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Background Loss of finger motion after zone II flexor tendon repair remains common and is largely caused by adhesion formation. Although intrinsic vascular and cellular contributions to tendon healing have been examined in canine, avian, and primate models, prior studies have emphasized biochemical or perfusion-based endpoints without comprehensive assessment of functional and mechanical outcomes after clinically relevant repair. Consequently, the influence of intrinsic healing elements on early postoperative function remains unclear. In this study, we employed a novel avian model of intrasynovial (zone II) tendon injury, which enables clinically relevant operative repair, postoperative rehabilitation, and quantitative assessment of tendon function and biomechanics, to investigate the contribution of intrinsic healing elements to tendon repair. Questions/purposes (1) Does operative ablation of intrinsic healing elements worsen early ROM after zone II flexor tendon repair? (2) Does disruption of intrinsic pathways increase adhesion formation, as measured by normalized work of flexion and gross adhesion scores? (3) Does intrinsic tendon component ablation compromise mechanical properties, including ultimate load to failure and stiffness? (4) Does removal of intrinsic elements alter the expression of fibrotic and matrix-related genes during early healing? Methods Using a clinically relevant, large-animal avian ( Meleagris gallopavo ) model of zone II flexor tendon repair, flexor digitorum longus (FDL) tendons underwent sharp transection and primary repair and were assigned to one of four groups: (1) control repair with intact intrinsic elements (3 weeks postinjury, n = 11; 6 weeks postinjury, n = 18), (2) vincular ligation and transection (3 weeks postinjury, n = 12; 6 weeks postinjury, n = 16), (3) tenocyte cryoablation via intraoperative freeze-thaw devitalization (3 weeks postinjury, n = 13; 6 weeks postinjury, n = 13), or (4) complete tendon devitalization (3 weeks postinjury, n = 13; 6 weeks postinjury, n = 16). A total of 112 male and female birds were used for this study. Harvested tendons were evaluated at 3 and 6 weeks postoperatively. Outcomes included interphalangeal ROM, normalized work of flexion, semiquantitative gross adhesion scoring, ultimate load to failure, stiffness, qualitative histologic assessment, qualitative immunofluorescence, and quantitative PCR for fibrotic and matrix-related genes. Results Operative ablation of the intrinsic healing elements did not worsen total ROM and/or increase normalized work of flexion. All experimental groups demonstrated reduced total ROM of the operative digit at 3 weeks postoperatively compared with the contralateral nonoperative digit: mean ± SD control repair with intact intrinsic healing elements (50° ± 10° versus 14° ± 6°, mean difference 36.41° [95% confidence interval (CI) 26.87° to 45.94°]; p < 0.001), vincular disruption group (50° ± 10° versus 14° ± 7°, mean difference 35.97° [95% CI 21.44° to 45.51°]; p < 0.001), tenocyte cryoablation group (50° ± 10° versus 15° ± 8°, mean difference 35.27° [95% CI 25.99° to 44.55°]; p < 0.001), and complete tendon devitalization group (50° ± 10° versus 11° ± 4°, mean difference 38.97° [95% CI 29.44° to 48.50°]; p < 0.001). However, no differences between the groups were detected. Similarly, the total ROM was impaired at 6 weeks postinjury compared with the nonoperative digit in all groups. We did not detect any differences between the groups, and results did not demonstrate time-dependent differences between the two time points. Furthermore, normalized work of flexion, a proxy for peritendinous adhesion severity, was increased in all experimental groups at 3 weeks postinjury: mean ± SD control repair with intact intrinsic healing elements (0 ± 0 N mm/° versus 4 ± 3 N mm/°, mean difference -3.33 [95% CI -5.73 to -0.93]; p = 0.003), vincular disruption group (0 ± 0 N mm/° versus 4 ± 2 N mm/°, mean difference -3.09 [95% CI -5.49 to -0.69]; p = 0.006), tenocyte cryoablation group (0 ± 0 N mm/° versus 3 ± 2 N mm/°, mean difference -2.99 [95% CI -5.33 to -0.66]; p = 0.006), and complete tendon devitalization group (0 ± 0 N mm/° versus 4 ± 2 N mm/°, mean difference -3.31 [95% CI -5.70 to -0.91]; p = 0.003). However, no group differences were detected. At the 6-week follow-up, the normalized work of flexion was also elevated in all groups without any differences between the treatments. Furthermore, the integrity of the tendon intrinsic components has been presumed to be a major determinant of flexor tendon healing strength after zone II tendon repair. However, our results do not support this assumption. At both time points, there were no differences in ultimate load and stiffness between the experimental groups, and there were no group × time interaction effects. Additionally, structural removal of the intrinsic healing elements did not result in meaningful qualitative histologic differences in extrinsic fibrosis, neovascularization, or collagen fiber organization. The profibrotic gene, transforming growth factor beta induced (TGFBI), was upregulated in all experimental groups compared with the normal FDL tendon. Matrix remodeling, measured by matrix metalloproteinase 7 (MMP7) activity, was also activated in all groups relative to the normal FDL tendon. However, no differences were detected between the groups. Conclusion Operative ablation of intrinsic healing elements, including the flexor vincular system and resident tenocytes, did not worsen early ROM, adhesion formation, or mechanical properties after zone II flexor tendon repair in a clinically relevant large-animal model. Early healing was characterized by a robust fibrovascular response across all groups, indicating that extrinsic mechanisms predominate during the early reparative phase. Paradigms that modulate the extrinsic tendon healing mechanisms could represent a more viable approach to flexor tendon healing outcomes than focusing on bolstering the intrinsic components. Clinical Relevance Our findings suggest that early functional recovery in this model may depend more on modulation of the extrinsic fibrotic response than on preservation of intrinsic vascular or cellular elements, supporting the development of antiadhesion therapies. Additional preclinical studies are needed to identify the cellular niches that drive extrinsic fibrosis and adhesion formation, determine whether they can be selectively modulated without impairing tendon healing, and establish the translational relevance of these mechanisms across species before clinical application.

