Reversal of intrapulmonary arteriovenous shunting detected by two-dimensional contrast-enhanced echocardiography after liver transplantation

BACKGROUND: Intrapulmonary arteriovenous shunting (IPS), occasionally associated with advanced liver disease, may reverse after liver transplantation (LTx). Two-dimensional contrast-enhanced echocardiography, a convenient noninvasive study, has never been used to demonstrate disappearance of IPS after LTx. METHODS: For an 8-month-old girl undergoing living-related LTx, two-dimensional contrast-enhanced echocardiography was performed with the microbubble injection. The opacification of the microbubble in the left heart emerging within 3-6 beats after detection in the right heart was compared with that in the right heart. RESULTS: Microbubble opacification in the left heart was almost the same as that in the right heart (grade 3) shortly after LTx. However, the contrast in the left heart diminished (grade 1) as the respiratory condition improved and subsequently disappeared (grade 0). CONCLUSIONS: Two-dimensional contrast-enhanced echocardiography may be a feasible noninvasive method to evaluate the degree of IPS in the peritransplant period and observe disappearance of IPS after LTx.     

Reduced anxious behavior in mice lacking the CCK2 receptor gene.

Cholecystokinin 2 (CCK2) receptors have been implicated as mediators of anxiety in standard mouse models such as exploratory behavior both in black and white test boxes and in elevated plus-mazes. We investigated the role of the CCK2 receptor in anxiety by evaluating the behavior of mice lacking the gene for this receptor in these standard anxiety models (i.e., exploratory behavior in a black and white test box and exploratory behavior in an elevated plus-maze). In the black and white test box, mice lacking the CCK2 receptor gene showed significantly increased numbers of transitions between the boxes compared to control mice. In the elevated plus-maze, mice lacking the CCK2 receptor gene displayed significantly more head dips than control mice. These results suggest that mice lacking the CCK2 receptor gene are less anxious than normal mice.     

Safety Profile of Ixazomib in Patients with Relapsed/Refractory Multiple Myeloma in Japan: An All-case Post-marketing Surveillance

Objective To evaluate the safety profile of ixazomib combined with lenalidomide and dexamethasone in patients with relapsed/refractory multiple myeloma (RRMM) in clinical practice in Japan through an all-case post-marketing surveillance. Methods This was a nationwide non-interventional observational study conducted in Japan. The study included all patients who received ixazomib from May 24 to September 24, 2017. Ixazomib was administered to RRMM patients according to the Japanese package insert. All enrolled patients were observed until the completion of the sixth treatment cycle or until ixazomib discontinuation. The patient treatment course, including adverse events (AEs), was reported. Results The safety analysis set included 741 patients; the median age was 71 (range 35-92) years old, and the median number of prior treatment lines was 3 (range 1-30). Adverse drug reactions (ADRs) occurred in 572 (77.2%) patients, most commonly being thrombocytopenia (49.9%), diarrhea (29.2%), and nausea (12.4%). Serious ADRs occurred in 193 (26.0%) patients, most commonly being thrombocytopenia (9.9%) and diarrhea (5.9%). Thrombocytopenia, severe gastrointestinal disorders, infections, skin disorders, and peripheral neuropathy were prespecified as ADRs of clinical importance; the frequency of these ADRs (grade ≥3) were 28.5%, 9.4%, 7.4%, 2.2%, and 1.3%, respectively. Treatment discontinuation was most common with thrombocytopenia and severe gastrointestinal disorders (49 and 43 patients, respectively). Eleven patients died due to ADRs (16 events). Conclusion These results suggest that ixazomib has a tolerable safety profile in clinical practice in Japan. However, close AE management for thrombocytopenia and gastrointestinal disorders should be considered.     

Radiotherapy plus cetuximab for locally advanced squamous cell head and neck cancer in patients with cisplatin-ineligible renal dysfunction: A retrospective study

Clinical trials have not fully demonstrated the efficacy and safety of radiotherapy plus cetuximab for locally advanced squamous cell head and neck cancer (LA-SCCHN) in patients with cisplatin-ineligible renal dysfunction. Patients who received radiotherapy plus cetuximab for LA-SCCHN at Chiba University Hospital (Chiba, Japan) between July 2013 and October 2018 were retrospectively reviewed. Background characteristics and locoregional control and overall survival rates were compared between patients with and without renal dysfunction. Survival was examined using Kaplan-Meier analysis and an adjusted Cox proportional hazards model. Kaplan-Meier analysis demonstrated that overall survival was shorter in patients with creatinine clearance of <45 ml/min (P=0.041; log-rank test). However, there was no difference in the locoregional control rate (P=0.477; log-rank test). Adjusted Cox analysis revealed that the risk of death was increased by 2.52-fold (hazard ratio, 2.52; 95% confidence interval, 1.01-6.30; P=0.048) if creatinine clearance was <45 ml/min. Moderate to severe renal dysfunction did not affect the locoregional control rate in patients with LA-SCCHN treated with radiotherapy plus cetuximab but was an adverse prognostic factor.     

