Dynamic change of gut microbiota in head and neck concurrent chemoradiotherapy patients and its potential value in the prediction of acute oral mucositis grade as well as quality of life.

PURPOSE: Radiotherapy is the major therapy for head and neck squamous cell carcinoma (HNSCC). However, whether gut microbiota changes in HNSCC patients who received concurrent chemoradiotherapy remains unclear. This study aimed to investigate the dynamic change of gut microbiota composition, construct the first radiotherapy-related gut microbiota database in these patients and identify the potential value of the gut microbiota changing in the prediction of acute oral mucositis grade as well as patients' life quality. METHODS: We enrolled 47 HNSCC patients who scheduled with concurrent chemoradiotherapy. The field was irradiated with a total dose of 66-70 Gy in 33-35 fractions. All the patients received 2-3 cycles of platinum-based chemotherapy. After feces specimens collected, bacterial genomic DNA was isolated using magnetic beads and then analyzed by the Illumina MiSeq Sequencing System based on the V3-V4 hypervariable regions of the 16S rRNA gene. RESULTS: 194 genera which belonged to 27 phyla were found in 141 samples. Increased abundance of microbiota in diversity and richness was observed in mid-radiotherapy group. Bacteroides, Blautia, Phascolarctobacterium were three main genera in all three groups and the mid-radiotherapy group had the highest relative abundance of Phascolarctobacterium. What is more, most significantly altered bacteria shared the same variation pattern which was increased in mid-radiotherapy while decreased to the almost same level of as pre-radiotherapy in post-radiotherapy group. Further analysis indicated that Bacteroidetes showing an upward trend while Proteobacteria declining in higher grade of acute mucositis. Moreover, relatively low abundant Proteobacteria was significantly correlated with high-grade acute oral mucositis. As for the quality of life, Lactobacillales and Actinomycetales were specifically found in better life quality group. However, Clostridia_UCG_014, Eubacteriaceae, UCG_010 and Moraxellaceae were unique abundantly present in worse life quality group. CONCLUSION: Chemoradiotherapy can affect the composition of the gut microbiota in HNSCC patients during the mid-term of treatment. Yet self-stabilized ability maintained the gut microbiota homeostasis. Dynamic change of specific species could help predict acute oral mucositis grade and characterize different quality of life group in these patients.

Accurate Airway Tree Segmentation in CT Scans via Anatomy-aware Multi-class Segmentation and Topology-guided Iterative Learning.

Intrathoracic airway segmentation in computed tomography is a prerequisite for various respiratory disease analyses such as chronic obstructive pulmonary disease, asthma and lung cancer. Due to the low imaging contrast and noises execrated at peripheral branches, the topological-complexity and the intra-class imbalance of airway tree, it remains challenging for deep learning-based methods to segment the complete airway tree (on extracting deeper branches). Unlike other organs with simpler shapes or topology, the airway's complex tree structure imposes an unbearable burden to generate the "ground truth" label (up to 7 or 3 hours of manual or semi-automatic annotation per case). Most of the existing airway datasets are incompletely labeled/annotated, thus limiting the completeness of computer-segmented airway. In this paper, we propose a new anatomy-aware multi-class airway segmentation method enhanced by topology-guided iterative self-learning. Based on the natural airway anatomy, we formulate a simple yet highly effective anatomy-aware multi-class segmentation task to intuitively handle the severe intra-class imbalance of the airway. To solve the incomplete labeling issue, we propose a tailored iterative self-learning scheme to segment toward the complete airway tree. For generating pseudo-labels to achieve higher sensitivity (while retaining similar specificity), we introduce a novel breakage attention map and design a topology-guided pseudo-label refinement method by iteratively connecting breaking branches commonly existed from initial pseudo-labels. Extensive experiments have been conducted on four datasets including two public challenges. The proposed method achieves the top performance in both EXACT'09 challenge using average score and ATM'22 challenge on weighted average score. In a public BAS dataset and a private lung cancer dataset, our method significantly improves previous leading approaches by extracting at least (absolute) 6.1% more detected tree length and 5.2% more tree branches, while maintaining comparable precision.

The efficacy and safety of percutaneous CT-guided iodine-125 brachytherapy combined with standard chemotherapy and brachytherapy alone for lung malignant nodule: a retrospective comparative cohort study.

