Chlorin e6 and BLZ945 Based Self-Assembly for Photodynamic Immunotherapy Through Immunogenic Tumor Induction and Tumor-Associated Macrophage Depletion.

Immunotherapeutic effect is restricted by the nonimmunogenic tumor phenotype and immunosuppression behaviors of tumor-associated macrophages (TAMs). In this work, a drug self-assembly (designated as CeBLZ) is fabricated based on chlorin e6 (Ce6) and BLZ945 to activate photodynamic immunotherapy through tumor immunogenic induction and tumor-associated macrophage depletion. It is found that Ce6 tends to assemble with BLZ945 without any drug excipients, which can enhance the cellular uptake, tumor penetration, and blood circulation behaviors. The robust photodynamic therapy effect of CeBLZ efficiently suppresses the primary tumor growth and also triggers immunogenic cell death to reverse the nonimmunogenic tumor phenotype. Moreover, CeBLZ can deplete TAMs in tumor tissues to reverse the immunosuppression microenvironment, activating abscopal effect for distant tumor inhibition. In vitro and in vivo results confirm the superior antitumor effect of CeBLZ with negligible side effect, which might promote the development of sophisticated drug combinations for systematic tumor management.

Preliminary study of a new online and equipment-free vision screening alternative for remote and isolated community.

INTRODUCTION: Vision screening has been initiated to detect potential vision problems, paving referral pathways towards a full eye examination. Time-cost-labour practicality challenges of equipment-based vision screening have lingered for decades. Going for the highest sensitivity and specificity or opting for a pragmatic and affordable vision screening program remains a dilemma in public eye health. We aimed to report the development of a new online and equipment-free vision screening called Eye: Questionnairebased Vision Screening (EyeQVS). We also analysed the visual profile of Orang Bateq resided in a remote locality, using findings from EyeQVS, single test vision screening and full eye examination. MATERIALS AND METHODS: Multi-perspective development strategies were employed in designing EyeQVS. The questionnaire items were constructed using the working backward technique, compiling common vision disorders from the literature and face validation using expert panels. Face validation and usability assessment were performed on EyeQVS. The vision screening was carried out using EyeQVS and single test visual acuity screening method. The full eye examination included visual acuity, refraction, binocular vision and ocular health assessment. The visual profile of indigenous people (Orang Bateq) at Kampung Bengoi and Kampung Atok, Jerantut, Pahang was analysed using EyeQVS, single test visual acuity screening method and full eye examination. RESULTS: The performance of EyeQVS was affirmative in both face validation and usability. About 95% of Orang Bateq failed full eye examination, while 55% failed EyeQVS screening. None of them failed single test vision screening. Binocular disorders and dry eye problems were commonly found in Orang Bateq. EyeQVS unearthed more various vision problems compared to the single test vision screening (visual acuity alone) as a screening tool in a remote location. CONCLUSION: EyeQVS can screen for binocular disorders and dry eyes problem commonly found among indigenous people, which might be missed using a single-test visual acuity screening approach. EyeQVS is a practical alternative for vision screening in places where financial or location hinders eye healthcare access.

Inflammatory factors mediated the effect of air pollution on ischemic stroke: a two-step, mediation Mendelian randomization study.