Combining the Tumor Contact Length and Apparent Diffusion Coefficient Better Predicts Extraprostatic Extension of Prostate Cancer with Capsular Abutment: A 3 Tesla MR Imaging Study

Purpose: To assess the diagnostic performance of the tumor contact length (TCL) and apparent diffusion coefficient (ADC) for predicting extraprostatic extension (EPE) of prostate cancer with capsular abutment (CA).Methods: Ninety-three patients with biopsy-proven prostate cancer underwent 3-Tesla MRI, including diffusion-weighted imaging (b value = 0, 2000 s/mm²) and radical prostatectomy. Two experienced radiologists, blinded to the clinicopathological data, retrospectively assessed the presence of CA on T2-weighted imaging (T2WI). TCL on T2WI and ADC values were measured on detecting CA in prostate cancer. We used the receiver operating characteristic curves to assess the diagnostic performance of TCL and ADC values for predicting EPE.Results: CA was present in 58 prostate cancers among 93 patients. The cut-off value for TCL was 6.9 mm, which yielded an area under the curve (AUC) of 0.75. This corresponded to a sensitivity, specificity, and accuracy of 84.2%, 61.5%, and 69.0%, respectively. The cut-off value for ADC was 0.63 × 10^–3 mm²/s, which yielded an AUC of 0.76. This, in turn, corresponded to a sensitivity, specificity, and accuracy of 84.2%, 59.0%, and 67.2%, respectively. The combined cut-off value of TCL and ADC yielded an AUC of 0.82. The specificity (84.6%) and accuracy (81.0%) of the combined value were superior to their individual values (P < 0.05).Conclusion: A combination of TCL and ADC values provided high specificity and accuracy for detecting EPE of prostatic cancer with CA.     

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.     

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.     

Efficacy and safety of once‐weekly semaglutide in Japanese individuals with type 2 diabetes by baseline age and body mass index

Aims/IntroductionMany East Asians with type 2 diabetes are elderly and have a low body mass index (BMI), especially in ''super‐aged'' populations, such as Japan. This post‐hoc analysis assessed once‐weekly semaglutide efficacy and safety in Japanese individuals with type 2 diabetes across baseline age and BMI subgroups.Materials and MethodsData were derived from the Semaglutide Unabated Sustainability in Treatment of Type 2 Diabetes (SUSTAIN) Japan monotherapy and SUSTAIN Japan oral antidiabetes drug (OAD) combination trials comparing once‐weekly semaglutide with sitagliptin or OADs, respectively. Participants were grouped by baseline age (<65 and ≥65 years) and/or BMI (<25 and ≥25 kg/m²). Reductions from baseline in glycosylated hemoglobin and bodyweight (efficacy), and adverse events (safety) were assessed.ResultsIn this analysis, participants from the SUSTAIN Japan monotherapy trial (n = 308; n per subgroup; range, 8–73) and SUSTAIN Japan OAD combination trial (n = 601; n per subgroup; range, 20–168) were included. Reductions in glycosylated hemoglobin and bodyweight were numerically greater with semaglutide versus comparators across all age and BMI subgroups. Reductions from baseline in glycosylated hemoglobin ranged from –1.7 to –2.1 with semaglutide 0.5 mg, –1.8 to –2.4 with semaglutide 1.0 mg and –0.6 to –1.0 with comparators. Corresponding ranges for bodyweight (kg) were –1.0 to –2.5, –2.4 to –4.3 and 1.0 to –1.0 kg, respectively. The safety profile of semaglutide was broadly similar across BMI and age subgroups.ConclusionsIn this post‐hoc analysis with modest subgroup numbers, once‐weekly semaglutide appeared consistently more efficacious versus comparators across age and BMI subgroups in Japanese patients, with a similar safety profile.