Chromosomal instability increases radiation sensitivity.

Continuous chromosome missegregation over successive mitotic divisions, known as chromosomal instability (CIN), is common in cancer. Increasing CIN above a maximally tolerated threshold leads to cell death due to loss of essential chromosomes. Here, we show in two tissue contexts that otherwise isogenic cancer cells with higher levels of CIN are more sensitive to ionizing radiation, which itself induces CIN. CIN also sensitizes HPV-positive and HPV-negative head and neck cancer patient derived xenograft (PDX) tumors to radiation. Moreover, laryngeal cancers with higher CIN prior to treatment show improved response to radiation therapy. In addition, we reveal a novel mechanism of radiosensitization by docetaxel, a microtubule stabilizing drug commonly used in combination with radiation. Docetaxel causes cell death by inducing CIN due to abnormal multipolar spindles rather than causing mitotic arrest, as previously assumed. Docetaxel-induced CIN, rather than mitotic arrest, is responsible for the enhanced radiation sensitivity observed in vitro and in vivo, challenging the mechanistic dogma of the last 40 years. These results implicate CIN as a potential biomarker and inducer of radiation response, which could provide valuable cancer therapeutic opportunities. Statement of Significance: Cancer cells and laryngeal tumors with higher chromosome missegregation rates are more sensitive to radiation therapy, supporting chromosomal instability as a promising biomarker of radiation response.

Beyond race: social vulnerability and access to metabolic and bariatric surgery.

BACKGROUND: Metabolic and bariatric surgery (MBS) is under-accessed by non-White patients, who are disproportionately affected by obesity. We hypothesized that unique barriers experienced by socially vulnerable patients drive disparate MBS utilization. OBJECTIVES: To determine whether socially vulnerable patients experience greater attrition and face more insurance-mandated medical weight management (MWM) requirements. SETTING: Urban, academic center. METHODS: This retrospective cohort study included adults evaluated for MBS in 2018. Social vulnerability was determined using the 2018 Social Vulnerability Index. Outcomes included attrition, or failure to undergo surgery within 1year, and the number and duration of MWM requirements. Multivariable logistic regression and negative binomial regression tested these associations. RESULTS: In 2018, 339 patients were evaluated for MBS (83% female, 70% Black). The attrition rate was 57%. On adjusted analyses, patients in the highest social vulnerability quartile had double the odds of attrition compared to their least vulnerable counterparts (OR 2.33, 95% CI 1.11-4.92, P = .03). Highly vulnerable patients had double the number (IRR 2.29, 95% CI 1.42-3.72, P = .001) and nearly quadruple the duration (IRR 3.90, 95% CI 1.93-7.86, P < .001) of MWM requirements compared to those with low social vulnerability. Odds of attrition increased by 11% and 20% for each additional MWM visit (OR 1.11, 95% CI 1.02-1.20, P = .02) and month (OR 1.20, 95% CI 1.08-1.33, P = .001), respectively. CONCLUSIONS: Patients with high social vulnerability were less likely to undergo MBS and faced more insurance-mandated preoperative requirements, which independently predicted attrition. Insurance-mandated MWM is inequitable and may contribute to disparate care of patients with severe obesity.

Process of Withdrawal of Mechanical Ventilation at End of Life in the ICU: Clinician Perceptions.

BACKGROUND: Nearly one-quarter of all Americans die in the ICU. Many of their deaths are anticipated and occur following the withdrawal of mechanical ventilation (WMV). However, there are few data on which to base best practices for interdisciplinary ICU teams to conduct WMV. RESEARCH QUESTION: What are the perceptions of current WMV practices among ICU clinicians, and what are their opinions of processes that might improve the practice of WMV at end of life in the ICU? STUDY DESIGN AND METHODS: This prospective two-center observational study conducted in Boston, Massachusetts, the Observational Study of the Withdrawal of Mechanical Ventilation (OBSERVE-WMV) was designed to better understand the perspectives of clinicians and experience of patients undergoing WMV. This report focuses on analyses of qualitative data obtained from in-person surveys administered to the ICU clinicians (nurses, respiratory therapists, and physicians) caring for these patients. Surveys assessed a broad range of clinician perspectives on planning, as well as the key processes required for WMV. This analysis used independent open, inductive coding of responses to open-ended questions. Initial codes were reconciled iteratively and then organized and interpreted using a thematic analysis approach. Opinions were assessed on how WMV could be improved for individual patients and the ICU as a whole. RESULTS: Among 456 eligible clinicians, 312 in-person surveys were completed by clinicians caring for 152 patients who underwent WMV. Qualitative analyses identified two main themes characterizing high-quality WMV processes: (1) good communication (eg, mutual understanding of family preferences) between the ICU team and family; and (2) medical management (eg, planning, availability of ICU team) that minimizes patient distress. Team member support was identified as an essential process component in both themes. INTERPRETATION: Clinician perceptions of the appropriateness or success of WMV prioritize the quality of team and family communication and patient symptom management. Both are modifiable targets of interventions aimed at optimizing overall WMV.

The Causes and Consequences of DNA Damage and Chromosomal Instability Induced by Human Papillomavirus.

