Prediction model for pheochromocytoma/paraganglioma using nCounter assay.

BACKGROUND: World Health Organization defined pheochromocytomas/paragangliomas (PPGL) as malignant tumors in 2017 because the existing classification system could not reflect locally aggressive behavior sufficiently. However, predicting the likelihood of metastasis remains a crucial part of the treatment strategy. METHODS: From one tertiary care hospital and one secondary hospital, 97 PPGL cases were selected. Medical records of PPGL cases with the presence of formalin-fixed and paraffin-embedded (FFPE) tissue of primary lesion were reviewed. For FFPE tissues, a nCounter assay was conducted to determine differently expressed genes between metastatic and non-metastatic PPGL groups. Performances of prediction models for the likelihood of metastasis were calculated. RESULTS: Of a total of 97 PPGL cases, 39, 20, and 38 were classified as benign, malignant, and validation, respectively. In the nCounter assay, CDK1, TYMS, and TOP2A genes showed significant differences in expression. Tumor size was positively correlated with CDK1 expression level. The Lasso regression model showed supreme performance of sensitivity 91.7% and specificity 95.5% when those significant factors were considered. CONCLUSION: Machine learning of multi-modal classifiers can be used to create a prediction model for metastasis of PPGL with high sensitivity and specificity using nCounter assay. Moreover, CDK1 inhibitors could be considered for developing drug treatment.

Trends and Risk Factors for Surgical Site Infection after Treatment of the Ankle Fracture: National Cohort Study.

Surgical site infection (SSI) is a major complication after the surgical treatment of ankle fractures that can result in catastrophic consequences. This study aimed to determine the incidence of SSI in several cohorts from national insurance databases over the past 12 years and identify its predictors. The claimed data for patients (n = 1,449,692) with ankle fractures between 2007 and 2019 were investigated, and a total of 41,071 patients were included in the final analysis. The covariates included were age, sex, season, fracture type (closed vs. open), type of surgical fixation procedure, and comorbidities of each patient. All subjects were divided into two groups according to the SSI after the surgical fixation of the ankle fracture (no infection group vs. infection group). The number of SSIs after the surgical treatment of ankle fractures was 874 (2.13%). Open fractures [odds ratio, (OR) = 4.220] showed the highest risk for SSI, followed by the male sex (OR = 1.841), an increasing number of comorbidities (3-5, OR = 1.484; ≥6, OR = 1.730), a history of dementia (OR = 1.720) or of myocardial infarction (OR = 1.628), and increasing age (OR = 1.010). The summer season (OR = 1.349) showed the highest risk among the four seasons for SSI after ankle fracture surgery.

Serum Zonulin Is a Biomarker for Severe Asthma.

Zonulin is a regulator of epithelial and endothelial barrier function. It regulates intestinal permeability through disrupting tight junctions. Defective epithelial barrier function is a hallmark of airway inflammation in asthma. This study aimed to investigate the role of zonulin in the pathogenesis of severe asthma. We enrolled 56 adult patients with asthma (29 severe asthma and 27 mild-to-moderate asthma) and 33 normal controls. The clinical data, sera, and lung tissues of the patients were provided by the Cohort for Reality and Evolution of adult Asthma in Korea (COREA) and the Biobank of Soonchunhyang University Bucheon Hospital, South Korea. Serum zonulin levels were estimated using an enzyme-linked immunosorbent assay, and zonulin expression in the bronchial tissue was evaluated by immunohistochemical staining. The serum zonulin levels were significantly higher in patients with severe asthma (51.98 ± 19.66 ng/mL) than in those with mild-to-moderate asthma and normal controls (26.35 ± 13.70 vs. 17.26 ± 10.29 ng/mL, P < 0.001). They significantly correlated with percent predicted forced expiratory volume in one second (%FEV1) (r = -0.35, P = 0.009). The zonulin expression in the bronchial epithelium was greater in patients with severe asthma. A serum zonulin cutoff value to distinguish between severe and mild-to-moderate asthmatics was 38.83 ng/mL. Zonulin may play an important role in the pathogenesis of severe asthma, and serum zonulin could be a potential biomarker for severe asthma.

