Overview and future prospects of out-of-hospital cardiac arrest registries in Japan.

Aim: Out-of-hospital cardiac arrest (OHCA) is a life-threatening emergency with high mortality. The "chain of survival" is critical to improving patient outcomes. To develop and enhance this chain of survival, measuring and monitoring the resuscitation processes and outcomes are essential for quality assurance. In Japan, several OHCA registries have successfully been implemented at both local and national levels. We aimed to review and summarise the conception, strengths, and challenges of OHCA registries in Japan. Method and results: The following representing registries in Japan were reviewed: the All-Japan Utstein registry, the Utstein Osaka Project/the Osaka-CRITICAL study, the SOS-KANTO study, the JAAM-OHCA study, and the SAVE-J II study. The All-Japan Utstein registry, operated by the Fire and Disaster Management Agency of Japan and one of the largest nationwide population-based registries in the world, collects data concerning all patients with OHCA in Japan, excluding in-hospital data. Other research- and hospital-based registries collect detailed out-of-hospital and in-hospital data. The Osaka-CRITICAL study and the SOS-KANTO study are organized at regional levels, and hospitals in the Osaka prefecture and in the Kanto area participate in these registries. The JAAM-OHCA study is managed by the Japanese Association of Acute Medicine and includes 107 hospitals throughout Japan. The Save-J II study focuses on patients with OHCA treated with extracorporeal cardiopulmonary resuscitation. Conclusion: Each OHCA registry has its own philosophy, strengths, perspectives, and challenges; however, all have been successful in contributing to the improvement of emergency medical service (EMS) systems through the quality improvement process. These registries are expected to be further utilized to enhance EMS systems and improve outcomes for patients with OHCA, while also contributing to the field of resuscitation science.

Novel and innovative resuscitation systems in Japan.

Aim: Out-of-hospital cardiac arrest (OHCA) is a life-threatening emergency that requires rapid and efficient intervention. Recently, several novel approaches have emerged and have been incorporated into resuscitation systems in some local areas of Japan. This review describes innovative resuscitation systems and highlights their strengths. Main text: First, we discuss the deployment of a physician-staffed ambulance, in which emergency physicians offer advanced resuscitation to patients with OHCA on site. In addition, we describe the experimental practice of extracorporeal membrane oxygenation (ECPR) in a prehospital setting. Second, we describe a physician-staffed helicopter, wherein a medical team provides advanced resuscitation at the scene. We also explain their initiative to provide early ECPR, even in remote areas. Finally, we provide an overview of the "hybrid ER" system which is a "one-fits-all" resuscitation bay equipped with computed tomography and fluoroscopy equipment. This system is expected to help swiftly identify and rule out irreversible causes of cardiac arrest, such as massive subarachnoid hemorrhage, and implement ECPR without delay. Conclusion: Although these revolutionary approaches may improve the outcomes of patients with OHCA, evidence of their effectiveness remains limited. In addition, it is crucial to ensure cost-effectiveness and sustainability. We will continue to work diligently to assess the effectiveness of these systems and focus on the development of cost-effective and sustainable systems.

Examination of age-related changes in the submandibular glands of male mice.

Salivary gland hypofunction adversely affects the oral environment and daily life by causing dry mouth (xerostomia). Senescence-related atrophy of salivary gland tissues is one cause of xerostomia, and it is particularly common among the elderly. However, the underlying mechanism is poorly understood, and no treatment has been established. Therefore, we examined age-related changes in senescence-associated secretory phenotype (SASP) factors, which regulate stemness and cellular senescence, in mouse submandibular glands. We analyzed the submandibular glands of 6-week-old (young group, n = 6) and 82-week-old mice (aged group, n = 6). We performed salivary flow rate measurements, histological analysis including immunohistochemistry, and quantitative real-time PCR. The salivary flow rate was significantly lower in the aged group than in the young group. In addition, immunostaining and quantitative real-time PCR illustrated that aquaporin-5 and α-amylase expressions were significantly decreased in aged mice, indicating salivary gland hypofunction. c-Kit and cytokeratin 5 expressions were also significantly decreased in this group, suggesting that the regenerative abilities of the submandibular glands were reduced because of decreased stem and progenitor cell counts. Furthermore, the levels of p16INK4a and p21 (the senescence markers) and TGF-ß1 and IL-6 (SASP factors) were significantly increased in mice, suggesting that senescence had been promoted. The decreased numbers of stem and progenitor cells and increased levels of SASP factors might be associated with age-related changes in mouse submandibular glands. These results might facilitate the development of treatments for senescence-related submandibular gland hypofunction.

