Cataract Surgery and Incidence of Retinal Vascular Occlusion: Population-Based Cohort Study Using a Target Trial Emulation Framework.

BACKGROUND: Previous studies suggested an association between cataract surgery and retinal vascular occlusion. However, the association may be attributable to detection bias because postoperative monitoring may be more frequent for those who receive cataract surgery than for those who do not. DESIGN: Population-based cohort study using target trial emulation framework. METHODS: We included patients with cataract aged 50 years and older receiving cataract surgery or nonsurgical interventions identified from the Taiwan National Health Insurance Research Database between 2003 and 2018, matched by propensity score. The primary outcome was retinal vascular occlusion. Cox proportional hazards models were used to compare surgery and control groups. Additional analyses were restricted to patients who had undergone fundoscopic examination within 6 months prior to cataract surgery to address the issue of detection bias. RESULTS: We included 577,129 cataract surgery and control pairs. We found the hazard ratio (HR) for retinal vascular occlusion after cataract surgery was 1.23 (95% confidence interval (CI): 1.17-1.29), compared with the control group. Secondary outcome analyses yielded similar results for retinal artery occlusion (HR: 1.13, 95% CI: 1.02-1.26) and retinal vein occlusion (HR: 1.26, 95% CI: 1.20-1.33). However, no risk of retinal vascular occlusion was observed among patients who had received fundoscopic examinations (HR: 1.06, 95% CI: 0.98-1.15) at baseline. CONCLUSIONS: Our study underscored the importance of conducting complete baseline fundoscopic examinations before cataract surgery to clarify whether postoperative conditions are due to patients' underlying diseases or unintended complications of cataract surgery.

Risk of age-related macular degeneration in men receiving 5α-reductase inhibitors: a population-based cohort study.

BACKGROUND: Recent studies suggest that 5α-reductase inhibitors (5ARIs) for benign prostate hyperplasia (BPH) result in abnormal retinal anatomical alteration. OBJECTIVE: To compare age-related macular degeneration (AMD) incidence in BPH patients receiving 5ARIs or tamsulosin. DESIGN: Retrospective, population-based cohort study using new-user and active-comparator design. SETTING: General population. SUBJECTS: Males with BPH, newly receiving 5ARIs or tamsulosin from 2010 to 2018. METHODS: Data were extracted from Taiwan's National Health Insurance Research Database. We used Cox proportional hazards model with 1:4 propensity score (PS) matching, based on intention-to-treat analysis to determine the risk of incident AMD. Sensitivity analyses included an as-treated approach and weighting-based PS methods. We also separately reported the risks of incident AMD in patients receiving finasteride and dutasteride to determine risk differences among different 5ARIs. RESULTS: We included 13 586 5ARIs users (mean age: 69 years) and 54 344 tamsulosin users (mean age: 68.37 years). After a mean follow-up of 3.7 years, no differences were observed in the risk of incident AMD between 5ARIs and tamsulosin users [hazard ratio (HR): 1.06; 95% confidence intervals (95% CI): 0.98-1.15], with similar results from sensitivity analyses. However, increased risk of incident age-related macular degeneration was observed in patients receiving dutasteride [HR: 1.13; 95% CI: 1.02-1.25], but not in those receiving finasteride [HR: 0.99; 95% CI: 0.87-1.12], in the subgroup analyses. CONCLUSIONS: We found no difference between 5ARIs and tamsulosin regarding the incidence of AMD in BPH patients. However, the risk profiles for AMD differed slightly between dutasteride and finasteride, suggesting that the potency of androgen inhibition is a factor related to AMD incidence.

Acute, long-term or non-vincristine-induced peripheral neuropathy among non-Hodgkin lymphoma survivors: Symptoms, daily activities, functional status, and quality of life.