Development and Application of an Active Pharmacovigilance Framework Based on Electronic Healthcare Records from Multiple Centers in Korea.

INTRODUCTION: With the availability of retrospective pharmacovigilance data, the common data model (CDM) has been identified as an efficient approach towards anonymized multicenter analysis; however, the establishment of a suitable model for individual medical systems and applications supporting their analysis is a challenge. OBJECTIVE: The aim of this study was to construct a specialized Korean CDM (K-CDM) for pharmacovigilance systems based on a clinical scenario to detect adverse drug reactions (ADRs). METHODS: De-identified patient records (n = 5,402,129) from 13 institutions were converted to the K-CDM. From 2005 to 2017, 37,698,535 visits, 39,910,849 conditions, 259,594,727 drug exposures, and 30,176,929 procedures were recorded. The K-CDM, which comprises three layers, is compatible with existing models and is potentially adaptable to extended clinical research. Local codes for electronic medical records (EMRs), including diagnosis, drug prescriptions, and procedures, were mapped using standard vocabulary. Distributed queries based on clinical scenarios were developed and applied to K-CDM through decentralized or distributed networks. RESULTS: Meta-analysis of drug relative risk ratios from ten institutions revealed that non-steroidal anti-inflammatory drugs (NSAIDs) increased the risk of gastrointestinal hemorrhage by twofold compared with aspirin, and non-vitamin K anticoagulants decreased cerebrovascular bleeding risk by 0.18-fold compared with warfarin. CONCLUSION: These results are similar to those from previous studies and are conducive for new research, thereby demonstrating the feasibility of K-CDM for pharmacovigilance. However, the low quality of original EMR data, incomplete mapping, and heterogeneity between institutions reduced the validity of the analysis, thus necessitating continuous calibration among researchers, clinicians, and the government.

Prognostic roles of leptin-signaling proteins, PD-L1, and tumor-infiltrating lymphocytes in surgically-resected biliary tract cancers.

BACKGROUND: Biliary tract cancers are rare, with a poor patient prognosis. Leptin and programmed death-ligand 1 (PD-L1) influence CD8+ and forkhead box P3 (FOXP3)+ lymphocytes, and thus, cancer cell growth. We aimed to define the prognostic implications of these variables and the clinicopathological features of biliary tract cancers. METHODS: Immunohistochemistry for leptin signaling-related proteins (leptin, leptin receptor, pSTAT3, extracellular-regulated kinase, mammalian target of rapamycin), PD-L1, CD8, and FOXP3 and in situ hybridization for Epstein-Barr virus-encoded small RNAs were performed in 147 cases of surgically-resected biliary tract cancers. RESULTS: Immune cell PD-L1-positivity, tumor size < 3 cm, adjuvant chemotherapy, no recurrence, and early-stage tumors were correlated with better 5-year survival in the tumoral PD-L1(-) and leptin(-) subgroups, and extrahepatic cholangiocarcinoma through multivariate analysis (all p < 0.05). Immune cell PD-L1 and adjuvant chemotherapy lost its prognostic significance in the tumoral PD-L1+ and leptin+ subgroups. CONCLUSIONS: The prognostic implication of the variables may depend upon tumoral protein expression and the anatomical site. Immune cell PD-L1-positivity and the administration of adjuvant chemotherapy may indicate the favorable survival of patients with surgically-resected biliary tract cancers, specifically, in the tumoral PD-L1(-) or tumor leptin(-) subgroups and extrahepatic cholangiocarcinoma. PD-L1- or leptin-targeted therapy combined with conventional chemotherapy may benefit the tumoral PD-L1+ or leptin+ subgroups.

A ZBTB16-RARα Variant of Acute Promyelocytic Leukemia with Concurrent Myeloid Sarcoma Presenting as Sudden Onset Paraplegia.

