High-dose post-transplantation cyclophosphamide (HD-PTCy), given at 50 mg/kg/day on days +3/+4, is a standard-of-care graft-versus-host disease (GVHD) prophylaxis for allogeneic hematopoietic cell transplantation (HCT). Our murine MHC-haploidentical HCT studies suggested intermediate-dose PTCy produces superior GVHD control compared with HD-PTCy and PTCy is maximally effective on day +4. We conducted a single-institutional prospective phase I/II trial (NCT03983850) to reduce PTCy dosing to 25 mg/kg/day on days +3/+4 or on day +4 only for myeloablative HLA-haploidentical bone marrow HCT using PTCy, sirolimus, and mycophenolate mofetil. Among 35 patients, 89% were ethnic/racial minorities, 46% had high/very-high-risk disease, and median comorbidity-score was 3. The phase I dose-limiting-toxicity, grade III-IV acute GVHD, was not observed after either reduced-PTCy dose-level. PTCy 25 mg/kg/day on days +3/+4 (intermediate-dose (ID)-PTCy; n=23), the phase II dose, resulted in no grade II-IV acute GVHD; 2-year cumulative incidences of chronic GVHD requiring systemic immunosuppression, non-relapse mortality, and relapse were 13%, 17%, and 22%, and 2-year overall survival, disease-free survival, and GVHD-free/relapse-free survival were 61%, 61%, and 52%. In exploratory analysis compared with HD-PTCy (n=5), ID-PTCy resulted in significantly faster engraftment and T-cell reconstitution, fewer transfusions, less mucositis, and reduced severity of BK-virus-associated cystitis; area-under-the-curve exposure of 4-hydroxycyclophosphamide (4HCY), a key cyclophosphamide metabolite, correlated with these outcomes but not with chronic GVHD occurrence. Ideal-body-weight-based PTCy dosing best approximated 4HCY exposure. Intermediate-dose PTCy is effective and has apparent clinical benefits compared with HD-PTCy. Before broader implementation, further studies are needed to confirm these findings and define optimal PTCy dosing across various donor/graft types. NCT03983850

Importance Cutaneous neurofibromas (cNFs) can cause itching, disfigurement, pain, and emotional difficulties in people with neurofibromatosis type 1 (NF1). ObjectiveTo determine the impact of the mitogen-activated protein kinase kinase inhibitor selumetinib on cNF including change in tumor volume and patient-reported outcome measures. Design, Setting, and Participants Adults with NF1 and 9 or more measurable cNFs were enrolled in this nonrandomized pilot trial at the National Cancer Institute and the University of Alabama at Birmingham, which spanned from August 26, 2017, to August 21, 2023. Intervention Participants received selumetinib for up to 24 cycles (1 cycle = 28 days) with restaging visits after every 4 cycles. Main Outcomes and Measures Photography and volumetric measurements of cNFs using calipers were used to evaluate the number and volume of tumors. Participants completed the Skindex-29 Quality of Life assessment to quantify the effect of treatment on symptoms, functioning, emotions, itching, and pain. Results Among the 11 participants who enrolled, the median (range) age was 54 (28-75) years, and 6 were female. The median (IQR) best response across all participants and tumors was a -28.5% (-40.9% to -12.5%) decrease in cNF volume from baseline. Some participants showed a visible improvement in cNF burden while receiving treatment in standardized photographs. The median (range) duration of treatment was 9 cycles (1-24), with only 4 participants completing the full 24 cycles of treatment. Two of these participants continued treatment beyond the original 24 cycles due to perceived clinical benefit. All participants experienced at least 1 reversible drug-related adverse event (AE), with cutaneous AEs such as dry skin and rash being the most common. Two participants were removed from treatment due to concern for drug reaction with eosinophilia and systemic symptoms. While the Skindex-29 assessment showed improvement in emotion scores after cycle 1, there were no other significant or durable changes in scores. Conclusions and Relevance In this nonrandomized pilot trial, selumetinib resulted in some decrease in cNF volume; however, there was no sustained improvement in patient-reported outcome measures. Study enrollment was incomplete, in part due to the COVID-19 pandemic, and highlights the challenges of treating patients with cNF with a drug that often leads to dermatologic AEs. Future larger studies using other measurement techniques, such as 3-dimensional photography, could help to yield results that are more generalizable to the phenotypically diverse NF1 population.