High-risk human papillomaviruses (HPVs) are the main cause of cervical, oropharyngeal, and anogenital cancers, which are all treated with definitive chemoradiation therapy when locally advanced. HPV proteins are known to exploit the host DNA damage response to enable viral replication and the epithelial differentiation protocol. This has far-reaching consequences for the host genome, as the DNA damage response is critical for the maintenance of genomic stability. HPV+ cells therefore have increased DNA damage, leading to widespread genomic instability, a hallmark of cancer, which can contribute to tumorigenesis. Following transformation, high-risk HPV oncoproteins induce chromosomal instability, or chromosome missegregation during mitosis, which is associated with a further increase in DNA damage, particularly due to micronuclei and double-strand break formation. Thus, HPV induces significant DNA damage and activation of the DNA damage response in multiple contexts, which likely affects radiation sensitivity and efficacy. Here, we review how HPV activates the DNA damage response, how it induces chromosome missegregation and micronuclei formation, and discuss how these factors may affect radiation response. Understanding how HPV affects the DNA damage response in the context of radiation therapy may help determine potential mechanisms to improve therapeutic response.

Trends in performance of hospital outpatient procedures and associated 30-day costs among Medicare beneficiaries from 2011 to 2018.

BACKGROUND: United States healthcare has increasingly transitioned to outpatient care delivery. The degree to which Academic Medical Centers (AMCs) have been able to shift surgical procedures from inpatient to outpatient settings despite higher patient complexity is unknown. METHODS: This observational study used a 20% sample of fee-for-service Medicare beneficiaries age 65 and older undergoing eight elective procedures from 2011 to 2018 to model trends in procedure site (hospital outpatient vs. inpatient) and 30-day standardized Medicare costs, overall and by hospital teaching status. RESULTS: Of the 1,222,845 procedures, 15.9% occurred at AMCs. There was a 2.42% per-year adjusted increase (95% CI 2.39%-2.45%; p < .001) in proportion of outpatient hospital procedures, from 68.9% in 2011 to 85.4% in 2018. Adjusted 30-day standardized costs declined from $18,122 to $14,353, (-$560/year, 95% CI -$573 to -$547; p < .001). Patients at AMCs had more chronic conditions and higher predicted annual mortality. AMCs had a lower proportion of outpatient procedures in all years compared to non-AMCs, a difference that was statistically significant but small in magnitude. AMCs had higher costs compared to non-AMCs and a lesser decline over time (p < .001 for the interaction). AMCs and non-AMCs saw a similar decline in 30-day mortality. CONCLUSIONS: There has been a substantial shift toward outpatient procedures among Medicare beneficiaries with a decrease in total 30-day Medicare spending as well as 30-day mortality. Despite a higher complexity population, AMCs shifted procedures to the outpatient hospital setting at a similar rate as non-AMCs. IMPLICATIONS: The trend toward outpatient procedural care and lower spending has been observed broadly across AMCs and non-AMCs, suggesting that Medicare beneficiaries have benefited from more efficient delivery of procedural care across academic and community hospitals.

Supervised weight loss requirements disproportionately affect Black patients seeking weight loss surgery.

BACKGROUND: We use our high-volume institutional experience with a majority Black population to examine the role of supervised weight loss (SWL) requirements perpetuating disparities in bariatric surgery. OBJECTIVE: To determine if there are racial disparities in the required amount of supervised weight loss prior to approval for bariatric surgery. SETTING: University hospital. METHODS: A retrospective review was conducted of all patients seen at our institution's bariatric surgery clinic in 2018. Odds of undergoing surgery within 1 year and mean number of SWL requirements were determined using descriptive statistics for Black patients as compared with non-Hispanic White patients. Finally, a logistic model was constructed to examine likelihood of undergoing an operation within 1 year for patients of varying SWL requirements. RESULTS: A total of 335 patients were included (75% Black, 25% White). Within 1 year, 37% of Black patients compared with 53% of White patients had undergone an operation (relative risk .7, P = .01). Mean insurance-mandated SWL sessions were significantly higher for Black patients (3.6 ± 2.8) versus non-Hispanic White patients (2.2 ± 2.7) (P < .01). Mean program-mandated SWL sessions were also significantly higher for Black patients (2.5 ± 2.6) versus non-Hispanic White patients (.8 ± 1.8) (P < .01). Increasing SWL requirements significantly reduced the odds of undergoing surgery at 1 year within the entire cohort (odds ratio .86, P < .01). CONCLUSIONS: Black patients are disproportionally affected by SWL requirements, which strongly correlate with decreased likelihood of undergoing a bariatric operation as compared with their White counterparts. Even after overcoming barriers to see a bariatric surgery provider, Black patients still face disproportionally more barriers to surgery. Bariatric centers must be sensitive to the effect of SWL requirements, as it is negatively associated with the likelihood of a patient receiving a bariatric operation.

Value of Ambulatory Modified Radical Mastectomy.