Background: Lung metastasis nodules and advanced-stage tumors are often considered inoperable conditions for thoracic surgery and remain major challenges to clinical decision-making. Brachytherapy has its advantages in treating localized solid tumors, which can be used in combination with other treatments to achieve good safety and efficacy. In this study, we aimed to determine the outcomes of patients who received a combination of standard chemotherapy and computed tomography (CT)-guided percutaneous brachytherapy treatment for advanced-stage lung malignant lesions. Methods: We retrospectively collected data on patients with advanced lung cancer or lung metastasis nodules who underwent percutaneous CT-guided iodine-125 (125I) brachytherapy treatment. Patients were divided into two groups: Group A (brachytherapy with chemotherapy) and Group B (brachytherapy-only). Patients were reevaluated 1 month after the operation and then followed up every 3 months. The primary endpoint of this study was overall survival. Results: Our results showed that the mean age in Group B was higher (62.32±8.79 years) than that of Group A (68.59±11.46 years; P=0.018). Patients receiving a combination of chemotherapy and brachytherapy had a median survival time of 20.5 months [95% confidence interval (CI), 16.5-24.5], while those receiving brachytherapy alone had a median survival time of 16.4 months (95% CI, 11.7-21.1) (P=0.026). Patients who received additional thermal ablation treatment and those who did not have median survival times of 16.4 (95% CI, 10.2-22.7) and 17.0 months (95% CI, 13.3-20.8) (P=0.607). The median survival time for patients with oligo lesions was 19.8 months (95% CI, 15.7-23.9), while it was 10.5 months (95% CI, 7.5-13.4) for those who had multiple lesions. Conclusions: The combination of percutaneous CT-guided 125I brachytherapy and standard chemotherapy was superior to brachytherapy alone in terms of overall survival for patients with inoperable pulmonary lesions. Our results showed no benefit from additional adjuvant thermal ablation treatment. Patients with a single oligo nodule seem to have a better prognosis than those with multiple lesions.

Upregulation of CoQ shifts ferroptosis dependence from GPX4 to FSP1 in acquired radioresistance.

Acquired radioresistance is the primary contributor to treatment failure of radiotherapy, with ferroptosis is identified as a significant mechanism underlying cell death during radiotherapy. Although resistance to ferroptosis has been observed in both clinical samples of radioresistant cells and cell models, its mechanism remains unidentified. Herein, our investigation revealed that radioresistant cells exhibited greater tolerance to Glutathione Peroxidase 4 (GPX4) inhibitors and, conversely, increased sensitivity to ferroptosis suppressor protein 1 (FSP1) inhibitors compared to their sensitive counterparts. This observation suggested that FSP1 might play a dominant role in the development of radioresistance. Notably, the knockout of FSP1 demonstrated considerably superior efficacy in resensitizing cells to radiotherapy compared to the knockout of GPX4. To elucidate the driving force behind this functional shift, we conducted a metabolomic assay, which revealed an upregulation of Coenzyme Q (CoQ) synthesis and a downregulation of glutathione synthesis in the acquired radioresistance cells. Mechanistically, CoQ synthesis was found to be supported by aarF domain containing kinase 3-mediated phosphorylation of CoQ synthases, while the downregulation of Solute carrier family 7 member 11 led to decreased glutathione synthesis. Remarkably, our retrospective analysis of clinical response data further validated that the additional administration of statin during radiotherapy, which could impede CoQ production, effectively resensitized radioresistant cells to radiation. In summary, our findings demonstrate a dependency shift from GPX4 to FSP1 driven by altered metabolite synthesis during the acquisition of radioresistance. Moreover, we provide a promising therapeutic strategy for reversing radioresistance by inhibiting the FSP1-CoQ pathway.

Combined effect of cortical superficial siderosis and cerebral microbleed on short-term and long-term outcomes after intracerebral haemorrhage.

