Citations

Background: Malignant mesenchymal tumors involving the parotid gland are uncommon, characteristically aggressive, and little is known with few reports documented. Study Design: Retrospective case series. Setting: Single institution tertiary care center, 2010 to 2022. Method: Patients were identified from an institutional parotid tumor database. Patient history, demographics, pathologic diagnosis, treatment, and follow up were documented. Results: Eight patients were identified, 3 were males. The average age was 61 years old, and the most common tumors identified were pleomorphic sarcomas (3 patients). Presenting symptoms included: preauricular/cheek mass in 7 patients, facial pain (4), otalgia (4), aural fullness (3), and numbness (1). All patients received a parotidectomy, and 4 patients received adjuvant therapy of either radiation or chemoradiation. Post-operatively, there were 3 cases of distant recurrence, 2 cases of regional recurrence, and 1 case of local recurrence. There were 2 reports of death. Conclusion: Malignant mesenchymal tumors of the parotid are rare, represent varied histologies. Due to their aggressive nature, surgical resection with radiation and close follow-up may be an appropriate treatment regimen in controlling the disease.

ABSTRACT Evidence indicates that the integrity of in utero development influences late life healthy or unhealthy aging; however, specific links between them are unclear. Histone chaperone HIRA is thought to play a role in both life stages, and here, we explore this role using the murine pigmentary system by investigating and comparing the effects of its lineage‐specific knockout, either conditionally during embryogenesis or postnatally. Embryonic knockout of Hira in tyrosinase+ neural crest‐derived lineages, including melanoblasts, led to reduced melanoblast numbers during embryogenesis, with single‐cell RNA sequencing analysis indicating evidence of lineage‐specificity defects. This was supported in an in vitro model using melb‐a melanoblasts in which Hira knockdown affected lineage identity and melanoblast differentiation potential, with ATAC‐seq data indicating a role of HIRA in orchestrating chromatin accessibility. Interestingly, however, newborn Hira knockout mice had wild type numbers of differentiated melanocytes, albeit functionally defective, as demonstrated by very mild hypopigmentation of the first hair coat, increased melanocyte telomere‐associated DNA damage foci, and impaired response to proliferative challenge. Moreover, as they aged, mice with embryonic melanoblast Hira knockout displayed marked defects in melanocyte stem cell maintenance and premature hair graying. Importantly, this phenotype was not observed after postnatal inducible knockout, indicating an essential role for HIRA at embryonic stages that is transmitted to adulthood, rather than a direct postnatal requirement within the pigmentary system. This genetic model shows that HIRA function during early development lays a foundation for maintaining lineage identity and subsequent maintenance of adult tissue‐specific stem cells during aging.

Importance Circulating tumor human papillomavirus DNA (ctHPVDNA) is an important biomarker for the presence of HPV-associated oropharyngeal squamous cell carcinoma (OPSCC), but little is known about early postoperative kinetics of ctHPVDNA clearance. Objective To investigate early postoperative kinetics of ctHPVDNA in patients with HPV-associated OPSCC. Design, Setting, and Participants This prospective cohort study was conducted at a single tertiary care center from January 4, 2020, to January 26, 2023. Patients with newly diagnosed HPV-associated OPSCC undergoing surgical management were enrolled. HPV status was defined as positive if findings of p16 immunohistochemistry and/or HPV DNA in situ hybridization and/or E6/E7 RNA in situ hybridization were positive. Exclusion criteria included history of prior head and neck cancer and metastatic disease at presentation. Data were analyzed from September 1, 2024, to April 25, 2025. Exposures Transoral robotic surgery with concurrent neck dissection. Main Outcomes and Measures Blood was drawn prior to surgery (pretreatment), 1 to 2 days after surgery (postoperative days 1 to 2), and approximately 2 weeks after surgery (postoperative week 2; range, 8 to 20 days). ctHPVDNA was quantified by a tumor tissue–modified viral (TTMV) HPV DNA test. Correlations were tested between the pretreatment and postoperative day 1 to 2 TTMV HPV DNA levels using Gaussian regression. Concordance between detectability at postoperative day 1 to 2 and postoperative week 2 was explored using negative predictive value and positive predictive value. Results Of 57 included patients with detectable pretreatment TTMV HPV DNA, 51 (89%) were male, and the median (IQR) age was 59 (54-66) years. A total of 35 patients (61%) had blood draws at all 3 time points; 16 (28%) had detectable TTMV HPV DNA on postoperative day 1 to 2. Pretreatment and postoperative day 1 to 2 TTMV HPV DNA levels had a medium positive linear correlation ( r = 0.31; 95% CI, 0.04-0.54). Undetectable TTMV HPV DNA on postoperative day 1 to 2 blood draw had a negative predictive value of 0.95 (95% CI, 0.74-1.00) for an undetectable level on postoperative week 2 blood draw, but a detectable level on postoperative day 1 to 2 blood draw only had a positive predictive value of 0.19 (95% CI, 0.04-0.46). Of the 16 patients with detectable TTMV HPV DNA pretreatment and at postoperative day 1 to 2, only 3 (19%) continued to have detectable TTMV HPV DNA at postoperative week 2. One patient had undetectable levels at postoperative day 1 to 2 and detectable levels at postoperative week 2. Conclusions and Relevance In this study, ctHPVDNA detectability early after surgery did not predict detectability at 2 weeks after surgery. ctHPVDNA clearance early after surgery could predict a negative test at 2 weeks. A negative blood draw finding on postoperative day 1 may be used to omit a postoperative blood draw at 2 weeks for minimal residual disease detection in future clinical trials.