BACKGROUND: The co-occurrence of myeloid sarcoma (MS) and acute promyelocytic leukemia (APL) is a rare clinical event. METHODS: A 56-year-old man presented with lower extremity paralysis that occurred 6 hours before admission. Magnetic resonance imaging revealed an epidural mass. RESULTS: Histopathological examination demonstrated an extramedullary myeloid malignancy. Bone marrow examination showed abnormal promyelocytes and dysplasia, and an immunophenotyping study indicated very strong myeloperoxidase activity, suggesting APL. CONCLUSIONS: The final diagnosis given was spinal MS with a ZBTB16-RARα variant of APL. The possibility that patients with rapidly progressive neurologic symptoms could have MS and concurrent APL should be considered.

Automated histological classification for digital pathology images of colonoscopy specimen via deep learning.

Colonoscopy is an effective tool to detect colorectal lesions and needs the support of pathological diagnosis. This study aimed to develop and validate deep learning models that automatically classify digital pathology images of colon lesions obtained from colonoscopy-related specimen. Histopathological slides of colonoscopic biopsy or resection specimens were collected and grouped into six classes by disease category: adenocarcinoma, tubular adenoma (TA), traditional serrated adenoma (TSA), sessile serrated adenoma (SSA), hyperplastic polyp (HP), and non-specific lesions. Digital photographs were taken of each pathological slide to fine-tune two pre-trained convolutional neural networks, and the model performances were evaluated. A total of 1865 images were included from 703 patients, of which 10% were used as a test dataset. For six-class classification, the mean diagnostic accuracy was 97.3% (95% confidence interval [CI], 96.0-98.6%) by DenseNet-161 and 95.9% (95% CI 94.1-97.7%) by EfficientNet-B7. The per-class area under the receiver operating characteristic curve (AUC) was highest for adenocarcinoma (1.000; 95% CI 0.999-1.000) by DenseNet-161 and TSA (1.000; 95% CI 1.000-1.000) by EfficientNet-B7. The lowest per-class AUCs were still excellent: 0.991 (95% CI 0.983-0.999) for HP by DenseNet-161 and 0.995 for SSA (95% CI 0.992-0.998) by EfficientNet-B7. Deep learning models achieved excellent performances for discriminating adenocarcinoma from non-adenocarcinoma lesions with an AUC of 0.995 or 0.998. The pathognomonic area for each class was appropriately highlighted in digital images by saliency map, particularly focusing epithelial lesions. Deep learning models might be a useful tool to help the diagnosis for pathologic slides of colonoscopy-related specimens.

Characteristics of adverse reactions among antipsychotic drugs using the Korean Adverse Event Reporting System database from 2010 to 2019.

BACKGROUND: Retrospective studies using spontaneous reporting system databases have provided a great understanding of adverse drug reactions (ADRs) in the real world, complementing the data obtained from randomized controlled trials. However, there have been few reports on large-scale epidemiological studies on the adverse effects of antipsychotics in Asia. AIM: This study aimed to investigate the characteristics of antipsychotic ADRs using a nationwide pharmacovigilance database. METHODS: Data were collected from the Korea Adverse Event Reporting System database between 2010 and 2019. The study subjects were selected using the International Classification of Disease codes for diseases related to psychosis and Electronic Data Interchange codes for amisulpride, aripiprazole, clozapine, haloperidol, olanzapine, paliperidone, quetiapine, risperidone, and ziprasidone. The causality assessment of "possible," "probable," or "certain" by the World Health Organization-Uppsala Monitoring Center System causality category was selected. All data were descriptively analyzed. RESULTS: In total, 5067 adverse events associated with antipsychotic drugs were reported. The antipsychotics that commonly resulted in ADRs were quetiapine (47.7%), olanzapine (11.3%), and clozapine (10.7%). Serious ADRs were most commonly observed with clozapine. Gastrointestinal and central nervous system problems occurred within a month when ADRs were classified according to the time of onset. In contrast, metabolic and bone marrow-related symptoms occurred after long-term use. Sedation and nausea were the most common ADRs in children and adolescents, whereas constipation and dizziness were common in adults and the elderly. CONCLUSIONS: This study extends our knowledge of antipsychotic ADRs in the Asian population.