BACKGROUND AND PURPOSE: Cortical superficial siderosis (cSS) and cerebral microbleed (CMB) have distinct effects on intracerebral haemorrhage (ICH). We aim to investigate the combined effect of cSS and CMB on outcomes after ICH. METHODS: Based on a single-centre stroke registry database, patients with spontaneous ICH who had CT scan within 48 hours after ictus and MRI subsequently were identified. Eligible patients were divided into four groups (cSS-CMB-, cSS-CMB+, cSS+CMB-, cSS+CMB+) according to cSS and CMB on susceptibility-weighted image of MRI. Primary outcomes were haematoma volume on admission and unfavourable outcome defined as modified Rankin Scale scores ≥3 at 3 months. Secondary outcomes were all-cause death, recurrence of stroke and ICH during follow-up (median follow-up 2.0 years, IQR 1.0-3.0 years). RESULTS: A total of 673 patients were identified from 1044 patients with spontaneous ICH. 131 (19.5%) had cSS and 468 (69.5%) had CMB. Patients with cSS+CMB+ had the highest rate of poor outcome at 3 months, as well as all-cause death, recurrent stroke and ICH during follow-up. In cSS- patients, CMB was associated with smaller haematoma (ß -0.13; 95% CI -0.22 to -0.03; p=0.009), but it still increased risks of recurrent ICH (OR 4.6; 95% CI 1.3 to 15.6; p=0.015) and stroke (OR 2.0; 95% CI 1.0 to 4.0; p=0.049). These effects of CMB became unremarkable in the context of cSS+. CONCLUSIONS: Patients with different combinations of cSS and CMB have distinct patterns of short-term and long-term outcomes. Although CMB is related to restrained haematoma, it does not improve long-term outcomes. TRIAL REGISTRATION NUMBER: NCT04803292.

Inhibition of LAR attenuates neuroinflammation through RhoA/IRS-1/Akt signaling pathway after intracerebral hemorrhage in mice.

Leukocyte common antigen-related phosphatase (LAR) is widely expressed in the central nervous system and is known to regulate a variety of processes including cell growth, differentiation, and inflammation. However, little is currently known about LAR signaling mediated neuroinflammation after intracerebral hemorrhage (ICH). The objective of this study was to investigate the role of LAR in ICH using autologous blood injection-induced ICH mouse model. Expression of endogenous proteins, brain edema and neurological function after ICH were evaluated. Extracellular LAR peptide (ELP), an inhibitor of LAR, was administered to ICH mice and outcomes were evaluated. LAR activating-CRISPR or IRS inhibitor NT-157 was administered to elucidate the mechanism. The results showed that expressions of LAR, its endogenous agonist chondroitin sulfate proteoglycans (CSPGs) including neurocan and brevican, and downstream factor RhoA increased after ICH. Administration of ELP reduced brain edema, improved neurological function, and decreased microglia activation after ICH. ELP decreased RhoA and phosphorylated serine-IRS1, increased phosphorylated tyrosine-IRS1 and p-Akt, and attenuated neuroinflammation after ICH, which was reversed by LAR activating-CRISPR or NT-157. In conclusion, this study demonstrated that LAR contributed to neuroinflammation after ICH via RhoA/IRS-1 pathway, and ELP may be a potential therapeutic strategy to attenuate LAR mediated neuroinflammation after ICH.

Deep Learning for Fully Automated Prediction of Overall Survival in Patients Undergoing Resection for Pancreatic Cancer: A Retrospective Multicenter Study.

OBJECTIVE: To develop an imaging-derived biomarker for prediction of overall survival (OS) of pancreatic cancer by analyzing preoperative multiphase contrast-enhanced computed topography (CECT) using deep learning. BACKGROUND: Exploiting prognostic biomarkers for guiding neoadjuvant and adjuvant treatment decisions may potentially improve outcomes in patients with resectable pancreatic cancer. METHODS: This multicenter, retrospective study included 1516 patients with resected pancreatic ductal adenocarcinoma (PDAC) from 5 centers located in China. The discovery cohort (n=763), which included preoperative multiphase CECT scans and OS data from 2 centers, was used to construct a fully automated imaging-derived prognostic biomarker-DeepCT-PDAC-by training scalable deep segmentation and prognostic models (via self-learning) to comprehensively model the tumor-anatomy spatial relations and their appearance dynamics in multiphase CECT for OS prediction. The marker was independently tested using internal (n=574) and external validation cohorts (n=179, 3 centers) to evaluate its performance, robustness, and clinical usefulness. RESULTS: Preoperatively, DeepCT-PDAC was the strongest predictor of OS in both internal and external validation cohorts [hazard ratio (HR) for high versus low risk 2.03, 95% confidence interval (CI): 1.50-2.75; HR: 2.47, CI: 1.35-4.53] in a multivariable analysis. Postoperatively, DeepCT-PDAC remained significant in both cohorts (HR: 2.49, CI: 1.89-3.28; HR: 2.15, CI: 1.14-4.05) after adjustment for potential confounders. For margin-negative patients, adjuvant chemoradiotherapy was associated with improved OS in the subgroup with DeepCT-PDAC low risk (HR: 0.35, CI: 0.19-0.64), but did not affect OS in the subgroup with high risk. CONCLUSIONS: Deep learning-based CT imaging-derived biomarker enabled the objective and unbiased OS prediction for patients with resectable PDAC. This marker is applicable across hospitals, imaging protocols, and treatments, and has the potential to tailor neoadjuvant and adjuvant treatments at the individual level.