PURPOSE: This study aimed to explore the incidence and severity of vincristine-induced peripheral neuropathy (VIPN) in non-Hodgkin lymphoma (NHL) survivors (primary aim) and its impact on daily life by comparing common cancer symptoms, functional status, and quality of life (QoL) among survivors with acute, long-term, and non-VIPN (secondary aim). METHODS: This cross-sectional study examined 144 NHL survivors. Standardized questionnaires were used to assess common cancer symptoms, functional status, and QoL with the European Organization for the Research and Treatment of Cancer - Quality of Life Questionnaire (EORTC-QLQ-C30). VIPN (Chemotherapy-Induced Peripheral Neuropathy) status was classified using EORTC-QLQ-CIPN20. A self-designed interference scale was developed to determine the impact of the VIPN on daily activities. The Kruskal-Wallis test and Spearman rank correlation were used in this study. RESULTS: Among the survivors of acute and long-term VIPN, the highest incidences and most severe symptoms were found for hand numbness and foot cramps. A significant moderate correlation was found between disturbances in daily activities and acute or long-term VIPN, including gait changes, going up or down the stairs, and imbalance-related falls. Acute and long-term VIPN survivors showed worse symptoms (fatigue, insomnia, and constipation) and lower QoL than non-VIPN survivors did. In acute VIPN, social function was significantly affected, whereas in long-term VIPN, emotional and cognitive functions were affected. CONCLUSION: Numbness and cramps should be addressed in survivors of acute and long-term VIPN. Preventing falls is recommended for NHL survivors with VIPN, and psychological support is suggested for long-term VIPN survivors.

Enhancing Prediction for Tumor Pathologic Response to Neoadjuvant Immunochemotherapy in Locally Advanced Esophageal Cancer by Dynamic Parameters from Clinical Assessments.

To develop accurate and accessible prediction methods for assessing pathologic response following NICT prior to surgery, we conducted a retrospective study including 137 patients with esophageal squamous cell carcinoma (ESCC) who underwent surgery after two cycles of NICT between January 2019 and March 2022 at our center. We collected clinical parameters to evaluate the dynamic changes in the primary tumor. Univariate and multivariate analyses were performed to determine the correlations between these parameters and the pathologic response of the primary tumor. Subsequently, we constructed prediction models for pCR and MPR using multivariate logistic regression. The MPR prediction Model 2 was internally validated using bootstrapping and externally validated using an independent cohort from our center. The univariate logistic analysis revealed significant differences in clinical parameters reflecting tumor regression among patients with varying pathologic responses. The clinical models based on these assessments demonstrated excellent predictive performance, with the training cohort achieving a C-index of 0.879 for pCR and 0.912 for MPR, while the testing cohort also achieved a C-index of 0.912 for MPR. Notably, the MPR prediction Model 2, with a threshold cut-off of 0.74, exhibited 92.7% specificity and greater than 70% sensitivity, indicating a low rate of underestimating residual tumors. In conclusion, our study demonstrated the high accuracy of clinical assessment-based models in pathologic response prediction, aiding in decision-making regarding organ preservation and radiotherapy adjustments after induction immunochemotherapy.

Subcellular Distribution of BALF2 and the Role of Rab1 in the Formation of Epstein-Barr Virus Cytoplasmic Assembly Compartment and Virion Release.

