The Gleason grading system, currently the most powerful prognostic predictor of prostate cancer, is based solely on the tumor’s histological architecture and has high inter-observer variability. We propose an automated Gleason scoring system based on deep neural networks for diagnosis of prostate core needle biopsy samples. To verify its efficacy, the system was trained using 1133 cases of prostate core needle biopsy samples and validated on 700 cases. Further, system-based diagnosis results were compared with reference standards derived from three certified pathologists. In addition, the system’s ability to quantify cancer in terms of tumor length was also evaluated via comparison with pathologist-based measurements. The results showed a substantial diagnostic concordance between the system-grade group classification and the reference standard (0.907 quadratic-weighted Cohen’s kappa coefficient). The system tumor length measurements were also notably closer to the reference standard (correlation coefficient, R = 0.97) than the original hospital diagnoses (R = 0.90). We expect this system to assist pathologists to reduce the probability of over- or under-diagnosis by providing pathologist-level second opinions on the Gleason score when diagnosing prostate biopsy, and to support research on prostate cancer treatment and prognosis by providing reproducible diagnosis based on the consistent standards.
Objectives Ground-glass opacity (GGO) on computed tomography is associated with prognosis in early-stage non-small cell lung cancer (NSCLC) patients. However, the stratification of the prognostic value of GGO is controversial. We aimed to evaluate clinicopathologic characteristics of early-stage NSCLC based on the consolidation-to-tumor ratio (CTR), conduct multi-pronged analysis, and stratify prognosis accordingly. Methods We retrospectively investigated 944 patients with clinical stage IA NSCLC, who underwent curative-intent lung resection between August 2018 and January 2020. The CTR was measured and used to categorize patients into six groups (1, 0%; 2, 0–25%; 3, 25–50%; 4, 50–75%; 5, 75–100%; and 6, 100%). Results Pathologic nodal upstaging was found in 1.8% (group 4), 9.0% (group 5), and 17.4% (group 6), respectively. The proportion of patients with a high grade of tumor-infiltrating lymphocytes tended to decrease as the CTR increased. In a subtype analysis of patients with adenocarcinoma, all of the patients with predominant micro-papillary patterns were in the CTR > 50% groups, and most of the patients with predominant solid patterns were in group 6 (47/50, 94%). The multivariate analysis demonstrated that CTR 75–100% (hazard ratio [HR], 3.85; 95% confidence interval [CI], 1.58–9.36) and CTR 100% (HR, 5.58; 95% CI, 2.45–12.72) were independent prognostic factors for DFS, regardless of tumor size. Conclusion We demonstrated that the CTR could provide various noninvasive clinicopathological information. A CTR of more than 75% is the factor associated with a poor prognosis and should be considered when making therapeutic plans for patients with early-stage NSCLC.
Aims The prognostic role of EGFR mutations remains controversial. We aimed to evaluate the prognostic role of EGFR mutation in consideration of the IASLC histological grade in patients with resected early‐stage lung adenocarcinoma. Methods and results A total of 3297 patients with stages I–IIA resected lung adenocarcinoma who had had EGFR mutation tests between January 2014 and December 2019 at the Samsung Medical Center, Seoul, Korea were included. Recurrence‐free survival (RFS) was compared by EGFR mutation status (EGFR‐M+ versus EGFR‐WT) and IASLC histological grade (G1, G2 and G3). Cox proportional hazards models were used to estimate the adjusted HRs (aHRs) and 95% confidence intervals (CIs). Results Compared to the EGFR‐WT group, the EGFR‐M+ group had a significantly lower proportion of G3 tumour (16 versus 33%, P < 0.001). During a median follow‐up of 41.4 months, 376 patients experienced recurrence. After adjusting for histological grade, the aHR for recurrence comparing the EGFR‐M+ to the EGFR‐WT was 1.30 (95% CI = 1.04–1.62, P = 0.022). The EGFR‐M+ group had a significantly lower 5‐year RFS than the EGFR‐WT group among G3 patients (58.4 versus 71.5%, P < 0.001), but not among G1 and G2 patients. Conclusions EGFR mutation status was associated with a risk of recurrence after consideration of the IASLC histological grading, especially in G3 tumours. The results of this study would be useful for developing a new staging system and identifying a subset of patients who may benefit from adjuvant targeted therapy.