Abstract Fibrosing mediastinitis is an infiltrative disease which may develop secondary to a variety of causes, including autoimmune, infectious, and malignant processes. Here, we present a case of fibrosing mediastinitis, with initial concerns for IgG4-related disease. A 36-year-old man presented to his primary provider with three months of intermittent dyspnea. CT chest was significant for a large, infiltrative mediastinal and left hilar mass with calcifications and involvement of the left upper and lower lobe bronchi, lingular bronchus, and left main pulmonary artery. Subsequent autoimmune and fungal studies were negative. The patient underwent bronchoscopy, with biopsy of a lymph node at station 11L showing increased IgG4 on immunostain (30 cells/hpf), though IgG immunostaining was not completed for comparison. Despite initial concerns for fibrosing mediastinitis, the patient was diagnosed with IgG4-related disease and initiated on rituximab and mycophenolate. Notably, the patient's serum IgG4 concentrations were consistently within normal limits before and after initiation of rituximab. The patient was referred to our clinic after lack of response to therapy on imaging. Laboratory evaluation redemonstrated a normal serum IgG4 concentration and fungal studies were consistent with previous histoplasma infection, suggesting fibrosing mediastinitis secondary to histoplasmosis. IgG4-related disease was determined to be unlikely considering repeatedly normal IgG4 levels and weakly positive IgG4 staining. Repeat CT chest demonstrated fibrosis of the left upper lobe; compression of the left atrial appendage; and occlusion and severe obstruction of the left superior pulmonary vein and left lower lobe pulmonary artery, respectively. VQ scan demonstrated significantly reduced perfusion of the left lung and the patient was referred for stenting of the affected vasculature. PET-CT revealed moderate FDG avidity of the left hilar nodes, concerning for ongoing active fibrosing mediastinitis, for which he was continued on rituximab. The indolent nature of fibrosing mediastinitis often leads to advanced disease at the time of presentation. Hilar structures are commonly involved, as in the case of this patient with a severe perfusion defect secondary to obstruction of the pulmonary vessels. A diagnosis of fibrosing mediastinitis merits careful investigation of the underlying cause. Fungal infections, specifically histoplasmosis in North America, are a leading cause of this condition. IgG4-related disease is also associated with fibrosing mediastinitis, and both conditions are driven by fibroinflammatory processes. However, it is important to note that IgG4 immunostaining is non-specific, and diagnosis of IgG4-related disease requires the meeting of rigorous criteria. Differentiation between these diagnoses is important given potential differences in management.

