Development of a Simple and Objective Prognostication Model for Patients with Advanced Solid Malignant Tumors Treated with Immune Checkpoint Inhibitors: A Pan-Cancer Analysis.

BACKGROUND: Systemic therapy using immune checkpoint inhibitors (ICIs) has recently become prevalent in the treatment of patients with various types of advanced cancers; however, difficulties are still associated with predicting the outcomes of patients receiving ICIs due to heterogenous responses to these agents. OBJECTIVE: To develop a prognostic model for advanced cancer patients treated with ICIs. PATIENTS AND METHODS: This study retrospectively analyzed the impact of clinical parameters on overall survival (OS) in 329 patients with several advanced solid malignant tumors who received systemic therapy using ICIs. RESULTS: The primary tumors of 329 patients were as follows: lung (n = 89), kidney (n = 70), urinary tract (n = 52), skin (n = 50), stomach (n = 30), esophagus (n = 21), and head and neck (n = 17). Median OS after the introduction of ICIs was 17.3 months. Among the factors that correlated with OS in a univariate analysis, body mass index, C-reactive protein, hemoglobin, lymphocytes, and platelets were identified as independent predictors of OS in a multivariate analysis. Following the classification of patients into 3 groups based on positive numbers of these independent risk factors, median OS was not reached in the favorable risk group with 0 or 1 risk factor (n = 76), 19.5 months in the intermediate-risk group with 2 or 3 risk factors (n = 182), and 7.2 months in the poor risk group (n = 71) with 4 or 5 risk factors. CONCLUSIONS: Although this is a simple and objective model, it may be used as a reliable tool to predict the outcomes of advanced cancer patients receiving ICIs across multiple tumor types.

Elevation of circulating neutrophil extracellular traps, interleukin (IL)-8, IL-22, and vascular endothelial growth factor in patients with venomous snake mamushi (Gloydius blomhoffii) bites.

Mamushi bites cause swelling and pain that extend from the bitten site. The coagulopathic, anti-coagulopathic, and vasculopathic actions of mamushi venom result in various laboratory abnormalities, occasionally with muscular, renal, and other organ damage. We investigated the serum biomarkers that were associated with the pathogenesis of mamushi bites, focusing on markers related to tissue-damage and neutrophil activation. Twenty patients (one case of grade 2, 13 cases of grade 3, and six cases of grade 4 of severity) seen by us in one summer season were enrolled. Peripheral blood samples were taken from the patients on day 0, day 2, and day 7 after mamushi bites. In addition to routine blood examination, serum samples were subjected to enzyme-linked immunosorbent assay for citrullinated histone H3 (CitH3), interleukin (IL)-8, IL-17A, IL-22, vascular endothelial growth factor (VEGF), high mobility group box protein 1 (HMGB1), tumor necrosis factor (TNF)-α, and IL-33. Creatinine kinase (CK) values significantly correlated with prothrombin time (PT) levels, suggesting that muscular damage is associated with exaggerated coagulation and fibrinolysis. In the vast majority of patients, HMGB1, TNF-α, and IL-33 were under detection levels. Neutrophil counts did not correlate with PT or CK, indicating that the coagulation disorder and muscular damage were virtually independent of the neutrophil activation. The neutrophil number significantly correlated with CitH3, a representative marker of neutrophil extracellular traps. Moreover, there were significant correlations between neutrophil number, CitH3, IL-8, IL-22, and VEGF. Our study suggests that there are two major cascades in mamushi bites. One is an already characterized venom effect on coagulation, vessels, and muscles. In the other novel cascade, we propose that neutrophil activation with IL-8 leads to the production of IL-22 and VEGF. This sequential event may contribute to both vascular damage and repair.

Azathioprine-induced severe myelosuppression accompanied by massive hair loss and painful oral ulcer in an autoimmune hepatitis patient with NUDT15 minor variant: A case report.

