Multi-omics analyses provide novel biological insights to distinguish lobular ductal types of invasive breast cancers.

BACKGROUND: Invasive lobular carcinoma (ILC) treatment is similar to invasive ductal carcinoma (IDC; now invasive carcinoma-no special type, IBC-NST), based on its intrinsic subtype. However, further investigation is required for an integrative understanding of differentially perturbed molecular patterns and pathways in these histotypes. METHODS: A dataset of 780 IDC and 201 ILC samples from the TCGA-BRCA project for cross-platform multi-omics was analyzed. We leveraged a consensus approach integrating different bioinformatic algorithms to analyze mutations, CNAs, mRNA, miRNA abundance, methylation, and protein abundance to understand the complex crosstalks that distinguish ILC and IDC samples. A histotype-matched comparison was performed. We performed Cox survival analyses for prognosis based on our identified 53 histotype-specific and four discordant genes. RESULTS: Approximately 90% of ILC cases were of the luminal subtype. Somatic mutations in CDH1 were higher in ILC than in IDC (FDR-adjusted p < 0.01). Fifty-three significant oncogenic or tumor-suppressive DEGs were identified in a single histotype. PPAR signaling and lipolysis regulation in adipocytes were significantly enriched in ILC tumors. CDH1 protein had the highest differential abundance (AUC: 0.85). Moreover, BTG2, GSTA2, GPR37L1, and PGBD5 amplification was associated with poorer OS in ILC compared with no alteration. RIMS2, NACA4P, MYC, ZFPM2, and POU5F1B amplification showed a lower overall survival in patients with IDC. miR-195 showed an IDC-specific downregulation, causing overexpression of CCNE1. Integrative multi-omics supervised analysis identified 296 differentially expressed genes that successfully distinguished IDC and ILC histotypes. CONCLUSIONS: Our findings identify novel molecular candidates that potentially drive and modify the disease differentially among these histotypes.

Analysis of the pan-Asian subgroup of patients in the NALA Trial: a randomized phase III NALA Trial comparing neratinib+capecitabine (N+C) vs lapatinib+capecitabine (L+C) in patients with HER2+metastatic breast cancer (mBC) previously treated with two or more HER2-directed regimens.

PURPOSE: Neratinib, an irreversible pan-HER tyrosine kinase inhibitor, has demonstrated systemic efficacy and intracranial activity in various stages of HER2+breast cancer. NALA was a phase III randomized trial that assessed the efficacy and safety of neratinib+capecitabine (N+C) against lapatinib+capecitabine (L+C) in HER2+ metastatic breast cancer (mBC) patients who had received ≥ 2 HER2-directed regimens. Descriptive analysis results of the Asian subgroup in the NALA study are reported herein. METHODS: 621 centrally assessed HER2+ mBC patients were enrolled, 202 of whom were Asian. Those with stable, asymptomatic brain metastases (BM) were eligible for study entry. Patients were randomized 1:1 to N (240 mg qd) + C (750 mg/m2 bid, day 1-14) with loperamide prophylaxis or to L (1250 mg qd) + C (1000 mg/m2 bid, day 1-14) in 21-day cycles. Co-primary endpoints were centrally assessed progression-free survival (PFS) and overall survival (OS). Secondary endpoints included time to intervention for central nervous system (CNS) disease, objective response rate, duration of response (DoR), clinical benefit rate, and safety. RESULTS: 104 and 98 Asian patients were randomly assigned to receive N+C or L+C, respectively. Median PFS of N+C and L+C was 7.0 and 5.4 months (P = 0.0011), respectively. Overall cumulative incidence of intervention for CNS disease was lower with N+C (27.9 versus 33.8%; P = 0.039). Both median OS (23.8 versus 18.7 months; P = 0.185) and DoR (11.1 versus 4.2 months; P < 0.0001) were extended with N+C, compared to L+C. The incidences of grade 3/4 treatment emergent adverse events (TEAEs) and TEAEs leading to treatment discontinuation were mostly comparable between the two arms. Diarrhea and palmar-plantar erythrodysesthesia were the most frequent TEAEs in both arms, similar to the overall population in incidence and severity. CONCLUSION: Consistent with the efficacy profile observed in the overall study population, Asian patients with HER2+ mBC, who had received ≥ 2 HER2-directed regimens, may also benefit from N+C. No new safety signals were noted. CLINICAL TRIAL REGISTRATION: NCT01808573.

