Citations

Abstract Spatial transcriptomics has been widely applied to study the spatial distribution of cell types, cell states, and specific gene expression in tissue samples. However, we show that there is a prevalent transcript leakage problem in spatial transcriptomics data, where transcripts expressed by a cell diffuse to its neighborhood and are recurrently detected in the nearby cells. By analyzing published data sets, we show that this problem is general across data produced from different tissues and different species using different imaging-based and sequencing-based spatial transcriptomics platforms. It affects both upstream tasks such as expression quantification as well as downstream tasks such as cell-type annotation and detection of spatially-dependent gene expression. To tackle the transcript leakage problem, we propose a reference-free Bayesian model-based method, DeLeakage, which cleans up the data much more effectively than existing denoising methods. DeLeakage also improves cell-type annotation and avoids false detection of spatially dependent expression.

Objective: Characterize pathogenic variants, rates of mosaicism, genetic testing yield, and disease severity among patients with NF2-related schwannomatosis dichotomized by diagnosis before or after the age of 30. Study design: Retrospective analysis. Setting: Tertiary referral center multidisciplinary NF2 clinic from 2021 to 2024. Patients: Patients with NF2-related schwannomatosis. Intervention: Next-generation sequencing. Main outcome measure: Rates of mosaicism, genetic testing rates and yield, and overall disease severity by tumor burden. Results: From 2021 to 2024, there were 32 patients ≥30 years of age and 39 patients diagnosed at younger ages. Patients diagnosed ≥30 years exhibited decreased likelihood of receiving genetic testing (53% vs. 85%; P =0.009) and decreased genetic yield (defined as identification of a pathogenic genetic variant in those undergoing testing; 65% vs. 85%; P =0.20). Both age groups demonstrated similar rates of pathogenic variant type with loss-of-function being the predominant variant detected in 73% vs. 67%, for ≥30 vs. <30 years of age; P =0.90. Those ≥30 years harbored fewer number of average anatomic regions involved by tumor (2.3 vs. 3.4; P <0.001) and decreased total number of tumors (7 vs. 12; P <0.001). Conclusions: Patients diagnosed with NF2-related schwannomatosis at age ≥30 years exhibited reduced disease severity compared with those diagnosed at a younger age despite harboring similar distributions of genetic pathogenic variants inclusive of loss-of-function pathogenic variants. These observations emphasize the importance of considering patient age in addition to genetic testing for diagnostic framing tailored to patients’ biology and clinical context to optimize care in the setting of NF2-related schwannomatosis.

Abstract Purpose This study evaluates associations with suicidal ideation (SI) of impact of work on personal relationships (IWPR), self-valuation (SV), and imposter phenomenon and compares the SI point prevalence in physicians vs other workers. Method This study used American Medical Association Physician Professional Data to sample US physicians across different specialties between November 2020-March 2021. Of 7360 survey respondents, 6497 (88.3%) completed the SI question. A probability-based sample included 2508 nonphysician individuals from the US population employed at the time of survey administration, with 2501 workers (99.7%) completing the SI item. Logistic regression was used to evaluate the associations of occupational distress factors, including IWPR, SV, imposter phenomenon, and other factors, with SI before and after adjusting for depression and compare the risk of SI among physicians with other US workers. Results The study included 6497 physicians and 2501 workers in other fields. Adjusting for sex, age, relationship status, parenting status, and depression, each 1-point higher IWPR score (range, 0-10) was associated with 10% increased SI odds (odds ratio [OR], 1.10; 95% confidence interval [CI], 1.05-1.15). Adjusting for the same variables, each 1-point higher SV score (range, 0-10) was associated with 10% lower SI odds (OR, 0.90; 95% CI, 0.85-0.95). The association between imposter phenomenon scores (range, 4-20) and SI was not statistically significant (OR, 1.03; 95% CI, 0.99-1.08). The unadjusted 1-year SI point prevalence was 6.6% (95% CI, 6.0%-7.4%) in physicians vs 5.6% (95% CI, 4.7%-6.6%) among workers in other fields (P = .09). In a multivariable model, workers in other fields with a bachelor’s or master’s degree had lower SI odds compared with physicians (OR, 0.64; 95% CI, 0.46-0.87). Conclusions IWPR and low SV are associated with SI among physicians, independent of depression. Development and evaluation of interventions designed to mitigate these factors in physicians may be warranted.