Epstein-Barr virus (EBV) replicates its genome in the nucleus and undergoes tegumentation and envelopment in the cytoplasm. We are interested in how the single-stranded DNA binding protein BALF2, which executes its function and distributes predominantly in the nucleus, is packaged into the tegument of virions. At the mid-stage of virus replication in epithelial TW01-EBV cells, a small pool of BALF2 colocalizes with tegument protein BBLF1, BGLF4 protein kinase, and the cis-Golgi marker GM130 at the perinuclear viral assembly compartment (AC). A possible nuclear localization signal (NLS) between amino acids 1100 and 1128 (C29), which contains positive charged amino acid 1113RRKRR1117, is able to promote yellow fluorescent protein (YFP)-LacZ into the nucleus. In addition, BALF2 interacts with the nucleocapsid-associated protein BVRF1, suggesting that BALF2 may be transported into the cytoplasm with nucleocapsids in a nuclear egress complex (NEC)-dependent manner. A group of proteins involved in intracellular transport were identified to interact with BALF2 in a proteomic analysis. Among them, the small GTPase Rab1A functioning in bi-directional trafficking at the ER-Golgi interface is also a tegument component. In reactivated TW01-EBV cells, BALF2 colocalizes with Rab1A in the cytoplasmic AC. Expression of dominant-negative GFP-Rab1A(N124I) diminished the accumulation of BALF2 in the AC, coupling with attenuation of gp350/220 glycosylation. Virion release was significantly downregulated by expressing dominant-negative GFP-Rab1A(N124I). Overall, the subcellular distribution of BALF2 is regulated through its complex interaction with various proteins. Rab1 activity is required for proper gp350/220 glycosylation and the maturation of EBV. IMPORTANCE Upon EBV lytic reactivation, the virus-encoded DNA replication machinery functions in the nucleus, while the newly synthesized DNA is encapsidated and transported to the cytoplasm for final virus assembly. The single-stranded DNA binding protein BALF2 executing functions within the nucleus was also identified in the tegument layer of mature virions. Here, we studied the functional domain of BALF2 that contributes to the nuclear targeting and used a proteomic approach to identify novel BALF2-interacting cellular proteins that may contribute to virion morphogenesis. The GTPase Rab1, a master regulator of anterograde and retrograde endoplasmic reticulum (ER)-Golgi trafficking, colocalizes with BALF2 in the juxtanuclear concave region at the midstage of EBV reactivation. Rab1 activity is required for BALF2 targeting to the cytoplasmic assembly compartment (AC) and for gp350/220 targeting to cis-Golgi for proper glycosylation and virion release. Our study hints that EBV hijacks the bi-directional ER-Golgi trafficking machinery to complete virus assembly.

Survival outcomes of patients with head and neck squamous cell cancer with hepatitis B virus infection: An analysis from an endemic tertiary center.

BACKGROUND: Hepatitis B virus (HBV) affects the occurrence and survival outcome of various malignant disorders. The study aimed to evaluate the survival outcome of head and neck squamous cell cancer (HNSCC) patients with or without HBV infection. METHODS: This study included patients with HNSCC who visited Taichung Veterans General Hospital from 2007 to 2015. HBV infection was defined by hepatitis B surface antigen (HBsAg) seropositivity. By propensity score matching, we compared survival outcomes, including progression-free survival (PFS) and overall survival (OS), among patients with or without HBV infection. RESULTS: The prevalence of HBV infection in our cohort was 12.3%. Among the 1,015 patients included in the matched analysis, a higher risk of baseline liver cirrhosis (11.3% vs. 3.4%, p < 0.001) and initial hepatic dysfunction (10.8% vs. 5.4%, p = 0.005) rates were observed than those without HBV infection at baseline. The 5-year OS was 43.1% and 53.2% (p < 0.001) and the 5-year PFS was 37.4% and 42.3% (p = 0.007) in patients with and without HBV infection, respectively. The incidence of subsequent hepatic dysfunction showed no difference between patients with and without HBV infection (29.6% vs. 26.8%, p = 0.439). CONCLUSIONS: Patients with HNSCC and HBV infection were younger and had a higher risk of cirrhosis compared to those without HBV infection. Moreover, HBV infection significantly influenced the OS and PFS outcomes but not subsequent hepatic dysfunction in patients with HNSCC.

Active-fluidics versus gravity-fluidics in lens extraction: A systematic review and meta-analysis of randomized controlled trials.

