Gundersen Health System

Abstract Ovarian cancer stem cells (CSCs) can seed recurrent drug-resistant disease. Likewise, non-CSCs can acquire CSC phenotypic properties. How this process is orchestrated is of interest to inform how it might be prevented. We tested the hypothesis that ovarian CSC and/or drug-resistant tumor cells confer stem-like properties via extracellular vesicles (EVs). We focused our investigation on how EVs might mediate EZH2 signaling to promote a phenotypic change in drug-sensitive, non-CSCs. To accomplish this, we utilized paired PARP inhibitor-sensitive and - resistant ovarian cancer (OvCa) cell lines, EZH2 knockdown lines, and patient-derived organoids (PDOs) originating from recurrent high-grade serous OvCa. Small EVs isolated from drug-sensitive, CSC and/or drug-resistant enriched cultures, PARP inhibitor (olaparib) resistant lines, or drug-treated (olaparib or carboplatin) lines were cultured with treatment naïve or sensitive lines for defined time points. The impact of small EV exposure was determined by assessing cell number, metabolic activity, viability, sphere and colony-forming capacity, ALDH activity, DNA damage, and changes in associated signaling pathways. We found that EVs from CSC or drug-resistant enriched cell fractions communicate CSC-like phenotypes to the more sensitive tumor cells via EZH2 canonical and non-canonical signaling pathways, promoting stemness. We conclude that EV-mediated activation of EZH2 signaling represents a targetable mechanism contributing to stemness-associated drug resistance in OvCa. Graphical abstract

Running-related Achilles tendon injuries have been observed more frequently in males, which may reflect sex differences in tendon morphology or mechanics during running. Males exhibit a larger Achilles tendon cross-sectional area and some measures of Achilles tendon loading in running, but sex differences in measures of tendon loading have not been thoroughly characterized. This study examines sex differences in the Achilles tendon cross-sectional area and Achilles tendon loading variables associated with running kinetics and kinematics. Cross-sectional. Recruited from a university population, 26 female and 23 male healthy recreational runners ran at 3.35m/s on an instrumented treadmill and were assessed using 3-dimensional motion capture, musculoskeletal modeling, and diagnostic ultrasound. A multivariate analysis examined differences between sexes in Achilles tendon loading and additional running variables with alpha set to .05. Mean differences (MD) and confidence intervals (CIs) were reported. Males displayed greater peak Achilles tendon force (MD = 0.94 body weight [BW]; 95% CI, -1.48 to -0.33), peak gastrocnemius force (MD = 0.52 BW; 95% CI, -0.75 to -0.29), and Achilles tendon cross-sectional area (MD = 0.1cm2; 95% CI, -0.15 to 0.04) compared with females (P < .05). No group differences were observed in peak Achilles tendon stress (MD = 4.13 kPa; 95% CI, -16.25 to 7.98), peak Achilles tendon strain (MD = 0.41; 95% CI, -1.60 to 0.78), peak soleus force (MD = 0.34 BW; 95% CI, -0.76 to 0.078), foot strike angle (MD = 3.1; 95% CI, -1.65 to 7.85), or peak vertical ground reaction force (MD = 0.106; 95% CI, -0.24 to 0.03) (P > .05). Male runners produced greater peak Achilles tendon force when running at the same speed, but similar peak Achilles tendon stress was observed between male and female recreation runners. Male runners had a greater Achilles tendon cross-sectional area. These findings may have implications to running-related injury based on sex.

ABSTRACT Standard pathology workup sometimes fails to definitively identify tumor tissue-of-origin in cancers with ambiguous diagnoses or unknown primary sites, complicating treatment decisions. Molecular assays can aid diagnosis but require additional tissue and increase healthcare costs. Intending to leverage routinely collected somatic mutation profiles from comprehensive genomic profiling, we developed Tumor-Origin.com, a machine learning platform to predict tumor tissue-of-origin from mutation data alone. We trained five classifiers on 10,945 tumor mutation profiles from the MSK-IMPACT cohort and validated performance on an independent set of 770 tumors from the Gundersen Precision Oncology cohort spanning 52 cancer types. Performance was strongest for the most common tumor types, reflecting their relative over-representation in training data. Among cancer types with more than five cases, the Logistic Regression classifier achieved the highest average top-3 accuracy of 49%, followed by the Support Vector Machine at 43%. At least one algorithm delivered ≥40% accuracy in 23 cancer types. Our integrated platform thus provides robust tumor origin predictions across diverse cancers. We have implemented a web-based tool ( https://tumor-origin.com ) to assist clinicians and researchers in refining diagnoses of cancers of unknown primary without requiring additional tissue or costly testing.

Despite the dire need for rural surgeons and increasing interest in exposing residents to rural practice, there remains little systematic information about how programs establish and sustain rural rotations. A website review (12/2022-7/2023) of the 342 civilian surgery programs listed by the ACGME identified those offering elective or required U.S. rural rotations. In addition, all programs were contacted by email to confirm or deny that they offered rural rotations to account for webpage inaccuracies. The effort identified 81 programs (24%). A qualitative design was then adopted, whereby the first author interviewed 58 general surgery program leaders (72% participation rate) to explore strategies used to arrange and sustain rural rotations. Interviews focused on the 2023-24 academic year, were conducted from August 2023 to August 2024, and were recorded, transcribed, and analyzed collaboratively to discern program strategies. Programs are more likely to use rural training sites outside their healthcare system (59% or 34/58) than inside (41% or 24/58), but system sites were preferred when available. At both site types, programs drew heavily upon professional ties, primarily to program graduates (64% or 37/58). Alumni were eager to help and knew program traditions and expectations. Their presence also bolstered confidence in the educational value of the rotation. Additional alumni joining rural sites were evidence of rotations as a recruitment pathway, thus fostering sustainable relationships. Within-system rotations were easier to arrange and finance than those outside the system. The results offer practical insights into how a diverse mix of surgery programs across the U.S. select and sustain required and elective rural rotations in the U.S. The prominence of professional ties to program graduates and healthcare-system links are especially notable. Variability across programs in how they select and sustain sites also suggests that many approaches are feasible.