OBJECTIVE: Numerous investigations have indicated a correlation between air pollution (AP) and an elevated ischemic stroke (IS) likelihood. The existing literature does not provide a consensus about the possible link between AP and IS. A two-sample Mendelian randomization (MR) analysis was utilized to systematically measure the causal link between AP and ischemic stroke. Furthermore, the mediating impact of inflammatory factors was also performed by a two-step MR. MATERIALS AND METHODS: A two-sample MR analysis was utilized to examine the AP impact on the incidence of IS. Additionally, a two-step MR approach was carried out to account for possible mediating variables. The indirect impact was determined by employing the product approach, which included multiplying the AP impact on inflammatory factors by the inflammatory factors' impacts on IS. The MR effect was identified through inverse variance-weighted (IVW) meta-analysis of each Wald Ratio. Additionally, complementary studies were conducted using the weighted median and MR-egger approaches. RESULTS: The IVW method with random effects showed that the per unit increase in genetically predicted PM2.5 was linked to the 0.362-fold elevated ischemic stroke risk (OR: 1.362, 95% CI: 1.032-1.796, p=0.029). Furthermore, the IVM technique, incorporating random effects, demonstrated that the per unit increase in genetically predicted PM2.5 was related to an elevated Interleukin (IL)-1ß risk (OR: 1.529, 95% CI: 1.191-1.963, p=0.001), IL-6 (OR: 1.498, 95% CI: 1.094-2.052, p=0.012) and IL-17 (OR: 1.478, 95% CI: 1.021-2.139, p=0.038). IL-1ß, IL-6, and IL-17 modulated the PM2.5 impact on ischemic stroke, while the proportion mediated by them was 59.5%. CONCLUSIONS: A positive correlation between genetically predicted PM2.5 levels and elevated ischemic stroke risk is mediated by IL-1ß, IL-6, and IL-17.

[Clinical analysis of 12 cases of ovarian yolk sac tumor].

Objective: To investigate the diagnosis, treatment and prognosis of ovarian yolk sac tumor (OYST). Methods: The clinicopathological data and follow-up data of 12 patients with OYST admitted to the Affiliated Hospital of Qingdao University from January 2013 to December 2020 were retrospectively analyzed, and the diagnosis, treatment and prognosis of OYST patients were summarized. Results: (1) The age of 12 patients with OYST ranged from 11 to 37 years, with a median age of 20 years. At the first visit, all 12 patients had pelvic masses. Reasons for seeing a doctor: 6 cases of abdominal distension and abdominal pain, 4 cases of mass in the lower abdomen, 1 case of vaginal bleeding, and 1 case of appendicitis. International Federation of Obstetrics and Gynecology (FIGO) 2014 staging: 4 cases in stage Ⅰa, 2 cases in stage Ⅰc, 1 case in stage Ⅱc, 4 cases in stage Ⅲc, and 1 case in stage Ⅳb. (2) All 12 patients were examined by color Doppler ultrasound before operation, among which 10 cases showed unilateral adnexal masses and 2 cases bilateral adnexal masses. The median maximum diameter of tumor was 16.5 cm (range: 6.0-28.0 cm). The preoperative levels of alpha fetoprotein (AFP) in 12 patients (all >1 210 µg/L) were significantly higher than normal (<25 µg/L). Among the 11 patients with cancer antigen 125 (CA125) detection results, 9 patients showed elevated serum CA125 levels. (3) Among the 12 patients, 8 young infertile patients who needed to preserve their reproductive function underwent appendectomy, 3 infertile patients underwent staged surgery for ovarian malignant germ cell tumor, and only one bilateral lesion and infertile patient underwent unsatisfactory staged surgery for ovarian malignant germ cell tumor. Of the 12 patients, 11 patients were given combined chemotherapy regimen of bleomycin, cisplatin, and etoposide (BEP) after operation. One patient without chemotherapy developed metastasis 3 months after operation, and was given BEP chemotherapy, and her condition was controlled. (4) The deadline for follow-up was December 31st, 2022, and the median follow-up time was 60 months (range: 25-115 months). All the 12 patients survived without tumor during the follow-up period, and the median disease-free survival time was 84.5 months (range: 25-115 months). Conclusions: OYST mostly occurs in children and young women. Color Doppler ultrasound examination and serum AFP and CA125 detection have diagnostic value for OYST. Surgical treatment after diagnosis of OYST includes surgery to preserve reproductive function and timely and standardized chemotherapy after operation. The prognosis of patients is good regardless of stage.

Tumor Homing Chimeric Peptide Rhomboids to Improve Photodynamic Performance by Inhibiting Therapy-Upregulated Cyclooxygenase-2.