Molecular Subtypes Based on Genomic and Transcriptomic Features Correlate with the Responsiveness to Immune Checkpoint Inhibitors in Metastatic Clear Cell Renal Cell Carcinoma.

Clear cell renal cell carcinoma (ccRCC) has been reported to be highly immune to and infiltrated by T cells and has angiogenesis features, but the effect of given features on clinical outcomes followed by immune checkpoint inhibitors (ICIs) in ccRCC has not been fully characterized. Currently, loss of function mutation in PBRM1, a PBAF-complex gene frequently mutated in ccRCC, is associated with clinical benefit from ICIs, and is considered as a predictive biomarker for response to anti-PD-1 therapy. However, functional mechanisms of PBRM1 mutation regarding immunotherapy responsiveness are still poorly understood. Here, we performed targeted sequencing (n = 60) and whole transcriptomic sequencing (WTS) (n = 61) of patients with metastatic ccRCC treated by ICIs. By integrating WTS data from the CheckMate 025 trial, we obtained WTS data of 177 tumors and finally identified three molecular subtypes that are characterized by distinct molecular phenotypes and frequency of PBRM1 mutations. Patient clustered subtypes 1 and 3 demonstrated worse responses and survival after ICIs treatment, with a low proportion of PBRM1 mutation and angiogenesis-poor, but were immune-rich and cell-cycle enriched. Notably, patients clustered in the subtype 2 showed a better response and survival after ICIs treatment, with enrichment of PBRM1 mutation and metabolic programs and a low exhausted immune phenotype. Further analysis of the subtype 2 population demonstrated that GATM (glycine amidinotransferase), as a novel gene associated with PBRM1 mutation, plays a pivotal role in ccRCC by using a cell culture model, revealing tumor, suppressive-like features in reducing proliferation and migration. In summary, we identified that metastatic ccRCC treated by ICIs have distinct genomic and transcriptomic features that may account for their responsiveness to ICIs. We also revealed that the novel gene GATM can be a potential tumor suppressor and/or can be associated with therapeutic efficacy in metastatic ccRCC treated by ICIs.

Prognostic Significance of HER3 Expression in Patients with Cervical Cancer.

HER3 has been recognized to have an oncogenic role in various types of cancer. However, its prognostic significance has not been elucidated in cervical cancer. The aim of this study was to investigate the prognostic significance of HER3 expression in cervical cancer using immunohistochemistry (IHC). HER3 immunohistochemical staining was performed on the tumor tissue samples of 336 cervical cancer patients. The association between the clinicopathological characteristics and patient survival analysis was assessed according to HER3 expression. HER3 IHC staining was positive in 31.0% (104/336) of the cervical cancer patients. A higher proportion of adeno-/adenosquamous carcinoma was observed in the HER3-positive group (34.6%) than in the HER3-negative group (18.8%). In survival analysis, HER3 expression was significantly associated with poorer disease-free survival (DFS) and overall survival (OS) (p < 0.001 and p = 0.002, respectively). Multivariate analysis also indicated that HER3 expression was an independent prognostic factor for DFS (hazard ratio (HR) = 2.58, 95% confidence interval (CI) 1.42−4.67, p = 0.002) and OS (HR = 3.21, 95% CI, 1.26−8.14, p = 0.014). HER3 protein expression was a poor prognostic factor of survival in patients with cervical cancer. This finding could help to provide individualized management for these patients.

Analysis of Adverse Drug Reactions to First-Line Anti-Tuberculosis Drugs Using the Korea Adverse Event Reporting System.