Abstract Varlilumab is a monoclonal antibody with agonistic activity on CD27. The efficacy of single-agent PD-1 inhibitors on aggressive B-cell non-Hodkin lymphoma is limited. Preclinical and phase 1 data suggest that Varlilumab is safe and may have synergistic activity with PD-1 inhibitors. In the DIAL study, we explored whether dual immunomodulatory therapy with Varlilumab and Nivolumab in patients with relapsed/refractory aggressive B-NHL was safe and effective. We conducted a randomized phase II clinical trial on adult patients with relapsed/refractory aggressive B-NHL. Patients were randomized to receive Nivolumab monotherapy in the control group and Varlilumab combined with Nivolumab in the experimental group. Crossover to the experimental group was allowed upon progression in the control group. The primary endpoint was the overall response rate based on the Lymphoma Response to Immunomodulatory Therapy Criteria (LYRIC). 54 patients underwent randomization, and 51 received assigned intervention and were included in the intention-to-treat analysis. Objective response was observed in 6 out of 51 patients (ORR 12%). There were 4 responders (ORR 16%) in the Nivolumab group and 2 responders (ORR 7.6%) in the Nivolumab and Varlilumab combination group (p = 0.3). None of the 7 patients that crossed over to the experimental group responded to the addition of Varlilumab. The ORR of patients who were previously exposed to CAR-T cell therapy was 13% (5 out of 39) compared to 8.3% (1 out of 12) in the unexposed patients (p > 0.99). The rate of treatment emergent adverse events was similar between groups, and there was no fatal TEAE in the study. The addition of Varlilumab to Nivolumb did not improve outcomes in patients with aggressive B-NHL. Even though this trial was not designed to evaluate immunotherapy as a rescue therapy after CAR-T failure, most patients (76%) had previously received CAR-T therapy, and their outcomes were equally poor.

The NCCN Guidelines for Survivorship offer guidance for health care providers who care for survivors of adult-onset cancer. These guidelines include screening, evaluation, and treatment recommendations for common physical and psychosocial problems resulting from cancer and its treatment and provide a framework for care coordination. They also present guidance for helping cancer survivors to enhance their wellness and maintain a healthy lifestyle. This article summarizes the panel’s current recommendations and recent updates regarding anxiety, depression, distress, and trauma in cancer survivors.

