Citations

The accumulation of senescent cells, a hallmark phenotype of aging tissues, elevates the risk of cardiovascular disease with age. Our prior studies have illustrated a crucial role played by senescent cells in promoting coagulation during murine atherosclerosis through the senescence-associated secretory phenotype (SASP). To explore the heterogeneity of senescent vascular cells in thrombotic vascular diseases and identify potential druggable pathways to counter senescence, we utilized the senescence reporter mouse p16TdTomato+/-, which was injected with an adeno-associated virus expressing Proprotein Convertase Subtilisin/Kexin type 9 to induce atherosclerosis when subjected to a high-fat diet (HFD). In a subset of HFD mice, some were left untreated, while others were treated with senolytic drug ABT-737 to selectively eliminate senescent cells. Aortas from ABT-737-treated mice exhibited increased collagen deposition and reduced arterial stiffness. Paired with pseudo-bulk RNA-sequencing analysis, we observed that HFD-induced extracellular matrix (ECM) remodeling genes were diminished by ABT-737, suggesting that ECM-platelet interactions may be influenced by senescence. Single-cell RNA-sequencing analysis from aortas identified 28 distinct cell clusters. Utilizing Gene Set Enrichment Analysis with the SenMayo and CellAge panels, we identified four cell clusters exhibiting increased senescent features that were mitigated by ABT-737. These included two VSMC clusters, fibroblasts, and neutrophil-like cells. Unbiased subclustering of potentially senescent clusters revealed a small population of cells enriched with HFD and reduced by ABT-737, confirming their senescent nature. In the most abundant cluster, Spp1 and Serpine2 strongly represented the senescent VSMC subpopulation, enriched for TGFβ signaling, ECM remodeling, and coagulation cascade genes. Further, we validated these findings through spatial transcriptomics and single-molecule FISH of brachiocephalic arteries from atherosclerotic mice and atherosclerotic mice depleted of senescent cells. Our results reveal a novel transcriptomic signature for senescent vascular cells that holds potential for therapeutic targeting in age-related vascular diseases.

Abstract Background Sinonasal malignancies with orbital invasion have dismal prognosis even when treated with orbital exenteration (OE). Sugawara et al. developed a surgical strategy called “extended‐OE (EOE),” showing encouraging outcomes. We hypothesized that a similar resection is achievable under endoscopic guidance through the exenterated orbit (endoscopic‐EOE). Methods The study was conducted in three institutions: University of Vienna; Mayo Clinic; University of Insubria; 48 orbital dissections were performed. A questionnaire was developed to evaluate feasibility and safety of each step, scoring from 1 to 10, (“impossible” to “easy,” and “high risk” to “low risk,” respectively), most likely complication(s) were hypothesized. Results The step‐by‐step technique is thoroughly described. The questionnaire was answered by 25 anterior skull base surgeons from six countries. Mean, median, range, and interquartile range of both feasibility and safety scores are reported. Conclusions Endoscopic‐EOE is a challenging but feasible procedure. Clinical validation is required to assess real‐life outcomes.

Abstract Breast pain is extremely common, occurring in 70% to 80% of women. Most cases of breast pain are from physiologic or benign causes, and patients should be reassured and offered treatment strategies to alleviate symptoms, often without diagnostic imaging. A complete clinical history and physical examination is key for distinguishing intrinsic breast pain from extramammary pain. Breast pain without other suspicious symptoms and with a negative history and physical examination result is rarely associated with malignancy, although it is a common reason for women to undergo diagnostic imaging. When breast imaging is indicated, guidelines according to the American College of Radiology Appropriateness Criteria should be followed as to whether mammography, US, or both are recommended. This review article summarizes the initial clinical evaluation of breast pain and evidence-based guidelines for imaging. Additionally, the article reviews cyclical and noncyclical breast pain and provides an image-rich discussion of the imaging presentation and management of benign and malignant breast pain etiologies.