The effects of breast density on the benefits of mammograms with adjunctive ultrasonography in breast screening.

OBJECTIVE: Various efforts have been made to improve the accuracy of breast cancer screening. This study aimed to report differences in the contribution of ultrasonography to cancer screening assessments of dense and non-dense breasts. METHODS: The participants in this study were 29,640 Japanese women in their 40 s who underwent breast cancer screening at the Iwate Cancer Society between 2018 and 2021. This included women who chose mammography alone or mammography with adjunctive ultrasonography (overall assessment). They were classified into two groups according to the breast density in mammography: dense breasts and non-dense breasts. Recall rate, breast cancer detection rate, and positive predictive value of the two screening-type groups were evaluated for each breast density group. RESULTS: Of the 29,640 women analyzed, 18,861 (63.6%) underwent mammography alone and 10,779 (36.3%) were by overall assessments. The number of women recalled was higher in the overall assessment group than in the mammography-alone group (2.9% vs. 1.9%, p < 0.01). The proportion of women in whom breast cancer was detected was higher in the overall assessment group than in the mammography-alone group (0.31% [n = 33] vs. 0.15% [n = 28], p < 0.01). For non-dense breasts, there were no significant differences in either the recall rate or the breast cancer detection rate between those who underwent mammography alone and those who underwent overall assessment. Conversely, for dense breasts, the recall rate after mammography alone was lower than that after overall assessment (1.8% vs. 3.8%, p < 0.01), and the breast cancer detection rate was higher after overall assessment than after mammography alone (0.40% vs. 0.18%, p < 0.01). CONCLUSION: We found the benefits of adjunctive ultrasonography with mammography to differ depending on breast density. This could be used to tailor the selection of screening modalities to individuals.

Bundling of collagen fibrils influences osteocyte network formation during bone modeling.

Osteocytes form a cellular network by gap junctions between their cell processes. This network is important since intercellular communication via the network is essential for bone metabolism. However, the factors that influence the formation of this osteocyte network remain unknown. As the early stage of osteocyte network formation occurs on the bone surface, we observed a newly formed trabecular bone surface by orthogonal focused ion beam-scanning electron microscopy. The embedding late osteoblast processes tended to avoid bundled collagen fibrils and elongate into sparse collagen fibrils. Then, we examined whether the inhibition of bundling of collagen fibrils using a potent lysyl oxidase inhibitor, ß-aminopropionitrile (BAPN) changed the cellular network of the chick calvaria. The osteocyte shape of the control group was spindle-shape, while that of the BAPN group was sphere-shaped. In addition, the osteocyte processes of the control group were elongated vertically to the long axis of the cell body, whereas the osteocyte processes of the BAPN group were elongated radially. Therefore, it was suggested that the bundling of collagen fibrils influences normal osteocyte network formation during bone modeling.

Rare case of exostosin 1/exostosin 2-related membranous lupus nephritis concomitant with dual ANCA- and anti-GBM antibody-associated crescentic glomerulonephritis effectively diagnosed by mass spectrometry: a case report.