Acute placental villitis is very rare and believed to reflect overwhelming fetal sepsis in utero, commonly caused by Escherichia coli or group B streptococci. We present a case of intrauterine fetal death associated with acute placental villitis and acute necrotizing chorioamnionitis by early-onset group B streptococcal infection. A 36-year-old woman presented with decreased fetal movement and fever at 21 weeks of gestation. Ultrasound demonstrated intrauterine fetal death. After delivery, the placenta revealed multifocal neutrophilic infiltration in chorionic villi, most prominently beneath the trophoblast basement membrane, which was also accompanied by acute necrotizing chorioamnionitis. Gram-positive microorganisms were detected in villous vessels as well as in the major organs of the fetus, which was consistent with Streptococcus agalactiae (group B) cultured from maternal blood. Acute placental villitis should be recognized as evidence of fetal sepsis that often has lethal clinical outcome, as compared to intra-amniotic infection associated with acute chorioamnionitis alone.
Most malignant tumors originate from epithelial tissues in which tight junctions mediate cell–cell interactions. Tight junction proteins, especially claudin-3 (CLDN3), are overexpressed in various cancers. Claudin-3 is exposed externally during tumorigenesis making it a potential biomarker and therapeutic target. However, the development of antibodies against specific CLDN proteins is difficult, because CLDNs are four-transmembrane domain proteins with high homology among CLDN family members and species. Here, we developed a human IgG1 monoclonal antibody (h4G3) against CLDN3 through scFv phage display using CLDN3-overexpressing stable cells and CLDN3-embedded lipoparticles as antigens. The h4G3 recognized the native conformation of human and mouse CLDN3 without cross-reactivity to other CLDNs. The binding kinetics of h4G3 demonstrated a sub-nanomolar affinity for CLDN3 expressed on the cell surface. The h4G3 showed antibody-dependent cellular cytotoxicity (ADCC) according to CLDN3 expression levels in various cancer cells by the activation of FcγRIIIa (CD16a). The biodistribution of h4G3 was analyzed by intravenous injection of fluorescence-conjugated h4G3 which showed that it localized to the tumor site in xenograft mice bearing CLDN3-expressing tumors. These results indicate that h4G3 recognizes CLDN3 specifically, suggesting its value for cancer diagnosis, antibody-drug conjugates, and potentially as a chimeric antigen receptor (CAR) for CLDN3-expressing pan-carcinoma.
PurposeThe incidence of <i>BRAF</i> V600E mutation in non-small cell lung carcinoma (NSCLC) is lower than 2%, which poses difficulties in finding legitimate patients for targeted therapy. We investigated the predictive factors pertaining to <i>BRAF</i> V600E and the effectiveness of the VE1 antibody as a screening method for patient selection.Materials and MethodsThe study was designed into two steps. In a first group, <i>BRAF</i>-mutated NSCLCs were identified from sequencing data to determine the features of <i>BRAF</i> V600E mutation. The results of the first group helped the collection of adenocarcinomas with a papillary or micropapillary pattern but without <i>EGFR</i> or <i>ALK</i> alterations as a second group so that the frequency of <i>BRAF</i> V600E mutation could be calculated. The sensitivity and specificity of the VE1 were compared with <i>BRAF</i> V600E status. ResultsAmong 39 <i>BRAF</i>-mutated NSCLCs in the first group, 20 (51%) were V600E. <i>BRAF</i> V600E mutation was more common in female patients and showed no significant correlation with smoking status. Nineteen cases were adenocarcinomas without <i>EGFR</i> and <i>ALK</i> alterations. The most common patterns of invasion were papillary and micropapillary along with central fibrosis. The sensitivity and specificity of the VE1 were 90.0% and 92.3%, respectively. In the second group, 6.7% of cases were VE1-positive, indicating that the prevalence was significantly higher than that reported in previous studies (0.3-1.8%). Conclusion<i>BRAF</i> V600E-mutated NSCLCs could be enriched with the application of clinicopathologic parameters, which are not perfect. Therefore, additional VE1 immunohistochemistry may be useful as a screening method.