Underlying microangiopathy and functional outcome of simultaneous multiple intracerebral hemorrhage.

Objective: To identify the predominant type of cerebral small vessel disease (SVD) and outcomes in patients with simultaneous multiple intracerebral hemorrhages (SMICH). Methods: Consecutive patients with intracerebral hemorrhage (ICH) from a single-center prospective cohort were retrospectively reviewed. Presumed etiology was classified according to the SMASH-U criteria. Demographics, clinical and laboratory variables, and neuroimaging data were compared between patients with primary SMICH and those with single ICH. Functional outcomes were assessed using the modified Rankin scale 90 days after ICH. Results: Of the 598 enrolled patients, 37 (6.2%) met the criteria for SMICH. Risk factors for SMICH included a high burden of deep cerebral microbleeds (CMBs) (odds ratio [OR] 1.06, 95% confidence interval [CI], 1.00-1.12; p = 0.040), white matter hyperintensity scores (OR 1.27, 95% CI 1.04-1.57; p = 0.021), history of ICH (OR 3.38, 95% CI 1.31-8.05; p = 0.008), and low serum magnesium levels (OR 0.01, 95% CI 0.00-0.25; p = 0.007). Based on the SMASH-U classification, 15(40.5%) SMICH were classified as hypertension, whereas 17 (45.9%) as undetermined-etiology. To further explore the potential microangiopathy underlying undetermined-SMICH, these patients with undetermined-etiology were compared to those with cerebral amyloid angiopathy-ICH, and were associated with a higher burden of deep CMBs but less severe centrum semiovale enlarged perivascular spaces. Likewise, compared with hypertension-ICH patients, those with undetermined SMICH were consistently associated with a higher deep CMB counts. Moreover, multivariate analysis revealed that SMICH was independently associated with poor outcomes (OR 2.23, 95%CI 1.03-4.76; p = 0.038). Conclusion: Our results suggest that most patients with primary SMICH harbor hypertensive-SVD as principal angiopathy. Patients with SMICH are at a high risk of poor outcomes. (ClinicalTrials.gov Identifier: NCT04803292).

Comprehensive and clinically accurate head and neck cancer organs-at-risk delineation on a multi-institutional study.

Accurate organ-at-risk (OAR) segmentation is critical to reduce radiotherapy complications. Consensus guidelines recommend delineating over 40 OARs in the head-and-neck (H&N). However, prohibitive labor costs cause most institutions to delineate a substantially smaller subset of OARs, neglecting the dose distributions of other OARs. Here, we present an automated and highly effective stratified OAR segmentation (SOARS) system using deep learning that precisely delineates a comprehensive set of 42 H&N OARs. We train SOARS using 176 patients from an internal institution and independently evaluate it on 1327 external patients across six different institutions. It consistently outperforms other state-of-the-art methods by at least 3-5% in Dice score for each institutional evaluation (up to 36% relative distance error reduction). Crucially, multi-user studies demonstrate that 98% of SOARS predictions need only minor or no revisions to achieve clinical acceptance (reducing workloads by 90%). Moreover, segmentation and dosimetric accuracy are within or smaller than the inter-user variation.

Metformin Preserves VE-Cadherin in Choroid Plexus and Attenuates Hydrocephalus via VEGF/VEGFR2/p-Src in an Intraventricular Hemorrhage Rat Model.