Negative therapeutic feedback of inflammation would extensively attenuate the antitumor effect of photodynamic therapy (PDT). In this work, tumor homing chimeric peptide rhomboids (designated as NP-Mel) are fabricated to improve photodynamic performance by inhibiting PDT-upregulated cyclooxygenase-2 (COX-2). The hydrophobic photosensitizer of protoporphyrin IX (PpIX) and palmitic acid are conjugated onto the neuropilin receptors (NRPs) targeting peptide motif (CGNKRTR) to obtain tumor homing chimeric peptide (Palmitic-K(PpIX)CGNKRTR), which can encapsulate the COX-2 inhibitor of meloxicam. The well dispersed NP-Mel not only improves the drug stability and reactive oxygen species (ROS) production ability, but also increase the breast cancer targeted drug delivery to intensify the PDT effect. In vitro and in vivo studies verify that NP-Mel will decrease the secretion of prostaglandin E2 (PGE2) after PDT treatment, inducing the downregulation of IL-6 and TNF-α expressions to suppress PDT induced inflammation. Ultimately, an improved PDT performance of NP-Mel is achieved without inducing obvious systemic toxicity, which might inspire the development of sophisticated nanomedicine in consideration of the feedback induced therapeutic resistance.

Tislelizumab, a novel PD-1 monoclonal antibody in urothelial cancer: A real-world study.

OBJECTIVE: Tislelizumab, a monoclonal antibody against programed death protein-1 (PD-1), has shown encouraging antitumor activity in urothelial cancer. This study was designed to assess the efficacy and safety of tislelizumab in urotelial cancer in a real-world setting. METHODS: The study was a real-world retrospective study undertaken at Liaoning Cancer Hospital & Institute, China. Eligible patients were ≥18 years. Patients received 200-mg tislelizumab monotherapy intravenously every 3 weeks until the disease progressed to intolerable toxicity. Outcomes included an objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS) and safety. RESULTS: Between March 2020 and December 2022, 33 patients were enrolled. The median follow-up was 10.17 (IQR 5.73-12.47) months. Of all 33 patients, ORR and DCR were 30.30% (95% CI 15.6%-48.7%) and 42.42% (95% CI 25.48%-60.78%), respectively. The median PFS was 5.73 (95% CI 3.27-13.00) months, with a 12-month PFS rate of 31.90% (95% CI 19.20%-53.00%). The median OS was 17.7 (95% CI 12.80-not reach) months, with a 12-month OS rate of 67.50% (95% CI 52.70%-86.40%). Eleven (33.33%) and 8 (24.24%) experienced ≥grade 3 treatment-related adverse events (TRAEs) and immune-related Aes, respectively. No treatment-related deaths occurred. CONCLUSION: The excellent efficacy and controllable safety of tislelizumab in locally advanced or metastatic urothelial cancer suggest that it may be a promising therapeutic option for this population.

[Feasibility study of immediate breast reconstruction with fusion fascia combined with implants].

Objective: To investigate the oncologic and surgical safety of the fused fascia method for immediate breast reconstruction with implants. Methods: The clinical data of 343 patients with immediate breast reconstruction with implants in Tianjin Medical University Cancer Hospital from 2014-2017 were retrospectively analyzed to compare the 5-year local recurrence-free survival, 5-year disease-free survival and 5-year overall survival of patients with breast reconstruction by fusion fascia and other methods, and to analyze the complication incidences of implant removal between different implant groups. Results: Of the 343 patients with breast reconstruction, 95 were in the fused fascia group (fascia group) and 248 were in the non-fascia group (25 in the bovine pericardial patch group and 223 in the muscle flap group). At a median follow-up of 49 months, the differences in 5-year local recurrence-free survival (90.1% and 94.9%, respectively), 5-year disease-free survival (89.2% and 87.6%, respectively), and 5-year overall survival (95.2% and 95.1%, respectively) between patients in the fascial and non-fascial groups were not statistically significant (P>0.05). The complication incidence of implant removal was 24.0% (6/25) in the patch group and 2.1% (2/95) and 2.2% (5/223) in the fascia and muscle flap groups, respectively. Conclusion: Immediate breast reconstruction with fused fascial combined with implant is safe and feasible, less invasive than muscle flaps, more economical and with fewer complications than patches.