BACKGROUND: Adverse drug reactions (ADRs) to first-line anti-tuberculosis (TB) drugs are common; however, there have been few reports of nationwide epidemiologic studies on ADRs to anti-TB drugs in Korea. This study aimed to investigate the clinical characteristics of various ADRs to first-line anti-TB drugs using a nationwide database of ADRs. METHODS: We used the Korea Adverse Event Reporting System (KAERS) database (2009-2018). The study subjects were selected using the Korean Standard Classification of Diseases codes for pulmonary and extrapulmonary TB and electronic data interchange codes for isoniazid (INH), rifampicin (RIF), ethambutol (ETB), and pyrazinamide (PZA). The causality assessment of "possible," "probable," or "certain" by World Health Organization-Uppsala Monitoring Center System causality category was selected. RESULTS: A total of 1,562,024 ADRs were reported in the KIDS-KAERS database from 2009 to 2018, where ADRs to first-line anti-TB drugs were 17,843 cases (1.14%). The most common causative drugs were RIF (28.7%), INH (24.0%), ETB (23.4%), and PZA (23.9%) in that order. 48.5% of cases were reported in the older patients (≥ 60 years). According to organ system, gastro-intestinal system disorder was most common (32.0%), followed by skin and appendage (25.9%), liver and biliary system (14.2%). Nausea was the most common ADR (14.6%), followed by hepatic enzyme elevation (14.2%), rash (11.7%), pruritus (9.1%), vomiting (8.9%), and urticaria (4.2%). Most ADRs appeared within 1 month, but ADRs such as neuropathy, paresthesia, hematologic abnormalities, renal function abnormalities and liver enzyme abnormality were also often reported after 2 months. CONCLUSION: Our data are clinically informative for recognizing and coping with ADRs of anti-TB drugs.

Sodium-Glucose Cotransporter-2 Inhibitor-Related Diabetic Ketoacidosis: Accuracy Verification of Operational Definition.

BACKGROUND: The most important aspect of a retrospective cohort study is the operational definition (OP) of the disease. We developed a detailed OP for the detection of sodium-glucose cotransporter-2 inhibitors (SGLT2i) related to diabetic ketoacidosis (DKA). The OP was systemically verified and analyzed. METHODS: All patients prescribed SGLT2i at four university hospitals were enrolled in this experiment. A DKA diagnostic algorithm was created and distributed to each hospital; subsequently, the number of SGLT2i-related DKAs was confirmed. Then, the algorithm functionality was verified through manual chart reviews by an endocrinologist using the same OP. RESULTS: A total of 8,958 patients were initially prescribed SGLT2i. According to the algorithm, 0.18% (16/8,958) were confirmed to have SGLT2i-related DKA. However, based on manual chart reviews of these 16 cases, there was only one case of SGLT2i-related DKA (positive predictive value = 6.3%). Even after repeatedly narrowing the diagnosis range of the algorithm, the effect of a positive predictive value was insignificant (6.3-10.0%, P > 0.999). CONCLUSION: Owing to the nature of electronic medical record data, we could not create an algorithm that clearly differentiates SGLT2i-related DKA despite repeated attempts. In all retrospective studies, a portion of the samples should be randomly selected to confirm the accuracy of the OP through chart review. In retrospective cohort studies in which chart review is not possible, it will be difficult to guarantee the reliability of the results.

Genomic Features and Clinical Implications of Intraductal Carcinoma of the Prostate.