Hydrocephalus induced by intraventricular hemorrhage (IVH) is associated with unfavorable prognosis. The increased permeability of choroid plexus and breakdown of the blood-brain barrier (BBB) was reported as a prominent mechanism of IVH-induced hydrocephalus, and vascular endothelial-cadherin (VE-cadherin) was demonstrated to be relevant. Metformin was reported to protect endothelial junction and preserve permeability widely; however, its role in hydrocephalus remains unclear. In this study, the decreased expression of VE-cadherin in the choroid plexus, accompanied with ventricle dilation, was investigated in an IVH rat model induced by intraventricular injection of autologous blood. Metformin treatment ameliorated hydrocephalus and upregulated VE-cadherin expression in choroid plexus meanwhile. We then observed that the internalization of VE-cadherin caused by the activation of vascular endothelial growth factor (VEGF) signaling after IVH was related to the occurrence of hydrocephalus, whereas it can be reversed by metformin treatment. Restraining VEGF signaling by antagonizing VEGFR2 or inhibiting Src phosphorylation increased the expression of VE-cadherin and decreased the severity of hydrocephalus after IVH. Our study demonstrated that the internalization of VE-cadherin via the activation of VEGF signaling may contribute to IVH-induced hydrocephalus, and metformin may be a potential protector via suppressing this pathway.

Bifidobacteria Was Decreased in Adult Patients With Irritable Bowel Syndrome Based on PCR and Bacterial Culture: A Systematic Review and Meta-Analysis.

The causes of irritable bowel syndrome remain unknown. Studies and meta-analyses revealed that intestinal microbiota disturbance was one of the causes of irritable bowel syndrome, but the results remained controversial. Therefore, we performed a systematic review and meta-analysis to identify the association between them. We performed a systematic meta-analysis of case-control studies from January 2000 to December 2020 to compare fecal microbes based on polymerase chain reaction and bacterial cul- ture between adult irritable bowel syndrome patients and healthy controls. The standardized mean difference value and a 95% CI were calculated. Two professional researchers used Newcastle-Ottawa Scale to reassess selected literature and extract high- quality studies. Six studies were included in our analysis. When all eligible studies were pooled into the meta-analysis, compared with healthy controls, the standardized mean differences of Bifidobacteria (standardized mean difference = -1.01, 95% CI =: -2.01 to -0.01) in irritable bowel syndrome patients decreased significantly, whereas the standardized mean differences of Enterococcus, Enterobacter, Lactobacillus, Bacteroides, and Escherichia coli did not change significantly in irritable bowel syndrome patients. However, heterogeneity was significant to perform sensitivity analysis and stratified analysis in all these special intestinal microbes. In summary, this study indicated that only Bifidobacteria was decreased in irritable bowel syndrome patients compared with healthy controls using Newcastle-Ottawa Scale standards to extract high-quality literature. Future studies are warranted to further dem- onstrate the relationship between them.

Radiation recall pneumonitis triggered by an immune checkpoint inhibitor following re-irradiation in a lung cancer patient: a case report.

BACKGROUND: Radiation recall pneumonitis (RRP) is unpredictable but associated with severe radiation damage in previously irradiated fields. Chemotherapy and targeted drugs have been reported to contribute to RRP. Here we report a case of a patient with non-small cell lung cancer (NSCLC) who developed RRP following administration of immune checkpoint inhibitor (ICI) 18 months after the end of re-irradiation. CASE PRESENTATION: A 69-year-old man received adjuvant chemoradiotherapy post-operatively. He underwent thoracic re-irradiation for oligometastatic NSCLC. On second recurrence, pembrolizumab combined with nab-paclitaxel were administered. After six months, he developed symptoms of persistent cough and dyspnea, with consistent pneumonitis on CT images. The clinical time frame and significant radiographic evidence raised suspicion for RRP. Symptoms resolved after steroids. CONCLUSIONS: RRP is a rare occurrence. Patients undergoing immunotherapy after prior irradiation may be at increased risk of this rare radiation pneumonitis.

A Multiparametric MR-Based RadioFusionOmics Model with Robust Capabilities of Differentiating Glioblastoma Multiforme from Solitary Brain Metastasis.