Performance enhancement of procalcitonin by high-sensitivity C-reactive protein at the optimal cutoff in predicting bacteremia in emergency department adult patients.

Pathogenic bacteremia portends a high mortality risk in adult patients admitted to an Emergency Department (ED). This study aims to investigate the effect of adding high-sensitivity C-reactive protein (hs-CRP) to procalcitonin (PCT) and lactate in predicting bacteremia, Gram-negative (GNB) and Gram-positive bacteremia (GPB), using the optimal cutoff derived from the receiver operating characteristics analysis. We evaluated the diagnostic measures, including the positive-test likelihood (LR+), the negative-test likelihood (LR-), and the diagnostic odds ratio (DOR) using a single-center retrospective analysis design. This Standards for Reporting Diagnostic-compliant study comprised 886 consecutive adults who were admitted to the ED in 2010; to this cohort, a 22.2% prevalence of true bacteremia was subsequently confirmed. At the cutoff of 3.9 µg/L, PCT had a DOR of 5.3 (95% confidence interval [CI]: 3.76-7.61) and LR + of 2.8 (95% CI: 2.3-3.4) in predicting overall bacteremia. Elevated PCT and lactate (cutoff at 2 mmol/L), increased the DOR and LR + to 6.3 (95% CI: 4.27-9.29) and 4.0 (95% CI: 3.1-5.2). The DOR and LR + were further improved to 7.1 (95% CI: 4.2-11.95) and 5.6 (95% CI: 3.7-8.6), respectively, when hs-CRP at the cutoff of 1238 nmol/L was added to PCT plus lactate. High-sensitivity CRP at the cutoff of 1,255 nmol/L can enhance the discriminative power raising DOR and LR + values for GPB. The elevation of hs-CRP at the optimal cutoff might improve the diagnostic performance to predict unspecified bacteremia and GPB, but not GNB.

Primary Vaginal Melanoma With Rhabdoid Features: A Case Report and Literature Review.

Primary vaginal melanoma is a rare mucosal neoplasm, which is more aggressive than cutaneous melanoma. Information regarding its morphologic patterns is limited. In particular, the rhabdoid phenotype, mostly observed in metastatic or recurrent cutaneous melanomas, has yet to be reported at this anatomic location. Hence, a potential diagnostic difficulty may arise because of the inability to recognize this unusual histologic variant and its immunohistochemical aberrance. In this report, we describe the case of a primary vaginal melanoma in a 62-year-old woman, who exhibited both rhabdoid and small blue round cell morphologies, absence of S100 protein, and aberrant expression of desmin, CD56, and FLI-1. This report can facilitate the task of expanding the morphologic spectrum of vaginal melanoma, and prevent misdiagnosis and inadequate medical treatment.

Risk of Autoimmune Disease in Adults with Chronic Insomnia Requiring Sleep-Inducing Pills: A Population-Based Longitudinal Study.

BACKGROUND: Recent studies indicate that chronic insomnia is associated with the development of certain somatic diseases. Whether it would be associated with the development of an autoimmune disease (AID) was unknown. OBJECTIVE: We aimed to examine the association and quantify the magnitude of risk for AID in individuals suffering from chronic insomnia requiring sleep-inducing pills. DESIGN: This was a population-based, nationwide longitudinal study. PARTICIPANTS: Using a claims data set containing 1 million randomly sampled, insured subjects derived from the National Health Insurance Research Database, we assembled a chronic insomnia group and a 1:3 propensity score-matched comparison group (CP), which were balanced in terms of sex, age, insurance premium, urbanization, alcohol use disorder, smoking-related diagnoses, and morbid obesity. MAIN MEASURES: Person-time data with incidence rate, adjusted hazard ratios (aHR) by the Cox model, AID-free survival functions compared with the log-rank test, and a sensitivity analysis on the time lag effect were presented. Incident AID within the first year of follow-up were excluded. The error rate was controlled using the Benjamini-Hochberg procedure. KEY RESULTS: With 39,550 and 129,914 person-years' follow-up for the chronic insomnia and CP groups (n = 5,736 and 17,208), respectively, we found an increased risk for subsequent AID, representing a 70 % increase in the aHR (1.7; 95 % confidence interval [CI], 1.5-1.9, p < 0.0001). A positive association between chronic insomnia and primary Sjögren's syndrome (pSS) was observed (aHR, 1.3; 95 % CI, 1.1-1.6). Sensitivity analysis disclosed that AID risk was even stronger after 5 years of follow-up (aHR, 2.0; 95 % CI, 1.7-2.4). CONCLUSION: Chronic insomnia requiring sleep-inducing pills may be associated with a 70 % increased risk for future AID, particularly pSS.