Intraductal carcinoma of the prostate (IDC-P) is a rare and unique form of aggressive prostate carcinoma, which is characterized by an expansile proliferation of malignant prostatic epithelial cells within prostatic ducts or acini and the preservation of basal cell layers around the involved glands. The vast majority of IDC-P tumors result from adjacent high-grade invasive cancer via the retrograde spreading of tumor cells into normal prostatic ducts or acini. A subset of IDC-P tumors is rarely derived from the de novo intraductal proliferation of premalignant cells. The presence of IDC-P in biopsy or surgical specimens is significantly associated with aggressive pathologic features, such as high Gleason grade, large tumor volume, and advanced tumor stage, and with poor clinical courses, including earlier biochemical recurrence, distant metastasis, and worse survival outcomes. These architectural and behavioral features of IDC-P may be driven by specific molecular properties. Notably, IDC-P possesses distinct genomic profiles, including higher rates of TMPRSS2-ERG gene fusions and PTEN loss, increased percentage of genomic instability, and higher prevalence of germline BRCA2 mutations. Considering that IDC-P tumors are usually resistant to conventional therapies for prostate cancer, further studies should be performed to develop optimal therapeutic strategies based on distinct genomic features, such as treatment with immune checkpoint blockades or poly (adenosine diphosphate-ribose) polymerase inhibitors for patients harboring increased genomic instability or BRCA2 mutations, as well as genetic counseling with genetic testing. Patient-derived xenografts and tumor organoid models can be the promising in vitro platforms for investigating the molecular features of IDC-P tumor.

COVID-19 vaccine-related axillary lymphadenopathy in breast cancer patients: Case series with a review of literature.

PURPOSE: Lymphadenopathy (LAP) after COVID-19 vaccination in patients with a diagnosis of cancer has been challenging. We analyzed imaging and clinical features from early cases of axillary LAP in six COVID-19 vaccine recipients with a history of breast cancer. METHOD: Among the patients with a history of breast cancer and recent COVID-19 vaccine administration, six patients who showed isolated axillary LAP were gathered. Radiologic features were reviewed from breast ultrasound, chest computed tomography, and breast magnetic resonance imaging. Clinical and pathological information were obtained for analysis. RESULTS: The interval between ultrasound detection of LAP and last COVID-19 vaccine administration ranged from 14 to 28 days (mean 21.67 days). Round shape of the lymph node and irregular cortex were noted in 2 and 0 cases, respectively. Mean maximum cortical thickness, length to width ratio and interval aggravation in maximum cortical thickening were 4.2 mm, 1.34, and 2.81-fold with cut-off value of 3 mm, 1.5, 2.0-fold, respectively. CONCLUSION: We observed axillary LAP ipsilateral to a recent vaccine administration persisting longer than what the Centers for Disease Control and Prevention announced. In our patients, COVID-19 vaccine-related LAP tended to show increased cortical thickness without cortical irregularity. Oncologist as well as radiologist should be familiar with the fact that COVID-19 vaccines, regardless of vaccine type or dosage, can frequently cause ipsilateral axillary LAP, showing some suspicious features more often than others, and can persist longer than anticipated so that both over- and underdiagnosis can be avoided. We report our observations in six patients and provide an exhaustive review of the published literature.

Prognostic Relevance of BRCA1 Expression in Survival of Patients With Cervical Cancer.

OBJECTIVE: BRCA1 expression can be lost by a variety of mechanisms including germline or somatic mutation and promotor hypermethylation. Given the potential importance of BRCA1 loss as a predictive and prognostic biomarker in several cancers, the objective of this study was to investigate BRCA1 expression using immunohistochemistry (IHC) in cervical cancer and its possible prognostic relevance. METHODS: Seventy patients with cervical cancer were enrolled in this study. Samples from each tumor were stained for BRCA1 and reviewed independently by gynecologic pathologists blinded to the BRCA status. Kaplan-Meier methods were used to estimate overall survival according to BRCA1 expression. Differentially expressed genes (DEGs) by BRCA1 expression were selected using GSE44001 dataset, which included 300 samples treated with radical hysterectomy. In addition, cox regression analysis with backward elimination was performed to select independent prognostic markers. Gene set enrichment analysis (GSEA) was done using these DEGs. RESULTS: BRCA1 IHC was positive in 62.9% (44/70) of cases. Patients with BRCA1 expression showed better overall survival (100% vs. 76.2%, HR 0.20, 95% CI 0.04 - 0.99, p = 0.028) than those without BRCA1 expression. Analysis of gene expression profiles according to BRCA1 expression identified 321 differentially expressed mRNAs. Gene set enrichment analysis results showed two dysregulated pathways (VEGF_A_UP.V1_DN and E2F1_UP.V1_UP). Of these DEGs, alterations of 20 gene signatures were found to be independently associated with survival outcomes of patients. CONCLUSIONS: BRCA1 expression in cervical cancer tissue is associated with survival. In addition, the identification of specific gene alterations associated with BRCA1 expression could help to provide individualized prediction in these patients.

