Citations

ABSTRACT Lung cancer is the leading cause of cancer-related deaths worldwide and, despite treatment advances, immune suppression remains an obstacle to effective therapy. Effector CD4 + T cells (CD4 + Teffs) are critical for antitumor immunity, but their function is often inhibited by regulatory T cells (Tregs), which accumulate in lung tumors and perform suppressive functions through multiple mechanisms. This suppression leads to tumor progression and poor patient outcomes. However, the mechanisms underlying Treg-mediated suppression are not fully understood. Here, we identify the extracellular ATP receptor P2RX7 as a key regulator of Treg function in lung tumors. Using a murine lung cancer model induced by Lewis lung carcinoma cells, we demonstrate that P2RX7 enhances the suppressive capacity of tumor-infiltrating Tregs, promoting tumor growth. In T cell-specific P2RX7-KO mice, reduced Treg infiltration was accompanied by increased CD4 + Teff accumulation and improved tumor control. Treg-specific P2RX7-KO mice exhibit reduced tumor growth, confirming a cell-intrinsic role of P2RX7 in Tregs. Suppression assays revealed that tumor-infiltrating WT Tregs have greater suppressive activity compared to P2RX7-KO Tregs, which failed to inhibit type 1 and Tfh-like responses. This was associated with increased tumor-specific IgG production by lung B cells in P2RX7-KO mice. We also observed that WT Tregs express higher levels of the immunosuppressive surface molecule CTLA-4 when compared to P2RX7-KO Tregs. In summary, we show that P2RX7 expression on Tregs is essential for their suppressive function in lung cancer, and targeting of P2RX7 may constitute a novel strategy to improve lung cancer treatment by alleviating Treg-mediated immune suppression.

Importance Use of modern neoadjuvant chemotherapy (NAC) regimens has markedly increased rates of pathologic complete response (pCR) in breast cancer, raising the question of whether surgical removal of the primary tumor is required for patients with pCR. For surgery to be omitted, one must be able to accurately predict pCR before surgery. Objective To investigate if adding post-NAC core needle biopsy of the tumor bed to trimodality imaging in patients who have clinical complete response (cCR) will predict pCR (resolution of both invasive disease and ductal carcinoma in situ) in 90% or more cases. Design, Setting, and Participants This was a phase 2, prospective, nonrandomized clinical trial. Patients were enrolled from August 2017 to June 2019. This is the final analysis, which was completed in December 2023. The setting included academic and community hospital center members of NRG (ie, the National Surgical Adjuvant Breast and Bowel Project, the Radiation Therapy Oncology Group, and the Gynecologic Oncology Group) in the US and Canada. Patients with operable (T1-T3, stage I-III) invasive ductal carcinoma who completed NAC and achieved cCR and radiological complete response (rCR) or near rCR by mammography (mass ≤1 cm and no malignant microcalcifications), ultrasound (mass ≤2 cm), and magnetic resonance imaging (no mass with rapid rise or washout kinetics). Interventions Patients underwent marker-directed stereotactic multiple-core needle biopsy of the tumor bed with marker placement before breast-conservation surgery. Main Outcomes and Measures End points were negative predictive value (NPV) and sensitivity of the biopsy. Results A total of 105 patients were enrolled with 101 evaluable (mean [SD] age, 52.8 [10.5] years); 77 patients (76.2%) were younger than 60 years, and all breast cancer subtypes were represented with 32 (31.7%) triple-negative breast cancer, 21 (20.8%) hormone receptor–positive/epidermal growth factor receptor 2 ( ERBB2 ; formerly HER2 )–negative ( ERBB2 −) breast cancer, and 46 (45.5%) ERBB2 -positive ( ERBB2 +) breast cancer. In 101 evaluable patients, 36 had residual disease at surgery (pCR = 64%). With imaging criteria, NPV of the biopsy was 78.3% (95% CI, 67.9%-86.6%), and the sensitivity of the biopsy was 50% (95% CI, 32.9%-67.1%). In an exploratory subset analysis, the NPV in patients with ERBB2 + breast cancer was 90% (95% CI, 76.3%-97.2%). On retrospective central review, 62 of 101 enrolled patients met imaging eligibility criteria. In this exploratory post hoc analysis, NPV in these patients was 86.8% (95% CI, 74.7%-94.5%). Conclusions and Relevance These findings do not support breast conservation treatment without surgery based on the study criteria for cCR and rCR/near rCR by trimodality imaging and negative tumor-bed biopsy. Strict adherence to imaging criteria may be required to achieve acceptable predictive values. TRIAL Registration ClinicalTrials.gov Identifier: NCT03188393