BACKGROUND: Recent developments in mass spectrometry (MS) have revealed target antigens for membranous nephropathy (MN), including phospholipase A2 receptor and exostosin 1/exostosin 2 (EXT1/2). EXT1/2 are known antigens of autoimmune disease-related MN, especially membranous lupus nephritis. We describe the case of an elderly man who developed nephrotic syndrome followed by progressive renal dysfunction. CASE PRESENTATION: A 78-year-old man presented with rapidly progressive renal dysfunction with proteinuria and hematuria. Three years previously, he had developed leg edema but did not receive any treatment. Laboratory tests showed elevated anti-nuclear antibody (Ab), anti-dsDNA Ab titer, and hypocomplementemia, indicating systemic lupus erythematous. Myeloperoxidase anti-neutrophil cytoplasmic Ab (ANCA) and anti-glomerular basement membrane (GBM) Ab were also detected. The renal pathologic findings were compatible with crescentic glomerulonephritis (GN), whereas non-crescentic glomeruli exhibited MN without remarkable endocapillary or mesangial proliferative change. Immunofluorescence microscopy revealed glomerular IgG, C3, and C1q deposition. All IgG subclasses were positive in glomeruli. Anti-PLA2R Ab in serum was negative. MS analysis was performed to detect the antigens of MN, and EXT1/2 was detected in glomeruli. Therefore, we reached a diagnosis of membranous lupus nephritis concurrent with both ANCA-associated vasculitis and anti-GBM-GN. The simultaneous occurrence of these three diseases is extremely rare. CONCLUSIONS: This is the first report of EXT1/2-related membranous lupus nephritis concurrent with ANCA-associated vasculitis and anti-GBM-GN. This case demonstrates the usefulness of MS in diagnosing complicated cases of MN.

Canna starch improves immune functions and the intestinal environment in mice.

The present study was conducted to elucidate the dietary effects of canna starch on the immune functions and intestinal luminal environment in mice. The amylose and resistant starch characteristics were determined for six types of starch, including edible canna. Canna starch was found to be higher in amylose and resistant starch compared with the other starches. BALB/c mice were fed 3.16% (low-canna group) and 6.32% (high-canna group) canna starch for 2 weeks, and then intestinal parameters were measured. Fecal IgA and mucin levels were markedly elevated by canna starch intake. IgA levels in serum and spleen lymphocytes were elevated by canna starch intake in the high-canna group, but not in the low-canna group. When the mice were fed canna starch, the cecum weight increased, and the pH in the cecum decreased. The high-canna group had significantly increased levels of Clostridium subcluster XIVa lactic acid, acetic acid, and n-butyric acid in the cecum compared with the control group. These results suggested that canna starch supplementation changed the intestinal microbiota and enhanced the intestinal immune and barrier functions and cecal organic acids in mice.

Quality Control of Targeted Plasma Lipids in a Large-Scale Cohort Study Using Liquid Chromatography-Tandem Mass Spectrometry.

High-throughput metabolomics has enabled the development of large-scale cohort studies. Long-term studies require multiple batch-based measurements, which require sophisticated quality control (QC) to eliminate unexpected bias to obtain biologically meaningful quantified metabolomic profiles. Liquid chromatography-mass spectrometry was used to analyze 10,833 samples in 279 batch measurements. The quantified profile included 147 lipids including acylcarnitine, fatty acids, glucosylceramide, lactosylceramide, lysophosphatidic acid, and progesterone. Each batch included 40 samples, and 5 QC samples were measured for 10 samples of each. The quantified data from the QC samples were used to normalize the quantified profiles of the sample data. The intra- and inter-batch median coefficients of variation (CV) among the 147 lipids were 44.3% and 20.8%, respectively. After normalization, the CV values decreased by 42.0% and 14.7%, respectively. The effect of this normalization on the subsequent analyses was also evaluated. The demonstrated analyses will contribute to obtaining unbiased, quantified data for large-scale metabolomics.

Specific Mutations near the Amyloid Precursor Protein Cleavage Site Increase γ-Secretase Sensitivity and Modulate Amyloid-ß Production.