OBJECTIVE: To investigate differences in outcomes between active-fluidics and gravity-fluidics phacoemulsification systems. METHODS: We searched PubMed, Embase, and Cochrane Library databases for randomized controlled trials (RCTs) published no later than December 1, 2021. The Cochrane Collaboration risk of bias tool was used for quality assessment. We presented the outcomes as standardized mean differences (SMDs) with 95% confidence intervals (CI). Sensitivity analysis was performed by removing studies that included ≥2 types of phacoemulsification tips. RESULTS: We analyzed six RCTs that totally enrolled 884 patients. Patients undergoing lens extraction with active-fluidics systems exhibited lower cumulative dissipated energy (CDE), total aspiration time (TAT), and estimated fluid usage (EFU) compared with patients who did not (SMD [95% CI]: CDE, - 0.818 [ - 1.054 to - 0.582]; TAT, - 0.664 [ - 0.850 to - 0.479]; EFU, - 0.655 [ - 0.932 to - 0.378]). A sensitivity analysis revealed similar results for CDE, TAT, and EFU. For endothelial cell density (ECD) 1 week after surgery, ECD 1 month after surgery, and central corneal thickness (CCT) 1 week after surgery, outcomes of both systems were comparable (ECD at 1 week, 0.074 [ - 0.177 to 0.325]; ECD at 1 month, 0.069 [ - 0.167 to 0.305]; CCT 1 week after surgery, 0.077 [ - 0.173 to 0.328]). No severe adverse events in patients treated with either system were reported in the studies. CONCLUSION: Active-fluidics systems are superior to gravity-fluidics systems with respect to CDE, TAT, and EFU; no differences in postoperative ECD and CCT were observed. Future studies are required to determine the reasons for heterogeneity and to detect rare adverse events.

Copper nanoclusters on specific-primer PCR fragments with magnetic capture for the label-free fluorescent sensing of the T315I single nucleotide variant in the BCR-ABL1 gene.

In this study, a simple and facile procedure using the all or none formation of double-stranded DNA-templated copper nanoclusters on specific-primer PCR fragments was designed to fluorescently identify the T315I single nucleotide variant on the BCR-ABL1 gene. Chronic myeloid leukaemia (CML), a disease caused by the BCR-ABL1 fusion of tyrosine kinase, is well known for the T315I mutation that causes tyrosine kinase inhibitors (TKIs) to be resisted due to the alternative structure of the drug-binding site. Therefore, it is an important single nucleotide variant for clinical detection. In this study, only specific functional primers and the digestion of the wild genotype from the T315I mutation site with specific restriction enzymes were designed, and the different digested products could then be captured using magnetic beads. The final products would allow for fluorescent sensing via the all or none formation of double-stranded DNA-templated copper nanoclusters for the detection of the T315I mutation. This study has been successfully applied for identifying wild and mutant homozygotes and the mutant/wild heterozygote of the T315I mutation. It is expected that this analytical system can serve as a tool for the clinical diagnosis of T315I mutations and be applied to real samples of CML patients in the future.

Comparative anatomical outcomes of high-flow vs. low-flow phacoemulsification cataract surgery: A systematic review and meta-analysis.

Background: Phacoemulsification is an effective and widely performed technique in cataract surgery, but the comparative anatomical outcomes, including endothelial cell loss (ECL), central corneal thickness (CCT), and central macular thickness (CMT), between high-flow and low-flow phacoemulsification cataract surgery remain unclear. Methods: This study followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Statement. Random-effects models were applied to measure pooled mean differences (MD) with 95% confidence intervals (CI) of anatomical outcomes between high-flow and low-flow phacoemulsification cataract surgery. We judged overall certainty of evidence (CoE) based on Grading of Recommendations Assessment, Development and Evaluation (GRADE) criteria. Results: We included six randomized controlled trials (RCTs) totaling 477 participants. The meta-analysis showed similar changes associated with these two surgery types in both ECL at postoperative days 2-14 (MD: -1.63%; 95% CI: -3.73 to 0.47%; CoE: very low), days 15-42 (MD: -0.65%; 95% CI -2.96 to 1.65%; CoE: very low) and day 43 to month 18 (MD: -0.35%; 95% CI: -1.48 to 0.78%; CoE: very low), and CCT at postoperative day 1 (MD: -16.37 µm; 95% CI: -56.91 to 24.17 µm; CoE: very low), days 2-14 (MD: -10.92 µm; 95% CI: -30.00 to 8.16 µm; CoE: very low) and days 15-42 (MD: -2.76 µm; 95% CI: -5.75 to 0.24 µm; CoE: low). By contrast, low-flow phacoemulsification showed less increase in CMT at postoperative days 15-42 (MD, -4.58 µm; 95% CI: -6.3 to -2.86 µm; CoE: low). Conclusions: We found similar anatomical outcomes, except in CMT, for both high-flow and low-flow phacoemulsification cataract surgery. Future head-to-head RCTs on visual outcomes should confirm our findings. Systematic review registration: PROSPERO, identifier: CRD42022297036.

