Pembrolizumab-related Immune Thrombocytopenia in a Patient with Lung Adenocarcinoma Treated by Radiotherapy: Potential Immune-related Adverse Event Elicited by Radiation Therapy

The effect of radiotherapy during immunotherapy on immune-related adverse events (irAEs) is not fully understood. We herein report a 74-year-old woman diagnosed with lung adenocarcinoma with programmed death ligand 1 expression ≥50% and treated with pembrolizumab. She developed fatal immune thrombocytopenia associated with pembrolizumab immediately following radiotherapy. A flow cytometry analysis of peripheral blood detected an increased expression of programmed death-1 (PD-1) and Ki-67 in CD4^＋ and CD8^＋ T cells after radiotherapy, compared with pre-irradiation measurements. This case suggests that radiotherapy may evoke irAEs during treatment with anti-PD-1 antibodies, which physicians should consider when using radiotherapy in patients treated with these drugs.     

Successful Treatment of Nephrotic Syndrome Due to Collapsing Focal Segmental Glomerulosclerosis Accompanied by Acute Interstitial Nephritis

A 39-year-old woman was hospitalized for nephrotic syndrome. Laboratory test results showed increased serum creatinine levels and urinary excretions of beta-2-microglobulin, and N-acetyl-beta-D-glucosaminidase. A renal biopsy revealed collapsing focal segmental glomerulosclerosis (FSGS) and acute interstitial nephritis. Despite treatment with pulse steroid followed by oral high-dose glucocorticoids and cyclosporines, heavy proteinuria persisted. After low-density lipoprotein apheresis (LDL-A) therapy was initiated, her proteinuria gradually decreased, leading to complete remission. A repeat renal biopsy after treatment revealed no collapsing glomeruli. Immediate LDL-A should be performed to treat cases of collapsing FSGS poorly responding to other treatments.     

Accumulation System: Distributed Neural Substrates of Perceptual Decision Making Revealed by fMRI Deconvolution

Neural substrates of evidence accumulation have been a central issue in decision-making studies because of the prominent success of the accumulation model in explaining a wide range of perceptual decision making. Since accumulation-shaped activities have been found in multiple brain regions, which are called accumulators, questions regarding functional relations among these accumulators are emerging. This study employed the deconvolution method of functional magnetic resonance imaging (fMRI) signals from human male and female participants during object-category decision tasks, taking advantage of the whole-brain coverage of fMRI with improved availability of temporal information of the deconvolved activity. We detected the accumulation activity in many non-category-selective regions (NCSRs) over the frontal, parietal, and temporal lobes as well as category-selective regions (CSRs) of the categorization task. Importantly, the frontal regions mostly showed activity peaks matching the decision timing (classified as “type-A accumulator”), while activity peaks of the parietal and temporal regions were behind the decision (classified as “type-B accumulator”). The CSRs showed activity peaks whose timing depended on both region and stimulus preference, plausibly reflecting the competition among the alternative choices (classified as “type-C accumulator”). The results suggest that these functionally heterogeneous accumulators form a system for evidence accumulation in which the type-A accumulator regions make decisions in a general manner while the type-B and type-C accumulator regions are employed depending on the modality and content of decision tasks. The concept of the accumulation system may provide a key to understanding the universality of the accumulation model over various kinds of decision tasks.SIGNIFICANCE STATEMENT Perceptual decision making, such as deciding to walk or stop on seeing the signal colors, has been explained theoretically by the accumulation model, in which sensory information is accumulated to reach a certain threshold for making decisions. Neural substrates of this model, however, are still under elucidation among candidate regions found over the brain. We show here that, taking advantage of the whole-brain coverage of functional magnetic resonance imaging (fMRI) with improving availability of temporal information by deconvolution method, the accumulation is conducted by a system comprising many regions in different abstraction levels and only a part of these regions in the frontal cortex make decisions. The system concept may provide a key to explaining the universality of the accumulation model.     

Absolute lymphocyte count and C-reactive protein-albumin ratio can predict prognosis and adverse events in patients with recurrent esophageal cancer treated with nivolumab therapy

Predicting the prognosis and adverse events (AEs) of nivolumab therapy for recurrent esophageal cancer is very important. The present study investigated whether a simple blood biochemical examination could be used to predict prognosis and AEs following nivolumab treatment for relapse of esophageal cancer. A total of 41 patients who received nivolumab treatment for recurrent esophageal cancer after esophagectomy were analyzed. The absolute lymphocyte count (ALC), neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), monocyte-lymphocyte ratio (MLR) and C-reactive protein-albumin ratio (CAR) were assessed at the time of nivolumab induction as indices that can be calculated by blood biochemical examinations alone. Median values were 1,015 for ALC, 3.401 for NLR, 242.6 for PLR, 0.458 for MLR and 0.119 for CAR, and patients were divided into two groups according to values. A high ALC, low NLR, low PLR, low MLR and low CAR were associated with a better response to nivolumab. In addition, patients with the aforementioned indices, with the exception of low PLR, or better response were more likely to develop AEs in univariate analysis. In multivariate analysis, a high ALC [odds ratio (OR): 4.857, P=0.043] and low CAR (OR: 9.099, P=0.004) were identified as independent risk factors for AEs. Survival analysis revealed that overall survival and progression-free survival (PFS) rates after nivolumab treatment differed significantly between the high and low groups of ALC, NLR, PLR, MLR and CAR. The multivariate analysis identified a low ALC [hazard ratio (HR): 3.710, P=0.003] and high CAR (HR: 2.953, P=0.007) as independent poor prognostic factors of PFS. In conclusion, ALC and CAR have potential as biomarkers for outcomes of recurrent esophageal cancer following nivolumab treatment.     

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.     

Direct visualization of glucagon‐like peptide‐1 secretion by fluorescent fusion proteins

Live‐cell imaging with fluorescent proteins (FPs) is a powerful tool for investigating the exocytosis processes of hormones. However, the secretion process of glucagon‐like peptide‐1 (GLP‐1) has not been visualized by FPs, which might be because tagging FPs inhibits GLP‐1 synthesis through the post‐translational processing from proglucagon. Here, we have developed FP‐tagged GLP‐1 by inserting FPs into the middle of GLP‐1 and adding the proglucagon signal peptide. Confocal imaging confirmed that GLP‐1 fused to FPs with high folding efficiency showed granular structure, in which secretory vesicle markers colocalized. The fluorescence intensity of FP in the culture supernatant from cells treated with KCl or forskolin was significantly increased compared with those from untreated cells. Furthermore, FP‐tagged GLP‐1 enables direct visualization of stimulation‐dependent exocytosis of GLP‐1 at a single granule resolution with total internal reflection fluorescence microscopy. FP‐tagged GLP‐1 might facilitate the screening of GLP‐1 secretagogues and the discovery of new antidiabetic drugs.     

Single-stage repair for ascending aortic aneurysm,artery stenosis and occlusion of neck vessels caused by Takayasu arteritis

Takayasu arteritis results in a variety of vascular symptoms, and there are some cases in which progressive vascular lesions require surgical intervention. We present a case with ascending aortic aneurysm, right common carotid artery stenosis, left common carotid artery occlusion and left subclavian artery stenosis caused by Takayasu arteritis that was successfully treated with total arch replacement and ascending aorta to right internal carotid artery bypass.     

Risk factors for postoperative pneumonia in elderly patients with colorectal cancer: a sub-analysis of a large,multicenter, case-control study in Japan

Surgery Today - Postoperative pneumonia affects the length of stay and mortality after surgery in elderly patients with colorectal cancer (CRC). We aimed to determine the risk factors of...