AbstractINTRODUCTIONPhosphorylated ubiquitin (p‐S65‐Ub) is generated during PINK1‐PRKN mitophagy as a specific marker of mitochondrial damage. Despite the widespread deposition of p‐S65‐Ub in aged and diseased human brain, the genetic contribution to its accumulation remains unclear.METHODSTo identify novel mitophagy regulators, we performed a genome‐wide association study using p‐S65‐Ub level as a quantitative trait in 1012 autopsy‐confirmed Lewy body disease (LBD) samples.RESULTSWe identified a significant genome‐wide association with p‐S65‐Ub for rs429358 (apolipoprotein E ε4 [APOE4]) and a suggestive association for rs6480922 (ZMIZ1). APOE4 was associated with higher p‐S65‐Ub levels and greater neuropathological burden. Functional validation in mouse and human induced pluripotent stem cell (iPSC) models confirmed APOE4‐mediated mitophagy alterations. Intriguingly, ZMIZ1 rs6480922 was associated with lower p‐S65‐Ub levels, reduced neuropathological load, and increased brain weight, indicating a potential protective role.DISCUSSIONOur findings underscore the importance of mitochondrial quality control in LBD pathogenesis and nominate regulators that may contribute to disease risk or resilience.Highlights p‐S65‐Ub levels were used as a quantitative marker of mitochondrial damage. A GWAS identified two genetic variants that modify mitophagy in LBD autopsy brain. APOE4 was associated with increased p‐S65‐Ub accumulation and neuropathology. APOE4 altered mitophagy via pathology‐dependent and pathology‐independent mechanisms. ZMIZ1 was linked to reduced p‐S65‐Ub and neuropathology indicative of protection.

Purpose To describe the clinical characteristics, histopathologic subtype distribution, treatment, and outcomes of patients with primary orbital lymphoma. Major Findings There were 126 biopsy-confirmed cases of primary orbital lymphoma, with 81 (64.3%) female and 110 (87.3%) white. The average age at diagnosis was 62.7 ± 13.9 years. There were 26 (20.6%) cases with bilateral involvement. The most frequent lymphoma subtype was MALT lymphoma (N = 76, 60.3%), followed by diffuse large B-cell lymphoma (N = 18, 14.3%) and follicular lymphoma (N = 12, 9.5%). Prognosis was generally favorable, as local recurrence occurred in only 14 (11.1%) patients and final best corrected visual acuity (BCVA) loss of >1 line was seen in 30 (28.0%) patients. Bilateral lymphoma and advanced stage (Ann Arbor Stage III or IV) at presentation were associated with increased risk of local recurrence ( p = 0.0025, p = 0.049). Improved disease-specific survival was associated with diagnosis at Stage I or II ( p = 0.013), MALT subtype ( p = 0.034), or lack of chemotherapy requirement as primary treatment ( p = 0.0073). Conclusions In this single center academic cohort, MALT lymphoma subtype was most common. Overall orbital recurrence frequency was low, and bilateral lymphoma and advanced stage were associated with increased risk of local recurrence. MALT lymphoma subtype was associated with improved disease-specific survival. Long-term follow-up showed that most patients retained good visual acuity in the affected eye(s).

Abstract Background/Aims Fibromyalgia has many unmet needs relating to treatment and delivery of effective and evidence-based healthcare is lacking. We analyzed social media conversations to understand patients’ perspectives of the lived experience of fibromyalgia, factors reported to trigger flares of pain, treatments being discussed; and identify barriers and opportunities to improve healthcare delivery. Methods A non-interventional retrospective analysis accessed detail rich conversations about fibromyalgia patients’ experiences with data curated from 400 million global documents and 714,000 documents, including a fibromyalgia language tag, between May 2019 and April 2021. Data were analyzed via qualitative and quantitative analyses. Results Fibromyalgia conversations were most numerous on Twitter and Reddit and conversations trends remained stable over time. There were numerous environmental and modifiable triggers ranging from (most frequently) stress and anxiety to various foods. Arthritis and irritable bowel syndrome (IBS) were the most frequently associated comorbidities. Patients with fibromyalgia reported a wide range of symptoms, with pain a cardinal feature. Massage, meditation and acupuncture domains were the most reported treatment modalities. Opportunities to improve healthcare delivered by medical providers were identified with current frustration relating to lack of acknowledgement of their disease, minimization of symptoms, and providers inadequately meeting their care needs. Conclusion We developed a comprehensive large-scale study which emphasizes advanced artificial intelligence algorithms application in real-world research design. Through the extensive encapsulation of patient perspectives, we have outlined habitual symptoms, triggers, and treatment modalities that provide a durable foundation to address gaps in healthcare provision. Disclosure L. Bell: Other; Lucy Bell was a former contractor based at Black Swan Data, and a volunteer at White Swan. She is currently a full-time employee at White Swan. B. Fordham: Other; Beth Fordham is an employee of White Swan Charity, who provided the dataset for this study, and was previously an employee of Black Swan Data, of which White Swan is a separate entity. S. Mumtaz: None. R. Yaman: None. L. Balistreri: None. R.R. Butendieck: None. A. Irani: None.