Abstract Introduction Extramedullary hematopoiesis (EMH) is the production of blood cells outside of bone marrow. It is associated with myeloproliferative neoplasms such as myelofibrosis and chronic myeloid leukemia. Most common sites for EMH are liver and spleen, but other sites may be involved. Pulmonary EMH is extremely rare. It is associated with symptoms of dyspnea, cough or chest pain. Chest imaging may demonstrate pulmonary nodules or masses, alveolar septal thickening, ground glass opacities, and/or patchy consolidations. We present a case of a woman with primary myelofibrosis who developed pulmonary hypertension (PH) in the setting of pulmonary EMH. Case description 73-year-old woman with history of primary myelofibrosis (diagnosed via bone marrow biopsy, grade 3 fibrosis, being treated with hydroxyurea) presented with progressive exertional dyspnea for 1.5 years. Exam was notable for elevated jugular venous pressure and mild peripheral edema. Labs revealed anemia with hemoglobin 8.2 g/dL, thrombocytosis with platelets 549K/dL and no leukocytosis. Brain natriuretic peptide was elevated at 1361 ng/L. Chest CT demonstrated few peripheral wedge-shaped opacities in the bilateral lower lobes were noted. Pulmonary function tests revealed normal spirometry and lung volumes but moderately reduced diffusion capacity. Echocardiogram showed normal left ventricular (LV) size and function with ejection fraction 60%, moderately enlarged right ventricle (RV) and RV systolic pressure 63 mmHg. Right heart catheterization showed RA pressure:14 mmHg, PA: 49/26/36 mmHg, PCWP 15mmHg, thermodilution CO 5.5 L/min, CI 3.1L/min/m2, Fick CO 4.6 L/min, CI 2.6 L/min/m2, pulmonary vascular resistance 3.8-4.6 Woods Units. Given her history of myelofibrosis, Tc-99m bone marrow scan was performed which showed diffuse radiotracer uptake in both lungs suggestive of pulmonary EMH. She subsequently underwent radiation therapy with 100cGy to bilateral lungs. On a follow-up visit two months later, she reported symptomatic improvement. Repeat NM bone scan showed decreased tracer uptake in the lungs. Discussion PH associated with myeloproliferative neoplasia is classified as group 5 in the latest clinical classification. It can be due to thrombocytosis, hypercoagulability, left ventricular failure, portal hypertension and/or hematopoietic infiltration of the pulmonary parenchyma. Tc-99m sulfur colloid scanning can be used to detect hematopoietic tissue in the lung. Treatment is usually radiation-therapy to the lungs to control the hematopoiesis. In patients with myeloproliferative neoplasms presenting with dyspnea, consider screening for PH with echocardiogram.

Abstract Rationale Patients with pulmonary hypertension (PH) often require significant assistance from caregivers. Caregivers frequently help patients with numerous PH-related tasks, such as medication administration and insurance coordination, in addition to emotional and other forms of support. However, little is known about optimal strategies for engaging and empowering caregivers in PH. We sought to improve understanding of PH patients’ and caregivers’ perspectives on the role of caregiving to identify ways to better support them. Methods We performed a cross-sectional survey of PH patients and/or their adult caregivers participating in the Pulmonary Hypertension Association conference in August 2024. Questions focused on roles and perspectives towards caregiving. Study participation was voluntary without monetary or other compensation. Results Sixteen patients and 18 caregivers completed the survey, with 9 patient and caregiver pairs. Patient characteristics and responses are detailed in Table 1. The majority of patients (87.5%) reported that caregivers play a “very important” role in their lives. (Table 1) Most surveyed caregivers were patients’ significant others (10/18, 55.5%) or parents (7/18, 38.9%), with average age 59 years, and were employed full-(10/18, 55.5%) or part-time (3/18, 16.7%). Regarding their role(s), all caregivers (18/18) reported providing emotional support, 7/18 (38.9%) physical support (e.g. mobility, hygiene assistance), 7/18 (38.9%) help with medications, and 13/18 (72.2%) help with transportation to appointments. 4/18 (22.2%) caregivers reported they spend more than 20 hours/week on caregiving-related tasks while most reported they spend 5-20 hours/week. Caregivers detailed challenges regarding emotional support (e.g. “Spouse seems to be very short with me most of the time. I think she hates this disease and takes it out on others”), among others. However, they also reported caregiving to be rewarding (e.g. “Seeing my husband improve, and getting to be on his side to advocate for him and other patients.”) Caregivers had many suggestions for what they would like to see in a program focused on supporting them, including “Online education such as resources and experts such as new treatments, insurance information…How to advocate better. Tips for self care” and “Connection to therapist who understand chronic diseases and the challenges of long term caregivers.” Conclusions Caregivers play an integral and multifaceted role in the lives of patients with PH. Caregivers would appreciate additional education, resources and support.