Coordination-Driven Self-Assembly of Biomedicine to Enhance Photodynamic Therapy by Inhibiting Proteasome and Bcl-2.

Tumor cells resist oxidative damage and apoptosis by activating defense mechanisms. Herein, a self-delivery biomedicine (designated as BSC) is developed by the self-assembly of Bortezomib (BTZ), Sabutoclax (Sab) and Chlorin e6 (Ce6). Interestingly, BTZ can be coordinated with Sab to promote the assembly of uniform ternary biomedicine through non-covalent intermolecular interactions. Moreover, BTZ as a proteasome inhibitor can prevent tumor cells from scavenging damaged proteins to reduce their oxidative resistance. Sab can downregulate B-cell lymphoma 2 (Bcl-2) to decrease the antiapoptotic protein. Both the proteasome and Bcl-2 inhibitions contribute to increasing cell apoptosis and amplifying photodynamic therapy (PDT) efficacy of Ce6. Encouragingly, carrier-free BSC receives all biological activities of these assembly elements, including photodynamic performance as well as inhibitory capabilities of proteasome and Bcl-2. Besides, BSC has a preferable cellular uptake ability and tumor retention property, which increase the drug delivery efficiency and bioavailability. In vitro and in vivo research demonstrate the superior PDT efficiency of BSC by proteasome and Bcl-2 inhibitions. Of special note, the coordination-driven self-assembly of BSC is pH-responsive, which can be disassembled for controlled drug release upon tumor acidic microenvironment. This study will expand the applicability of self-delivery nanomedicine with sophisticated mechanisms for tumor treatment.

Development and multicenter validation of a novel radiomics-based model for identifying eosinophilic chronic rhinosinusitis with nasal polyps.

BACKGROUND: Reliable noninvasive methods are needed to identify endotypes of chronic rhinosinusitis with nasal polyps (CRSwNP) to facilitate personalized therapy. Previous computed tomography (CT) scoring system has limited and inconsistent performance in identifying eosinophilic CRSwNP. We aimed to develop and validate a radiomics-based model to identify eosinophilic CRSwNP. METHODS: Surgical patients with CRSwNP were recruited from Tongji Hospital and randomly divided into training (n = 232) and internal validation cohort (n = 61). Patients from two additional hospitals served as external validation cohort-1 (n = 84) and cohort-2 (n = 54), respectively. Data were collected from October 2013 to May 2021. Eosinophilic CRSwNP was determined by histological criterion. The least absolute shrinkage and selection operator and the logistic regression (LR) algorithm were used to develop a radiomics model. Univariate and multivariate LR were employed to build models based on CT scores, clinical characteristics, and the combination of radiological and clinical characteristics. Model performance was evaluated by assessing discrimination, calibration, and clinical utility. RESULTS: The radiomics model based on 10 radiomic features achieved an area under the curve (AUC) of 0.815 in the training cohort, significantly better than the CT score model based on ethmoid-to-maxillary sinus score ratio with an AUC of 0.655. The combination of radiomic features and blood eosinophil count had a further improved performance, achieving an AUC of 0.903. The performance of these models was confirmed in all validation cohorts with satisfying predictive calibration and clinical application value. CONCLUSIONS: A CT radiomics-based model is promising to identify eosinophilic CRSwNP. This radiomics-based method may provide novel insights in solving other clinical concerns, such as guiding personalized treatment and predicting prognosis in patients with CRSwNP.

Clinical feasibility of deep learning-based automatic head CBCT image segmentation and landmark detection in computer-aided surgical simulation for orthognathic surgery.