This study aimed to evaluate the diagnostic potential of a novel RFO model in differentiating GBM and SBM with multiparametric MR sequences collected from 244 (131 GBM and 113 SBM) patients. Three basic volume of interests (VOIs) were delineated on the conventional axial MR images (T1WI, T2WI, T2_FLAIR, and CE_T1WI), including volumetric non-enhanced tumor (nET), enhanced tumor (ET), and peritumoral edema (pTE). Using the RFO model, radiomics features extracted from different multiparametric MRI sequence(s) and VOI(s) were fused and the best sequence and VOI, or possible combinations, were determined. A multi-disciplinary team (MDT)-like fusion was performed to integrate predictions from the high-performing models for the final discrimination of GBM vs. SBM. Image features extracted from the volumetric ET (VOIET) had dominant predictive performances over features from other VOI combinations. Fusion of VOIET features from the T1WI and T2_FLAIR sequences via the RFO model achieved a discrimination accuracy of AUC = 0.925, accuracy = 0.855, sensitivity = 0.856, and specificity = 0.853, on the independent testing cohort 1, and AUC = 0.859, accuracy = 0.836, sensitivity = 0.708, and specificity = 0.919 on the independent testing cohort 2, which significantly outperformed three experienced radiologists (p = 0.03, 0.01, 0.02, and 0.01, and p = 0.02, 0.01, 0.45, and 0.02, respectively) and the MDT-decision result of three experienced experts (p = 0.03, 0.02, 0.03, and 0.02, and p = 0.03, 0.02, 0.44, and 0.03, respectively).

Dietary Risk-Related Colorectal Cancer Burden: Estimates From 1990 to 2019.

Background: Colorectal cancer remains a public health problem worldwide. Dietary risk factors play a key role in the carcinogenesis and progression of colorectal cancer. This study aimed to explore the geographical and temporal trends in various dietary factor-related colorectal cancers. Methods: Data were extracted from the Global Burden of Disease (GBD) 2019 study, including the deaths, disability-adjusted life-years (DALYs), age-standardized rate (ASR), and summary exposure value (SEV) among 4 world regions, 11 age groups, 21 regions, and 204 countries and territories between 1990 and 2019. The estimated annual percentage changes (EAPCs) were calculated to evaluate the variation trend of ASR. Results: Dietary factors were the leading cause of colorectal cancer death and DALY rate, regardless of age. Dietary factor-related deaths and DALYs accounted for 32 and 34% of global colorectal cancer, respectively. Further analysis showed that low whole grain intake remained the leading cause of cancer death and DALY rate, followed by milk and calcium. Diets that were low in whole grains, milk, and calcium accounted for 81.61% of deaths and 81.64% of DALYs. Deaths and DALYs of dietary factors related to colorectal cancer grew by half from 1990 to 2019. All ASRs remained higher for men than women. Asia carried the highest colorectal cancer burden attributed to dietary risks, especially for East Asia [age-standardized death rate (ASDR): EAPC = 1.15, 95% CI:0.88-1.42; DALY: EAPC = 1.08, 95% CI:0.82-1.34]. The heavy burden also existed in high-middle and middle socio-demographic index (SDI) quintiles. China has always had the highest deaths and DALYs of colorectal cancer attributable to dietary risks, followed by the USA, India, and Japan. Conclusions: Large variations existed in the dietary risk-related colorectal cancer burdens among sexes, regions, and countries. More targeted interventions to address modifiable dietary risk factors would save 32% of deaths and 34% of DALYs for colorectal cancer.

Association Between Insulin Resistance and Remote Diffusion-Weighted Imaging Lesions in Primary Intracerebral Hemorrhage.

Background: Abnormal glucose metabolism was shown to be associated with the occurrence of remote diffusion-weighted imaging lesions (R-DWILs) after primary intracerebral hemorrhage (ICH) onset. Insulin resistance is a metabolic disorder that was regarded as an indicator of chronic systemic inflammation. In this study, we aimed to determine the effect of insulin resistance on the occurrence of R-DWILs in ICH. Methods: Patients with primary ICH within 14 days after onset were prospectively enrolled from November 2017 to October 2019. R-DWILs was defined as remote focal hyperintensity from the hematoma in DWI, with corresponding hypointensity in apparent diffusion coefficient. The homeostasis model assessment of insulin resistance (HOMA-IR) was used for insulin resistance estimation and calculated as fasting insulin (µU/ml) × fasting glucose (mmol/L)/22.5. Patients in our cohort were divided into four groups according to HOMA-IR index quartiles. Logistic regression analysis and smoothing plots were used to evaluate the association of HOMA-IR with R-DWIL occurrence. Sensitivity analysis was performed in non-diabetic patients, non-obese patients, hypertensive ICH patients, and patients 60 years and older separately. The association between HOMA-IR and systemic inflammatory immune indices neutrophil to lymphocyte ratio (NLR) and monocyte to lymphocyte ratio (MLR) was examined with multiple linear regression analysis. Results: Among the 345 patients, 54 (15.7%) had R-DWILs. Both the third and fourth quartiles of HOMA-IR index were robustly associated with an increased risk of R-DWIL occurrence (adjusted OR 3.58, 95% CI 1.33-9.65; adjusted OR 3.91, 95%CI 1.47-10.41) when compared with the first quartile. The association was consistent in non-diabetic, non-obese, hypertensive ICH patients, as well as in patients 60 years and older. Furthermore, both NLR and MLR were independently associated with HOMA-IR. Conclusions: Our study suggested that insulin resistance evaluated with HOMA-IR index was independently associated with the presence of R-DWILs in patients with acute and subacute primary ICH. It may provide new insights into the metabolism-related brain injury after ICH ictus.

