5057 Background: RB function is often attenuated in tumors through hyperphosphorylation; thus, RB activity can be “re-awakened” in RB+ tumors by suppressing key kinases that phosphorylate RB (CDK4/6). We report a phase Ib/II trial to determine the safety, tolerability and antitumor activity rib with enza in patients (pts) with mCRPC (NCT02555189). Methods: RiboX was a multicenter, phase Ib/II, open label trial which enrolled taxane-naïve pts with progression to mCRPC and retained RB expression. For phase Ib, a traditional 3x3 dose-escalation was used to establish the RP2D for the phase II portion. Pts received rib at 200, 400 or 600mg once daily (QD) Days (D) 1-21 in combination with fixed dose enza (160mg QD D1-28). In phase II, pts were randomized 1:1 to enza monotherapy (Arm A) or enza + rib (Arm B). The study was later modified to a single arm Simon two-stage design using the RP2D of 600mg rib with 160mg enza. The primary phase II endpoint was the proportion of pts a PSA50 response at 12 weeks. The null hypothesis was that the PSA50 response was ≤78% and 31 responses were required to reject the null hypothesis. Secondary endpoints were rPFS, PSA PFS, OS and safety. Results: 12 pts were enrolled in the phase Ib portion across three dose levels upon confirmation of RB expression on tumor biopsy. No DLTs were observed in dose-escalation and the RP2D was established at rib 600mg QD D 1-21 + enza 160mg QD D 1-28. The phase II portion included 12 pts treated with enza mono; 28 phase II pts and 6 phase 1b pts yielded 34 pts treated with combination at RP2D. The PSA50 response at 12 weeks was 75% (95% CI, 43-95) for enza mono and 82% (95% CI, 65-93) for the combination, failing to reject the null hypothesis. Median rPFS for evaluable pts was 10.9 mo (95% CI, 2.5-45.9) for enza mono (n = 12) and 27.0 mo (95% CI, 11.3-37.0) for combination (n = 30). PSA PFS was 10.1 months (95% CI, 1.8-33.1) for enza mono (n = 12) and 14.8 mo (95% CI, 6.7-35.9) for combination (n = 34). OS was 31.2 mo (95% CI, 15.0-NA) for enza mono (n = 12) and 58.1 mo (95% CI, 33.4-NA) for combination (n = 34). Four pts treated with combination were included for PSA PFS but did not have data for rPFS. Among pts treated at RP2D in the combination arm, the most common TEAE’s included fatigue 59%, nausea 26.9%, neutropenia 26.7% (grade 3, 12%), diarrhea 20.9%, dizziness 14.7%, arrhythmia 2.9%, seizure 2.9%. Conclusions: The combination of enza + rib was well tolerated; however, no significant difference in PSA50 response was observed, and the primary endpoint was not met. A disease-stabilizing effect was observed in a subset of patients treated with the enza + rib combination, with evidence of prolonged survival. Further investigation into this disease-stabilizing effect and refinement of patient selection criteria beyond RB expression may be warranted. Funding: Novartis Pharmaceuticals and DOD (W81XWH-22-2-0020). Clinical trial information: NCT02555189 .

Supplement Figure 3: Signature-based Biomarkers. A: Signature-Based biomarkers for HPV negative patients. B: Signature-based biomarkers for HPV positive patients. ‘Primary Path Response’ refers to analysis based on the pTR at the primary site alone. ‘Overall path response’ refers to analysis based on primary + lymph node response.

Supplement Table 4A-4B: The following is a comprehensive list of the top 20 functional enrichments in the B cell (A) and CAF2 (B) gene sets utilizing STRING database to analyze protein-protein interaction pairs among the leading edge.