Cancer risk in East Asian patients associated with acquired haemolytic anaemia: a nationwide population-based cohort study.

BACKGROUND: This study investigated whether patients with acquired haemolytic anaemia (AHA) would have elevated cancer risk including that for non-haematological solid tumours. We further examined whether the cancer risk would be different between patients with autoimmune type AHA (AIHA) and patients of non-AIHA. METHODS: Using nationwide population-based insurance claims data of Taiwan we identified a cohort of patients with AHA with no pre-existing cancer, (n = 3902) and a comparison cohort (n = 39020) without AHA, frequency-matched by gender, age, urbanization of residency and diagnosis date. Incidence and Cox method estimated adjusted hazard ratios (aHR) of cancers controlling covariates by the end of 2010 were calculated. Risks between patients with AIHA and non-AIHA were compared. Sensitivity analysis was carried out to measure the risk of cancer between patients with and without AHA by follow-up years. RESULTS: Patients with AHA had a 90% greater incidence of cancer than controls, with an aHR of 1.78 (95% confidence interval (CI), 1.50-2.12)]. The overall aHRs of cancer for patients with AIHA and non-AIHA were 2.01 (95% CI, 1.56-2.59) and 1.87 (95% CI, 1.53-2.29), respectively, compared with the comparison cohort. The aHRs for lymphatic-haematopoietic malignancy were 19.5 and 9.59 in the AIHA and non-AIHA cohorts, respectively. No hazard of colorectal, lung, liver or breast cancer was significant. CONCLUSIONS: There is a near 2-fold elevated risk for subsequent cancer in patients with AHA, particularly for lymphatic-haematopoietic malignancy, which is much greater for patients with AIHA than non-AIHA. These findings can help clinicians decide patient-centred personalized long-term management.

Pazopanib as a second-line treatment for non-cytokine-treated metastatic renal cell carcinoma: a meta-analysis of the effect of treatment.

BACKGROUND: The currently recommended treatment algorithm for patients with advanced renal cell carcinoma who fail the first-line targeted therapy does not normally include pazopanib as a second-line treatment option. It would therefore be of interest to determine the efficiency of pazopanib in this setting in terms of the partial response rate (PRR), disease control rate (DCR), and progression-free survival (PFS). METHODS: Peer-reviewed clinical reports without language restriction, both full papers and conference abstracts, which assessed the second-line use of pazopanib following failure of first-line non-cytokine-targeted therapy, were included. After the literature retrieval, we conducted a Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA)-compliant systematic review of the literature and meta-analysis of the size of the effect of each outcome measure (PRR, DCR, and PFS). The effect size and 95 % confidence interval (CI) were calculated using fixed-effect or random-effects models based on the heterogeneity represented by I(2) of selected studies. Meta-analysis forest plots with a fixed-effect model showing the PRR and DCR were created. RESULTS: Our results show that there are no available comparative studies on pazopanib second-line treatment. Only phase II trials or retrospective analysis reports were retrievable. Six studies (comprising 217 patients) were included in the qualitative and quantitative analysis. Pazopanib as a second-line treatment resulted in a PRR of 23 % (95 % CI, 17-31 %; I(2) = 52.6 %) and a DCR of 73 % (95 % CI, 65-80 %; I(2) = 0.00 %). The meta-analysis with fixed-effect model revealed that PFS was 6.5 months (95 % CI, 5.6-7.5 months; I(2) = 86.2 %). CONCLUSIONS: In conclusion, the effectiveness and indication of pazopanib for use in the second-line setting has not yet been examined in-depth; however, this meta-analysis has shown that the treatment effects in terms of PRR, DCR, and PFS may be similar to other well-studied second-line targeted therapies. Rigorous comparative phase III trials testing this hypothesis are required.