Supplemental Figure S4. Sample partitioning for training a MYOD1 mutation predictive model using K-fold cross-validation.

Differentially methylated regions with at least five CpGs, and a mean difference of greater than 20% between day 14 and baseline white blood cells

Small cell carcinoma of the bladder is a rare, aggressive malignancy accounting for less than 1% of all bladder malignancies. Treatment regimens are drawn from the small cell lung cancer (SCLC) literature, with platinum and etoposide commonly used in the first-line setting. Unfortunately, responses are generally short-lived, and most patients relapse. There is little evidence to guide selection of later lines of therapy. Lurbinectedin is an alkylating agent with accelerated US FDA approval for use in patients with SCLC. Immune checkpoint inhibitors have also been approved for SCLC, improving survival when added to chemotherapy. This article describes the design and rationale behind LASER, an open-label phase II trial of lurbinectedin with or without avelumab.Clinical trial registration: NCT06228066 (ClinicalTrial.gov).

Fusion-positive RMS enhancer sites; Universal DNAase-hypersensitivity sites; YES1 and IGF1R region sets

IMPORTANCE Patients who experience progression of advanced human papillomavirus (HPV)-associated cancers and who have previously received first-line systemic treatment have a poor prognosis and limited therapeutic options. OBJECTIVE To assess the clinical activity of the combination of the HPV type 16 therapeutic vaccine PDS0101, the tumor-targeting interleukin 12 antibody-drug conjugate PDS01ADC, and the bifunctional anti-programmed cell death ligand 1 (PD-L1)/transforming growth factor beta (TGF-beta) bintrafusp alfa in advanced HPV-associated cancers. DESIGN, Setting, and Participants This nonrandomized clinical trial was phase 1/2 and investigator initiated, and was conducted at a single US cancer research center between June 2020 and July 2022. Patients with advanced or metastatic HPV-associated cancers were eligible, including patients who were both immune checkpoint blockade (ICB) naive and ICB resistant. The cutoff date for data analysis was May 13, 2024. INTERVENTION Patients received 1 mL of PDS0101 subcutaneously every 4 weeks for 6 doses then every 12 weeks for 2 additional doses, PDS01ADC, 16.8 mu g/kg, subcutaneously every 4 weeks or PDS01ADC, 8 mu g/kg, subcutaneously every 2 weeks, and bintrafusp alfa, 1200 mg, intravenously every 2 weeks. MAIN OUTCOMES AND MEASURES Objective response rate (ORR) by Response Evaluation Criteria in Solid Tumors version 1.1 in ICB-naive patients. RESULTS Of the 50 eligible patients, 26 (52%) were men and the median age was 56 years (range, 28-80 years). The median (IQR) follow-up was 37.7 (30.6-42.0) months. Fourteen patients (28%) were ICB naive, with an ORR of 35.7% (95% CI, 12.8%-64.9%), and median overall survival (OS) 42.4 months (95% CI, 8.3 months-not estimable); in ICB-resistant patients, the ORR was 16.7% (6 of 36 patients; 95% CI, 6.4%-32.8%) and median OS was 15.8 months (95% CI, 9.0-21.3 months). Among patients with HPV-16-positive tumors (37 patients [74%]), in the ICB-naive group (8 patients [21.6%]) the ORR was 62.5% (95% CI, 24.5%-91.5%) and a median OS measure was not reached. Grade 3 and 4 treatment-related adverse events occurred in 26 of 50 patients (52%). There were no treatment-related deaths. CONCLUSIONS AND RELEVANCE In this trial, the combination of PDS0101, PDS01ADC, and bintrafusp alfa showed an acceptable safety profile and promising antitumor activity and improved OS in patients with HPV-16-positive cancers, in both ICB-naive and ICB-resistant patients, warranting further evaluation of the combination of PDS0101 and PDS01ADC with simultaneous PD-L1/TGF-beta inhibition in these populations.