This report highlights azathioprine-induced severe myelosuppression in the patient with NUDT15 minor variant. This case report is particularly instructive because several typical symptoms are the clues to this critical adverse drug reaction.

Three-dimensional histological explanation of the dermoscopy patterns in acral melanocytic lesions.

Dermoscopic images of pigmented lesions have distinct features on the sole where skin ridges and furrows exist. Pigmentation of benign nevus usually locates on the skin furrow, while the malignant melanoma is pigmented on the skin ridge. Correspondence between dermoscopy and pathology in the pigmented lesions on soles have been studied based on conventional vertical pathological images. However, for the full understanding of the correspondence, observation of horizontal histological images would be required, because the epidermis constructs unique horizontal structures, namely crista profunda limitans, crista profunda intermedia, and transverse ridge. In this study, we analyzed basic dermoscopic images of the representative acral melanocytic lesions (nevus, lentigo, and malignant melanoma) by horizonal histological images. We created serial horizontal pathological images by digital reconstruction of a hundred of serial vertical images. We could show that parallel furrow pattern is created by the pigmentation of crista profunda limitans, parallel ridge pattern by the pigmentation of both of crista profunda limitans and crista profunda intermediate, and lattice-like pattern by the pigmentation of transverse ridge. Our results would be useful for the intuitive histological understanding of dermoscopy.

An intuitive explanation of dermoscopic structures by digitally reconstructed pathological horizontal top-down view images.

Dermoscopy is a convenient tool to diagnose melanocytic lesions, especially nevus and melanoma. Various pigmented structures, including pigment network, dots and globules, and streaks, are observed in dermoscopy. Usually, 2D vertical images are used to explain the correlation of dermoscopy and histopathology. However, because the image of dermoscopy is horizontal, it is difficult for the horizontal view of dermoscopy to refer to the vertical view of histopathology. In our study, we digitally reconstructed 2D horizontal top-down view images and 3D aerial images from 50-100 serial 2D vertical sections by using high-speed scanner and 3D software in 6 cases of melanocytic lesion. Our new technology intuitively explained the histopathological structures corresponding to the dermoscopic structures. This technique could be used as a good educational tool for beginners.

Induction of plasmablasts by follicular helper T cell-CXCL13 axis upon occurrence of herpes zoster.

Herpes zoster (HZ) is a recurrent varicella zoster virus (VZV) infection. Follicular helper T (Tfh) cells produce IL-21 and CXCL13, which contributes to the differentiation of plasmablasts. Plasmablasts are involved in the VZV-specific antibody production. We investigated the kinetics of circulating plasmablasts and circulating Tfh (cTfh) cells in 43 HZ patients. Plasma IL-21 and CXCL13 levels were also measured. We found an increase of circulating plasmablasts during the clinical course of HZ. The frequency of circulating plasmablasts positively correlated with VZV-specific IgG titers, frequency of activated cTfh cells, and plasma CXCL13 levels, but did not correlate with plasma IL-21 levels. In a representative case, the kinetics peaked in the order of cTfh cells, CXCL13, plasmablasts, and VZV IgG titer. These results suggest that cTfh-CXCL13 may have a crucial role in the differentiation of B cells into VZV-specific IgG-producing plasmablasts, resulting in boosting immunity against VZV reactivation.

Familial acanthosis nigricans with p.K650T FGFR3 mutation.

Acanthosis nigricans (AN) is a pigmentary skin disorder, which may present in association with clinical disorders such as obesity and malignancy. Occasionally, this unique skin manifestation is seen in alliance with several skeletal disorders, such Crouzon syndrome, achondroplasia and hypochondroplasia (HCH). These orthopedic disorders are known to have genetic changes in FGFR3. Recently, AN was reported in HCH with p.K650T mutation in FGFR3, and to date, there are only three reports, comprising 18 cases, describing AN harboring this specific gene mutation. Herein, we detail three new cases of AN with p.K650T FGFR3 mutation, and review the 21 known cases.