The Risks for Ovarian, Endometrial, Breast, Colorectal, and Other Cancers in Women With Newly Diagnosed Endometriosis or Adenomyosis: A Population-Based Study.

OBJECTIVE: Recent studies report a link between endometriosis and ovarian cancer (OC). Using a population-based cohort study to confirm the association between endometriosis and cancer is desirable. We thus examined the magnitude of the risks of OC, endometrial cancer (EC), breast cancer, colorectal cancer (CRC), and other cancers in women with newly diagnosed endometriosis or adenomyosis (internal endometriosis). METHODS/MATERIALS: Women older than 20 years with claims data between 2003 and 2005 were identified from the Longitudinal Health Insurance Dataset containing 1 million individuals randomly sampled from the National Health Insurance Research Database. Those with preexisting malignancies, hysterectomy, or oophorectomy were excluded. The endometriosis cohort (n = 2266, including 768 cases of pure adenomyosis) and comparison cohort (n = 9064), formed by 1:4 matching, were followed up until incidence cancer, dropout, or December 31, 2008. Outcome measures included cancer incidence and adjusted hazard ratio by Cox model adjusted for age group, comorbidities, and endometriosis medication use. RESULTS: With 9842 person-years of follow-up in endometriosis cohort and 36,274 person-years of follow-up in comparison cohort, there were increased risks of all cancers (adjusted hazard ratio, 1.8; 95% confidence interval, 1.4-2.4), OC (4.56, 1.72-12.11), and EC (4.05, 1.20-13.66). The ovarian endometriosis group was associated with increased risk of subsequent OC (4.37, 1.07-17.83). The adenomyosis group was strongly associated with both OC (5.50, 1.95-15.50) and EC (5.13, 1.36-19.40). Increased risk of subsequent CRC was observed in women with adenomyosis with coexistent endometriosis at other sites (13.04, 2.21-77.04). However, no statistically significant increased risk of breast or other cancers was observed. CONCLUSIONS: Having limitations such as lacking of parity information which may affect the magnitude of risk estimates, this study demonstrates that ovarian endometriosis has a 4-fold increased risk of OC. Adenomyosis may associate with a 4- to 5-fold increased risk of OC and EC, and unexpectedly, a 13-fold increased risk of CRC.

Population-based cohort study on the risk of malignancy in East Asian children with juvenile idiopathic arthritis.

BACKGROUND: To investigate the association and magnitude of risk between JIA, its associated treatment and cancer development in Taiwanese children. METHODS: Nationwide population-based 1:4 age- and gender-matched retrospective cohort study was designed using the National Health Insurance Research Database of Taiwan. A cohort of 2,892 children <16 years old with JIA was formed as well as a non-JIA cohort of 11,568 in year 2003 to 2005. They were followed up till a diagnosis of malignancy or up to 8 years until 2010. Relative risk (RR), incidence rate ratio (IRR), and adjusted hazard ratio (aHR) of developing malignancy were calculated. RESULTS: The female to male ratio was 0.79:1. There were 3 cases of incident cancer in the "MTX use, biologics-naïve" group, only 1 in the anti-TNF biologics-containing group and 29 in the "both MTX- and biologics-naïve" group, in comparison, there were 50 cases of cancer in the non-JIA comparator group. During a 16114.16 patient-years follow-up, the RR and IRR for developing a malignancy in both methotrexate- and anti-tumor necrosis factor (TNF) biologics-naïve JIA children were 2.75 (95% confidence interval, 1.75 - 4.32) and 3.21 (2.01 - 5.05), respectively. For leukemia, the IRR was 7.38 (2.50 - 22.75); lymphoma, 8.30 (1.23 - 69.79); and soft tissue sarcoma, 11.07 (0.84 - 326.4). The IRR of other cancers was 2.08 (1.11 - 3.71). The aHR on cancer risk was 3.14 (1.98 - 4.98) in methotrexate- and biologics-naïve group. There were no statistically significant increased risk in JIA patients treated with methotrexate and/or anti-TNF biologics. CONCLUSIONS: Compared with children without JIA, children with JIA have 3-fold increase of risk on malignancy in East Asia. Seemingly neither methotrexate nor anti-TNF biologics increases the risk further.

