Objectives: Perineural invasion (PNI) was quantitatively analyzed in oral squamous cell carcinoma (OSCC) specimens obtained by radical surgery to correlate with survival outcomes. Methods: This is a ...retrospective study that reviewed the Cancer registry data between 2009 and 2015. Inclusion criteria were oral cavity cancer, treatment by radical surgery, presence of PNI, and available pathologic samples for S100 staining. Patients with M1 disease and those with synchronous or metachronous cancer during staging work-up were excluded. All pathologic samples were reviewed to confirm PNI status and processed by immunohistochemical staining for S100 to quantify PNI. Pathologic information and staging results were also reviewed, and clinical outcomes were analyzed. Results: The retrospective study included 92 patients; 63 had intratumoral PNI (IPNI) and 29 had extratumoral PNI (EPNI). The average number of PNI foci (APNI) was higher in the EPNI group than in the IPNI group (6.7 vs 3.8, t-test 2-tail significance = 0.021). The 3-year overall survival (OS) and time-to-recurrence (TTR) rates of all patients were 82.5% and 81.2%, respectively. Univariate analysis showed that pathological T4 or N2-3 stage correlated with poor OS, whereas APNI ≥4 correlated with poor TTR. In multivariate analysis, only the pathological N2-3 stage was significantly correlated with poor OS, whereas only APNI ≥ 4 was an independent factor of poor TTR. The 3-year TTR rates were 92.4% and 65.6% for diseases with APNI < 4 and ≥ 4, respectively (P = .008). Conclusions: In patients with OSCC with PNI, a greater amount of PNI identified by S100 staining indicated a poorer TTR regardless of stage and other prognostic factors. Quantification of PNI by S100 immunohistochemistry is a potential method for prognosis prediction.
Summary Beclin 1 plays a critical role not only in autophagy, but also in apoptosis and differentiation. The prognostic significance of beclin 1 in diffuse large B-cell lymphoma is largely ...unexplored. Immunohistochemical protein expression of beclin 1 in 118 tumor specimens from patients newly diagnosed with diffuse large B-cell lymphoma treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone regimen from 2003 to 2007 was analyzed. Beclin 1 expression was observed in 101 (85.6%) patients. Low beclin 1 expression was related to B symptoms ( P = .018), advanced Ann Arbor stage ( P = .009), International Prognostic Index of 2 or higher ( P = .049), elevated serum lactate dehydrogenase level ( P = .037), and poor outcome using the revised International Prognostic Index model ( P = .013). The complete remission rate after standard treatment was higher in patients with high beclin 1 expression than in those with low beclin 1 expression (77.5% versus 55.3%, P = .013). Beclin 1 expression was inversely associated with bcl-2 expression ( P = .019) and positively associated with longer overall survival ( P = .035) and progression-free survival ( P = .013). In multivariate analysis, beclin 1 expression and the revised International Prognostic Index model independently predicted survival. The proposed clinicopathologic prognostic model including these 2 independent prognostic factors allowed classification of patients into 3 risk groups ( P < .0001, respectively). Beclin 1 expression predicts superior clinical outcome in patients with diffuse large B-cell lymphoma treated with standard treatment. The novel prognostic model which divides patients with diffuse large B-cell lymphoma into different risk categories may help guide treatment planning.
Summary Background The clinical outcome of extranodal natural killer T-cell lymphoma (ENKTL) has improved substantially as a result of new treatment strategies with non-anthracycline-based ...chemotherapies and upfront use of concurrent chemoradiotherapy or radiotherapy. A new prognostic model based on the outcomes obtained with these contemporary treatments was warranted. Methods We did a retrospective study of patients with newly diagnosed ENKTL without any previous treatment history for the disease who were given non-anthracycline-based chemotherapies with or without upfront concurrent chemoradiotherapy or radiotherapy with curative intent. A prognostic model to predict overall survival and progression-free survival on the basis of pretreatment clinical and laboratory characteristics was developed by filling a multivariable model on the basis of the dataset with complete data for the selected risk factors for an unbiased prediction model. The final model was applied to the patients who had complete data for the selected risk factors. We did a validation analysis of the prognostic model in an independent cohort. Findings We did multivariate analyses of 527 patients who were included from 38 hospitals in 11 countries in the training cohort. Analyses showed that age greater than 60 years, stage III or IV disease, distant lymph-node involvement, and non-nasal type disease were significantly associated with overall survival and progression-free survival. We used these data as the basis for the prognostic index of natural killer lymphoma (PINK), in which patients are stratified into low-risk (no risk factors), intermediate-risk (one risk factor), or high-risk (two or more risk factors) groups, which were associated with 3-year overall survival of 81% (95% CI 75–86), 62% (55–70), and 25% (20–34), respectively. In the 328 patients with data for Epstein-Barr virus DNA, a detectable viral DNA titre was an independent prognostic factor for overall survival. When these data were added to PINK as the basis for another prognostic index (PINK-E)—which had similar low-risk (zero or one risk factor), intermediate-risk (two risk factors), and high-risk (three or more risk factors) categories—significant associations with overall survival were noted (81% 95% CI 75–87%, 55% (44–66), and 28% (18–40%), respectively). These results were validated and confirmed in an independent cohort, although the PINK-E model was only significantly associated with the high-risk group compared with the low-risk group. Interpretation PINK and PINK-E are new prognostic models that can be used to develop risk-adapted treatment approaches for patients with ENKTL being treated in the contemporary era of non-anthracycline-based therapy. Funding Samsung Biomedical Research Institute.