Amyloid-ß peptides (Aßs) are produced via cleavage of the transmembrane region of the amyloid precursor protein (APP) by γ-secretase and are responsible for Alzheimer's disease. Familial Alzheimer's disease (FAD) is associated with APP mutations that disrupt the cleavage reaction and increase the production of neurotoxic Aßs, i.e., Aß42 and Aß43. Study of the mutations that activate and restore the cleavage of FAD mutants is necessary to understand the mechanism of Aß production. In this study, using a yeast reconstruction system, we revealed that one of the APP FAD mutations, T714I, severely reduced the cleavage, and identified secondary APP mutations that restored the cleavage of APP T714I. Some mutants were able to modulate Aß production by changing the proportions of Aß species when introduced into mammalian cells. Secondary mutations include proline and aspartate residues; proline mutations are thought to act through helical structural destabilization, while aspartate mutations are thought to promote interactions in the substrate binding pocket. Our results elucidate the APP cleavage mechanism and could facilitate drug discovery.

Ferroelectric Ionic Molecular Crystals with Significant Plasticity and a Low Melting Point: High Performance in Hot-Pressed Polycrystalline Plates and Melt-Grown Crystalline Sheets.

Among ferroelectric crystals based on small molecules, plastic/ferroelectric crystals are currently receiving particular attention because they can be used as bulk polycrystals. Herein, we show that an ionic molecular ferroelectric crystal, guanidinium tetrafluoroborate, exhibits significant malleability and multiaxial ferroelectricity despite the absence of a plastic crystal phase. Powder samples of this crystal can be processed into transparent bulk crystalline plates either by press-forming or by melt-growing. The plates show high ferroelectric performance and related properties, demonstrating the largest hitherto reported spontaneous polarization for bulk polycrystals of small-molecule-based ferroelectrics. Owing to the ready availability of large-scale materials and processability into various bulk crystalline forms, this ferroelectric crystal represents a highly promising functional material that will boost research on diverse applications as bulk crystals.

An In Vivo Study of Local Administration of Low-dose Anti-PD-1 Antibody Using an Oral Cancer Cell Line.

BACKGROUND/AIM: The immunotherapy approach using anti-programmed cell death 1 (PD-1) antibody has been demonstrated in oral cancer treatment. However, serious immune-related adverse events (irAE) have been reported. If local administration of small doses of anti-PD-1 antibody via intraarterial chemoradiotherapy could have the same antitumor effect of systemic administration, this can reduce irAE and medical expenses. In this study, we investigate the antitumor effects of local and systemic administration of a small amount of anti-PD-1 antibody, the overall survival (OS), and the immune environment around cancer. MATERIALS AND METHODS: A mouse buccal mucosal oral squamous cell carcinoma cell line (Sq-1979) was used, and anti-mouse PD-1 was used as the drug. The cell line was transplanted to mouse, and the drug was locally (30 mg/body) and systemically (300 mg/body) administered in a dose. The tumor shrinkage rate and antitumor effect were examined 21 and 29 days after the start of administration. The OS was also compared in each of the groups. Furthermore, the subcutaneous growth of the tumors was inhibited, and the expressions of PD-L1, CD8T cells, perforin, and granzyme B were examined. RESULTS: We found that the local low-dose and systemic groups had the same antitumor effect, OS also showed a significant prolongation. In addition, indicated that the expression of granzyme B was higher in the local low-dose group. CONCLUSION: Local low-dose administration of anti-PD-1 antibody showed the same antitumor effect and OS as systemic normal-dose administration. Therefore, local low-dose administration in oral cancer can be useful.

Distinct transcriptome architectures underlying lupus establishment and exacerbation.