From apparent pseudoprogression to durable complete remission of expansile destructive sinonasal mucosal melanoma under pembrolizumab after primary endoscopic resection: A case report.

Head and neck mucosal melanoma is a rare but highly aggressive malignant tumor that usually has a poor prognosis. We describe a 53-year-old male patient, having no any medical history, with left maxillary sinus mucosal melanoma causing bilateral lung metastasis. Rapid tumor regrowth was observed on the 49th day after radical tumor resection. Subsequent pembrolizumab immunotherapy initially elicited pseudoprogression, for which add-on radiation therapy was carried out during maintenance pembrolizumab. A gradual decrease in tumor volume and complete remission were observed by a series of magnetic resonance imaging scans and lung windows of a computer tomography scan of chest. At the 29-month follow-up, the patient was rendered disease-free. In conclusion, head and neck mucosal melanoma may regrow rapidly after surgical resection and pseudoprogression could be frightening during immunotherapy. Subsequent single-agent pembrolizumab plus localized radiation therapy aiming to release more tumor antigens may offer the possibility of long-term remission.

Successful Recanalization and Neurological Restoration in Cancerous Embolic Cerebral Infarction via Endovascular Stent-Retriever Embolectomy.

Mechanical thrombectomy has emerged as a promising treatment for acute ischemic stroke caused by large vessel occlusion. However, cases involving cancerous emboli retrieved during endovascular embolectomy are rare. We present a case of a 65-year-old man with a history of heavily treated rectal cancer, who developed a middle cerebral artery (MCA) infarction due to metastatic adenocarcinoma. The patient presented with sudden onset right-side weakness, right facial palsy, global aphasia, and left gaze deviation, with a National Institutes of Health Stroke Scale (NIHSS) score of 16. Following intravenous thrombolysis, endovascular thrombectomy was performed, achieving nearly complete recanalization. Pathological examination of the retrieved thrombus revealed metastatic adenocarcinoma of rectal origin. The patient's neurological deficits gradually improved, and he was successfully discharged to undergo further palliative therapy. This case underscores the importance of considering mechanical thrombectomy for patients with advanced solid organ malignancy presenting with acute ischemic stroke, even when the etiology could be a tumor embolus. Our findings highlight the potential for mechanical thrombectomy to restore neurological function in such cases, allowing patients to proceed to the next level of care with a reasonably good post-stroke quality of life.

Select gene mutations associated with survival outcomes in ER-positive ERBB2-negative early-stage invasive breast cancer: A single-institutional tissue bank study.