Chronic urticaria (CU) is a debilitating skin disease that lasts for more than 6 weeks with wheals and/or angioedema, including chronic spontaneous urticaria (CSU) and chronic inducible urticaria ...(CIndU). In China, the prevalence of this disease is high, more than 1%, and on the rise. CU has a major impact on the quality of life (QoL) of patients who frequently experience sleep disturbance, depression, and anxiety. Nearly one-third of patients with CSU, in China, are resistant to second-generation H1-antihistamines (sgAHs), even at a fourfold dose (second line; off-label). Omalizumab is approved for the treatment of CSU treatment in Europe and shows remarkable efficacy and safety. In China, regulatory approval for the use of omalizumab is pending, and its use in clinical practice varies widely. Consensus on omalizumab CU treatment in China is urgently needed. The aim of this article is to propose a practical omalizumab treatment algorithm for the management of antihistamine-resistant CSU and CIndU in adults and special population including children and adolescents, and pregnant or breast feeding women, to guide daily clinical practice in China. In the development of this consensus, an expert group including mainly dermatologists, allergists, but also pulmonologists, ENTs, immunologists, and pediatricians in Allergic Disease Prevention and Control Committee, Chinese Preventive Medicine Association, reviewed the existing evidence and developed consensus on the use of omalizumab in CU patients from China. The goal of this consensus is to assist clinicians in making rational decisions in the management of refractory CU with omalizumab. The key clinical questions covered by the treatment algorithm are: 1) Omalizumab treatment routine strategy in both CSU and CIndU patients; 2) Recommended dose and treatment duration for different age stratification; 3) Treatment duration for CU patients with other allergic comorbidities; 4) Recommendation on omalizumab stopping strategy.
Objective In this study, we evaluated the clinical efficacy of mandible reconstruction with preoperative virtual planning, which focused on esthetics and occlusion. Study Design A series of 9 ...patients were enrolled prospectively to undergo mandibulectomy and simultaneous reconstruction. Preoperative spiral CT scans of the maxillofacial region and the fibula region were performed. Virtual surgery of tumor resection and fibula reconstruction was performed in the Mimics platform. The reconstructed mandible models were fabricated with CAD/CAM technique. The reconstruction plate and the positioning template were accommodated to the stereolithographic model as the surgical template. Results Surgery was performed accurately according to the templates. All the fibula flaps survived. The appearance and occlusion of the patients were satisfactory. Conclusions With preoperative virtual planning, the spatial relationship of the mandible and the fibula graft can be planned individually, which helps achieve optimum appearance and occlusion relationship.
The novel coronavirus disease (COVID-19) pandemic and associated restrictive measures have implications for depressive symptoms (henceforth depression) of young people and risk may be associated with ...their reduced physical activity (PA) level. Therefore, we aimed to examine the association between depressive symptoms and PA among college students with different gender and gender role (masculinity traits and femininity traits) during the COVID-19 pandemic.
Cross-sectional study included 628 healthy college students from nineteen different locations. The Center for Epidemiological Studies Depression Scales (CES-D), the International Physical Activity Questionnaire - Short Form (IPAQ-SF), and the 50-item Chinese Sex-Role Inventory (CSRI-50) were used to measure depressive symptoms, PA continuous (weekly metabolic equivalent minutes, MET-minutes/week) and categorical indicators (activity level category) and gender role, respectively. The statistical analyses were used in partial correlation analysis,
-test, one-way ANOVA, moderation model tests, and linear regression model tests.
Total of 34.72% participants had clinically relevant depression (16, CES-D scale). Total of 58.6% participants were classified as a "low" activity level for spending less time on PA. Depression significantly negatively correlated with MET-minutes/week in moderate-intensity PA but not vigorous and walking scores. Of note, the depression-PA association was only moderated by the "low" activity level group in terms of categorical scores across gender groups. Participants with higher masculinity traits were less likely to have depression among all participants. Moreover, more recovered cases and fewer deaths could also predict the lower depression risk in the "high" activity level group.
Moderate-intensity PA is beneficial for reducing depression risk among college students at a low activity level. College students with fewer masculinity traits (regardless of gender) are highly vulnerable to depression during the outbreak of COVID-19. Effective control of the COVID-19 pandemic seems critical to alleviating the burden of mental disorders of the public including depression.
