ß-catenin signaling via binding and removal of ZNRF3 from the cell surface. OBJECTIVE: This work aimed to explore a novel genetic form of PAI. METHODS: We analyzed 9 patients with childhood-onset PAI of biochemically and genetically unknown etiology using array comparative genomic hybridization. To examine the functionality of the identified single-exon deletions of ZNRF3 exon 2, we performed three-dimensional (3D) structure modeling and in vitro functional studies. RESULTS: We identified various-sized single-exon deletions encompassing ZNRF3 exon 2 in 3 patients who showed neonatal-onset adrenal hypoplasia with glucocorticoid and mineralocorticoid deficiencies. Reverse-transcriptase polymerase chain reaction (RT-PCR) analysis showed that the 3 distinct single-exon deletions were commonly transcribed into a 126-nucleotide deleted mRNA and translated into 42-amino acid deleted protein (ΔEx2-ZNRF3). Based on 3D structure modeling, we predicted that interaction between ZNRF3 and RSPO1 would be disturbed in ΔEx2-ZNRF3, suggesting loss of RSPO1-dependent activation of Wnt/ß-catenin signaling. Cell-based functional assays with the TCF-LEF reporter showed that RSPO1-dependent activation of Wnt/ß-catenin signaling was attenuated in cells expressing ΔEx2-ZNRF3 as compared with those expressing wild-type ZNRF3. CONCLUSION: We provided genetic evidence linking deletions encompassing ZNRF3 exon 2 and congenital adrenal hypoplasia, which might be related to constitutive inactivation of Wnt/ß-catenin signaling by ΔEx2-ZNRF3.

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.

Novel non-stop variant of the NR0B1 gene in two siblings with adrenal hypoplasia congenita.

OBJECTIVES: Mutations in the dosage-sensitive sex reversal-AHC critical region on the X chromosome, gene 1 (DAX-1, officially NR0B1), cause X-linked adrenal hypoplasia congenita (AHC) and hypogonadotropic hypogonadism (HHG). Salt-losing adrenal insufficiency usually occurs during the neonatal period or early childhood. We report a novel non-stop variant of NR0B1 in two siblings and their unusual clinical course. CASE PRESENTATION: The proband was a boy who presented with an unusual form of AHC with neonatal onset of growth failure and mild salt loss, but without cutaneous pigmentation or plasma ACTH elevation. His 4-year-old elder brother had been growing healthily, but carried an AHC diagnosis. A non-stop variant of NR0B1 (p.*471K) was demonstrated in the patients and their mother. CONCLUSIONS: We identified a novel non-stop variant of NR0B1 in two siblings. Mild salt loss associated with hyperkalemia is a crucial diagnostic clue for AHC, even without apparent symptoms of glucocorticoid deficiency.

Adeno-Associated Virus-Mediated Gene Therapy for Patients' Fibroblasts, Induced Pluripotent Stem Cells, and a Mouse Model of Congenital Adrenal Hyperplasia.

Congenital adrenal hyperplasia (CAH) is an autosomal recessive disorder caused by steroidogenic enzymes containing monogenetic defects. Most steroidogenic enzymes are cytochrome P450 groups that can be categorized as microsomal P450s, including 21-hydroxylase and 17α-hydroxylase/17,20 lyase, and mitochondrial P450s, including 11ß-hydroxylase. It has been shown that ectopic administration of Cyp21a1 ameliorates steroid metabolism in 21-hydroxylase-deficient mice. However, the effectiveness of this approach for mitochondrial P450 has not yet been evaluated. In this study, primary fibroblasts from patients with 21-hydroxylase deficiency (CYP21A2D) (n = 4), 17α-hydroxylase/17,20 lyase deficiency (CYP17A1D) (n = 1), and 11ß-hydroxylase deficiency (CYP11B1D) (n = 1) were infected with adeno-associated virus type 2 (AAV2) vectors. Steroidogenic enzymatic activity was not detected in the AAV2-infected CYP11B1D fibroblasts. Induced pluripotent stem cells (iPSCs) of CYP11B1D were established and differentiated into adrenocortical cells by induction of the NR5A1 gene. Adrenocortical cells established from iPSCs of CYP11B1D (CYP11B1D-iPSCs) were infected with an AAV type 9 (AAV9) vector containing CYP11B1 and exhibited 11ß-hydroxylase activity. For an in vivo evaluation, we knocked out Cyp11b1 in mice by using the CRISPR/Cas9 method. Direct injection of Cyp11b1-containing AAV9 vectors into the adrenal gland of Cyp11b1-deficient mice significantly reduced serum 11-deoxycorticosterone/corticosterone ratios at 4 weeks after injection and the effect was prolonged for up to 12 months. This study indicated that CYP11B1D could be ameliorated by gene induction in the adrenal glands, which suggests that a defective-enzyme-dependent therapeutic strategy for CAH would be required. Defects in microsomal P450, including CYP21A2D and CYP17A1D, can be treated with extra-adrenal gene induction. However, defects in mitochondrial P450, as represented by CYP11B1D, may require adrenal gene induction.

