Association Between the Occurrence and Spectrum of Immune-Related Adverse Events and Efficacy of Pembrolizumab in Asian Patients With Advanced Urothelial Cancer: Multicenter Retrospective Analyses and Systematic Literature Review

An association between the development of overall or specific immune-related adverse events (irAEs) and outcomes of immune checkpoint inhibitors has recently been suggested. To address this emerging association in patients with urothelial cancer receiving pembrolizumab, we conducted a multicenter retrospective analysis, which is the first and largest in an Asian cohort as well as a systematic literature review. We retrospectively evaluated 97 patients with advanced urothelial cancer treated with pembrolizumab as second- or later-line treatment between January 2018 and March 2019. irAEs were categorized by the involved organs and graded using Common Terminology Criteria for Adverse Events version 5.0. Associations between irAEs and pembrolizumab efficacy, including objective response rate (ORR), progression-free survival (PFS), and overall survival (OS), were evaluated. In our review of the literature, 28 studies, including 9 studies involving patients with urothelial cancer and 19 studies reporting the association between outcomes and spectrum of irAEs, were analyzed. Patients with irAEs had significantly higher ORR (52% vs. 16%, P < .01), longer PFS (11.0 months vs. 3.6 months, P < .01) and OS (median not reached vs. 13.1 months, P = .12) than in patients without irAEs. Endocrine (P = .02), pneumological (P = .06), and other (gastrointestinal, hematological, hepatic) (P = .04) irAEs were associated with increased ORR, whereas skin irAEs were not. Endocrine irAEs (P = .04) was associated with improved OS, whereas pneumological and skin irAEs were not. The association between the occurrence of irAEs and clinical efficacy of immune checkpoint inhibitors was consistently supported by the multiple studies we reviewed. The association between clinical outcomes and the spectrum of organs/systems affected by irAEs seems to be inconsistent and could be dependent on tumor type. irAEs were associated with a higher ORR and better survival of patients with advanced urothelial cancer treated with pembrolizumab.     

Advantages of Using Both Voxel- and Surface-based Morphometry in Cortical Morphology Analysis: A Review of Various Applications

Surface-based morphometry (SBM) is extremely useful for estimating the indices of cortical morphology, such as volume, thickness, area, and gyrification, whereas voxel-based morphometry (VBM) is a typical method of gray matter (GM) volumetry that includes cortex measurement. In cases where SBM is used to estimate cortical morphology, it remains controversial as to whether VBM should be used in addition to estimate GM volume. Therefore, this review has two main goals. First, we summarize the differences between the two methods regarding preprocessing, statistical analysis, and reliability. Second, we review studies that estimate cortical morphological changes using VBM and/or SBM and discuss whether using VBM in conjunction with SBM produces additional values. We found cases in which detection of morphological change in either VBM or SBM was superior, and others that showed equivalent performance between the two methods. Therefore, we concluded that using VBM and SBM together can help researchers and clinicians obtain a better understanding of normal neurobiological processes of the brain. Moreover, the use of both methods may improve the accuracy of the detection of morphological changes when comparing the data of patients and controls.In addition, we introduce two other recent methods as future directions for estimating cortical morphological changes: a multi-modal parcellation method using structural and functional images, and a synthetic segmentation method using multi-contrast images (such as T1- and proton density-weighted images).     

Advances in Myocardial Perfusion MR Imaging: Physiological Implications,the Importance of Quantitative Analysis,and Impact on Patient Care in Coronary Artery Disease

Stress myocardial perfusion imaging (MPI) is the preferred test in patients with intermediate-to-high clinical likelihood of coronary artery disease (CAD) and can be used as a gatekeeper to avoid unnecessary revascularization. Cardiac magnetic resonance (CMR) has a number of favorable characteristics, including: (1) high spatial resolution that can delineate subendocardial ischemia; (2) comprehensive assessment of morphology, global and regional cardiac functions, tissue characterization, and coronary artery stenosis; and (3) no radiation exposure to patients. According to meta-analysis studies, the diagnostic accuracy of perfusion CMR is comparable to positron emission tomography (PET) and perfusion CT, and is better than single-photon emission CT (SPECT) when fractional flow reserve (FFR) is used as a reference standard. In addition, stress CMR has an excellent prognostic value. One meta-analysis study demonstrated the annual event rate of cardiovascular death or non-fatal myocardial infarction was 4.9% and 0.8%, respectively, in patients with positive and negative stress CMR. Quantitative assessment of perfusion CMR not only allows the objective evaluation of regional ischemia but also provides insights into the pathophysiology of microvascular disease and diffuse subclinical atherosclerosis. For accurate quantification of myocardial perfusion, saturation correction of arterial input function is important. There are two major approaches for saturation correction, one is a dual-bolus method and the other is a dual-sequence method. Absolute quantitative mapping with myocardial perfusion CMR has good accuracy in detecting coronary microvascular dysfunction. Flow measurement in the coronary sinus (CS) with phase contrast cine CMR is an alternative approach to quantify global coronary flow reserve (CFR). The measurement of global CFR by quantitative analysis of perfusion CMR or flow measurement in the CS permits assessment of microvascular disease and diffuse subclinical atherosclerosis, which may provide improved prediction of future event risk in patients with suspected or known CAD. Multi-institutional studies to validate the diagnostic and prognostic values of quantitative perfusion CMR approaches are required.     