The purpose of this ambispective study was to investigate whether deep learning-based automatic segmentation and landmark detection, the SkullEngine, could be used for orthognathic surgical planning. Sixty-one sets of cone beam computed tomography (CBCT) images were automatically inferred for midface, mandible, upper and lower teeth, and 68 landmarks. The experimental group included automatic segmentation and landmarks, while the control group included manual ones that were previously used to plan orthognathic surgery. The qualitative analysis of segmentation showed that all of the automatic results could be used for computer-aided surgical simulation. Among these, 98.4% of midface, 70.5% of mandible, 98.4% of upper teeth, and 93.4% of lower teeth could be directly used without manual revision. The Dice similarity coefficient was 96% and the average symmetric surface distance was 0.1 mm for all four structures. With SkullEngine, it took 4 minutes to complete the automatic segmentation and an additional 10 minutes for a manual touchup. The results also showed the overall mean difference between the two groups was 2.3 mm for the midface and 2.4 mm for the mandible. In summary, the authors believe that automatic segmentation using SkullEngine is ready for daily practice. However, the accuracy of automatic landmark digitization needs to be improved.

Uniformity calibration for large area XY strip parallel plate ionization chamber.

Demand for large area parallel plate ionization chamber (PPIC) or large area ionization chamber (LAIC) has risen in recent years due to several advantages of the large effective area in monitoring therapeutic radiation beams. PPICs are designed for the measurements of beam profile and dosimetry in radiation therapy quality assurance (QA) procedures.Objective. Heterogeneous responses over the large sensitive area pose an undeniable concern for the straightforward applications of PPICs in clinical dosimetry. Uniformity calibration for the detector response is thus essential for the accurate performance of each PPIC unit.Approach.A large area XY strip PPIC, characterized by a large effective area of 345.44 × 345.44 mm2and 256 readout channels, was investigated in this study. A new systematic uniformity calibration is developed to improve the lateral response of the PPIC over the measurements for both narrow beams and large square field beams. A 2D response map of the PPIC was obtained by a spot-scanning method using a compact x-ray tube (mini x-ray). The mini x-ray, providing stable radiation (uncertainty <0.1%), was moved with a step size of 20 mm in 2 dimensions across the entire PPIC surface to collect a complete spot scan. Different uniformity calibration methods were introduced for the measurement of the PPIC by adopting the information from the detector 2D response map.Main results.Deviation of the detector response, before calibration, was observed to reach about 7% for the testing PPIC unit which is much higher than the recommended uniformity response of 1% (IAEA TRS-398). The uniformity response of the PPIC improved significantly to less than 1% across the detector surface after calibration.Significance.The proposed methods enable the practical application of PPIC in routine clinical dosimetry and can be reliably adopted by any radiation facility to perform daily and monthly QA.

[Application progress of home self-sampling for human papillomavirus and human immunodeficiency virus testing].

Self-sampling is a method by which the subject collects the own specimens for disease detection. It has the advantages of strong privacy, convenient and simple operation, free time and place, etc. It can improve the compliance of people in remote areas, affected by traditional concepts, limited by working hours and underdeveloped transportation and medical treatment to participate in disease detection and screening. With the development of "Internet+health care" and "Internet+nursing service", home-based self-sampling testing will become a developing situation for disease detection and screening. Human immunodeficiency virus and Human papillomavirus infection bring a heavy burden to individuals and society. In the absence of effective and widespread primary prevention, secondary prevention, namely "early detection, early diagnosis and early treatment" is an effective measure to control the adverse consequences. At present, there are many researches on HPV and HIV self-sampling test, whose test results are highly reliable and highly accepted in the population, and is of great significance for improving the coverage rate of cervical cancer screening and the diagnosis rate of HIV carriers.

Evaluation of the causal relationship between smoking and schizophrenia in East Asia.

