Phase IIb study of pembrolizumab combined with S‐1 + oxaliplatin or S‐1 + cisplatin as first‐line chemotherapy for gastric cancer

The KEYNOTE‐659 study evaluated the efficacy and safety of first‐line pembrolizumab plus S‐1 and oxaliplatin (SOX) (cohort 1) or S‐1 and cisplatin (SP) (cohort 2) for advanced gastric/gastroesophageal junction (G/GEJ) cancer in Japan. Herein, we update the results of cohort 1 and describe the results of cohort 2. This open‐label phase IIb study enrolled patients with advanced programmed death‐ligand 1 (PD‐L1)‐positive (combined positive score ≥ 1) human epidermal growth factor receptor 2 (HER2)‐negative G/GEJ adenocarcinoma. The primary end‐point was the objective response rate (ORR). Other end‐points were duration of response (DOR), disease control rate (DCR), progression‐free survival (PFS), overall survival (OS), and safety. One hundred patients were enrolled. In cohorts 1 and 2, median follow‐up time was 16.9 and 17.1 months; ORR (central review), 72.2% and 80.4%; DOR, 10.6 and 9.5 months; DCR (central review), 96.3% and 97.8%; median PFS (central review), 9.4 and 8.3 months; and median OS, 16.9 and 17.1 months, respectively. Treatment‐related adverse events (TRAEs) occurred in all patients, including peripheral sensory neuropathy (94.4%, cohort 1), decreased neutrophil count (82.6%, cohort 2), nausea (59.3% and 60.9% in cohorts 1 and 2), and decreased appetite (61.1% and 60.9% in cohorts 1 and 2). Grade 3 or higher TRAEs were reported by 59.3% (cohort 1) and 78.3% (cohort 2), including decreased platelet count (14.8%, cohort 1) and decreased neutrophil count (52.2%, cohort 2). Pembrolizumab in combination with SOX or SP showed favorable efficacy and safety in patients with PD‐L1‐positive, HER2‐negative G/GEJ adenocarcinoma.     

Preclinical and first‐in‐human phase I studies of KW‐2450, an oral tyrosine kinase inhibitor with insulin‐like growth factor receptor‐1/insulin receptor selectivity

Numerous solid tumors overexpress or have excessively activated insulin‐like growth factor receptor‐1 (IGF‐1R). We summarize preclinical studies and the first‐in‐human study of KW‐2450, an oral tyrosine kinase inhibitor with IGF‐1R and insulin receptor (IR) inhibitory activity. Preclinical activity of KW‐2450 was evaluated in various in vitro and in vivo models. It was then evaluated in a phase I clinical trial in 13 patients with advanced solid tumors (NCT00921336). In vitro, KW‐2450 inhibited human IGF‐1R and IR kinases (IC₅₀ 7.39 and 5.64 nmol/L, respectively) and the growth of various human malignant cell lines. KW‐2450 40 mg/kg showed modest growth inhibitory activity and inhibited IGF‐1‐induced signal transduction in the murine HT‐29/GFP colon carcinoma xenograft model. The maximum tolerated dose of KW‐2450 was 37.5 mg once daily continuously; dose‐limiting toxicity occurred in two of six patients at 50 mg/day (both grade 3 hyperglycemia) and in one of seven patients at 37.5 mg/day (grade 3 rash). Four of 10 evaluable patients showed stable disease. Single‐agent KW‐2450 was associated with modest antitumor activity in heavily pretreated patients with solid tumors and is being further investigated in combination therapy with lapatinib/letrozole in patients with human epidermal growth factor receptor 2‐postive metastatic breast cancer.     

Acute promyelocytic leukemia: an unusual cause showing prolonged disseminated intravascular coagulation after placental abruption

Background Disseminated intravascular coagulation (DIC) caused by placental abruption usually improves rapidly after prompt delivery and adequate anti-DIC treatment. Case A 30-year-old nulliparous woman suffered from placental abruption at the 25th week of pregnancy, and emergent cesarean section was done immediately. She exhibited DIC, which continued even after termination of the pregnancy and anti-DIC treatment. She also showed neutropenia. We closely observed her, and at the 58th day postpartum, blast cells appeared in the peripheral blood and she was diagnosed with acute promyelocytic leukemia (APL). Induction chemotherapy was done successfully. The close observation after delivery enabled us to make the prompt diagnosis/treatment, leading to the complete remission. Conclusion APL should be added to the list of differential diagnosis when DIC persists even after prompt delivery and appropriate anti-DIC treatment after placental abruption.     