Summary Background Improvements to prognostic models in metastatic castration-resistant prostate cancer have the potential to augment clinical trial design and guide treatment strategies. In ...partnership with Project Data Sphere, a not-for-profit initiative allowing data from cancer clinical trials to be shared broadly with researchers, we designed an open-data, crowdsourced, DREAM (Dialogue for Reverse Engineering Assessments and Methods) challenge to not only identify a better prognostic model for prediction of survival in patients with metastatic castration-resistant prostate cancer but also engage a community of international data scientists to study this disease. Methods Data from the comparator arms of four phase 3 clinical trials in first-line metastatic castration-resistant prostate cancer were obtained from Project Data Sphere, comprising 476 patients treated with docetaxel and prednisone from the ASCENT2 trial, 526 patients treated with docetaxel, prednisone, and placebo in the MAINSAIL trial, 598 patients treated with docetaxel, prednisone or prednisolone, and placebo in the VENICE trial, and 470 patients treated with docetaxel and placebo in the ENTHUSE 33 trial. Datasets consisting of more than 150 clinical variables were curated centrally, including demographics, laboratory values, medical history, lesion sites, and previous treatments. Data from ASCENT2, MAINSAIL, and VENICE were released publicly to be used as training data to predict the outcome of interest—namely, overall survival. Clinical data were also released for ENTHUSE 33, but data for outcome variables (overall survival and event status) were hidden from the challenge participants so that ENTHUSE 33 could be used for independent validation. Methods were evaluated using the integrated time-dependent area under the curve (iAUC). The reference model, based on eight clinical variables and a penalised Cox proportional-hazards model, was used to compare method performance. Further validation was done using data from a fifth trial—ENTHUSE M1—in which 266 patients with metastatic castration-resistant prostate cancer were treated with placebo alone. Findings 50 independent methods were developed to predict overall survival and were evaluated through the DREAM challenge. The top performer was based on an ensemble of penalised Cox regression models (ePCR), which uniquely identified predictive interaction effects with immune biomarkers and markers of hepatic and renal function. Overall, ePCR outperformed all other methods (iAUC 0·791; Bayes factor >5) and surpassed the reference model (iAUC 0·743; Bayes factor >20). Both the ePCR model and reference models stratified patients in the ENTHUSE 33 trial into high-risk and low-risk groups with significantly different overall survival (ePCR: hazard ratio 3·32, 95% CI 2·39–4·62, p<0·0001; reference model: 2·56, 1·85–3·53, p<0·0001). The new model was validated further on the ENTHUSE M1 cohort with similarly high performance (iAUC 0·768). Meta-analysis across all methods confirmed previously identified predictive clinical variables and revealed aspartate aminotransferase as an important, albeit previously under-reported, prognostic biomarker. Interpretation Novel prognostic factors were delineated, and the assessment of 50 methods developed by independent international teams establishes a benchmark for development of methods in the future. The results of this effort show that data-sharing, when combined with a crowdsourced challenge, is a robust and powerful framework to develop new prognostic models in advanced prostate cancer. Funding Sanofi US Services, Project Data Sphere.
South Asians are at high risk of developing type 2 diabetes (T2D). We carried out a genome-wide association meta-analysis with South Asian T2D cases (n = 16,677) and controls (n = 33,856), followed ...by combined analyses with Europeans (n
= 231,420). We identify 21 novel genetic loci for significant association with T2D (P = 4.7 × 10
to 5.2 × 10
), to the best of our knowledge at the point of analysis. The loci are enriched for regulatory features, including DNA methylation and gene expression in relevant tissues, and highlight CHMP4B, PDHB, LRIG1 and other genes linked to adiposity and glucose metabolism. A polygenic risk score based on South Asian-derived summary statistics shows ~4-fold higher risk for T2D between the top and bottom quartile. Our results provide further insights into the genetic mechanisms underlying T2D, and highlight the opportunities for discovery from joint analysis of data from across ancestral populations.
Exposure to inorganic arsenic (iAs), a class I carcinogen, affects several hundred million people worldwide. Once absorbed, iAs is converted to monomethylated (MMA) and then dimethylated forms (DMA), ...with methylation facilitating urinary excretion. The abundance of each species in urine relative to their sum (iAs%, MMA%, and DMA%) varies across individuals, reflecting differences in arsenic metabolism capacity.
The association of arsenic metabolism phenotypes with participant characteristics and arsenical skin lesions was characterized among 4,794 participants in the Health Effects of Arsenic Longitudinal Study (Araihazar, Bangladesh). Metabolism phenotypes include those obtained from principal component (PC) analysis of arsenic species.
Two independent PCs were identified: PC1 appears to represent capacity to produce DMA (second methylation step), and PC2 appears to represent capacity to convert iAs to MMA (first methylation step). PC1 was positively associated (P <0.05) with age, female sex, and BMI, while negatively associated with smoking, arsenic exposure, education, and land ownership. PC2 was positively associated with age and education but negatively associated with female sex and BMI. PC2 was positively associated with skin lesion status, while PC1 was not. 10q24.32/AS3MT region polymorphisms were strongly associated with PC1, but not PC2. Patterns of association for most variables were similar for PC1 and DMA%, and for PC2 and MMA% with the exception of arsenic exposure and SNP associations.
Two distinct arsenic metabolism phenotypes show unique associations with age, sex, BMI, 10q24.32 polymorphisms, and skin lesions.
This work enhances our understanding of arsenic metabolism kinetics and toxicity risk profiles.
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