Cigarette smoking has been suggested to be associated with the risk of schizophrenia in observational studies. A significant causal effect of smoking on schizophrenia has been reported in European populations using the Mendelian randomization approach; however, no evidence of causality was found in participants from East Asia. Using Taiwan Biobank (TWBB), we conducted genome-wide association studies (GWAS) to identify susceptibility loci for smoking behaviors, including smoking initiation (N = 79,989) and the onset age (N = 15,582). We then meta-analyzed GWAS from TWBB and Biobank Japan (BBJ) with the total sample size of 245,425 for smoking initiation and 46,000 for onset age of smoking. The GWAS for schizophrenia was taken from the East Asia Psychiatric Genomics Consortium, which included 22,778 cases and 35,362 controls. We performed a two-sample Mendelian randomization to estimate the causality of smoking behaviors on schizophrenia in East Asia. In TWBB, we identified one locus that met genome-wide significance for onset age. In a meta-analysis of TWBB and BBJ, we identified two loci for smoking initiation. In Mendelian randomization, genetically predicted smoking initiation (odds ratio (OR) = 4.00, 95% confidence interval (CI) = 0.89-18.01, P = 0.071) and onset age (OR for a per-year increase = 0.96, 95% CI = 0.91-1.01, P = 0.098) were not significantly associated with schizophrenia; the direction of effect was consistent with European Ancestry samples, which had higher statistical power. These findings provide tentative evidence consistent with a causal role of smoking on the development of schizophrenia in East Asian populations.

p120 regulates E-cadherin expression in nasal epithelial cells in chronic rhinosinusitis.

BACKGROUND: The epithelial barrier plays an important role in the regulation of immune homeostasis. The effect of the immune environment on E-cadherin has been demonstrated in previous studies. This discovery prompted new research on the targeting mechanism of E-cadherin in chronic rhinosinusitis (CRS). METHODS: E-cadherin and p120 expression was determined by quantitative RT-PCR, and western blot. The interaction between E-cadherin and p120 was assessed by immunofluorescence staining and coimmunoprecipitation assays. Human nasal epithelial cells (HNECs) were cultured with submerged methods and transfected with p120-specific small interfering RNA. In other experiments, HNECs differentiated with the air-liquid interface (ALI) method were stimulated with various cytokines and Toll-like receptor (TLR) agonists. The barrier properties of differentiated HNECs were determined by assessing fluorescent dextran permeability. RESULTS: E-cadherin and p120 expression was decreased in HNECs from patients with CRS, and the p120 protein expression level was positively correlated with that of E-cadherin. Two isoforms of p120 (p120-1 and p120-3) were expressed in HNECs, with p120-3 being the main isoform. Knocking down p120 in HNECs cultured under submerged conditions significantly reduced the E-cadherin protein expression. The Rac1 inhibitor NSC23766 reversed the protein expression of E-cadherin in p120 knockdown experiments. Inflammatory mediators, including IL-4, TNF-α, TGF- ß, LPS and IFN-Î, reduced E-cadherin and p120 protein expression and increased paracellular permeability. Dexamethasone abolished the downregulation of E-cadherin and p120 caused by inflammatory mediators. CONCLUSIONS: p120 is involved in regulating E-cadherin protein expression in CRS. Dexamethasone may alleviate the reduction in E-cadherin and p120 protein expression caused by inflammatory mediators.

[Significance of aspergillus fumigatus-specific IgG in the diagnosis of allergic bronchopulmonary aspergillosis].

The data of 18 patients with allergic bronchopulmonary aspergillosis (ABPA) who received aspergillus fumigatus-specific IgG detection from 2015 to 2021 in Peking University Third Hospital were retrospectively analyzed. Among them, 11 were male and 7 were female, aged 18-79 years. All patients had a history of asthma or symptoms of cough and asthma, and aspergillus fumigatus-specific IgE was positive; 16 patients had total serum IgE>500 U/ml, of which 13 patients had total serum IgE>1 000 U/ml. Among other diagnostic indicators, peripheral blood eosinophils were >0.5×109/L in 16 cases; lung CT showed bronchiectasis in 15 cases; serum aspergillus fumigatus-specific IgG was positive (>120 AU/ml) in 10 cases. There was no significant difference in serum total IgE level, peripheral blood eosinophil count, and bronchiectasis ratio between positive and negative cases of aspergillus fumigatus-specific IgG (all P>0.05). In this study, the positive rate of aspergillus fumigatus-specific IgG in patients with ABPA was more than 50%, which has auxiliary value in the diagnosis of ABPA.

Bendamustine is safe and effective for lymphodepletion before tisagenlecleucel in patients with refractory or relapsed large B-cell lymphomas.