Risk of dialysis in patients receiving intravitreal anti-vascular endothelial growth factor treatment: a population-based cohort study.

We utilized the Longitudinal Health Insurance Database which was stemmed from the Taiwan's National Health Insurance Research Database to conduct a retrospective cohort study investigating the risk of becoming dialysis dependent after receiving intravitreal anti-vascular endothelial growth factor (VEGF) agents for retinal diseases. Patients newly receiving intravitreal ranibizumab or aflibercept from 2000 to 2017 for age-related macular degeneration, polypoidal choroidal vasculopathy, diabetic macular edema, retinal vein occlusions, or myopic choroid neovascularization were included as the study group, and patients with same retinal diseases but did not receive intravitreal anti-VEGFs served as controls extracted by age- and sex-matched (1:4) and further propensity score matching (PSM). Cox proportional hazards models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for the risk of dialysis. A cohort of 2447 anti-VEGF users and 2447 controls by PSM were evaluated. Higher dialysis risks were observed among patients newly receiving anti-VEGF agents compared to controls (adjusted HR: 1.849; 95% CI: 1.378-2.482) in the PSM cohort. For subgroup analysis, patients newly receiving anti-VEGF treatment for diabetic macular edema had significant risk (adjusted HR: 1.834; 95% CI: 1.448-2.324) of becoming dialysis-dependent, while patients in other subgroups demonstrated similar risks as the controls. In conclusion, intravitreal anti-VEGF agents might increase the risk of becoming dialysis-dependent, especially in patients who are treated for diabetic macular edema.

Clinical Features and Immunophenotypes of Double-Hit Diffuse Large B-Cell Lymphoma.

Double-hit (DH) genetics induces a reduction in the complete remission (CR) and, consequently, in poor overall survival (OS) in diffuse large B-cell lymphoma (DLBCL) patients. Unfortunately, DH identification is time-consuming. Here, we retrospectively reviewed 92 newly diagnosed DLBCL patients, stratified them into the DH (n = 14) and non-DH groups (n = 78), and compared their clinical features and outcomes. The results revealed that the DH group had a higher percentage of bulky disease than the non-DH group (64.3% vs. 28.2%; p = 0.013). More patients in the DH group tested positive for double expresser (DE) (50.0% vs. 21.8%; p = 0.044). The three-year OS rates of patients with and without DH were 33.3% and 52.2%, respectively (p = 0.016). Importantly, advance stage and multiple comorbidities were correlated with a high mortality rate in multivariate analysis. Furthermore, by combining DE and the bulky disease, a specificity of 89.7% for DH prediction was achieved. In summary, DH genetics, not DE immunopositivity, could be a factor for an inferior OS in DLBCL. A combination of bulky disease and a positive DE immunophenotype could facilitate DH genetics prediction in newly diagnosed DLBCL patients.

Redefining Remission Induction Chemotherapy Ineligibility by Early Mortality in De Novo Acute Myeloid Leukemia.

The therapeutic strategies for acute myeloid leukemia (AML) patients ineligible for remission induction chemotherapy have been improving in the past decade. Therefore, it is important to define ineligibility for remission induction chemotherapy. We retrospectively assessed 153 consecutive adult de novo AML patients undergoing remission induction chemotherapy and defined early mortality as death within the first 60 days of treatment. The 153 patients were stratified into the early mortality group (n = 29) and the non-early mortality group (n = 124). We identified potential factors to which early mortality could be attributed, investigated the cumulative incidence of early mortality for each aspect, and quantified the elements. The early mortality rate in our study cohort was 19.0%. Age ≥ 65 years (odds ratio (OR): 3.15; 95% confidence interval (CI): 1.05-9.44; p = 0.041), Eastern Cooperative Oncology Group performance status ≥ 2 (OR: 4.87; 95% CI: 1.77-13.41; p = 0.002), and lactate dehydrogenase ≥ 1000 IU/L (OR: 4.20; 95% CI: 1.57-11.23; p = 0.004) were the risk factors that substantially increased early mortality in AML patients. Patients with two risk factors had a significantly higher early mortality rate than those with one risk factor (68.8% vs. 20.0%; p < 0.001) or no risk factors (68.8% vs. 9.2%; p < 0.001). In conclusion, older age, poor clinical performance, and a high tumor burden were risks for early mortality in AML patients receiving remission induction chemotherapy. Patients harboring at least two of these three factors should be more carefully assessed for remission induction chemotherapy.