INTRODUCTION: The prognostic capability of targeted sequencing of primary tumors in patients with estrogen receptor-positive, human epidermal growth factor receptor-2-negative early-stage invasive breast cancer (EBC) in a real-world setting is uncertain. Therefore, we aimed to determine the correlation between a 22-gene mutational profile and long-term survival outcomes in patients with ER+/ERBB2- EBC. PATIENTS AND METHODS: A total of 73 women diagnosed with ER+/ERBB2- EBC between January 10, 2004, and June 2, 2008, were followed up until December 31, 2022. Univariate and multivariate Cox models were constructed to plot the relapse-free survival (RFS) and overall survival (OS). The log-rank test derived p-value was obtained. For external validation, we performed a survival analysis of 1163 comparable patients retrieved from the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) dataset. RESULTS: At follow-up, 16 (21.9%) patients had relapsed, while 21 (nearly 29%) harbored mutant genes. Thirty-three missense mutations were detected in 14 genes. The median ages were 51 and 46 years in patients with and without mutations, respectively. Patients with any mutation had a 1.85-fold higher risk of relapse (hazard ratio [HR]: 1.85, 95% confidence interval [CI]: 0.60-5.69) compared to those without any mutation. Patients who harbored any of the six genes (MAP2K4, FGFR3, APC, KIT, RB1, and PTEN) had a nearly 6-fold increase in the risk of relapse (HR: 5.82, 95% CI: 1.31-18.56; p = 0.0069). Multivariate Cox models revealed that the adjusted HR for RFS and OS were 6.67 (95% CI: 1.32-27.57) and 8.31 (p = 0.0443), respectively. METABRIC analysis also demonstrated a trend to significantly worse RFS (p = 0.0576) in the subcohort grouped by having a mutation in any of the six genes. CONCLUSIONS: Our single-institution tissue bank study of Taiwanese women with ER+/ERBB2- EBC suggests that a novel combination of six gene mutations might have prognostic capability for survival outcomes.

Gout and subsequent increased risk of cardiovascular mortality in non-diabetics aged 50 and above: a population-based cohort study in Taiwan.

BACKGROUND: Limited data are available on the risk ratios for fatal cardiovascular disease (CVD) outcome from gout and chronic kidney disease (CKD) in non-diabetic individuals. METHODS: Nationwide population-based retrospective prospective study with a 5-year follow-up to investigate the association between physician-diagnosed gout and CKD in non-diabetics aged 50 and above who had no pre-existing serious CVD and the subsequent risk of death from CVD. Hazard ratios (HR) of CVD mortality were adjusted for gender, age, smoking- and alcoholism-related diagnoses, hypertension, hyperlipidemia, atrial fibrillation and Charlson's comorbidity index score. RESULTS: A case cohort (n=164,463) having gout and a control cohort (n=3,694,377) having no gout were formed. The prevalence of gout in this study was 4.26% whereas that of gout plus CKD was 8.17%. Male to female ratio among the individuals with gout was 3.2:1. The relative risk (RR) of subsequent cardiovascular mortality between the case and control cohort was 1.71 (95% confidence interval (CI), 1.66-1.75). The presence of CKD in nondiabetic subjects with no gout (control group) has a RR of CVD mortality at 3.05 (95% CI, 2.94-3.15). The presence of gout has protective effect on subjects with CKD with a RR of 1.84 (95% CI, 1.71-1.98). As compared with individuals with no gout, the adjusted HR (aHR) for CVD mortality among the individuals with gout was 1.10 (95% CI 1.07-1.13). In a Cox model, when compared with subjects having neither gout nor CKD, the aHR in subjects with no gout but with CKD is 1.76 (95% CI, 1.70-1.82); in subjects with gout but without CKD, 1.10 (1.07-1.13); interestingly, the aHR is attenuated in subjects with concomitant gout plus CKD which is 1.38 (1.29-1.48). CONCLUSIONS: Among non-diabetic individuals aged 50 years or above who had no preceding serious CVD, those with gout were 1.1 times more likely to die from CVD as were individuals without gout. The presence of gout appears to attenuate the risk of subsequent CV mortality in subjects with CKD. Further studies should focus on finding an explanation for the protective effect of gout on CV mortality in patients with CKD.

Cross-Platform in-silico Analyses Exploring Tumor Immune Microenvironment with Prognostic Value in Triple-Negative Breast Cancer.