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7540 Background: The combination of a proteasome inhibitor (PI) with lenalidomide (R) and dex (d) has been a common initial therapy for newly diagnosed myeloma (NDMM). We designed a randomized phase 3 trial to examine if carfilzomib (K), a next generation PI, improved progression free survival (PFS) compared with bortezomib (V) when either is combined with Rd for initial treatment of NDMM. Initial analysis at a median follow up of 15.3 months (mos) showed comparable PFS for both triplets. We present the long-term results of the trial with ~70 months median follow up. Methods: Patients (Pts) with NDMM, were randomized 1:1 to receive VRd or KRd for 36 weeks followed by a 2 nd randomization (1:1) to indefinite versus 2 yrs of R maintenance. Pts without del17p, t(14;16), t(14;20), plasma cell leukemia or high-risk GEP70 profile, were enrolled. VRd arm included V 1.3 mg/m 2 on days(d) 1, 4, 8, and 11 (d1, 8 for cycles 9-12), R 25 mg d1-14, and d 20 mg d1, 2, 4, 5, 8, 9, 11, 12 of a 3-week (wk) cycle for 12 cycles, while pts in the KRd arm received K 36 mg/m 2 d1, 2, 8, 9, 15, 16 with R 25 mg daily on d1-21 and d 40 mg wkly, in 4 wk cycles for 9 cycles. Maintenance used 15 mg R d1-21 q4 wks. Results: The study accrued 1087 pts (VRd=542, KRd=545). Median age was 65y; baseline characteristics including intent to transplant were similar across the arms. Median induction duration (mos; IQR) was 7.2 (3.4-8.9) and 8.4 (5.1-9.1) for VRd and KRd, respectively; 59.8% in VRd and 45.3% in KRd did not proceed to Step 2. Median PFS (mos) was VRd=41.9 and KRd=44.6; HR = 0.89 (0.76-1.04). Toxicity data, PFS sensitivity analyses and OS probabilities are as in the table. Conclusions: In this randomized trial, with median follow up of nearly 6 years, KRd and VRd had comparable PFS and OS in an intent to treat analysis. While similar numbers proceeded to SCT in the 2 arms, more did so during induction in the VRd arm while more patients in the KRd arm went to SCT later. VRd remains a standard triplet induction regimen in standard and intermediate risk NDMM, and a suitable backbone for 4 drug combinations. Clinical trial information: NCT01863550 . N (%) VRd(n=527) KRd(n=526) SCT anytime 186 (34.3) 183 (33.6) SCT without Step 2 registration 146 112 Median Time to SCT (mos; range) 7.7 (3.5-83.9) 10.6 (3.7-70.6) Grade 3-4 Treatment-Related Toxicity 315 (59.8) 344 (65.4) Grade 5 Treatment-Related Toxicity 2 (0.4) 9 (1.7) Grade 5 All Events 11 (2.1) 20 (3.8) Survival outcomes HR Median (95% CI) Median (95% CI) PFS Primary: PD or death within 3 months of last evaluation as events 0.89(0.76-1.04) 41.9(35.7, 50.3) 44.6(38.2, 51.9) PFS Sensitivity: All deaths as events, 0.87(0.75-1.02) 39.5(34.9, 46.0) 42.8(37.4, 49.7) PFS Sensitivity: Censor at alternate Rx 0.83(0.69-0.99) 35.0(31.3, 42.6) 38.7(34.7, 49.0) PFS Sensitivity: Event at alternate Rx 0.84(0.73-0.97) 18.0(14.2, 23.0) 24.4(20.9, 27.9) Overall survival 0.92(0.75-1.12) 119(100, NE) 118(103-NE)

BackgroundLung cancer is the second-most common cancer and leading cause of cancer-related deaths. American adults aged 55 to 80 years are at heightened risk for lung cancer; only 4.5% underwent screening history by computed tomography. The hypothesis is that lung cancers diagnosed on screening were an earlier stage which broadens treatment options and improves survival.MethodsThe electronic health record (EHR) was retrospectively queried to identify patients with lung cancer from 2017 to 2020. Kaplan-Maier curves were used to compare survival based on screening history.Results764 patients with lung cancer were included. 14.7% (112/764) had a history of lung cancer screening. Patients with a history of screening were significantly more likely to be diagnosed at early stages (66/112, 59% vs 215/652, 33%; P < .0001). They were significantly more likely to have surgery (46/112, 41% vs 97/652, 15%, respectively; P < 0.0001). Patients diagnosed in late stages were significantly more likely than those diagnosed at early stages to receive chemotherapy (318/483, 66% vs 76/281, 27%, respectively; P < .0001). Three-year survival was higher with screening (P < .0001). Survival rates at 3 years after initial diagnosis with screening history is 47.4% (95% CI, 34.8-59.0) while the rate without screening is 25.2% (95% CI, 21.2-29.4).DiscussionLung cancer diagnosed via screening was more likely to be earlier stages. Patients diagnosed at early stages were more likely to undergo surgery. Those diagnosed via screening had a higher 3-year survival. These findings indicate that early routine screening leads to improved treatment options and survival.