Systemic lupus erythematosus (SLE) is a complex autoimmune disease involving multiple immune cells. To elucidate SLE pathogenesis, it is essential to understand the dysregulated gene expression pattern linked to various clinical statuses with a high cellular resolution. Here, we conducted a large-scale transcriptome study with 6,386 RNA sequencing data covering 27 immune cell types from 136 SLE and 89 healthy donors. We profiled two distinct cell-type-specific transcriptomic signatures: disease-state and disease-activity signatures, reflecting disease establishment and exacerbation, respectively. We then identified candidate biological processes unique to each signature. This study suggested the clinical value of disease-activity signatures, which were associated with organ involvement and therapeutic responses. However, disease-activity signatures were less enriched around SLE risk variants than disease-state signatures, suggesting that current genetic studies may not well capture clinically vital biology. Together, we identified comprehensive gene signatures of SLE, which will provide essential foundations for future genomic and genetic studies.

A morphometric analysis of the osteocyte canaliculus using applied automatic semantic segmentation by machine learning.

INTRODUCTION: Osteocytes play a role as mechanosensory cells by sensing flow-induced mechanical stimuli applied on their cell processes. High-resolution imaging of osteocyte processes and the canalicular wall are necessary for the analysis of this mechanosensing mechanism. Focused ion beam-scanning electron microscopy (FIB-SEM) enabled the visualization of the structure at the nanometer scale with thousands of serial-section SEM images. We applied machine learning for the automatic semantic segmentation of osteocyte processes and canalicular wall and performed a morphometric analysis using three-dimensionally reconstructed images. MATERIALS AND METHODS: Six-week-old-mice femur were used. Osteocyte processes and canaliculi were observed at a resolution of 2 nm/voxel in a 4 × 4 µm region with 2000 serial-section SEM images. Machine learning was used for automatic semantic segmentation of the osteocyte processes and canaliculi from serial-section SEM images. The results of semantic segmentation were evaluated using the dice similarity coefficient (DSC). The segmented data were reconstructed to create three-dimensional images and a morphological analysis was performed. RESULTS: The DSC was > 83%. Using the segmented data, a three-dimensional image of approximately 3.5 µm in length was reconstructed. The morphometric analysis revealed that the median osteocyte process diameter was 73.8 ± 18.0 nm, and the median pericellular fluid space around the osteocyte process was 40.0 ± 17.5 nm. CONCLUSION: We used machine learning for the semantic segmentation of osteocyte processes and canalicular wall for the first time, and performed a morphological analysis using three-dimensionally reconstructed images.

Coexistence of sensory qualities and value representations in human orbitofrontal cortex.

Despite the multiple regions and neural networks associated with value-based decision-making, the orbitofrontal cortex (OFC) is possible a particularly important one. Although the role of the OFC in reinforcer devaluation tasks, which assess the ability to represent identity, sensory qualities, and subjective values of the expected outcomes, has been established, the specific aspect represented in this area remains unclear. In this study, using functional magnetic resonance imaging, wherein participants rated the palatability of 128 food items using photographs, we investigated whether the human OFC represents object identity, sensory qualities, or value. Employing many items helped us dissociate object identity from sensory qualities and values; the inferred sensory qualities of identical items were manipulated by a change in metabolic state. Moreover, value differences between items were analytically controlled by employing a technique similar to age adjustment. The palatability ratings for food items significantly decreased after a meal. Using representational similarity analysis, we confirmed that the OFC represents value. Moreover, identical items were represented similarly in the lateral OFC in a given metabolic state; however, these representations were altered post-feeding. Importantly, this change was not explained by subjective value, suggesting that the OFC represents sensory quality and value, but not object identity.

Long-term clinical course of immunotactoid glomerulopathy complicated with diffuse large B-cell lymphoma.