Abstract RATIONALE: Many ICU patients experience physical, psychological, and cognitive impairments following resolution of critical illness, collectively referred to as post-intensive care syndrome (PICS). PICS has become widely recognized within the critical care field, but how to screen for PICS does not currently have consensus. Development of a validated, concise PICS screening tool would allow for rapid identification of this vulnerable and understudied population. Therefore, this study's goal was to develop and evaluate a screening tool to identify patients at risk for PICS. METHODS: We performed a prospective cohort study in a quaternary academic hospital. We included adults ≥ 18 years old with ≥48 hours spent in an ICU. Exclusion criteria were admission for suicide attempt, severe cognitive impairment/dementia, life expectancy <3 months, and non-English speaking. We assessed mental, cognitive, and physical function following ICU discharge and at 3 months using Hospital Anxiety and Depression Scale, Impact of Event Scale-Revised, Montreal Cognitive Assessment-blind, and Barthel Index. Our team, including critical care physicians, psychiatrists, psychologists, physical and occupational therapists, and nurses, developed a brief 15-item PICS screening tool (5 questions/domain). This tool was administered after patients were discharged from ICU stay to general care to assess its effectiveness in predicting impairments in all 3 domains at discharge and again at three months after hospital discharge, in comparison to previously mentioned validated questionnaires. Youden index statistical methods were used to determine potential “cutoff” values (scores) for the tool to maximize sensitivity and specificity. RESULTS: A total of 194 patients from 6 ICUs were recruited and completed the initial questionnaire, and 109 (56%) patients completed 3-month follow-up. Median age was 65 years (IQR 57-72) and 49% (95/194) were female. Screening tool is depicted in Figure 1. Overall, the screening tool weakly-to-moderately correlated with continuous outcomes of the validated measures upon ICU discharge and 3-month follow-up. When evaluating sensitivity and specificity for individual domains, the tool had an area under the receiver operating curve of >0.7 for the following domains: cognitive, anxiety, and physical impairments, indicating moderate-to-good sensitivity and specificity. CONCLUSIONS: This PICS screening tool was correlated with validated measures of PICS upon ICU discharge and at 3-month follow-up for all three domains. The tool's strength lies in its concise nature, making it easier for those caring for this patient population to screen for long-term effects of an ICU stay. Our proposed next step is validation of the PICS screening tool in an external cohort.

Importance Many older adults with advanced cancer never communicate goals of care or treatment preferences to their clinicians, raising the risk that care received will not match their values. Scalable models of care may help surmount this barrier. Objective To test whether a combined patient and clinician intervention increased the rate of advance care planning (ACP) documentation in large health care systems. Design, Setting, and Participants This stepped-wedge cluster randomized clinical trial using an open cohort design included patients aged 65 years or older with advanced cancer seen at oncology clinics in 3 health care systems located in the US South, Midwest, and Mid-Atlantic regions from April 1, 2020, to November 30, 2022. Data collection ended in 2024. Intervention The intervention involved delivering brief evidence-based patient-facing video decision aids available in 25 languages as well as goals-of-care communication training to oncology clinicians. Patients in the control period received usual care. Main Outcomes and Measures The primary outcome was ACP documentation, which included any electronic health record documentation of a goals-of-care conversation, palliative care, hospice, or limitation of life-sustaining treatments, identified via a validated natural language processing program. Analysis was performed on an intention-to-treat basis. Results Twenty-nine practices, comprising 13 800 unique eligible patients with a total of 29 357 repeated measurements, were included (mean [SD] age, 74.5 [6.6] years; 52.3% men [15 344 of 29 357 measurements]). The proportion of patients with ACP documentation was greater in the intervention phase compared with the usual care phase (adjusted rate difference, 6.8% [95% CI, 2.8%-10.8%]; P < .001). ACP documentation in the intervention phase occurred among 3980 of 15 754 patients (25.3%) (goals-of-care conversation, 21.4% [3377 of 15 754]; palliative care, 9.6% [1517 of 15 754]; hospice, 5.4% [847 of 15 754]; and limitation of life-sustaining treatments, 7.2% [1128 of 15 754]). In comparison, ACP documentation in the usual care phase occurred among 2834 of 13 603 patients (20.8%) (goals-of-care conversation, 16.8% [2281 of 13 603]; palliative care, 9.5% [1287 of 13 603]; hospice, 5.3% [724 of 13 603]; and limitation of life-sustaining treatments, 8.4% [1149 of 13 603]). Conclusions and Relevance In this stepped-wedge cluster randomized clinical trial for older adults with advanced cancer, a bundled evidence-based decision aid and communication training intervention increased the proportion of older patients with ACP documentation. This approach offers an innovative paradigm with a clinically meaningful increase in ACP documentation, a widely used quality metric that reflects high-quality patient-centered care delivery. Trial Registration ClinicalTrials.gov Identifier: NCT03609177