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.

Nivolumab Versus Gemcitabine or Pegylated Liposomal Doxorubicin for Patients With Platinum-Resistant Ovarian Cancer: Open-Label, Randomized Trial in Japan (NINJA).

PURPOSE: This phase III, multicenter, randomized, open-label study investigated the efficacy and safety of nivolumab versus chemotherapy (gemcitabine [GEM] or pegylated liposomal doxorubicin [PLD]) in patients with platinum-resistant ovarian cancer. MATERIALS AND METHODS: Eligible patients had platinum-resistant epithelial ovarian cancer, received ≤ 1 regimen after diagnosis of resistance, and had an Eastern Cooperative Oncology Group performance score of ≤ 1. Patients were randomly assigned 1:1 to nivolumab (240 mg once every 2 weeks [as one cycle]) or chemotherapy (GEM 1000 mg/m2 for 30 minutes [once on days 1, 8, and 15] followed by a week's rest [as one cycle], or PLD 50 mg/m2 once every 4 weeks [as one cycle]). The primary outcome was overall survival (OS). Secondary outcomes included progression-free survival (PFS), overall response rate, duration of response, and safety. RESULTS: Patients (n = 316) were randomly assigned to nivolumab (n = 157) or GEM or PLD (n = 159) between October 2015 and December 2017. Median OS was 10.1 (95% CI, 8.3 to 14.1) and 12.1 (95% CI, 9.3 to 15.3) months with nivolumab and GEM or PLD, respectively (hazard ratio, 1.0; 95% CI, 0.8 to 1.3; P = .808). Median PFS was 2.0 (95% CI, 1.9 to 2.2) and 3.8 (95% CI, 3.6 to 4.2) months with nivolumab and GEM or PLD, respectively (hazard ratio, 1.5; 95% CI, 1.2 to 1.9; P = .002). There was no statistical difference in overall response rate between groups (7.6% v 13.2%; odds ratio, 0.6; 95% CI, 0.2 to 1.3; P = .191). Median duration of response was numerically longer with nivolumab than GEM or PLD (18.7 v 7.4 months). Fewer treatment-related adverse events were observed with nivolumab versus GEM or PLD (61.5% v 98.1%), with no additional or new safety risks. CONCLUSION: Although well-tolerated, nivolumab did not improve OS and showed worse PFS compared with GEM or PLD in patients with platinum-resistant ovarian cancer.

[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.

Two girls with a neonatal screening-negative 21-hydroxylase deficiency requiring treatment with hydrocortisone for virilization in late childhood.

Herein, we report two girls with a neonatal screening (NS)-negative 21-hydroxylase deficiency (21-OHD) requiring treatment with hydrocortisone due to virilization that developed in late childhood. Patient 1 was born prematurely on the 30th gestational week with normal external genitalia at birth. She passed the NS for 21-OHD. At 6 yr of age, she was referred to a hospital for evaluation of premature pubarche and clitoromegaly. Her diagnosis was central precocious puberty, and GnRH agonist was initiated. However, her symptoms did not improve despite treatment for over 4 years. She was then referred to our hospital where she was diagnosed with 21-OHD. Although she was started on hydrocortisone therapy, her adult height reached only 140 cm (-3.4 SD). Patient 2 was delivered at 37 weeks of gestation and passed the NS for 21-OHD. She was referred to a hospital because of premature pubarche at the age of 6 yr. She was diagnosed with 21-OHD, and hydrocortisone replacement therapy was initiated. Her present height at 13 yr of age is 148 cm (-1.3 SD). These cases reminded us that the possibility of 21-OHD should be considered when patients show premature pubarche or precocious puberty, even if they passed the NS test for 21-OHD.

Prognostic Role of Tumor-Infiltrating Lymphocytes and Tumor Budding in Early Oral Tongue Carcinoma.