BackgroundTumor mutational burden (TMB) measurement is limited by low tumor purity of samples, which can influence prediction of the immunotherapy response, particularly when using whole-exome sequencing-based TMB (wTMB). This issue could be overcome by targeted panel sequencing-based TMB (pTMB) with higher depth of coverage, which remains unexplored.MethodsWe comprehensively reanalyzed four public datasets of immune checkpoint inhibitor (ICI)-treated cohorts (adopting pTMB or wTMB) to test each biomarker’s predictive ability for low purity samples (cut-off: 30%). For validation, paired genomic profiling with the same tumor specimens was performed to directly compare wTMB and pTMB in patients with breast cancer (paired-BRCA, n=165) and ICI-treated patients with advanced non-small-cell lung cancer (paired-NSCLC, n=156).ResultsLow tumor purity was common (range 30%–45%) in real-world samples from ICI-treated patients. In the survival analyzes of public cohorts, wTMB could not predict the clinical benefit of immunotherapy when tumor purity was low (log-rank p=0.874), whereas pTMB could effectively stratify the survival outcome (log-rank p=0.020). In the paired-BRCA and paired-NSCLC cohorts, pTMB was less affected by tumor purity, with significantly more somatic variants identified at low allele frequency (p<0.001). We found that wTMB was significantly underestimated in low purity samples with a large proportion of clonal variants undetected by whole-exome sequencing. Interestingly, pTMB more accurately predicted progression-free survival (PFS) after immunotherapy than wTMB owing to its superior performance in the low tumor purity subgroup (p=0.054 vs p=0.358). Multivariate analysis revealed pTMB (p=0.016), but not wTMB (p=0.32), as an independent predictor of PFS even in low-purity samples. The net reclassification index using pTMB was 21.7% in the low-purity subgroup (p=0.016).ConclusionsOur data suggest that TMB characterization with targeted deep sequencing might have potential strength in predicting ICI responsiveness due to its enhanced sensitivity for hard-to-detect variants at low-allele fraction. Therefore, pTMB could act as an invaluable biomarker in the setting of both clinical trials and practice outside of trials based on its reliable performance in mitigating the purity-related bias.
BackgroundWe reviewed a series of 188 resected pulmonary mucinous adenocarcinomas (MAs) to clarify the prognostic significance of lepidic and non-lepidic patterns.MethodsNon-lepidic patterns were divided into bland, non-distorted acini with uncertain invasiveness (pattern 1), unequivocal invasion into stroma (pattern 2), or invasion into alveolar spaces (pattern 3).ResultsThe mean proportion of invasive patterns (patterns 2 and 3) was lowest in small (≤ 3 cm) tumors, and gradually increased in intermediate (> 3 cm and ≤ 7 cm) and large (> 7 cm) tumors (8.4%, 34.3%, and 50.1%, respectively). Adjusted T (aT) stage, as determined by the size of invasive patterns, was positively correlated with adverse histologic and clinical features including older age, male sex, and ever smokers. aTis tumors, which were exclusively composed of lepidic pattern (n = 9), or a mixture of lepidic and pattern 1 (n = 40) without any invasive patterns, showed 100% disease- free survival (DFS). The aT1mi tumors, with minimal (≤ 5 mm) invasive patterns (n = 63), showed a 95.2% 5-year DFS, with recurrences (n = 2) limited to tumors greater than 3 cm in total size (n = 23). Both T and aT stage were significantly associated with DFS; however, survival within the separate T-stage subgroups was stratified according to the aT stage, most notably in the intermediatestage subgroups. In multivariate analysis, the size of invasive patterns (p = .020), pleural invasion (p < .001), and vascular invasion (p = .048) were independent predictors of recurrence, whereas total size failed to achieve statistical significance (p = .121).ConclusionsThis study provides a rationale for histologic risk stratification in pulmonary MA based on the extent of invasive growth patterns with refined criteria for invasion.
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