Risk of diabetic macular oedema with sodium-glucose cotransporter-2 inhibitors in type 2 diabetes patients: A multi-institutional cohort study in Taiwan.

AIMS: To investigate the risk of diabetic macular oedema (DMO) associated with the use of sodium-glucose cotransporter-2 (SGLT2) inhibitors in patients with type 2 diabetes mellitus (T2DM). MATERIALS AND METHODS: We conducted a retrospective cohort study by analysing a large multi-institutional electronic medical records database in Taiwan. We included adult patients with T2DM without DMO newly receiving either SGLT2 inhibitors or glucagon-like peptide-1 receptor agonists (GLP-1RAs) during the period 2016 to 2018. We used propensity scores with inverse probability of treatment weighting to generate comparable groups. The study outcome was incident DMO, determined by clinical diagnosis during outpatient visits or admissions. We followed patients from the index date to either DMO occurrence, last clinical visit, patient death, or December 31, 2020. We performed Cox proportional hazards regression models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the risk of DMO. RESULTS: We included 9986 new users of SGLT2 inhibitors (mean [SD] age 59.6 (12.1) years, median [interquartile range {IQR}] glycated haemoglobin [HbA1c] 70 (61-81)mmol/mol, estimated glomerular filtration rate [eGFR] 89.1 [71.4-108.7] mL/min/1.73 m2 and urine albumin-creatinine ratio [UACR] 26.1 [9.7-117.6] mg/g) and 1067 new users of GLP-1RAs (mean [SD] age 58.4 (41.5) years, median [IQR] HbA1c 73 [64-84] mmol/mol, eGFR 91.6 [68.6-114.0] mL/min/1.73 m2 and UACR 37.6 [11.1-153.2] mg/g) with similar baseline characteristics. Lower DMO risks were observed among patients newly receiving SGLT2 inhibitors (7.9/1000 person-years), compared to those receiving GLP-1RAs (10.7/1000 person-years) with an HR of 0.75 (95% CI 0.64-0.88). CONCLUSIONS: Our findings suggest use of SGLT2 inhibitors was associated with lower risk of DMO in T2DM patients in clinical practice, compared to use of GLP-1RAs. Future studies are necessary to confirm this observation.

Chemoresponse of de novo Acute Myeloid Leukemia to "7+3" Induction can Be Predicted by c-Myc-facilitated Cytogenetics.

Background: Identifying patients with de novo acute myeloid leukemia (AML) who will probably respond to the "7 + 3" induction regimen remains an unsolved clinical challenge. This study aimed to identify whether c-Myc could facilitate cytogenetics to predict a "7 + 3" induction chemoresponse in de novo AML. Methods: We stratified 75 untreated patients (24 and 51 from prospective and retrospective cohorts, respectively) with de novo AML who completed "7 + 3" induction into groups with and without complete remission (CR). We then compared Myc-associated molecular signatures between the groups in the prospective cohort after gene set enrichment analysis. The expression of c-Myc protein was assessed by immunohistochemical staining. We defined high c-Myc-immunopositivity as > 40% of bone marrow myeloblasts being c-Myc (+). Results: Significantly more Myc gene expression was found in patients who did not achieve CR by "7 + 3" induction than those who did (2439.92 ± 1868.94 vs. 951.60 ± 780.68; p = 0.047). Expression of the Myc gene and c-Myc protein were positively correlated (r = 0.495; p = 0.014). Although the non-CR group did not express more c-Myc protein than the CR group (37.81 ± 25.13% vs. 29.04 ± 19.75%; p = 0.151), c-Myc-immunopositivity could be a surrogate to predict the "7 + 3" induction chemoresponse (specificity: 81.63%). More importantly, c-Myc-immunopositivity facilitated cytogenetics to predict a "7 + 3" induction chemoresponse by increasing specificity from 91.30 to 95.92%. Conclusion: The "7 + 3" induction remains the standard of care for de novo AML patients, especially for those without a high c-Myc-immunopositivity and high-risk cytogenetics. However, different regimens might be considered for patients with high c-Myc-immunopositivity or high-risk cytogenetics.