We report a case of immunotactoid glomerulopathy (ITG) complicated with diffuse large B-cell lymphoma (DLBCL). A 68-year-old woman presented with leg edema and was diagnosed with nephrotic syndrome (NS). Renal biopsy revealed ITG. We treated the patient with prednisolone (20 mg/day) and she achieved complete remission of NS. Steroids were gradually reduced. After 1 year, the patient presented with a breast mass determined on biopsy to be DLBCL. She underwent six cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone) therapy. Follow-up revealed complete remission of both DLBCL and ITG. NS recurred after 5 years and she was simultaneously diagnosed with recurrence of DLBCL in bone marrow. She underwent four cycles of R-EPOCH (rituximab, etoposide, prednisolone, vincristine, cyclophosphamide, doxorubicin) therapy and entered remission for DLBCL. NS improved, but the treatment did not lead to remission. After 2 additional years, NS and DLBCL recurred again. She was administered rituximab and NS improved, although proteinuria tended to increase thereafter. One year later, we started prednisolone (10 mg/day), and proteinuria tended to decrease. She is currently undergoing outpatient follow-up. This case suggests that ITG with MGUS should be treated with the possibility of developing malignant hematological disease during the course.

Wearing a face mask during controlled-intensity exercise is not a risk factor for exertional heatstroke: A pilot study.

AIM: This study aimed to measure the influence of wearing face masks on individuals' physical status in a hot and humid environment. METHODS: Each participant experienced different physical situations: (i) not wearing a mask (control), (ii) wearing a surgical mask, (iii) wearing a sport mask. An ingestible capsule thermometer was used to measure internal core body temperature during different exercises (standing, walking, and running, each for 20 min) in an artificial weather room with the internal wet-bulb globe temperature set at 28°C. The change in the participants' physical status and urinary liver fatty acid-binding protein (L-FABP) were measured. RESULTS: Six healthy male volunteers were enrolled in the study. In each participant, significant changes were observed in the heart rate and internal core temperatures after increased exercise intensity; however, no significant differences were observed between these parameters and urinary L-FABP among the three intervention groups. CONCLUSION: Mask wearing is not a risk factor for heatstroke during increased exercise intensity.

Contribution of Neuropilin-1 in Radiation-Survived Subclones of NSCLC Cell Line H1299.

Non-small cell lung cancer (NSCLC) is an aggressive lung cancer accounting for approximately 85% of all lung cancer patients. For the patients with Stages IIIA, IIIB, and IIIC, the 5-year survival is low though with the combination with radiotherapy and chemotherapy. In addition, the occurrence of tumor cells (repopulated tumors) that survive irradiation remains a challenge. In our previous report, we subcloned the radiation-surviving tumor cells (IR cells) using the human NSCLC cell line, H1299, and found that the expression of neuropilin-1 (NRP-1) was upregulated in IR cells by the microarray analysis. Here, we investigated the contribution of neuropilin-1 to changes in the characteristics of IR cells. Although there were no differences in angiogenic activity in the tube formation assay between parental and IR cells, the cell motility was increased in IR cells compared to parental cells in the cell migration assay. This enhanced cell motility was suppressed by pretreatment with anti-NRP-1 antibody. Although further studies are necessary to identify other molecules associated with NRP-1, the increase in cellular motility in IR cells might be due to the contribution of NRP-1. Inhibition of NRP-1 would help control tumor malignancy in radiation-surviving NSCLC.

Systemic Elevation of n-3 Polyunsaturated Fatty Acids (n-3-PUFA) Is Associated with Protection against Visual, Motor, and Emotional Deficits in Mice following Closed-Head Mild Traumatic Brain Injury.