ABSTRACT Background Cerebrospinal fluid (CSF) leak after retrosigmoid vestibular schwannoma resection remains a challenging complication. Historically, surgeons reopened the prior retrosigmoid incision for transmastoid repair because the safety of creating a separate postauricular incision was uncertain, with concerns regarding wound breakdown and infection. However, limited data support this practice, and a focused mastoid incision may offer improved access and patient tolerance. This study evaluated wound healing outcomes following transmastoid repair using a new postauricular incision for persistent CSF leak after retrosigmoid surgery in patients without serviceable hearing. Methods We retrospectively reviewed 27 patients who underwent transmastoid repair for persistent postoperative CSF leak after retrosigmoid craniotomy for vestibular schwannoma (2000–2025). Demographics, operative details, timing of leak diagnosis and repair, wound complications, readmissions, antibiotic use, and culture results were analyzed. Results Median age was 48 years (IQR 41–56); 67% were male, and mean BMI was 29.0 kg/m 2 . Mastoid obliteration was performed in 96%, with fat grafting in 93%. A new postauricular incision was used in all cases. Median time to leak diagnosis was 13 days (IQR 4–79), and median time to repair was 2 days (IQR 1–5). One patient (3.7%) developed a superficial wound abscess; no dehiscence or flap necrosis occurred. At median follow‐up of 34 months (IQR 2.9–87.7), all wounds were healed. CSF leak recurred in two patients (7.4%) and three (11.1%) required reoperation. Conclusion A separate postauricular incision for transmastoid CSF leak repair was not associated with increased wound morbidity. Durable wound healing was achieved in all patients, with 93% legal control, supporting this anatomy‐driven approach. Level of Evidence 4

TPS11598 Background: Fibroblast Activation Protein (FAP) is expressed on the surface of cancer-associated fibroblasts and is involved in the formation, maintenance, and spread of tumors. Sarcoma frequently demonstrates high expression of FAP on the tumor cells themselves in contrast to other solid tumors, where it is mainly expressed on CAFs within the tumor stroma. Radioligand therapies utilizing alpha emitting isotopes such as Ac-225 have emerged as promising treatment strategies across multiple targets and indications in oncology. Ac-225 and its daughter radionuclides emit high-energy alpha particles capable of inducing double-stranded DNA breaks, leading to significant cytotoxic effects within cells. Early clinical data for other Ac-225-labeled compounds have shown promising outcomes, particularly in settings where traditional therapies have failed. [Ac-225] RTX-2358 (Ratio Therapeutics Inc, Boston, MA) is a novel FAP-targeted radioligand designed for specific high-affinity binding, resulting in prolonged tumor residence and limited normal tissue uptake. This sustained tumor retention leads to extended delivery of cytotoxic radiation to FAP-expressing tumors. A beta-emitting analog, [Lu-177]RTX-2358, has been administered to more than 25 patients under the German §13.2b compassionate use framework across multiple tumor types. Longitudinal SPECT imaging performed as late as 14 days after administration demonstrated persistent tumor retention with minimal washout. Based on time–activity curve analysis from these data, tumor biological half-time is estimated to be well in excess of 1,000 hours. Renal clearance was observed to be consistent with that reported for established lutetium-177–labeled radioligand therapies. Methods: This study is a seamless Phase 1 / 2 dose escalation study. The Phase 1 portion consists of a 3 x 3 dose escalation design, with patients treated in 3 planned dose escalation cohorts (7.5, 11.25 and 15 MBq) with up to 6, 8-week cycles of [Ac-225]RTX-2358. Backfill of phase 1 cohorts is permitted to facilitate selection of the recommended administered activity level for the subsequent Phase 2 expansion cohort. Dose escalation / de-escalation decisions will be made by a Safety Review Committee. Patients over 18yrs with a history of histologically confirmed relapsed or refractory soft tissue sarcoma (measurable disease per RECIST v1.1) are eligible if they have a positive [Cu-64]LNTH-1363S FAP PET, an ECOG PS 0 to 1, and adequate organ reserve and renal function. Recruitment of the first cohort was completed in December 2025. The ATLAS Study: NCT07156565 Clinical trial information: NCT07156565 .

Importance Little is known about how factors external to the workplace, such as spousal support, influence physician attrition. Objectives To explore associations of spousal support among married/partnered physicians with both ‘hard’ attrition ((HA), considering leaving academic medicine within 2 years) and ‘soft’ attrition ((SA), having ever considered part-time work), before and after adjusting for demographic variables, burnout and satisfaction with work-life integration (WLI). Design This cross-sectional survey study was conducted among faculty physicians employed at Mayo Clinic. Outcomes and measures Survey items measured demographics, spousal support (five items), HA, SA, satisfaction with WLI (single-item measure) and burnout (two-item measure). Check-all-that-apply questions explored reasons for considering attrition. We investigated associations of spousal career support with attrition consideration using logistic regression analyses, adjusting for demographic variables then for WLI satisfaction and burnout. Results 739/2103 physicians responded (response rate 35.1%); 666 (90.1%) were married or partnered and responded to the HA question. 42.5% (283/666) reported considering HA and 60.9% of full-time employees (288/473) had ever considered SA. 65.5% (437/666) considered any attrition (AA). Respondents reporting more frequent spousal career support had lower odds of HA (OR 0.80, 95% CI 0.68 to 0.94, p=0.006), though this was not significant when considering AA (OR 0.85, 95% CI 0.71 to 1.01, p=0.07). Neither association was significant after adjusting for WLI satisfaction and burnout (OR 1.01, 95% CI 0.80 to 1.29, p=0.91 (HA), OR 1.10, 95% CI 0.86 to 1.37, p=0.45 (any attrition)). Conclusions While spousal support was no longer significantly associated with attrition after adjusting for WLI satisfaction and burnout, it may mitigate attrition.