OBJECTIVES/HYPOTHESIS: Occult lymph metastasis is an important prognosticator for the treatment of early oral tongue squamous cell carcinoma (SCC). The objective of this study was to evaluate the prognostic significance of tumor-infiltrating lymphocytes (TILs) in early oral tongue SCC. The combination of the TIL subtype and intermediate- or high-grade budding scores was investigated as a prognostic marker for occult neck metastases. STUDY DESIGN: Retrospective study. METHODS: Specimens from 62 patients with early oral tongue SCC treated with only primary surgery were analyzed by immunohistochemistry for CD4+, CD8+, FoxP3+, and CD45RO+ T cells and CD163+ macrophages. The highest number of each TIL subtype was counted in two areas of parenchyma and stroma in the tumor (Tumor) and peripheral stroma of the invasion margin. RESULTS: Based on multivariate analysis, a high density of Tumor CD163+ macrophages served as the poorest prognostic factor for regional control (RC) and disease-free survival (DFS). Patients with both a high density of Tumor CD163+ macrophages and an intermediate- or a high-grade budding score had a poor prognosis for RC according to the log-rank test. CONCLUSIONS: In summary, each TIL subtype may use different mechanisms during early and advanced stages of oral tongue SCC. A high density of Tumor CD163+ macrophages was determined to be a risk factor for RC and DFS as well as an additional stratification factor for RC in patients with intermediate- or high-grade budding scores. Therefore, identifying TIL subtypes in daily clinical practice can help determine a more successful and individualized therapeutic approach for early oral tongue SCC. LEVEL OF EVIDENCE: Step 4 (Level 4) Laryngoscope, 131:2512-2518, 2021.

Japanese Dermatological Association Guidelines: Outlines of Guidelines for Cutaneous Squamous Cell Carcinoma 2020.

In consideration of the development of treatment options for squamous cell carcinoma (SCC), the Japanese Skin Cancer Society issued the first guidelines of SCC in 2007 and revised them in 2015. Here, we report the English version of the 2020 edition of the Japanese SCC guidelines. The first half of this article is an overview of SCC including actinic keratosis and Bowen's disease, and the second half discusses three clinical questions: (i) treatment of actinic keratosis; (ii) determination of the resection margin of the primary lesion; and (iii) treatment of radically incurable cases, as contemporary problems encountered in treating SCC. In these evaluations, all processes were implemented according to the Grading of Recommendations, Assessment, Development, Evaluation system. Also, items of recommendation concerning each clinical question were determined by a multidisciplinary expert panel consisting of dermatologists, plastic/reconstructive surgeons, radiologists, and oncologists through a comprehensive literature search and systematic reviews.

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.

Japanese Dermatological Association Guidelines: outlines of guidelines for cutaneous squamous cell carcinoma 2020

In consideration of the development of treatment options for squamous cell carcinoma (SCC), the Japanese Skin Cancer Society issued the first guidelines of SCC in 2007 and revised them in 2015. Here, we report the English version of the 2020 edition of the Japanese SCC guidelines. The first half of this article is an overview of SCC including actinic keratosis and Bowen's disease, and the second half discusses three clinical questions: (i) treatment of actinic keratosis; (ii) determination of the resection margin of the primary lesion; and (iii) treatment of radically incurable cases, as contemporary problems encountered in treating SCC. In these evaluations, all processes were implemented according to the Grading of Recommendations, Assessment, Development, Evaluation system. Also, items of recommendation concerning each clinical question were determined by a multidisciplinary expert panel consisting of dermatologists, plastic/reconstructive surgeons, radiologists, and oncologists through a comprehensive literature search and systematic reviews.

Clinical Features of 57 Patients with Lipoid Congenital Adrenal Hyperplasia: Criteria for Nonclassic Form Revisited.

CONTEXT: Lipoid congenital adrenal hyperplasia (LCAH) is caused by mutations in STAR. Classic (CLCAH) and nonclassic (NCLCAH) forms were reported as total and partial deficiencies, respectively, of adrenal and gonadal steroid hormones. The rarity of LCAH has precluded large-scale epidemiological and clinical investigations. OBJECTIVE: To determine the epidemiological and clinical characteristics of 2 forms of LCAH. DESIGN: A multicenter cross-sectional cohort study in Japan on December 1, 2017. PARTICIPANTS: Fifty-seven patients with LCAH (median age, 23.7 years; range, 0.0-47.5 years). MAIN OUTCOME MEASURES: Patient demographics, STAR genotype, Quigley grade, endocrinological and imaging data, treatment, and prognosis. RESULTS: Fifty-three and 4 patients fulfilled definite and probable diagnostic criteria for LCAH, respectively. When NCLCAH was defined as either Quigley grade 1 in XY karyotype, no episode of salt losing or requirement of fludrocortisone, or onset of primary adrenal insufficiency (PAI) at 1 year or older, patients were divided into groups of 43 patients with CLCAH (75.4%), 11 with NCLCAH (19.3%), and 3 with unclassified LCAH (5.3%). All of the patients with CLCAH and 7/11 NCLCAH (63.6%) were treated with fludrocortisone. CLCAH was diagnosed at a significantly younger age than NCLCAH (median, 0.0 vs 4.0 years). STAR-Arg272Cys or -Met225Thr was identified only in NCLCAH (8/11, 72.7%). CONCLUSIONS: We demonstrated the relative proportions and clinical and molecular characteristics of NCLCAH and CLCAH in Japan. These criteria for NCLCAH correspond to all previously published cases and our cases whose masculinization of the external genitalia, ability of mineralocorticoid production, and onset of PAI were described.