Introduction: Only a proportion of triple-negative breast cancer (TNBC) is immunotherapy-responsive. We hypothesized that the tumor microenvironment (TME) influences the outcomes of TNBC and investigated the relevant signaling pathways. Materials and Methods: Immune score (IS) and stromal score (SS) were calculated using the ESTIMATE and correlated with the overall survival (OS) in TNBC. RNA-seq data from 115 TNBC samples and 112 normal adjacent tissues were retrieved. Validations in the methylation levels in 10 TNBC and five non-TNBC cell lines were obtained. Cox model overall survival (OS) validated the derived transcription factor (TF) genes in cBioPortal breast cancer patients. Results: SS-low predicts a higher OS compared with SS-high patients (P = 0.0081 IS-high/SS-low patients had better OS (P = 0.045) than IS-low/SS-high patients. More macrophages were polarized to the M2 state in patients with IS-low/SS-high patients (P < 0.001). Moreover, CIBERSORTx showed more CD8+ cytotoxic T-cells in IS-high/SS-low patients (p = 0.0286) and more resting NK cells in the IS-low/SS-high TME (P = 0.0108). KEGG pathway analysis revealed that overexpressed genes were enriched in the IL-17 and cytokine-cytokine receptor interaction pathways. The lncRNA DRAIC, a tumor suppressor, was consistently deactivated in the 10 TNBC cell lines. On the cBioPortal platform, we validated that 13% of ER-negative, HER2-unamplified BC harbored IL17RA deep deletion and 25% harbored TRAF3IP2 amplification. On cBioPortal datasets, the nine altered TF genes derived from the X2K analysis showed significantly worse relapse-free survival in 2377 patients and OS in 4819 invasive BC patients than in the unaltered cohort. Conclusion: Of note, the results of this integrated in silico study can only be generalized to approximately 17% of patients with TNBC, in which infiltrating stromal cells and immune cells play a determinant prognostic role.

Long-term ambient hydrocarbon exposure and incidence of urinary bladder cancer.

Particulate matter and volatile organic compounds, including total hydrocarbons (THCs), are major ambient air pollutants. Primary nonmethane hydrocarbons (NMHCs) originate from vehicle emissions. The association between air pollution and urinary bladder cancer (UBC) is debatable. We investigated whether long-term exposure to ambient hydrocarbons increases UBC risk among people aged ≥ 20 years in Taiwan. Linkage dataset research with longitudinal design was conducted among 589,135 initially cancer-free individuals during 2000-2013; 12 airborne pollutants were identified. Several Cox models considering potential confounders were employed. The study outcomes were invasive or in situ UBC incidence over time. The targeted pollutant concentration was divided into three tertiles: T1/T2/T3. The mean age of individuals at risk was 42.5 (SD 15.7), and 50.5% of the individuals were men. The mean daily average over 10 years of airborne THC concentration was 2.25 ppm (SD 0.13), and NMHC was 0.29 ppm (SD 0.09). Both pollutants show long-term monotonic downward trend over time using the Mann-Kendall test. There was a dose-dependent increase in UBC at follow-up. UBC incidence per 100,000 enrollees according to T1/T2/T3 exposure to THC was 60.9, 221.2, and 651.8, respectively; it was 170.0/349.5/426.7 per 100,000 enrollees, corresponding to T1/T2/T3 exposure to NMHC, respectively. Without controlling for confounding air pollutants, the adjusted hazard ratio (adj.HR) was 1.83 (95% CI 1.75-1.91) per 0.13-ppm increase in THC; after controlling for PM2.5, adj.HR was even higher at 2.09 (95% CI 1.99-2.19). The adj.HR was 1.37 (95% CI 1.32-1.43) per 0.09-ppm increase in ambient NMHC concentration. After controlling for SO2 and CH4, the adj.HR was 1.10 (95% CI 1.06-1.15). Sensitivity analyses showed that UBC development risk was not sex-specific or influenced by diabetes status. Long-term exposure to THC and NMHC may be a risk factor for UBC development. Acknowledging pollutant sources can inform risk management strategies.

The role of the circadian clock in cancer hallmark acquisition and immune-based cancer therapeutics.