Femur fracture during abdominal breech delivery

BACKGROUND: While vaginal breech delivery, although rare, can cause femur fracture, abdominal breech delivery is not expected to cause it. CASE: A 2,490-g female infant was delivered at term by elective cesarean section for breech presentation. She sustained a fracture of the femur shaft. A simple splinting led to a complete healing of the fracture without sequelae. CONCLUSION: Although abdominal breech delivery reduces the risk of birth trauma, we must be aware that femur fracture can occur regardless of the mode of delivery.     

A case of pulmonary type of ovarian small cell carcinoma

Small cell carcinoma is a rare form of ovarian cancer with a poor prognosis. It is divided into two types, the hypercalcemic and the pulmonary type, of which the latter is extremely rare. A 49-year-old woman presented with an acute abdomen and was suspected to have torsion of a left ovarian tumor, which was followed up with an emergency operation. Postoperative pathological examination gave a diagnosis of the pulmonary type of ovarian small cell carcinoma. Six courses of paclitaxel and carboplatin therapy were given as adjuvant chemotherapy. The patient has survived for 36 months without recurrence. Here we present an extremely rare patient with the pulmonary type of ovarian small cell carcinoma.     

Chronic Pulmonary Disease Caused by Tsukamurella toyonakaense

Unidentified Mycobacterium species are sometimes detected in respiratory specimens. We identified a novel Tsukamurella species (Tsukamurella sp. TY48, RIMD 2001001, CIP 111916^T), Tsukamurella toyonakaense, from a patient given a misdiagnosis of nontuberculous mycobacterial pulmonary disease caused by unidentified mycobacteria. Genomic identification of this Tsukamurella species helped clarify its clinical characteristics and epidemiology.     

Stages of a Transtheoretical Model as Predictors of the Decline in Estimated Glomerular Filtration Rate: A Retrospective Cohort Study

BackgroundThe transtheoretical model (TTM) is composed of the multiple stages according to patient’s consciousness and is believed to lead people to realize the importance of healthier behaviors. We examined the association of TTM stages with the decline of estimated glomerular filtration rate (eGFR).MethodsWe used the annual health checkup data and health insurance claims data of the Japan Health Insurance Association in Kyoto Prefecture between April 2012 and March 2016. TTM stages of change obtained from questionnaires at the first health checkup and categorized into six groups. The primary outcome was defined as a more than 30% decline in eGFR from the first health checkup. We fitted multivariable Cox proportional-hazards model for time-to-event analyses adjusting for age, sex, eGFR, body mass index, blood pressure, blood sugar, dyslipidemia, uric acid, urinary protein, and existence of kidney diseases at first health checkup.ResultsWe analyzed 239,755 employees and the mean follow-up was 2.9 (standard deviation, 1.2) years. As compared with the stage 1 group, the risk of eGFR decline was significantly low in the stage 3 group (hazard ratio [HR] 0.77; 95% confidence interval [CI], 0.65–0.91); stage 4 group (HR 0.80; 95% CI, 0.65–0.98); and stage 5 group (HR 0.79; 95% CI, 0.66–0.95).ConclusionCompared with the precontemplation stage (stage 1), the preparation, action and maintenance stages (stages 3, 4, and 5), were associated with a lower risk of eGFR decline.Key words: transtheoretical model, chronic kidney disease, kidney injury, stage of change, more than 30% decline in estimated glomerular filtration rate     

TP53 variants in p53 signatures and the clonality of STICs in RRSO samples

ObjectivePrecursor lesions may be identified in fallopian tube tissue after risk-reducing salpingo-oophorectomy (RRSO) in patients with pathogenic variants of BRCA1/2. Serous tubal intraepithelial carcinoma (STIC) is considered a precursor of high-grade serous carcinoma, whereas the significance of the p53 signature remains unclear. In this study, we investigated the relationship between the p53 signature and the risk of ovarian cancer.MethodsWe analyzed the clinicopathological findings and conducted DNA sequencing for TP53 variants of p53 signatures and STIC lesions isolated using laser capture microdissection in 13 patients with pathogenic variants of BRCA1/2 who underwent RRSO and 17 control patients with the benign gynecologic disease.Results TP53 pathogenic variants were detected significantly higher in RRSO group than control (p<0.001). No difference in the frequency of p53 signatures were observed between groups (53.8% vs 29.4%; p=0.17). TP53 sequencing and next-generation sequencing analysis in a patient with STIC and occult cancer revealed 2 TP53 mutations causing different p53 staining for STICs and another TP53 mutation shared between STIC and occult cancer.ConclusionThe sequence analysis for TP53 revealed 2 types of p53 signatures, one with a risk of progression to STIC and ovarian cancer with pathological variants in TP53 and the other with a low risk of progression without pathological variants in TP53 as seen in control.