Abstract The Mayo Clinic Breast Disease Registry (MCBDR) was developed to serve as a cohort of newly diagnosed breast cancer patients to address questions of etiology, prognosis, and survivorship. Eligibility is limited to patients 18 years or older with a confirmed first stage 0-4 breast cancer diagnosis within the last year. Consent is completed via phone, patient portal, or in-person. Upon enrollment, a baseline questionnaire and blood collection are completed. Annual follow-up surveys that capture BC outcomes are sent to all living participants. The MCBDR cohort (N=9,215, enrolled between 2001 and 2023) is 99% female, with an average age at diagnosis of 58 years (SD=12.7). Currently, MCBDR has an average time since diagnosis of 9.8 years (SD=6.4). The participants are 94% white, and 55% live in Minnesota. At the time of baseline questionnaire completion, 77% were married, 84% had a bachelor’s degree or higher, and 8% reported financial hardship. Further, 35% reported a history of smoking, 11% consumed more than two drinks per day, and 9% reported fair or poor social relationships. Within MCBDR, 53% of the participants had stage 0 or 1 cancer at diagnosis, while 28% had stage 2, 9% stage 3, and 3% stage 4 BC. Tumors were triple negative in 9%, HER 2 positive in 9%, hormone receptor-positive and HER2 low or negative in 55%, and 27% had missing HER2 status. Pathological TNM staging was available on 98%, among which 33% were staged at T2 or higher and 27% were node-positive. Definitive BC surgery was completed at Mayo Clinic for 73%, with 35% undergoing mastectomies and 44% having lumpectomies. 74% were treated with radiation, 56% underwent chemotherapy, and 79% were treated with endocrine therapy. Clinical genetic testing results have been nurse-abstracted for 94% of the cohort. Of those known to be tested, 521 (6%) had a pathogenic or likely pathogenic mutation identified in a BC causing gene. In addition, whole exome sequencing was completed on 71% of MCBDR participants in 2020, in which 167 previously unknown pathogenic or likely pathogenic mutations were identified. After the initial diagnosis and active treatment phase, nurse abstraction identified 151 (2%) participants known to have been diagnosed with a contralateral BC diagnosis, and 4% known to have been diagnosed with a second primary other than breast. Recurrence in the same breast has been reported for 242 (3%), with 72% of those recurrences occurring within 5 years of initial diagnosis and another 19% occurring 5-10 years post diagnosis. Among the 1,262 (14%) who are deceased, 24% died from BC and 19% had distant metastases at diagnosis or a distant recurrence. Amongst all deceased, 6% died within 1 year of their diagnosis and 43% died within 5 years of diagnosis. For participants who died from BC, 10% died within 1 year of their diagnosis and 64% died within 5 years of diagnosis. MCBDR data has been used in numerous publications and is an essential resource for efficient observational research analyses. Citation Format: Nicole L. Larson, Janet Olson, Kathryn Ruddy, Fergus Couch, Denise Herman, Feven Abraha. Mayo Clinic breast cancer cohort: A valuable resource for breast cancer research [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7339.

664 Background: Postoperative complications in patients with borderline resectable pancreatic cancer treated with neoadjuvant therapy and pancreatectomy in the national cooperative group setting have not been previously characterized. Further, the impact of preoperative hypofractionated radiotherapy on postoperative outcomes is largely unknown. We sought to quantify perioperative morbidity among patients with pancreatic cancer who received neoadjuvant modified FOLFIRINOX chemotherapy with or without hypofractionated radiotherapy on a multicenter clinical trial. Methods: The A021501 phase 2 trial randomized patients with borderline resectable pancreatic ductal adenocarcinoma to 8 doses of mFOLFIRINOX (Arm 1) or 7 doses of mFOLFIRINOX then hypofractionated radiotherapy (Arm 2), followed by pancreatectomy (Dec 31, 2016-Jan 1, 2019). Patients underwent resection according to defined operative standards at enrolling centers without specific requirements for either surgeon or hospital volume. Surgical complications and adverse events were assessed and captured at a single time point of 90 days after surgery and compared between treatment arms. Results: Of 126 enrolled patients, 51 (40%) underwent pancreatectomy (n=32, Arm 1; n=19, Arm 2) at 28 institutions. Vascular resection was performed in 19 patients (37%). One patient in Arm 2 died within 90 days after surgery. Rates of any surgical complication were 19% (n=6) in Arm 1 and 42% (n=8) in Arm 2 (p=0.07). Median length of stay was 7 days (range 5-38 days). Five (10%) patients required reoperation within 90 days. Readmission rates were higher in Arm 2 than Arm 1 (16% vs. 42%, p=0.04) but there were no differences in rates of reoperation, pancreatic fistula or abscess requiring drainage, or wound infection between study arms. 54% of patients (n=26/48) experienced a grade 3 or higher adverse event, with no difference between treatment arms (47% versus 67%, p=0.7). Rates of initiation of adjuvant therapy did not differ between treatment arms (66% vs. 68%, p=0.4). Pancreatic fistula and abscess were associated with adjuvant therapy (p<0.01). No difference in overall survival was observed based on occurrence of surgical complications (HR 1.1; 95% CI 0.5-2.6). Conclusions: In this national cooperative group study of patients with borderline resectable pancreatic cancer,postoperative complications following neoadjuvant chemotherapy, radiation, and surgical resection were consistent with rates previously reported by high-volume institutions and using large datasets. Multimodality trials of preoperative therapy for locoregionally advanced pancreatic cancer may be safely performed in the cooperative group setting. Clinical trial information: NCT02839343 .