Efficacy and Safety of Innovative Experimental Chimeric Antigen Receptor (CAR) T-cells versus Axicabtagene ciloleucel (Yescarta) for the Treatment of Relapsed/Refractory Large B-Cell Lymphoma (LBCL): Matching Adjusted Indirect Comparisons (MAICs) and Systematic Review.

Despite favorable results of CAR T-cell therapy for relapsed/refractory large B-cell lymphoma (R/R LBCL), several challenges remain, including incomplete response, immune-mediated toxicity, and antigen-loss relapse. We delineated the relative clinical benefit of the novel approaches compared to the currently approved CAR T-cell therapies. In the absence of head-to-head comparisons and randomized controlled trials, we performed Matching Adjusted Indirect Comparisons to quantify the relative efficacy and safety of experimental CARs against Axicabtagene ciloleucel (Yescarta), the first FDA-approved CAR. A total of 182 R/R LBCL patients from 15 clinical trials with individual patient data (IPD) were pooled into eight populations by their CAR T-cell constructs and +/- ASCT status. The study endpoints were Progression-Free Survival (PFS), grade ≥ 3 cytokine release syndrome (CRS), and grade ≥ 3 neurotoxicity (NT). Tandem CD19.CD20.4-1BBζ CARs indicated favorable efficacy and safety, whereas the co-infusion of CD19 & CD20 with 4-1BBζ showed no clinical benefit compared to Yescarta. Third generation CD19. CD28. 4-1BBζ, and sequential administration of autologous stem cell transplantation (ASCT) and CD19. CARs presented statistically insignificant yet improved PFS and safety except for ASCT combined intervention which had suggestively higher NT risk than Yescarta. CARs with modified co-stimulatory domains to reduce toxicity (Hu19. CD8.28Zζ and CD19. BBz.86ζ) presented remarkable safety with no severe adverse events; however, both presented worse PFS than Yescarta. Third-generation CARs demonstrated statistically significantly lower NT than Yescarta. CD20. 4-1BBζ data suggested targeting CD20 antigen alone lacks clinical or safety benefit compared to Yescarta. Further comparisons with other FDA-approved CARs are needed.

Does previous transurethral prostate surgery affect oncologic and continence outcomes after RARP?

We examined the effect of previous transurethral resection of the prostate (TURP) on multiple oncologic and continence outcomes after robotic-assisted radical prostatectomy (RARP). We performed a retrospective cohort study of a total of 2693 patients from 2007 to 2014 who underwent RARP. Patients were stratified into 49 patients who had previous TURP prior to RARP (group 1) and 2644 patients who had no TURP prior to RARP (group 2). We collected operative variables including estimated blood loss, operative time, and positive surgical margin (PSM) rates. Urinary continence, defined as 0 pads per day (PPD), and social continence, defined as 1-PPD, were also assessed. American Urological Association Symptoms Score (AUASS), overall ability to function sexually, and Expanded Prostate Cancer Index Composite (EPIC) questionnaire were evaluated at 3 and 12 months after RARP. Weakness of urinary stream (EPIC #4d) at 12 months imposed a greater problem for group 1 patients with prior TURP compared to group 2 patients without prior TURP (p = 0.012). PSM was not statistically significant between the two groups (p = 0.110). Group 1 patients had a greater PSM rate (30.61 %) as compared to group 2 (20.95 %). PSM locations in group 1 patients showed the most common locations at the posterior and apex. The difference between the two groups for AUASS, overall sexual function, estimated blood loss, operative time, urinary continence, and social continence was not statistically significant. We examined the effect of previous TURP on postoperative RARP continence and oncologic outcomes. This data can be used to counsel those with prior TURP before RARP.