Abstract Purpose: We evaluated whether indoleamine 2,3-dioxygenase (IDO1) inhibitor (IDOi) BMS986205 + PD-1 inhibitor nivolumab enhanced T-cell activity and augmented immune-mediated antitumor responses in untreated, resectable head and neck squamous cell carcinoma (HNSCC). We employed response-adaptive surgical timing to identify responders to immunotherapy and enhance their response. Patients and Methods: Patients with HNSCC were 3:1 randomized to receive nivolumab with or without BMS986205 orally daily (NCT03854032). In the combination arm, BMS986205 was initiated 7 days prior to nivolumab. Patients were stratified by human papillomavirus (HPV) status. Response-adaptive surgical timing involved response assessment by radiographic criteria 4 weeks after treatment with nivolumab in both arms. Nonresponders underwent surgical resection, whereas responders received 4 more weeks of randomized therapy before surgery. Biomarker analysis utilized pathologic treatment response (pTR) and RNA sequencing. Results: Forty-two patients were enrolled, and the addition of IDOi to nivolumab did not result in greater rate of radiographic response (P = 0.909). Treatment was well tolerated, with only 2 (5%) patients experiencing grade 3 immune-related adverse events. The addition of IDOi augmented rates of pTR in patients with high baseline IDO1 RNA expression (P < 0.05). Response-adaptive surgical timing demonstrated reliability in differentiating pathologic responders versus nonresponders (P = 0.009). A pretreatment NK cell signature, PD-L1 status, and IFN-γ expression in the HPV− cohort correlated with response. The HPV+ cohort found B-cell and cancer-associated fibroblast signatures predictive of response/nonresponse. Conclusions: Response-adaptive surgical timing enhanced treatment response. IDOi BMS986205 augmented pTR in patients with high IDO1 expression in baseline samples, indicating a need for identifying and targeting resistant nodes to immunotherapy. HPV status–dependent signatures predicting response to immunotherapy in HNSCC warrant further study.

Supplement Figure 1: Waterfall Plots. A: Degree of pathologic treatment response (pTR) at the lymph nodes. B: Degree of pathologic response at the primary site, stratifed by treatment arm. C: Degree of RECIST response of primary tumor site (yellow) and lymph nodes (purple), stratifed by treatment arm.

Supplement Table 2A-2E: GSEA quantitative data for the B cell gene sets and CAF2 gene set for Post- vs Pre-treatments Responders vs Non responders. The following is a comprehensive list of supervised B-cell (A-C) and CAF (D-E) enrichment scores, normal enrichment scores, p-values, and q-values for the included gene sets.

Background At least 37 % emergency department (ED) patients are discharged without a definitive diagnosis, resulting in diagnostic uncertainty. Transitions of care are high-risk periods for patient safety, especially for patients discharged with diagnostic uncertainty. Effective communication between clinicians and patients improves these care transitions. Previous research developed tools to support high quality discharge in the setting of diagnostic uncertainty, including: a communication checklist, a physician training program, and a patient-facing information sheet. Methods This study aims to enhance transitions for patients leaving the ED with diagnostic uncertainty through an electronic health record (EHR)-based strategy. The intervention, the Targeted EHR-based Communication about Uncertainty strategy, integrates use of an Uncertainty Communication Checklist and an Uncertainty Discharge Document into routine ED discharge workflows. The checklist aids clinicians in addressing topics of chief concern for ED patients discharged with diagnostic uncertainty. The patient-centered discharge document explains the concept of diagnostic uncertainty to patients. The pre-post trial seeks to test the intervention's effectiveness in reducing patient uncertainty and return ED visits compared to standard of care with 300 participants. It also aims to evaluate the intervention's adoption and implementation barriers and facilitators. Discussion This trial builds on previous research to establish a communication strategy that equips patients with essential information for safe transitions amidst diagnostic uncertainty. The EHR-based strategy seeks to standardize communication and minimize bias and variation. Findings will be disseminated, to inform future trials and improve understanding of patient experiences with diagnostic uncertainty. Trial registration This trial was prospectively registered on 10/9/2024 with ClinicalTrials.gov (# NCT06638021).

Supplement Table. 3A-3C: Pro-B (A), Second Messenger (B), and CAF2 (C) leading edge genes unique to non-responders, shared between non-responders and responders, and unique to responders.