Dietary intake of seaweed and minerals and prevalence of allergic rhinitis in Japanese pregnant females: baseline data from the Osaka Maternal and Child Health Study

PURPOSE: It may be worthwhile to assess the possible protective effect of the traditional Japanese diet on allergic disorders. This cross-sectional study investigated the relationship between dietary intake of seaweed, vegetables, fruit, antioxidants, fiber, and minerals and the prevalence of allergic rhinitis. METHODS: Study subjects were 1002 Japanese pregnant women. Allergic rhinitis (including cedar pollinosis) was defined as present if subjects had received drug treatment at some point during the previous 12 months. Information on dietary factors was collected by using a self-administered diet history questionnaire. RESULTS: Seaweed intake was associated independently with a decreased prevalence of allergic rhinitis. Significant inverse dose-response relationships were found between calcium and phosphorus intake and allergic rhinitis prevalence. There also was a tendency for an inverse association between magnesium consumption and allergic rhinitis. Additional adjustment for calcium or magnesium intake apparently did not influence the inverse association with seaweed consumption. Consumption of vegetables, fruit, vitamins C and E, fiber, and zinc showed no association with allergic rhinitis, whereas a significant positive relationship was observed between beta-carotene intake and allergic rhinitis. CONCLUSIONS: High dietary intake of seaweed, calcium, magnesium, and phosphorus may be associated with a decreased prevalence of allergic rhinitis.     

Atrazine-induced aromatase expression is SF-1 dependent: implications for endocrine disruption in wildlife and reproductive cancers in humans

BACKGROUND: Atrazine is a potent endocrine disruptor that increases aromatase expression in some human cancer cell lines. The mechanism involves the inhibition of phosphodiesterase and subsequent elevation of cAMP. METHODS: We compared steroidogenic factor 1 (SF-1) expression in atrazine responsive and non-responsive cell lines and transfected SF-1 into nonresponsive cell lines to assess SF-1's role in atrazine-induced aromatase. We used a luciferase reporter driven by the SF-1-dependent aromatase promoter (ArPII) to examine activation of this promoter by atrazine and the related simazine. We mutated the SF-1 binding site to confirm the role of SF-1. We also examined effects of 55 other chemicals. Finally, we examined the ability of atrazine and simazine to bind to SF-1 and enhance SF-1 binding to ArPII. RESULTS: Atrazine-responsive adrenal carcinoma cells (H295R) expressed 54 times more SF-1 than nonresponsive ovarian granulosa KGN cells. Exogenous SF-1 conveyed atrazine-responsiveness to otherwise nonresponsive KGN and NIH/3T3 cells. Atrazine induced binding of SF-1 to chromatin and mutation of the SF-1 binding site in ArPII eliminated SF-1 binding and atrazine-responsiveness in H295R cells. Out of 55 chemicals examined, only atrazine, simazine, and benzopyrene induced luciferase via ArPII. Atrazine bound directly to SF-1, showing that atrazine is a ligand for this "orphan" receptor. CONCLUSION: The current findings are consistent with atrazine's endocrine-disrupting effects in fish, amphibians, and reptiles; the induction of mammary and prostate cancer in laboratory rodents; and correlations between atrazine and similar reproductive cancers in humans. This study highlights the importance of atrazine as a risk factor in endocrine disruption in wildlife and reproductive cancers in laboratory rodents and humans.     

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.     

Willingness to pay for suicide prevention in Japan

The present study aimed to establish willingness to pay for suicide prevention among taxpayers in Japan. We conducted an internet-based questionnaire survey using a double-bounded dichotomous choice contingent valuation, and analyzed data for 956 participants. The median willingness to pay to reduce the mortality risk from suicide by 25% was JPY 1,572 ($13.67 USD). Being married was significantly associated with willingness to pay. The willingness to pay to reduce the mortality risk from suicide may be lower than that to reduce other mortality risks such as traffic accidents.     

Contrast‐enhanced harmonic endoscopic ultrasonography for differential diagnosis of localized gallbladder lesions

Background and Aim

Differential diagnosis of localized gallbladder lesions is challenging. The aim of the present study was to evaluate the utility of contrast‐enhanced harmonic endoscopic ultrasonography (CH‐EUS) for diagnosis of localized gallbladder lesions.

Methods

One hundred and twenty‐five patients with localized gallbladder lesions were evaluated by CH‐EUS between March 2007 and February 2014. This was a single‐center retrospective study. Utilities of fundamental B‐mode EUS (FB‐EUS) and CH‐EUS in the differentiation of gallbladder lesions and sludge plug were initially compared. Thereafter, these two examinations were compared with respect to their accuracy in the diagnosis of malignant lesions. Five reviewers blinded to the clinicopathological results evaluated microcirculation patterns in the vascular and perfusion images.

Results

In the differentiation between gallbladder lesions and sludge plug, FB‐EUS had a sensitivity, specificity, and accuracy of 82%, 100%, and 95%, respectively, whereas CH‐EUS had a sensitivity, specificity, and accuracy of 100%, 99%, and 99%, respectively. FB‐EUS‐based diagnosis of carcinomas based on tumor size and/or shape had a sensitivity, specificity, and accuracy of 61–87%, 71–88%, and 74–86%, respectively. Additional information regarding irregular vessel patterns in the vascular image and/or heterogeneous enhancement in the perfusion image on CH‐EUS increased the sensitivity, specificity, and accuracy for the diagnosis of carcinomas to 90%, 98%, and 96%, respectively. There was a significant difference between FB‐EUS and CH‐EUS in terms of carcinoma diagnosis.

Conclusion

CH‐EUS was useful for the evaluation of localized gallbladder lesions.