Adverse events possibly, probably, or definitely related to ganitumab across all 28 cycles (maximum grade per patient)

Supplemental Figure S3. Sample partitioning for training and testing a RAS pathway mutation predictive model using K-fold cross-validation. Three independent experiments were trained on a random selection of samples for training, validation and testing.

Supplemental Figure S6. Graphical User Interface for tissue segmentation, MYOD1 mutation prediction, and risk prediction models.

Supplemental Fig. 3. ERB-B-2 Status of Patients.

Supplemental methods and figures

Supplemental Protocol Information. A: Study Eligibility; B: Dasatinib dosing nomogram; C: Dasatinib dose modifications

Supplemental Fig 2. Total mutation Burden by MB.

IMPORTANCE Patients who experience progression of advanced human papillomavirus (HPV)–associated cancers and who have previously received first-line systemic treatment have a poor prognosis and limited therapeutic options. OBJECTIVE To assess the clinical activity of the combination of the HPV type 16 therapeutic vaccine PDS0101, the tumor-targeting interleukin 12 antibody-drug conjugate PDS01ADC, and the bifunctional anti–programmed cell death ligand 1 (PD-L1)/transforming growth factor β (TGF-β) bintrafusp alfa in advanced HPV-associated cancers. DESIGN, Setting, and Participants This nonrandomized clinical trial was phase 1/2 and investigator initiated, and was conducted at a single US cancer research center between June 2020 and July 2022. Patients with advanced or metastatic HPV-associated cancers were eligible, including patients who were both immune checkpoint blockade (ICB) naive and ICB resistant. The cutoff date for data analysis was May 13, 2024. INTERVENTION Patients received 1 mL of PDS0101 subcutaneously every 4 weeks for 6 doses then every 12 weeks for 2 additional doses, PDS01ADC, 16.8 µg/kg, subcutaneously every 4 weeks or PDS01ADC, 8 µg/kg, subcutaneously every 2 weeks, and bintrafusp alfa, 1200 mg, intravenously every 2 weeks. MAIN OUTCOMES AND MEASURES Objective response rate (ORR) by Response Evaluation Criteria in Solid Tumors version 1.1 in ICB-naive patients. RESULTS Of the 50 eligible patients, 26 (52%) were men and the median age was 56 years (range, 28-80 years). The median (IQR) follow-up was 37.7 (30.6-42.0) months. Fourteen patients (28%) were ICB naive, with an ORR of 35.7% (95% CI, 12.8%-64.9%), and median overall survival (OS) 42.4 months (95% CI, 8.3 months-not estimable); in ICB-resistant patients, the ORR was 16.7% (6 of 36 patients; 95% CI, 6.4%-32.8%) and median OS was 15.8 months (95% CI, 9.0-21.3 months). Among patients with HPV-16–positive tumors (37 patients [74%]), in the ICB-naive group (8 patients [21.6%]) the ORR was 62.5% (95% CI, 24.5%-91.5%) and a median OS measure was not reached. Grade 3 and 4 treatment-related adverse events occurred in 26 of 50 patients (52%). There were no treatment-related deaths. CONCLUSIONS AND RELEVANCE In this trial, the combination of PDS0101, PDS01ADC, and bintrafusp alfa showed an acceptable safety profile and promising antitumor activity and improved OS in patients with HPV-16–positive cancers, in both ICB-naive and ICB-resistant patients, warranting further evaluation of the combination of PDS0101 and PDS01ADC with simultaneous PD-L1/TGF-β inhibition in these populations. Trial Registration ClinicalTrials.gov Identifier: NCT04287868

Supplemental Figure S5. Frequency of mutations in COG and A.I. designated risk groups.