Validation of Potential Protein Markers Predicting Chemoradioresistance in Early Cervical Cancer by Immunohistochemistry.

BACKGROUND: In a previous study, a proteomic panel consisting of BCL-2, HER2, CD133, CAIX, and ERCC1 significantly predicted survival in patients with locally advanced cervical cancer. However, the prognostic significance of these proteins has not been assessed in early cervical cancer. The present study investigated the clinical significance and chemoradioresistance prediction power of these proteins in patients with early-stage cervical cancer. MATERIALS AND METHODS: BCL-2, HER2, CD133, CAIX, and ERCC1 expression was determined by the immunohistochemical staining of 336 cervical cancer tissue microarrays. The associations of these proteins with clinicopathologic characteristics and disease progression were assessed. RESULTS: There was a trend of low CAIX expression (p=0.082) and high ERCC1 expression (p=0.059) in patients with a favorable response to adjuvant radiation. High HER2 expression was significantly associated with shorter disease-free survival (DFS) in the total group (5-year DFS of 80.1% vs. 92.2%, p=0.004). A prognostic significance remained in multivariate analysis (Hazard ratio, HR=2.10, p=0.029). In the adjuvant radiation group, low CAIX and high ERCC1 expression indicated significantly unfavorable DFS (75.0% vs. 89.0%, p=0.026 and 76.8% vs. 88.6%, p=0.022, respectively). Low CAIX expression remained an independent prognostic marker in multivariate analysis (HR=0.45, p=0.037). The combined molecular-clinical model using random survival forest method predicted DFS with improved power compared with that of the clinical variable model (C-index 0.77 vs. 0.71, p=0.006). CONCLUSION: HER2, CAIX, and ERCC1 expression can be predictive protein markers for clinical outcomes in early cervical cancer patients treated primarily with radical surgery with or without adjuvant radiation.

Estimation of sodium-glucose cotransporter 2 inhibitor-related genital and urinary tract infections via electronic medical record-based common data model.

WHAT IS KNOWN AND OBJECTIVES: In Korea, the side effects of sodium-glucose cotransporter 2 inhibitors (SGLT2i) have not been clearly reported, aside from voluntary reporting. We aimed to develop detection algorithms for SGLT2i-related genital tract infections (GTIs) and urinary tract infections (UTIs) via a common data model (CDM), an electronic medical record-based database for supporting multi-hospital clinical research. We estimated the occurrence of GTIs and UTIs and-by assessing the status of each step of the algorithm-we also aimed to determine how clinicians responded to the SGLT2i-related GTIs and UTIs. METHODS: We targeted all patients who were prescribed SGLT2i at Catholic University Seoul St. Mary's Hospital and Hallym University Dongtan Sacred Heart Hospital from January 2014 to August 2018. We developed algorithms for detection of SGLT2i-related GTIs or UTIs that divided patients into "most likely," "possibly" or "less likely" categories of GTIs or UTIs. The numbers of patients at each step were extracted. RESULTS AND DISCUSSION: A total of 4253 patients received their first prescription of SGLT2i. According to the algorithm used in this study, the proportions of "most likely GTI" and "possibly GTI" were 0.9% (37 out of 4253) and 19.4% (826 out of 4253 patients), respectively. Similarly, the proportions of "most likely UTI" and "possibly UTI" were 0.9% (38 out of 4253) and 20.2% (858 out of 4253 patients), respectively. Compared to the various existing prospective studies, both GTIs and UTIs showed lower occurrence among patients who met "most likely" criteria and higher occurrence among those who met "possibly" criteria. When a GTI or UTI occurred or was suspected, the overall rate of discontinuing SGLT2i was 51.8% (1721 out of 3323). Despite a confirmed or suspected GTI and an UTI, 62.8% (1460 out of 2323) and 14.2% (142 out of 1000) of patients continued to take SGLT2i, respectively. The discontinuation rate for suspected GTIs was significantly lower than that for suspected UTIs (37.2% vs. 85.8%, p < 0.001). WHAT IS NEW AND CONCLUSION: In this study, although the GTIs appeared to have a similar occurrence as UTIs, however, the discontinuation rate of SGLT2i for suspected GTIs was relatively lower. Our study is novel in that we identified how the physicians approached SGLT2i-related GTIs or UTIs at each step in a real-world clinical practice setting. Although we could estimate SGLT2i-related GTIs and UTIs via CDM, we were limited in our ability to accurately detect mild drug side effects via CDM, which lacked data for operational definition.