The circadian system temporally regulates physiology to maintain homeostasis. Co-opting and disrupting circadian signals appear to be distinct attributes that are functionally important for the development of a tumor and can enable or give rise to the hallmarks that tumors use to facilitate their initiation, growth and progression. Because circadian signals are also strong regulators of immune cell proliferation, trafficking and exhaustion states, they play a role in how tumors respond to immune-based cancer therapeutics. While immuno-oncology has heralded a paradigm shift in cancer therapeutics, greater accuracy is needed to increase our capability of predicting who will respond favorably to, or who is likely to experience the troubling adverse effects of, immunotherapy. Insights into circadian signals may further refine our understanding of biological determinants of response and help answer the fundamental question of whether certain perturbations in circadian signals interfere with the activity of immune checkpoint inhibitors. Here we review the body of literature highlighting circadian disruption as a cancer promoter and synthesize the burgeoning evidence suggesting circadian signals play a role in how tumors respond to immune-based anti-cancer therapeutics. The goal is to develop a framework to advance our understanding of the relationships between circadian markers, cancer biology, and immunotherapeutics. Bolstered by this new understanding, these relationships may then be pursued in future clinical studies to improve our ability to predict which patients will respond favorably to, and avoid the adverse effects of, traditional and immune-based cancer therapeutics.

Extensive-Stage Small Cell Carcinoma Transformation From EGFR Del19-Mutant Lung Adenocarcinoma on Gefitinib at the Twelfth-Year Follow-Up Case Report.

INTRODUCTION: The acquired resistance mechanisms in patients with epidermal growth factor receptor (EGFR)-mutant lung cancer, particularly adenocarcinoma (ADC), following treatment with an EGFR tyrosine kinase inhibitor (TKI) have received extensive investigations. The phenotypic transformation to small cell carcinoma (SCCT) has been estimated to occur in approximately 3 to 10% of patients treated with an EGFR-TKI. The prognosis after SCCT is extremely poor. CASE STUDY: We report about SCCT that occurred 45 months after the initial diagnosis of ADC in an East Asian never-smoker woman with advanced-stage EGFR Del-19-mutant lung ADC treated with combined chemoradiotherapy before the era of insurance coverage for EGFR-TKIs in this country and subsequently gefitinib; deletion at codon 746-750 in exon 19 of the EGFR gene was ascertained in the original formalin-fixed paraffin-embedded lung biopsy tissue. Spinal cord compression at thoracic-12 level from SCCT was successfully relieved with neurosurgical treatment, chemotherapy with etoposide and cisplatin, and radiotherapy, while gefitinib treatment was maintained. Eleven months later, SCCT relapsed in the lung parenchyma, which was resected and was found to be sensitive to second-line weekly topotecan. Prophylactic cranial irradiation was subsequently administered. SCCT was confirmed by MALDI-TOF MS analysis of formalin-fixed paraffin-embedded tissues demonstrating the same exon 19 deletion. At the 12th-year follow-up, the patient remains relapse free with very good performance status. The novelty of this case is the successful interdisciplinary team effort to correct the spinal cord compression by maintaining the patient in an ambulatory state, non-stop use of gefitinib justified by the presence of activating EGFR mutation in SCCT tumor cells, and aggressive dose-intensive chemotherapy and radiotherapy for the SCCT that leads to an unprecedented prolonged remission and survival. This case also supports the observation that SCCT is chemotherapy sensitive, and thus, re-biopsy or complete tumor excision is recommended to understand the mutation profiles of the current tumor. Aggressive prudent administration of systemic chemotherapy obtaining optimal dose intensity leads to the successful management of the patient.

Late-onset epilepsy and subsequent increased risk of dementia.

Inflammation is considered as a key pathogenesis factor of dementia and epilepsy. However, epilepsy's association with dementia, particularly its role in the development of dementia, remains unclear. To evaluate the association between epilepsy and the risk of dementia, in Taiwan, we have now conducted a retrospective cohort study comprising 675 individuals (age, ≥50 years) with epilepsy and 2,025 matched control subjects without epilepsy. In order to match individuals diagnosed with epilepsy with those with no diagnosis of epilepsy (comparison cohort), we utilized exact matching at a ratio of 1:3. Compared with those in the comparison cohort, individuals in the epilepsy cohort had a significantly increased risk of developing dementia (adjusted hazard ratio = 2.87, p < 0.001). A similar result has been observed after stratifying for sex (adjusted hazard ratio in males = 2.95, p < 0.001; adjusted hazard ratio in females = 2.66, p < 0.001). To conclude, based on these data, epileptic individuals ≥50 years were at a greater risk of developing dementia than people who do not have epilepsy, which indicates that a diagnosis of epilepsy presents a greater risk for the development of dementia.