Positive Surgical Margin Trends in Patients with Pathologic T3 Prostate Cancer Treated with Robot-Assisted Radical Prostatectomy.

INTRODUCTION: We analyzed the trends of positive surgical margin (PSM) location in patients who had pT3 disease at robot-assisted radical prostatectomy (RARP). We aimed to describe our changing incidence of PSMs in the largest series to date of patients with pT3 disease who were treated by RARP. METHODS: A single-institution, single-surgeon review was performed of all patients who underwent RARP from 2005 to 2011. Perioperative data were collected for all patients with pT3 prostate cancer from a prospectively maintained RARP database. The PSM incidence and rates were stratified by location. The PSM rates per location were trended over time. RESULTS: In total, 2478 consecutive patients underwent RARP between July 2005 and December 2011. Of these patients, 555 were found to have pT3 disease. The PSM rate for patients with pT3 disease was 47%. The PSM rate for patients with pT3a and pT3B disease was 42.8% and 60.6%, respectively. Over the duration of this study, the PSM rate in patients with pT3 disease decreased significantly from 70.6% in 2005 to 32.3% in 2011 (p=0.002). The apical PSM rate showed the greatest decrease during this period going from 52.9% in 2005 to 5.2% in 2011 (p=0.018). CONCLUSION: We present the largest series to date involving the treatment of locally advanced prostate cancer initially managed with RARP. Our findings suggest that patients with locally advanced prostate cancer can be treated with RARP with acceptable positive margin rates. Overall PSM rates improved nearly 40% over the 6.5-year period of this study.

Hormone metabolism pathway genes and mammographic density change after quitting estrogen and progestin combined hormone therapy in the California Teachers Study.

INTRODUCTION: Mammographic density (MD) is a strong biomarker of breast cancer risk. MD increases after women start estrogen plus progestin therapy (EPT) and decreases after women quit EPT. A large interindividual variation in EPT-associated MD change has been observed, but few studies have investigated genetic predictors of the EPT-associated MD change. Here, we evaluate the association between polymorphisms in hormone metabolism pathway genes and MD changes when women quit EPT. METHODS: We collected mammograms before and after women quit EPT and genotyped 405 tagging single nucleotide polymorphisms (SNPs) in 30 hormone metabolism pathway genes in 284 non-Hispanic white participants of the California Teachers Study (CTS). Participants were ages 49 to 71 years at time of mammography taken after quitting EPT. We assessed percent MD using a computer-assisted method. MD change was calculated by subtracting MD of an 'off-EPT' mammogram from MD of an 'on-EPT' (that is baseline) mammogram. Linear regression analysis was used to investigate the SNP-MD change association, adjusting for the baseline 'on-EPT' MD, age and BMI at time of baseline mammogram, and time interval and BMI change between the two mammograms. An overall pathway and gene-level summary was obtained using the adaptive rank truncated product (ARTP) test. We calculated 'P values adjusted for correlated tests (P(ACT))' to account for multiple testing within a gene. RESULTS: The strongest associations were observed for rs7489119 in SLCO1B1, and rs5933863 in ARSC. SLCO1B1 and ARSC are involved in excretion and activation of estrogen metabolites of EPT, respectively. MD change after quitting was 4.2% smaller per minor allele of rs7489119 (P = 0.0008; P(ACT) = 0.018) and 1.9% larger per minor allele of rs5933863 (P = 0.013; P(ACT) = 0.025). These individual SNP associations did not reach statistical significance when we further used Bonferroni correction to consider the number of tested genes. The pathway level summary ARTP P value was not statistically significant. CONCLUSIONS: Data from this longitudinal study of EPT quitters suggest that genetic variation in two hormone metabolism pathway genes, SLCO1B1 and ARSC, may be associated with change in MD after women stop using EPT. Larger longitudinal studies are needed to confirm our findings.