Longitudinal Analysis of Cancer Risk in Children and Adults With Germline PTEN Variants.

Importance: Identifying hereditary cancer predisposition facilitates high-risk organ-specific cancer surveillance and prevention. In PTEN hamartoma tumor syndrome (PHTS), longitudinal studies remain lacking, and there are insufficient data on cancers in children and young adults, as well as individuals with neurodevelopmental disorders (NDD). Objective: To evaluate lifetime cancer risks, including second malignant neoplasms (SMN), among patients with PHTS. Design, Setting, and Participants: Prospective longitudinal cohort study (September 1, 2005, through January 6, 2022). General population risks from the Surveillance, Epidemiology, and End Results database. Patients with PHTS, molecularly defined as carrying germline PTEN variants, were accrued from community and academic medical centers throughout North America, South America, Europe, Australia, and Asia. Data were analyzed from July 2022 to February 2023. Exposures: Review of physical and electronic medical records, and follow-up through clinical visits or telephone interviews. Main Outcomes and Measures: Lifetime cancer risks in PHTS relative to the general population. Results: A total of 7302 patients were prospectively accrued, 701 of whom had germline PTEN variants (median [IQR] age at consent, 38 [12-52] years; 413 female patients [59%]). Longitudinal follow-up data could be obtained for 260 patients (37%), with a median (IQR) follow-up of 4 (2-8) years. Of the 701 patients, 341 (49%) received at least 1 cancer diagnosis, with 144 (42%) of those having SMN. The study found significantly elevated lifetime risks for breast (91%), endometrial (48%), thyroid (33%), kidney (30%), and colorectal cancers (17%), as well as melanoma (5%). Cancer diagnoses were also observed in children and young adults with PHTS (15%) and in patients with PHTS with neurodevelopmental disorders (11%). Elevated risks (P < .001) of thyroid (age-adjusted standardized incidence ratios [SIR], 32.1; 95% CI, 26.0-39.0), kidney (SIR, 26.5; 95% CI, 18.8-36.3), endometrial (SIR, 26.0; 95% CI, 19.5-34.1), breast (SIR, 20.3; 95% CI, 17.3-23.7), and colorectal (SIR, 7.9; 95% CI, 5.2-11.7) cancers, and melanoma (SIR, 6.3; 95% CI, 3.5-10.5) were observed. Of the 341 patients with PHTS with cancer, 51 (15%) had 1 or more cancers diagnosed at age 29 years or younger, and 16 (31.4%) of those developed SMN at final follow-up. Twenty-three patients with PHTS with NDD and cancer were identified, with 5 (22%) having developed SMN at final follow-up. Individuals with PHTS and NDD showed higher lifetime cancer risks compared with individuals with PHTS but without NDD (hazard ratio, 2.7; 95% CI, 1.7-4.2; P < .001). Conclusions and Relevance: This cohort study found consistently elevated lifetime cancer risks in PHTS. Organ-specific surveillance should continue in patients with PHTS. Additional study is required to ascertain elevated cancer risks in patients with PHTS with NDD.

The Impact of Travel Distance on Rhegmatogenous Retinal Detachment Presentation and Outcomes.

BACKGROUND AND OBJECTIVE: Rhegmatogenous retinal detachment (RRD) requires urgent surgical intervention. The effect of travel distance on RRD outcomes is unclear. PATIENTS AND METHODS: This retrospective cohort study included 642 patients who underwent RRD repair at Cole Eye Institute from 2012 to 2020. Google Maps was used to calculate the travel distance in miles from the residential zip code to the presenting and surgery location addresses. Multivariable logistic and bivariate linear regressions were used to compare macula-off status and best-corrected visual acuity (BCVA) in ETDRS letters at presentation and at 6-month follow-up, with patient travel distance divided into < 25 miles, 25 to 50 miles, and > 50 miles. RESULTS: Four hundred sixty-two patients were examined in the final cohort. The retinal reattachment rate was 94.3% for less than 25 miles, 96.3% for 25 to 50 miles, and 95.9% for greater than 50 miles (P = 0.63). In multivariable analysis, distance to presenting location was not associated with macula-off status (P = 0.69) or BCVA at follow-up (P = 0.27). Oneway analysis of distance and time from presentation to surgery in days revealed that distance to surgical site was associated with longer time to surgery (P = 0.003). Subset analysis of patients with income less than $25,520 (n = 18) revealed greater distance to presenting and surgical location was associated with longer time to surgery (P < .0001), but was not associated with BCVA at follow-up (P = 0.53). CONCLUSIONS: This data suggests that patients who live further from the hospital achieve equivalent outcomes from RRD repair, despite delays in surgery. [Ophthalmic Surg Lasers Imaging Retina 2022;53:666-672.].

Intraosseous delivery of platelet-targeted factor VIII lentiviral vector in humanized NBSGW mice.

We previously showed that intraosseous (IO) delivery of factor VIII (FVIII, gene F8) lentiviral vector (LV) driven by the megakaryocyte-specific promoter Gp1bα (G-F8-LV) partially corrected the bleeding phenotype in hemophilia A (HemA) mice for up to 5 months. In this study, we further characterized and confirmed the successful transduction of self-regenerating hematopoietic stem and progenitor cells (HSPCs) in treated mice. In addition, secondary transplant of HSPCs isolated from G-F8-LV-treated mice corrected the bleeding phenotype of the recipient HemA mice, indicating the potential of long-term transgene expression following IO-LV therapy. To facilitate the translation of this technology to human applications, we evaluated the safety and efficacy of this gene transfer therapy into human HSPCs. In vitro transduction of human HSPCs by the platelet-targeted G-F8-LV confirmed megakaryocyte-specific gene expression after preferential differentiation of HSPCs to megakaryocyte lineages. Lentiviral integration analysis detected a polyclonal integration pattern in G-F8-LV-transduced human cells, profiling the clinical safety of hemophilia treatment. Most importantly, IO delivery of G-F8-LV to humanized NBSGW mice produced persistent FVIII expression in human platelets after gene therapy, and the megakaryocytes differentiated from human CD34+ HSPCs isolated from LV-treated humanized mice showed up to 10.2% FVIII expression, indicating efficient transduction of self-regenerating human HSPCs. Collectively, these results indicate the long-term safety and efficacy of the IO-LV gene therapy strategy for HemA in a humanized model, adding further evidence to the feasibility of translating this method for clinical applications.