Traumatic brain injury (TBI) causes neuroinflammation and neurodegeneration leading to various pathological complications such as motor and sensory (visual) deficits, cognitive impairment, and depression. N-3 polyunsaturated fatty acid (n-3 PUFA) containing lipids are known to be anti-inflammatory, whereas the sphingolipid, ceramide (Cer), is an inducer of neuroinflammation and degeneration. Using Fat1+-transgenic mice that contain elevated levels of systemic n-3 PUFA, we tested whether they are resistant to mild TBI-mediated sensory-motor and emotional deficits by subjecting Fat1-transgenic mice and their WT littermates to focal cranial air blast (50 psi) or sham blast (0 psi, control). We observed that visual function in WT mice was reduced significantly following TBI but not in Fat1+-blast animals. We also found Fat1+-blast mice were resistant to the decline in motor functions, depression, and fear-producing effects of blast, as well as the reduction in the area of oculomotor nucleus and increase in activated microglia in the optic tract in brain sections seen following blast in WT mice. Lipid and gene expression analyses confirmed an elevated level of the n-3 PUFA eicosapentaenoic acid (EPA) in the plasma and brain, blocking of TBI-mediated increase of Cer in the brain, and decrease in TBI-mediated induction of Cer biosynthetic and inflammatory gene expression in the brain of the Fat1+ mice. Our results demonstrate that suppression of ceramide biosynthesis and inflammatory factors in Fat1+-transgenic mice is associated with significant protection against the visual, motor, and emotional deficits caused by mild TBI. This study suggests that n-3 PUFA (especially, EPA) has a promising therapeutic role in preventing neurodegeneration after TBI.

Stabilization of Interfacial Polarization and Induction of Polarization Hysteresis in Organic MISIM Devices.

Molecule-based ferroelectrics has attracted much attention because of its advantages, such as flexibility, light weight, and low environmental load. In the present work, we examined an organic metal|insulator|semiconductor|insulator|metal (MISIM) device structure to stabilize the interfacial polarization in the S layer and to induce polarization hysteresis even without bulk ferroelectrics. The MISIM devices with I = parylene C and S = TMB (=3,3',5,5'-tetramethylbenzidine)-TCNQ (=tetracyanoquinodimethane) exhibited hysteresis loops in the polarization-voltage (P-V) curves not only at room temperature but also over a wide temperature range down to 80 K. The presence of polarization hysteresis for MISIM devices was theoretically confirmed by an electrostatic model, which also explained the observed thickness dependence of the I layers on the P-V curves. Polarization hysteresis curves were also obtained in MISIM devices using typical organic semiconductors (ZnPc, C60, and TCNQ) as the S layer, demonstrating the versatility of the interfacial polarization mechanism.

Possible Pseudo-progression of Non-small Cell Lung Carcinoma in a Patient With Clinical Hyper-progression Associated With Trousseau Syndrome Who Was Treated With Pembrolizumab: A Case Report.

BACKGROUND/AIM: Immune checkpoint inhibitors (ICIs), including nivolumab and pembrolizumab, have recently been shown to have clinical benefits in patients with advanced non-small cell lung cancer (NSCLC). The novel tumour responses to these agents are changing the management of patients with cancer. Pseudo-progression of disease (pseudo-PD), that is, an initial flare followed by shrinkage of the tumour, has been described as a distinctive response to ICIs. However, pseudo-PD manifest initial progression and is difficult to segregate with hyper progressive disease (HPD). We, therefore, analysed a case with pseudo-PD histologically. PATIENTS AND METHODS: A 68-year-old Japanese man with stage IV non-small cell lung carcinoma (NSCLC) was treated by anti-PD-1 antibody (pembrolizumab). Four weeks later after second time treatment with pembrolizumab, the patient showed severe melena followed by Trousseau syndrome and died at day 174 after first treatment by pembrolizumab, suggesting HPD clinically. Primary lesion and metastatic lesions were analysed histologically. RESULTS: Histological analysis revealed that NSCLC cells expressed PD-L1, and CD8+ tumor-infiltrated lymphocytes (TILs) were observed. CD8+ TILs showed higher rates of PD-1 indicating that lesions were of the inflamed type and the case was pseudo-PD. Furthermore, it was found that cancer cells expressed MUC1. CONCLUSION: The clinical appearance of the case was aggressive after treatment by pembrolizumab, and the case seemed to be HPD; however, histological analysis revealed that the case was likely pseudo-PD. Therefore, careful histological evaluation is important when investigating the clinical response to an ICI and mucin expression might be a predictive marker for Trousseau syndrome.