Pubertal and Adult Testicular Functions in Nonclassic Lipoid Congenital Adrenal Hyperplasia: A Case Series and Review.

Lipoid congenital adrenal hyperplasia (LCAH) is caused by mutations in STAR and characterized by a defect in steroidogenesis and lipid droplet accumulation in steroidogenic cells. Patients with 46,XY and classic LCAH will typically present with female-type external genitalia. However, those with nonclassic LCAH will have masculinized external genitalia. The rarity of the nonclassic form has precluded the clarification of the long-term outcomes of testicular function in nonclassic LCAH. We report the cases of three adult males with nonclassic LCAH in whom primary adrenal insufficiency had been diagnosed at 5 days, 4 years, and 5 years of age. All exhibited complete male external genitalia and had completed pubertal development without androgen replacement. The endocrinological data showed preserved gonadal function in patients 1 and 2 and hypergonadotropic hypogonadism in patient 3. Semen analyses showed normozoospermia in patient 1 and mild oligozoospermia in patient 2. Electron microscopic analysis of a testicular biopsy specimen from patient 2 at 13 years of age revealed prominent lipid accumulation in the cytosol of Leydig cells. Patients 1 and 2 shared the same compound heterozygous mutations in STAR (p.Glu258* and p.Arg272Cys). Patient 3 possessed a heterozygous dominant-negative mutation in STAR (p.Gly22_Leu59del). A functional assay of a variant STAR-Arg272Cys determined the residual activity as 35% of the wild-type STAR. The results from the present case series and a review of four previously reported adult cases indicate that testosterone synthesis can be preserved in most males with nonclassic LCAH to complete pubertal development and induce germ cell maturation despite lipid accumulation in the Leydig cells.

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.

Reliability of Cancer Treatment Information on the Internet: Observational Study.

BACKGROUND: Finding the correct medical information in a flood of information from the internet is a significant issue for patients with cancer. OBJECTIVE: We investigated the reliability of the information on cancer treatment methods available on the internet based on an evaluation by medical oncologists, medical students, and cancer survivors. METHODS: Using Google and Yahoo as the search engines, we carried out the information search using 2 keywords, "cancer treatment" and "cancer cure," and the top 20 information sites were identified. A similar search was conducted on 5 types of cancer. The reliability of the information presented was rated on a 3-level scale (A, B, or C). Level A referred to reliable sites (providing information complying with the clinical practice guidelines for various types of cancer), Level B included sites not falling under either Level A or Level C, and Level C comprised dangerous or harmful sites (providing information on treatment not approved by the regulatory authority in Japan and bombastic advertisements without any relevant clinical evidence). The evaluation was conducted by medical oncologists, medical students, and cancer survivors. The consistency of the information reliability level rating between the medical students or cancer survivors with that of the medical oncologists was assessed by using the kappa value. RESULTS: A total of 247 sites were evaluated for reliability. The ratings provided by the medical students' group were as follows: Level A, 12.1% (30/247); Level B, 56.3% (139/247); and Level C, 31.6% (78/247). The ratings provided by the cancer survivors' group were as follows: Level A, 16.8% (41/244); Level B, 44.7% (109/244); and Level C, 38.5% (94/244). The ratings provided by the oncologists' group were as follows: Level A, 10.1% (25/247); Level B, 51.4% (127/247); and Level C, 38.5% (95/247). The intergroup rating consistency between the medical students' group and oncologists' group was 87.4% (216/247, kappa=0.77) and that between the cancer survivors' group and oncologists' group was 76.2% (186/244, kappa=0.61). CONCLUSIONS: Of the investigated sites providing information on cancer treatment on the internet, the percentage of sites that seemed to provide harmful information was much higher than that of sites providing reliable information. The reliability level rating was highly consistent between the medical students' group and the medical oncologists' group and also between the cancer survivors' group and the medical oncologists' group.

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.

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.