Evaluation of association studies and a systematic review and meta-analysis of VDR polymorphisms in type 2 diabetes mellitus risk.

ABSTRACT: Numerous original studies and 4 published meta-analyses have reported the association between the Vitamin D receptor (VDR) BsmI, FokI, ApaI, and TaqI polymorphisms and type 2 diabetes mellitus (T2DM) risk. However, the results were inconsistent. Therefore, an updated meta-analysis was performed to further explore these issues.To further explore the association between the VDR BsmI, FokI, ApaI, and TaqI polymorphisms and T2DM risk.PubMed, EMBASE, Scopus, and Wanfang databases were searched. The following search strategy were used: (VDR OR vitamin D receptor) AND (polymorphism OR variant OR mutation) AND (diabetes OR mellitus OR diabetes mellitus). Pooled crude odds ratios with 95% confidence intervals were applied to evaluate the strength of association in 5 genetic models. Statistical heterogeneity, the test of publication bias, and sensitivity analysis were carried out using the STATA software (Version 12.0). To evaluate the credibility of statistically significant associations, we applied the false-positive report probabilities (FPRP) and Bayesian false discovery probability (BFDP) test.Overall, the VDR BsmI polymorphism was associated with a significantly decreased T2DM risk in Asians; the VDR FokI polymorphism was associated with a significantly decreased T2DM risk in Asians, African countries, and Asian countries; the VDR ApaI polymorphism was associated with a significantly decreased T2DM risk in Caucasians and North American countries.On the VDR ApaI polymorphism, a significantly increased T2DM risk was found in a mixed population. However, when we further performed a sensitivity analysis, FPRP, and BFDP test, less-credible positive results were identified (all FPRP > 0.2 and BFDP > 0.8) in any significant association.In summary, this study strongly indicates that all significant associations were less credible positive results, rather than from true associations.

Successful Treatment with Ensartinib After Alectinib-induced Hyperbilirubinemia in ALK-Positive NSCLC.

BACKGROUND: Alectinib is approved for the treatment of advanced non-small-cell lung cancer (NSCLC) harboring ALK rearrangements. Although generally well tolerated, alectinib can cause serious or life-threatening side effects. CASE PRESENTATION: Here, we report a case of a patient with NSCLC with an EML4-ALK fusion and was treated with alectinib but who developed grade 4 hyperbilirubinemia after five months on therapy. Alectinib was discontinued, and an artificial liver support system (ALSS) was used with an impressive decline in bilirubin levels. After two months drug-free, the patient experienced disease progression. Ensartinib was initiated as second-line treatment with a best response of stable disease after three months of therapy with no evidence of hyperbilirubinemia. CONCLUSION: This is the first report of ensartinib treatment after alectinib-induced hyperbilirubinemia which was successfully relieved by ALSS treatment and targeted drug cessation.

Deep Learning for Fully Automated Prediction of Overall Survival in Patients with Oropharyngeal Cancer Using FDG-PET Imaging.