Background Dedicator of cytokinesis 8 (DOCK8) deficiency is a primary immunodeficiency in which allogeneic hematopoietic cell transplantation (HCT) represents the only known cure. We tested the ability of a busulfan-based regimen to achieve reliable engraftment and high levels of donor chimerism with acceptable toxicity in a prospective clinical trial in DOCK8 deficiency. Objective To both evaluate the ability of HCT to reverse the clinical phenotype and to correct the immunologic abnormalities by 1-year post-HCT. Methods We conducted a prospective HCT trial for recipients with DOCK8 deficiency. Subjects were recruited from October 5th, 2010, to December 30th, 2022. Donor sources included fully matched related (MRD) and unrelated (MUD) and haploidentical (Haplo) donors. The reduced toxicity, myeloablative conditioning regimen contained no serotherapy. Graft-versus-host disease (GVHD) prophylaxis included either a calcineurin inhibitor (CNI) with methotrexate (MTX) or post-HCT cyclophosphamide (PT/Cy) followed by tacrolimus and mycophenolate mofetil (MMF). The trial was later amended to study PT/Cy in all patients. (ClinicalTrials.gov NCT01176006). Results Thirty-six subjects, children, and adults (median age 16.4 years) underwent HCT for DOCK8 deficiency. Most patients, 33 of 36 (92%), achieved full (≥98%) donor chimerism in whole blood as early as day +30. With a median potential follow-up of 7.4 years, 29 (80.6%) were alive with no evidence of new DOCK8 deficiency-related complications. PT/Cy was effective in reducing the risk of acute GVHD in patients who had received MUDs and Haplo transplants, but it was associated with transient delays in immune-reconstitution and hemorrhagic cystitis (HC). Conclusion A busulfan-based HCT regimen using PT/Cy for GVHD prophylaxis and a broad range of donor types and hematopoietic cell sources were well-tolerated, leading to the reversal of the clinical immunophenotype.

Sacituzumab govitecan (SG) is a TROP2-directed antibody-drug conjugate with a payload of SN-38, a topoisomerase inhibitor. SG monotherapy has demonstrated activity in multiple solid tumors, including metastatic breast and bladder cancer. Rare tumors of the genitourinary tract often exhibit aggressive clinical behavior yet lack effective treatment options. This article describes the design and rationale for an open-label, non-randomized, phase 2 trial of SG monotherapy or concomitant SG plus atezolizumab in locally advanced/metastatic bladder/urinary tract adenocarcinoma/urachal adenocarcinoma, squamous cell carcinoma, or high-grade neuroendocrine carcinoma; renal medullary carcinoma; and penile squamous cell carcinoma.Clinical Trial Registration: NCT06161532 (ClinicalTrials.gov).

Serial samples demonstrate recurrent loci with copy number alterations for each patient.

This study examines the success of surgeon-scientists compared with nonsurgeon physician-scientists in obtaining National Institutes of Health (NIH) funding after participation in a research training grant. Dedicated research time during postgraduate training for physician-scientists is advantageous for obtaining future independent funding from NIH. NIH Reporter was used to identify F32 and T32 grants awarded to internal medicine and surgery departments from 2005 to 2015, and an internal NIH database was used to determine funding outcomes. Success rates were recorded for surgeon versus internist PIs who applied for either a mentored career grant or research project grant (RPG). The median time in years from the final year of the training grant and clinical graduation to the first awarded grant was investigated. χ 2 tests, Fisher exact tests, and Wilcoxon rank sum tests were used. A greater proportion of surgeons transitioned directly to an RPG, 27% (68 internist PIs) compared with 72% (63 surgeon PIs) ( P <0.001). Both T32 and F32 trained surgeons were able to obtain an RPG sooner than internists, taking a median of 5 years from the end of clinical training versus a median of 7 years for internists [ P =0.033 (F32), P =0.034 (T32)]. Although fewer F32 and T32-funded surgeons apply for subsequent NIH funding compared with nonsurgeons, more surgeons apply for an RPG instead of a K-grant. Remarkably, surgeons obtained independent funding sooner after clinical graduation compared with internists, despite the extensive gap in time between postgraduate training and first faculty appointment, an amazing accomplishment given their clinical training and surgical practice challenges.