Digital image analysis in pathologist-selected regions of interest predicts survival more accurately than whole-slide analysis: a direct comparison study in 153 gastric carcinomas.

Automatic quantification of biomarkers such as tumor-infiltrating lymphocytes and PD-L1 is one of the most studied topics in digital pathology image analysis (DIA). However, direct comparison between the DIA of a whole-slide image (WSI) and that of regions of interest (ROIs) chosen by pathologists has not been performed. In this study, we aimed to compare the prognostic value of tumor microenvironment markers CD8 and PD-L1, measured by DIA of WSIs and ROIs. We selected 153 primary gastric cancer tissues and stained them with CD8 and PD-L1. All IHC slides were scanned at ×200 magnification and ratios of CD8 and PD-L1 were measured in WSIs and ROIs from the invasive front, within the tumor, and the mucosa. Patients with high CD8 and PD-L1 ratios showed more favorable outcomes compared to those with low ratios. Pathologist-aided DIA predicted the survival of patients more accurately than WSI analysis (CD8, p = 0.025 versus p = 0.068; PD-L1, p = 0.008 versus p = 0.2). Although a high density of CD8+ T cells at the invasive front correlated best with patient survival, CD8 ratio in the mucosa could also predict patient outcome. In conclusion, CD8 and PD-L1 ratios measured by pathologist-aided DIA predicted survival more accurately than WSI analyses and ROIs at the invasive front correlated best with patient outcome.

An increase of CD8+ T cell infiltration following recurrence is a good prognosticator in HNSCC.

Programmed death-ligand 1 (PD-L1) expression and CD8-positive tumor-infiltrating lymphocyte (CD8+ TIL) infiltration are essential biomarkers for immune checkpoint inhibitor therapy. The objective of this study was to compare the expression of those biomarkers between initial and recurrent HNSCCs using paired analysis. Prognostic significance of those immunological changes was also investigated. Forty-two consecutive patients with locally recurrent HNSCCs were included. Immunohistochemical staining of CD8 and PD-L1 was done for both initial and recurrent tumor specimens. The IHC findings were verified with mRNA expression profiling. Also, the prognostic impact was analyzed based on overall survival (OS). Recurrent-to-initial (R/I) ratios of CD8+ TILs and PD-L1 were widely variable. CD8+ TIL density and PD-L1 expression decreased in 59.5% and 69% of patients, respectively (R/I ratio < 1). The R/I ratio of CD8A mRNA was significantly higher in patients with a CD8 R/I ratio > 1 (1.7 ± 1.5 vs. 0.6 ± 0.6, p = 0.042). CD8 R/I ratio (> 1) was a good prognosticator for OS (HR 0.293, 95% CI 0.091-0.945, p = 0.040). CD8+ TIL infiltration and PD-L1 expression changed variably following local recurrence of HNSCC. The increase of CD8+ TILs at recurrence was an excellent independent prognosticator.