Supplementary Figure 2: Effect of IDO inhibitor BMS986205 on response rate and the tryptophan kynurenine pathway. A and B: IDO1 gene expression levels and tryptophan kynurenine pathway activity score, respectively, compared between baseline samples of responders (R) and non-responders (NR) on nivolumab + BMS986205 and nivolumab-only therapies. C: Tryptophan kynurenine pathway activity score compared between baseline and post-treatment samples of R and NR on nivolumab + BMS986205 and nivolumab-only therapies. - ns, *p < 0.05, **p < 0.01, ***p < 0.001.

BACKGROUND:In locally-advanced resectable squamous cell carcinoma of the head and neck (SCCHN), patients treated with neoadjuvant chemotherapy with major pathologic response (MPR) or pathologic complete response (pCR) have overall survival (OS) rates superior to those of patients with poorer pathologic responses. To improve efficacy, we added the PD-1 inhibitor, nivolumab, to neoadjuvant chemotherapy and evaluated the combination. METHODS:In this single-arm, open-label phase II trial, patients with newly-diagnosed stage III-IV HPV-negative SCCHN in the oral cavity, oropharynx, hypopharynx, and larynx or stage II-III HPV-positive oropharyngeal SCCHN received neoadjuvant carboplatin and paclitaxel (6 weeks) plus nivolumab (every other week) followed by surgery and adjuvant radiotherapy+/-chemotherapy. Primary endpoint was pCR at the primary site. RESULTS:Thirty-four patients were enrolled and received neoadjuvant therapy. Thirty-three patients received surgery (R0 resection=100%). Disease sites included the oral cavity (79%), oropharynx (12%), hypopharynx (6%), and larynx (3%). Twenty-eight (85%) patients had stage IVA disease. Median postsurgical follow-up was 35.3 months. Fourteen (41%) patients experienced Grade 3/ 4 treatment-related adverse events. Twenty-seven (82%) patients completed all cycles of neoadjuvant therapy. Twenty-four (73%) patients had at least an MPR at the primary site, and 15(45%) had a pCR. In an unplanned analysis at 3-years, recurrence-free survival and OS were 74% and 83%, respectively. CONCLUSIONS:This phase II trial of neoadjuvant nivolumab plus carboplatin and paclitaxel in previously untreated, locally-advanced, resectable SCCHN was well tolerated and reached its primary endpoint of pCR at the primary site. A phase III confirmatory study is warranted in advanced-stage, resectable HPV-negative SCCHN.

Supplement Figure 4: STRING Networks enlarged. The STRING networks of B cell (A) and CAF (B) as visualized in Figure 5.

Cytotoxic T lymphocytes (CTLs) destroy virally infected cells and are critical for the elimination of viral infections such as those caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Delayed and dysfunctional adaptive immune responses to SARS-CoV-2 are associated with poor outcomes. Treatment with allogeneic SARS-CoV-2-specific CTLs may enhance cellular immunity in high-risk patients providing a safe, direct mechanism of treatment. Thirty high-risk ambulatory patients with COVID-19 were enrolled in a phase 1 trial assessing the safety of third party, SARS-CoV-2-specific CTLs. Twelve interventional patients, 6 of whom were immunocompromised, matched the HLA-A*02:01 restriction of the CTLs and received a single infusion of 1 of 4 escalating doses of a product containing 68.5% SARS-CoV-2-specific CD8(+) CTLs/total cells. Symptom improvement and resolution in these patients was compared with an observational group of 18 patients lacking HLA-A*02:01 who could receive standard of care. No dose-limiting toxicities were observed at any dosing level. Nasal swab polymerase chain reaction testing showed >= 88% and >99% viral elimination from baseline in all patients at 4 and 14 days after infusion, respectively. The CTLs did not interfere with the development of endogenous anti- SARS-CoV-2 humoral or cellular responses. T-cell receptor beta analysis showed persistence of donor-derived SARS-CoV-2-specific CTLs through the end of the 6-month follow-up period. Interventional patients consistently reported symptomatic improvement 2 to 3 days after infusion, whereas improvement was more variable in observational patients. SARS-CoV-2-specific CTLs are a potentially feasible cellular therapy for COVID-19 illness. This trial was registered at www.clinicaltrials.gov as #NCT04765449.