Abstract Background Immunosuppression is a recognized risk factor for severe and disseminated coccidioidomycosis; however, data describing outcomes in patients with inflammatory bowel disease (IBD) receiving advanced therapy, including biologics and small molecules, remain limited. We aim to describe the prevalence, clinical presentation, treatment patterns, and outcomes of coccidioidomycosis in IBD patients receiving advanced therapy at an endemic tertiary care center. Methods We performed a retrospective observational study of adult patients with IBD at Mayo Clinic Arizona diagnosed with coccidioidomycosis between 2023 and 2026. Patients were included if IBD diagnosis preceded coccidioidomycosis diagnosis and advanced therapy had been active for at least 4 weeks before infection. Cases were classified as proven, probable, or possible based on microbiologic, clinical, radiographic, and serologic criteria. Clinical outcomes included antifungal treatment duration, hospitalization related to coccidioidomycosis or IBD, IBD treatment modification after diagnosis, re-emergence of coccidioidomycosis symptoms, and IBD-related surgery. Results A total of 48 patients met inclusion criteria. Among 1083 tested IBD patients receiving advanced therapy, coccidioidomycosis positivity prevalence was 4.4% when including all serologically positive patients and 1.9% when restricted to proven or probable cases. The median age at coccidioidomycosis diagnosis was 40 years (range 19-87 years), and 30 (62.5%) of 48 had Crohn’s disease. Proven or probable infection was identified in 21 (43.8%) of 48 patients, while 14 (29.2%) of 48 patients were classified as possible. Antifungal therapy was prescribed in 32 (66.7%) of 48 patients, including all proven cases, 15 (88.2%) of 17 probable cases, 9 (64.3%) of 14 possible cases, and 3 (25.0%) of 12 nondiagnostic cases. Among proven/probable/possible cases, the median antifungal treatment duration was 174 days (range 8-831 days). Advanced IBD therapy was continued in 3 (75.0%) of 4 proven cases, 9 (52.9%) of 17 probable cases, 12 (85.7%) of 14 possible cases, and all nondiagnostic cases. Hospitalization occurred in 6 (12.5%) of 48 of the cohort, all of which were proven/probable cases. Most patients remained on advanced therapy after diagnosis, although tumor necrosis factor α inhibitors were the most interrupted or discontinued agents. Conclusions In this endemic tertiary care cohort, management decisions varied according to diagnostic certainty. Patients with proven or probable coccidioidomycosis were more likely to receive antifungal therapy and undergo advanced IBD therapy modification, whereas most patients with possible or nondiagnostic serologic findings remained on advanced therapy without major IBD-related complications. Prolonged antifungal treatment was common, highlighting the complexity of managing coccidioidomycosis in immunosuppressed patients with IBD.

Abstract Cellular senescence has been implicated in the pathophysiology of radiotherapy-associated bone loss. Based on our previous work, clearance of senescent cells using genetic and pharmacological tools alleviates the anomalies associated with radiation-associated bone deterioration. The pro-inflammatory senescence associated secretome referred to as senescence associated secretory phenotype (SASP), is a hallmark of cellular senescence. The modulation of SASP by senomorphic drugs, potentially can suppress the pro-inflammatory secretome of senescent cells, irrespective of the underlying senescence mechanism. In this study we tested a senomorphic drug, ruxolitinib, a Janus kinase inhibitor (JAKi), during acute and chronic radiotherapy related effects on the bone. Our clinical data indicate an early increase in several pro-inflammatory SASP proteins following radiotherapy of spinal metastasis in prostate cancer patients. Longitudinal assessment of SASP-related genes confirmed this acute elevation in several SASP markers in systemic circulation following irradiation of male mouse femurs. In studies done in male mice, following three preclinical radiotherapy regimens of 30Gy (5 x 6Gy), 60Gy (5 x 12Gy) and a single dose of 24Gy, suppression of SASP by JAKi was efficacious in suppressing radiation-induced bone damage. In comparison and as shown before, the senolytic combination of D+Q was also able to alleviate radiation-associated bone loss. Early and intermittent suppression of SASP using JAK inhibitors in male mice alleviated chronic bone deterioration, diminished telomere dysfunction, lowered senescence and SASP marker expression and reduced bone-marrow adiposity. Overall, our study shows that early targeting of SASP proteins could be a potential therapeutic to prevent radiotherapy-related chronic bone loss and risk of fractures.