Objective: To characterize the current state of mental health within the surgical workforce in the United States. Background: Mental illness and suicide is a growing concern in the medical community; however, the current state is largely unknown. Methods: Cross-sectional survey of the academic surgery community assessing mental health, medical error, and suicidal ideation. The odds of suicidal ideation adjusting for sex, prior mental health diagnosis, and validated scales screening for depression, anxiety, post-traumatic stress disorder (PTSD), and alcohol use disorder were assessed. Results: Of 622 participating medical students, trainees, and surgeons (estimated response rate=11.4%–14.0%), 26.1% (141/539) reported a previous mental health diagnosis. In all, 15.9% (83/523) of respondents screened positive for current depression, 18.4% (98/533) for anxiety, 11.0% (56/510) for alcohol use disorder, and 17.3% (36/208) for PTSD. Medical error was associated with depression (30.7% vs. 13.3%, P<0.001), anxiety (31.6% vs. 16.2%, P=0.001), PTSD (12.8% vs. 5.6%, P=0.018), and hazardous alcohol consumption (18.7% vs. 9.7%, P=0.022). Overall, 13.2% (73/551) of respondents reported suicidal ideation in the past year and 9.6% (51/533) in the past 2 weeks. On adjusted analysis, a previous history of a mental health disorder (aOR: 1.97, 95% CI: 1.04–3.65, P=0.033) and screening positive for depression (aOR: 4.30, 95% CI: 2.21–8.29, P<0.001) or PTSD (aOR: 3.93, 95% CI: 1.61–9.44, P=0.002) were associated with increased odds of suicidal ideation over the past 12 months. Conclusions: Nearly 1 in 7 respondents reported suicidal ideation in the past year. Mental illness and suicidal ideation are significant problems among the surgical workforce in the United States.

AbstractBackgroundTobacco use is associated with adverse outcomes among patients diagnosed with cancer. Socioeconomic determinants influence access and utilization of tobacco treatment; little is known about the relationship between neighborhood socioeconomic disadvantage (NSD) and tobacco assessment, assistance, and cessation among patients diagnosed with cancer.MethodsA modified Cancer Patient Tobacco Use Questionnaire (C‐TUQ) was administered to patients enrolled in nine ECOG‐ACRIN clinical trials. We examined associations of NSD with (1) smoking status, (2) receiving tobacco cessation assessment and support, and (3) cessation behaviors. NSD was classified by tertiles of the Area Deprivation Index. Associations between NSD and tobacco variables were evaluated using logistic regression.ResultsA total of 740 patients completing the C‐TUQ were 70% male, 94% White, 3% Hispanic, mean age 58.8 years. Cancer diagnoses included leukemia 263 (36%), lymphoma 141 (19%), prostate 131 (18%), breast 79 (11%), melanoma 69 (9%), myeloma 53 (7%), and head and neck 4 (0.5%). A total of 402 (54%) never smoked, 257 (35%) had formerly smoked, and 81 (11%) were currently smoking. Patients in high disadvantaged neighborhoods were approximately four times more likely to report current smoking (odds ratio [OR], 3.57; 95% CI, 1.69–7.54; p = .0009), and more likely to report being asked about smoking (OR, 4.24; 95% CI, 1.64–10.98; p = .0029), but less likely to report receiving counseling (OR, 0.11; 95% CI, 0.02–0.58; p = .0086) versus those in the least disadvantaged neighborhoods.ConclusionsGreater neighborhood socioeconomic disadvantage was associated with smoking but less cessation support. Increased cessation support in cancer care is needed, particularly for patients from disadvantaged neighborhoods.

Introduction Postdural puncture headache (PDPH) can follow unintentional dural puncture during epidural techniques or intentional dural puncture during neuraxial procedures such as a lumbar puncture or spinal anesthesia. Evidence-based guidance on the prevention, diagnosis or management of this condition is, however, currently lacking. This multisociety guidance aims to fill this void and provide practitioners with comprehensive information and patient-centric recommendations to prevent, diagnose and manage patients with PDPH. Methods Based on input from committee members and stakeholders, the committee cochairs developed 10 review questions deemed important for the prevention, diagnosis and management of PDPH. A literature search for each question was performed in MEDLINE (Ovid) on 2 March 2022. The results from each search were imported into separate Covidence projects for deduplication and screening, followed by data extraction. Additional relevant clinical trials, systematic reviews and research studies published through March 2022 were also considered for the development of guidelines and shared with contributors. Each group submitted a structured narrative review along with recommendations graded according to the US Preventative Services Task Force grading of evidence. The interim draft was shared electronically, with each collaborator requested to vote anonymously on each recommendation using two rounds of a modified Delphi approach. Results Based on contemporary evidence and consensus, the multidisciplinary panel generated 50 recommendations to provide guidance regarding risk factors, prevention, diagnosis and management of PDPH, along with their strength and certainty of evidence. After two rounds of voting, we achieved a high level of consensus for all statements and recommendations. Several recommendations had moderate-to-low certainty of evidence. Conclusions These clinical practice guidelines for PDPH provide a framework to improve identification, evaluation and delivery of evidence-based care by physicians performing neuraxial procedures to improve the quality of care and align with patients’ interests. Uncertainty remains regarding best practice for the majority of management approaches for PDPH due to the paucity of evidence. Additionally, opportunities for future research are identified.