Objectives: Recovery from traumatic brain injury (TBI) is extremely difficult to predict, with TBI severity usually demonstrating weak predictive validity for functional or other outcomes. A possible explanation may lie in the statistical phenomenon called suppression, according to which a third variable masks the true association between predictor and outcome, making it appear weaker than it actually is. Age at injury is a strong candidate as a suppressor because of its well-established main and moderating effects on TBI outcomes. We tested age at injury as a possible suppressor in the predictive chain of effects between TBI severity and functional disability, up to 10 years post-TBI. Setting: Follow-up interviews were conducted during telephone interviews. Participants: We used data from the 2020 NDILRR Model Systems National Dataset for 4 successive follow-up interviews: year 1 ( n = 10,734), year 2 ( n = 9174), year 5 ( n = 6,201), and year 10 ( n = 3027). Design: Successive cross-sectional multiple regression analyses. Main Measures: Injury severity was operationalized using a categorical variable representing duration of posttrauma amnesia. The Glasgow Outcomes Scale—Extended (GOS-E) operationally defined functioning. Sociodemographic characteristics having significant bivariate correlations with GOS-E were included. Results: Entry of age at injury into the regression models significantly increases the association between TBI severity and functioning up to 10 years post-TBI. Conclusions: Age at injury is a suppressor variable, masking the true effect of injury severity on functional outcomes. Identifying the mediators of this suppression effect is an important direction for TBI rehabilitation research.

Background:Focal chondral defects are often treated with cartilage restoration procedures. Malalignment often accompanies chondral defects. High tibial osteotomy (HTO), classically utilized to treat uni-compartmental knee osteoarthritis, corrects malalignment. HTO combined with cartilage restoration procedures can treat uni-compartmental osteoarthritis and focal chondral defects. Purpose:To assess outcomes of combined HTO and cartilage restoration procedures and review prognostic factors that may assist in preoperative planning and patient counseling. Study design:Systematic Review of published literature. Methods:A systematic review of PubMed and Scopus was performed following PRISMA guidelines. Thirty-four papers were included in qualitative considerations. Results:Thirty-four papers that reported the combined outcome of HTO and cartilage repair were included. Twenty of the 34 included papers reported prognostic factors that affected the success or failure of combined HTO and cartilage repair surgery for focal articular defect and uni-compartmental knee osteoarthritis. Cartilage repair techniques that were combined with HTO and included in this review are bone marrow stimulation, allograft transplantation, osteochondral autograft transplantation, autologous chondrocyte implantation, and mesenchymal stem cell implantation. Conclusions:HTO with adjunctive cartilage repair procedures improve clinical outcome scores and restore alignment in patients with medial compartment osteoarthritis and isolated focal chondral defects. HTO with adjunctive cartilage procedures produces optimal results in younger, non-obese patients with focal chondral defects and varus malalignment, without significant lateral compartment and patellofemoral involvement.