BACKGROUND: Anti-CD19 chimeric antigen receptor T-cell immunotherapy (CAR-T) is now a standard treatment of relapsed or refractory B-cell non-Hodgkin lymphomas; however, a significant portion of patients do not respond to CAR-T and/or experience toxicities. Lymphodepleting chemotherapy is a critical component of CAR-T that enhances CAR-T-cell engraftment, expansion, cytotoxicity, and persistence. We hypothesized that the lymphodepletion regimen might affect the safety and efficacy of CAR-T. PATIENTS AND METHODS: We compared the safety and efficacy of lymphodepletion using either fludarabine/cyclophosphamide (n = 42) or bendamustine (n = 90) before tisagenlecleucel in two cohorts of patients with relapsed or refractory large B-cell lymphomas treated consecutively at three academic institutions in the United States (University of Pennsylvania, n = 90; Oregon Health & Science University, n = 35) and Europe (University of Vienna, n = 7). Response was assessed using the Lugano 2014 criteria and toxicities were assessed by the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 and, when possible, the American Society for Transplantation and Cellular Therapy (ASTCT) consensus grading. RESULTS: Fludarabine/cyclophosphamide led to more profound lymphocytopenia after tisagenlecleucel infusion compared with bendamustine, although the efficacy of tisagenlecleucel was similar between the two groups. We observed significant differences, however, in the frequency and severity of adverse events. In particular, patients treated with bendamustine had lower rates of cytokine release syndrome and neurotoxicity. In addition, higher rates of hematological toxicities were observed in patients receiving fludarabine/cyclophosphamide. Bendamustine-treated patients had higher nadir neutrophil counts, hemoglobin levels, and platelet counts, as well as a shorter time to blood count recovery, and received fewer platelet and red cell transfusions. Fewer episodes of infection, neutropenic fever, and post-infusion hospitalization were observed in the bendamustine cohort compared with patients receiving fludarabine/cyclophosphamide. CONCLUSIONS: Bendamustine for lymphodepletion before tisagenlecleucel has efficacy similar to fludarabine/cyclophosphamide with reduced toxicities, including cytokine release syndrome, neurotoxicity, infectious and hematological toxicities, as well as reduced hospital utilization.

Psychiatric manifestations of rare variation in medically actionable genes: a PheWAS approach.

BACKGROUND: As genomic sequencing moves closer to clinical implementation, there has been an increasing acceptance of returning incidental findings to research participants and patients for mutations in highly penetrant, medically actionable genes. A curated list of genes has been recommended by the American College of Medical Genetics and Genomics (ACMG) for return of incidental findings. However, the pleiotropic effects of these genes are not fully known. Such effects could complicate genetic counseling when returning incidental findings. In particular, there has been no systematic evaluation of psychiatric manifestations associated with rare variation in these genes. RESULTS: Here, we leveraged a targeted sequence panel and real-world electronic health records from the eMERGE network to assess the burden of rare variation in the ACMG-56 genes and two psychiatric-associated genes (CACNA1C  and TCF4) across common mental health conditions in 15,181 individuals of European descent. As a positive control, we showed that this approach replicated the established association between rare mutations in LDLR and hypercholesterolemia with no visible inflation from population stratification. However, we did not identify any genes significantly enriched with rare deleterious variants that confer risk for common psychiatric disorders after correction for multiple testing. Suggestive associations were observed between depression and rare coding variation in PTEN (P = 1.5 × 10-4), LDLR (P = 3.6 × 10-4), and CACNA1S (P = 5.8 × 10-4). We also observed nominal associations between rare variants in KCNQ1 and substance use disorders (P = 2.4 × 10-4), and APOB and tobacco use disorder (P = 1.1 × 10-3). CONCLUSIONS: Our results do not support an association between psychiatric disorders and incidental findings in medically actionable gene mutations, but power was limited with the available sample sizes. Given the phenotypic and genetic complexity of psychiatric phenotypes, future work will require a much larger sequencing dataset to determine whether incidental findings in these genes have implications for risk of psychopathology.