PURPOSE: Accurate prognostic stratification of patients with oropharyngeal squamous cell carcinoma (OPSCC) is crucial. We developed an objective and robust deep learning-based fully-automated tool called the DeepPET-OPSCC biomarker for predicting overall survival (OS) in OPSCC using [18F]fluorodeoxyglucose (FDG)-PET imaging. EXPERIMENTAL DESIGN: The DeepPET-OPSCC prediction model was built and tested internally on a discovery cohort (n = 268) by integrating five convolutional neural network models for volumetric segmentation and ten models for OS prognostication. Two external test cohorts were enrolled-the first based on the Cancer Imaging Archive (TCIA) database (n = 353) and the second being a clinical deployment cohort (n = 31)-to assess the DeepPET-OPSCC performance and goodness of fit. RESULTS: After adjustment for potential confounders, DeepPET-OPSCC was found to be an independent predictor of OS in both discovery and TCIA test cohorts [HR = 2.07; 95% confidence interval (CI), 1.31-3.28 and HR = 2.39; 95% CI, 1.38-4.16; both P = 0.002]. The tool also revealed good predictive performance, with a c-index of 0.707 (95% CI, 0.658-0.757) in the discovery cohort, 0.689 (95% CI, 0.621-0.757) in the TCIA test cohort, and 0.787 (95% CI, 0.675-0.899) in the clinical deployment test cohort; the average time taken was 2 minutes for calculation per exam. The integrated nomogram of DeepPET-OPSCC and clinical risk factors significantly outperformed the clinical model [AUC at 5 years: 0.801 (95% CI, 0.727-0.874) vs. 0.749 (95% CI, 0.649-0.842); P = 0.031] in the TCIA test cohort. CONCLUSIONS: DeepPET-OPSCC achieved an accurate OS prediction in patients with OPSCC and enabled an objective, unbiased, and rapid assessment for OPSCC prognostication.

Tracheal, bronchus, and lung cancer burden and related risk factors in the United States and China.

Tracheal, bronchus, and lung (TBL) cancer is the most common malignant tumor worldwide. This study aims to grasp the characteristics of the TBL cancer burden in China and the United States (USA). Data included incidence, deaths, and disability-adjusted life years (DALYs) as well as their age-standardized rates (ASRs) among different gender, age and risk factors. Joinpoint Regression Model and Age-period-cohort (APC) analysis were used to evaluate the variation tendency and effect of the risk factors. China and USA bore almost half of the TBL cancer burden, especially for males. ASRs of TBL cancer increased in China, but decreased in USA. In China, three factors related to TBL cancer deaths and DALYs related were tobacco, air pollution, and diet low in fruits; in USA, these are tobacco, occupational carcinogens, and high fasting plasma glucose. The younger the population, the less impact of birth cohort on morbidity and mortality. According to APC analysis, age effect played a key role in morbidity and mortality of TBL cancer, and the risk increased with age. Period effect kept increasing over time, while cohort effect decreased with the time of birth. Tobacco was always the top risk factor of death and DALYs in both countries. The policy should be tilted towards air pollution and a diet low in fruits in China, as well as occupational carcinogens and high fasting plasma glucose in USA. Healthcare reform in both countries should focus on planning how its health system could effectively prevent and manage TBL cancer at low cost.

Evaluation of Association Studies and an Updated Meta-Analysis of VDR Polymorphisms in Osteoporotic Fracture Risk.

Background: Several studies have examined the association between vitamin D receptor (VDR) polymorphisms and osteoporotic fracture risk; however, the results are not uniform. Furthermore, many new articles have been published, and therefore, an updated meta-analysis was performed to further explore these issues. Objectives: The aim of the study was to investigate the association between VDR, BsmI, ApaI, TaqI, FokI, and Cdx2 polymorphisms and osteoporotic fracture risk. Methods: The odds ratios (ORs) and 95% confidence intervals (CIs) were used to assess the association between VDR BsmI, ApaI, TaqI, FokI, and Cdx2 polymorphisms and the risk of osteoporotic fracture. We also used the false-positive reporting probability (FPRP) test and the Venice criteria to evaluate the credibility of the statistically significant associations. Results: Overall, this study found that the VDR ApaI and BsmI polymorphisms significantly increased the risk of osteoporotic fracture in European countries and America, respectively. However, when sensitivity analysis was performed after excluding low-quality and Hardy-Weinberg disequilibrium (HWD) studies, it was found that only individuals with the double-mutated genotype have an increased risk of osteoporotic fracture in European countries. In addition, when the credibility of the positive results was assessed, it was found that the positive results were not credible. Conclusion: This meta-analysis indicates that there may be no significant association among the polymorphisms of VDR BsmI, ApaI, TaqI, FokI, and Cdx2 and the risk of osteoporotic fracture. The increased risk of osteoporotic fracture is most likely due to false-positive results.