478 Background: Radiation therapy (RT) is an integral component of the multimodal therapy of pelvic malignancies, either as primary treatment or in combination with surgical resection. In addition to local treatment effects on nearby pelvic organs, RT has been established to be a risk factor for delayed secondary malignancies. In this study, we examine the rate of any secondary malignancies following RT for primary pelvic malignancies, with a specific emphasis on secondary pelvic malignancies Methods: Using the SEER (Surveillance, Epidemiology, and Ends Results) database, we retrospectively examined 2,102,192 patients with primary pelvic malignancies (prostate, bladder, uterine, rectal, cervical). For each disease site, we compared the rate of all secondary malignancies in radiated patients to non-radiated patients. Secondary malignancies were then stratified as pelvic and non-pelvic, in order to determine the local effect of RT on malignancy risk. Results: A total of 2,102,192 patients were examined (1,189,108 prostate, 315,026 bladder, 88,809 cervical, 249,535 uterine, 259,714 rectal). A total of 113,322 patients developed secondary malignancies after RT (Table), with 26,299 developing secondary pelvic malignancies after RT (18,411 prostate, 1,026 bladder, 1,410 cervical, 2,179 uterine, 3,273 rectal) (Table). The overall relative risk (RR) of RT on developing a secondary malignancy was 1.79 (1.77-1.80 CI, P<0.0001), particularly in patients with prostate (RR 2.57), uterine (RR 1.24) and cervical cancer (1.09). The overall RR of RT on developing a secondary pelvic malignancy was 2.09 (2.06-2.13 CI, P<0.0001), particularly in patients with bladder (RR 6.90), prostate (RR 2.74), and uterine cancer (RR 1.21). Conclusions: Radiation treatment for pelvic malignancies increases the risk of developing secondary malignancies over the patient’s lifetime. Further work needs to done to identify at risk populations.[Table: see text]

Posttransplant cyclophosphamide (PtCy) has been shown to decrease post-hematopoietic stem cell transplant acute and chronic graft-versus-host disease (GVHD). In this study, PtCy was used in 44 patients along with mycophenolate and tacrolimus with HLA matched (29) and mismatched (15) unrelated donors to determine the impact of graft content on outcome; thus, all patients had flow cytometric analysis of their graft content including the number of B cells, NK cells, and various T cell subsets. Higher gamma delta T cell dose was associated with the development of acute GVHD (p = .0038). For PtCy, further studies of the cell product along with further graft manipulation, such as selective gamma delta T cell depletion, could potentially improve outcomes.

The great majority of spinal cord injury (SCI) patients have debilitating chronic pain. Despite decades of research, these pain pathways of neuropathic pain (NP) are unknown. SCI patients have been shown to have abnormal brain pain pathways. We hypothesize that SCI NP patients' pain matrix is altered compared to SCI patients without NP. This study examines the functional connectivity (FC) in SCI patients with moderate-severe chronic NP compared to SCI patients with mild-no NP. These groups were compared to control subjects. The Neuropathic Pain Questionnaire and neurological evaluation based on the International Standard Neurological Classification of SCI were utilized to define the severity and level of injury. Of the 10 SCI patients, 7 (48.6???17.02 years old, 6 male and 1 female) indicated that they had NP and 3 did not have NP (39.33???8.08 years old, 2 male and 1 female). Ten uninjured neurologically intact participants were used as controls (24.8???4.61 years old, 5 male and 5 female). FC metrics were obtained from the comparisons of resting-state functional magnetic resonance imaging among our various groups (controls, SCI with NP, and SCI without NP). For each comparison, a region-of-interest (ROI)-to-ROI connectivity analysis was pursued, encompassing a total of 175 ROIs based on a customized atlas derived from the AAL3 atlas. The analysis accounted for covariates such as age and sex. To correct for multiple comparisons, a strict Bonferroni correction was applied with a significance level of p?<?0.05/NROIs. When comparing SCI patients with moderate-to-severe pain to those with mild-to-no pain, specific thalamic nuclei had altered connections. These nuclei included: medial pulvinar; lateral pulvinar; medial geniculate nucleus; lateral geniculate nucleus; and mediodorsal magnocellular nucleus. There was increased FC between the lateral geniculate nucleus and the anteroventral nucleus in NP post-SCI. Our analysis additionally highlights the relationships between the frontal lobe and temporal lobe with pain. This study successfully identifies thalamic neuroplastic changes that occur in patients with SCI who develop NP. It additionally underscores the pain matrix and involvement of the frontal and temporal lobes as well. Our findings complement that the development of NP post-SCI involves cognitive, emotional, and behavioral influences.