Importance Few studies have assessed whether factors outside the workplace, such as support from a spouse or partner, are associated with work-life integration (WLI) satisfaction and burnout among physicians. Evaluating such an association may help with developing novel strategies to address burnout and improve WLI satisfaction among this group. Objectives To compare spousal support among female and male physicians and explore associations of spousal support with WLI satisfaction and burnout. Design, Setting, and Participants This cross-sectional, multispecialty survey study was conducted among 661 faculty physicians employed at an academic medical center from March 26 to May 22, 2024. Main Outcomes and Measures Survey items measured spousal support (5 items), WLI satisfaction (1 item), and burnout (2 Maslach Burnout Inventory items). Associations of spousal support and gender with WLI and burnout were assessed using logistic regression analyses adjusting for age, race and ethnicity, weekly work hours, and weekly hours spent on household or childcare duties. Results Overall, 739 of 2103 faculty physicians (response rate, 35.1%) completed the survey, of whom 661 (89.4%) were currently married or partnered (359 of 661 men [54.3%]). In this subset, 322 of 351 male physicians (91.7%) and 276 of 298 of female physicians (92.6%) reported frequent career support (defined as often, most of the time, or always) over the last year from their spouse or partner. Physicians reporting high levels of career support from their spouse or partner had higher odds of WLI satisfaction (odds ratio [OR], 1.50 [95% CI, 1.22-1.86]; P < .001) and lower odds of burnout (OR, 0.73 [95% CI, 0.61-0.87]; P < .001), independent of gender and adjusted for age, race and ethnicity, weekly work hours, and weekly hours spent on household or childcare duties. Male physicians had higher odds of WLI satisfaction than female physicians (OR, 1.95 [95% CI, 1.32-2.90]; P < .001), even after adjusting for spousal career support and other covariates listed, whereas odds of burnout did not significantly differ by gender (OR, 0.84 [95% CI, 0.57-1.23]; P = .37). Conclusions and Relevance This study suggests that the level of career support from a spouse or partner is associated with WLI satisfaction and burnout among physicians, independent of gender. Future studies should explore whether interventions designed to enhance career support can improve WLI and well-being among physicians.

Importance A subset of Union for International Cancer Control ( UICC )/ American Joint Committee on Cancer ( AJCC ) eighth edition TNM stage I and II human papillomavirus–positive oropharyngeal carcinoma has undesirable outcomes, which might have contributed to a lack of success in phase III deintensification trials. Refining clinical stage groups, especially in the overabundant cN1/stage I group, has become important for treatment selection. Objective To assess the prognostic importance of pretreatment lymph node (LN) characteristics to optimize case distribution and outcome homogeneity within the N classification system. Design, Setting, and Participants This is an international multi-institutional retrospective prognostic cohort study. Analysis of human papillomavirus–positive oropharyngeal carcinoma treated curatively from 4 institutions (International Collaboration of Oropharyngeal Cancer Network for N-Classification [ICON-N] dataset) provided a refined clinical staging proposal; an independent dataset (Centre Hospitalier de l’Université de Montréal [CHUM] dataset) validated the proposal. Neuroradiologists reviewed pretreatment computed tomography and/or magnetic resonance imaging for nodal features, including presence or absence of abnormal LN(s), retropharyngeal LN, laterality, number of abnormal LN, and imaging-detected extranodal extension (iENE). Data were collected from February to May 2023, and data were analyzed from June to July 2023. Exposures Definitive chemoradiotherapy/radiotherapy or definitive surgery with or without postoperative chemoradiotherapy/radiotherapy. Main Outcomes and Measures The primary end point was overall survival. A Cox proportional hazards multivariable model was used to estimate adjusted hazard ratios (AHRs) and to derive an optimal clinical TNM stage classification (AHR-stage schema) incorporating the strongest prognostic nodal features within the UICC/AJCC eighth edition TNM framework after confirming the prognostication of iENE status. The performance (according to overall normalized scores and ranking) of the AHR-stage schema against the current UICC/AJCC eighth edition TNM staging system was evaluated for hazard consistency, hazard discrimination, prognostic importance, and sample size balance. Validation was performed in the CHUM dataset. Results The ICON-N dataset comprised 2053 patients, including 1898 (92.5%) with cN-positive disease and 155 (7.5%) with cN0 disease; a total of 298 (14.5%) were female, and the mean (SD) age was 60.6 (9.3) years. iENE-positive disease was identified in 710 of 1898 patients with cN-positive disease (37.4%). The median (range) follow-up was 5.1 (0.1-14.7) years. iENE was the strongest prognostic nodal feature in multivariable analysis; the AHR for iENE-positive vs iENE-positive disease was 2.43 (95% CI, 1.96-3.03) in the ICON-N dataset and 2.04 (95% CI, 1.28-3.23) in the CHUM dataset (n = 451). Reclassifying iENE-positive cases 1 stratum higher for N categorization without altering iENE-negative cases yielded an AHR-stage schema that outperformed the current TNM staging system in disease-free and overall survival with a lower (ie, better) overall normalized score (2 vs 3). Conclusions and Relevance In this study, reclassifying each N category 1 stratum higher for iENE-positive disease resulted in better disease-free and overall survival. The proposed new classification outperformed the currently TNM staging system in risk stratification and may facilitate future clinical trial design, outcomes research, and patient care.