Abstract Background Lupus nephritis remains a major cause of chronic kidney disease and kidney failure in systemic lupus erythematosus. Glucocorticoids are central to treatment but are limited by systemic toxicity. We evaluated whether a previously characterized collagen IV α3-targeted liposomal nanoparticle formulation carrying low-dose prednisolone could attenuate established lupus nephritis in MRL/lpr mice. Methods Female MRL/lpr mice with disease present at treatment initiation and C57BL/6J control mice received saline or collagen IV α3-targeted prednisolone-loaded nanoparticles (Col4-α3-Pred-NPs). Renal outcomes were assessed by longitudinal proteinuria, glomerular filtration rate (GFR), survival, kidney histopathology, renal IgG and C3d deposition, dUTP/TUNEL-associated injury staining, and renal cytokine/chemokine profiling. Body weight, food and water intake, and blood glucose were monitored as measures of general condition and preliminary tolerability. Results Col4-α3-Pred-NPs improved survival in MRL/lpr mice, reduced cumulative proteinuria burden, and attenuated terminal GFR decline compared with saline-treated MRL/lpr controls. Treatment reduced glomerular and tubulointerstitial injury, lowered composite EGTI histopathology scores, decreased terminal kidney enlargement, reduced glomerular IgG deposition and renal dUTP-positive injury signals, and reduced renal signals for IL-28A/B, IL-7, PD-ECGF, IL-11, CCL6/C10, and IL-15. C3d deposition was not significantly altered. Nanoparticle treatment was not associated with sustained treatment-related increases in blood glucose or body-weight loss during the measured study period. Conclusions Collagen IV α3-targeted liposomal delivery of low-dose prednisolone attenuated established lupus nephritis in MRL/lpr mice and improved renal structural, functional, inflammatory, and survival outcomes. These findings support further evaluation of glomerulus-targeted nanotherapy as a potential strategy to improve the precision and therapeutic index of glucocorticoid treatment in lupus nephritis.

Importance Pyoderma gangrenosum (PG) is a rare neutrophilic dermatosis characterized by sterile ulcerative skin lesions. Multiple comorbidities and clinical features have been associated with PG, but no standardized guidelines exist for classifying PG phenotypes. Objective To develop an expert-established classification framework for PG phenotypes to inform treatment guidelines and future research endeavors. Evidence Review In this modified Delphi consensus study that included 23 board-certified dermatologists and Medical Dermatology Society members with expertise in PG, panelists completed 5 rounds of anonymous, iterative online surveys that were administered from December 2023 through July 2025. Before the beginning of the consensus exercise, a literature review was performed by nonvoting researchers to summarize existing data on PG clinical associations and comorbidities. A PubMed search from inception to September 2023 identified observational studies, narrative reviews, systematic reviews, and meta-analyses describing PG clinical associations and comorbidities that were published in English. Experts indicated their agreement with proposed PG phenotypes and disease modifiers with a consensus threshold of 70% or greater. Anonymous comments and aggregated results were presented in each subsequent round. In the final round, a framework of PG phenotypes and disease modifiers was proposed for agreement. Findings Twenty-three board-certified dermatologists and Medical Dermatology Society members with expertise in PG completed 5 rounds of iterative surveys. Consensus was reached on the final set of PG phenotypes and disease modifiers, with 83% of experts in agreement. PG phenotypes were overall classified into 2 major groups: PG with autoinflammatory syndromes and nonsyndromic PG. Nonsyndromic PG included 4 phenotypes: inflammatory bowel disease–associated PG, PG in association with hematologic cancers and blood dyscrasias, drug-induced PG, and other (including idiopathic) PG. Disease modifiers of PG phenotype presentations included involvement of special sites (head/neck, genitals, or peristomal skin) and extracutaneous manifestations. Conclusions and Relevance This expert-established, descriptive framework provides a standardized classification system for distinct PG phenotypes and its modifiers. This nomenclature may inform upcoming clinical guidelines and allow for consistency in reporting epidemiological research and outcomes among patients with PG.

ABSTRACT Chemotherapy-induced peripheral neuropathy (CIPN) is a common, debilitating complication of cancer therapy. Although axonal degeneration defines CIPN, the initiating cellular events remain unknown. Here, we show that CIPN is initiated by senescent peripheral fibroblasts rather than by the neuron itself. Across the mechanistically distinct chemotherapeutic agents paclitaxel and cisplatin, chemotherapy-induced senescence is unexpectedly restricted to peripheral fibroblasts rather than neurons and acts upstream of neuronal SARM1 activation. Genetic or pharmacological ablation of senescent fibroblasts prevents neuropathy and reverses established disease, demonstrating that these cells are required for both disease initiation and maintenance. Mechanistically, senescent fibroblasts drive neuropathic injury through an MK2-dependent senescence-associated secretory phenotype (SASP), and genetic or pharmacological inhibition of MK2 suppresses the SASP, preserves peripheral innervation and restores sensory function. Together, these findings redefine the cellular origin of CIPN and identify MK2-dependent fibroblast senescence as a therapeutic target.