BACKGROUND: Modified radical mastectomy (MRM) still is largely performed in inpatient settings. This study sought to determine the value (expenditures and complications) of ambulatory MRM. METHODS: Health Care Utilization Project (HCUP) state databases from 2016 were queried for patients who underwent MRM. The study examined rates of 30-day readmission for surgical-site infection (SSI) or hematoma, charges by index care setting, and predictors of 30-day readmission. RESULTS: Overall, 8090 patients underwent MRM: 5113 (63 %) inpatient and 2977 (37 %) ambulatory patients. Compared with the patients who underwent inpatient MRM, those who underwent ambulatory MRM were older (61 vs. 59 years), more often white (66 % vs. 57 %), in the lowest income quartile (28 % vs. 21 %), insured by Medicare (43 % vs. 33 %) and residents in a small metro area (6 % vs. 4 %) (all p < 0.01). Of the 5113 patients treated as inpatients, 126 (2.5 %) were readmitted, whereas 50 (1.7 %) of the ambulatory patients were readmitted (p = 0.02). The adjusted charge for inpatient MRM without readmission was $113,878 (range, $107,355-120,402) compared with $94,463 (range, $86,021-102,907) for ambulatory MRM, and the charge for inpatient MRM requiring readmission was $159,355 (range, $147,142-171,568) compared with $139,940 (range, $125,808-154,073) for ambulatory MRM (all p < 0.01). This difference remained significant after adjustment for hospital length of stay. Adjusted logistic regression showed that the ambulatory setting was protective for readmission (odds ratio, 0.49; 95 % confidence interval, 0.35-0.70; p < 0.01). CONCLUSIONS: The analyses suggest that ambulatory MRM is both safe and less expensive. The findings advocate that MRM, a last holdout of inpatient care within breast surgical oncology, can be transitioned to the ambulatory setting for appropriate patients.

Longitudinal Trends in 30-Day Mortality Between Multi-Site and Single-Site Surgeons.

BACKGROUND: Quality leaders are concerned that creation of multi-hospital health systems may lead to surgeons traveling to and from distant hospitals and thus to more fragmented surgical care and worse outcomes for their patients. Despite this concern, little empirical data exist on outcomes of multi-site versus single-site surgeons. METHODS: Using national Medicare data, we assessed trends in the number of multi-site vs. single-site surgeons from 2011 to 2016. We performed a multivariable regression analysis to compare overall 30-day mortality differences, stratified by system and rural status, and examined trends over time. RESULTS: The number of multi-site surgeons and the percentage of multi-site surgeons per hospital decreased over time (24.2%-19.0%; 44.3%-41.8%). Overall, multi-site surgeons had lower 30-day mortality than single-site surgeons (2.24% vs 2.50%, P < 0.01). When stratified by system status, multi-site surgeons performed better in-system (2.47% vs 2.58%, P < 0.01); by rural status, multi-site surgeons had lower mortality in non-rural hospitals (2.42% vs 2.51%, P < 0.01). The statistically significant but small mortality advantage of multi-site versus single-site surgeons decreased over time, such that by 2016 there was no difference in outcomes between multi-site and single-site surgeons. CONCLUSION: For the majority of study years, multi-site surgeons had lower 30-day mortality than single-site surgeons, but this trend narrowed until outcomes were equivalent by 2016. Surgeons operating at multiple hospitals can provide surgical care to patients without any evidence of increased mortality.

How Should We Respond to Health Sector Emissions That Exacerbate Climate Change and Inequity?

A warming climate poses substantial risk to public health and worsens existing health inequity. As a contributor to greenhouse gas emissions and air pollution, the health sector has obligations and ample opportunities to protect health by decreasing waste and motivating more system-wide sustainable clinical practices. Such efforts will have important ethical implications for health equity.

Assessment of Oncologists' Perspectives on Omission of Sentinel Lymph Node Biopsy in Women 70 Years and Older With Early-Stage Hormone Receptor-Positive Breast Cancer.

Importance: Randomized clinical trial data have demonstrated that omission of surgical axillary evaluation does not affect overall survival in women 70 years and older with early-stage (clinical tumor category 1 [cT1] with node-negative [N0] disease) hormone receptor (HR)-positive and erb-B2 receptor tyrosine kinase 2 (ERBB2; formerly HER2)-negative breast cancer. Therefore, the Choosing Wisely initiative has recommended against routine use of sentinel lymph node biopsy (SLNB) in this population; however, retrospective data have revealed that more than 80% of patients eligible for SLNB omission still undergo the procedure. Multidisciplinary factors involved in these patterns remain unclear. Objective: To describe surgical, medical, and radiation oncologists' perspectives on omission of SLNB in women 70 years and older with cT1N0 HR-positive, ERBB2-negative breast cancer. Design, Setting, and Participants: This qualitative study used in-depth semi-structured interviews to explore the factors involved in oncologists' perspectives on providing care to older women who were eligible for SLNB omission. Purposive snowball sampling was used to recruit a sample of surgical, medical, and radiation oncologists representing a wide range of practice types and number of years in practice in the US and Canada. A total of 29 oncologists who finished training and were actively treating patients with breast cancer were interviewed. Interviews were conducted between March 1, 2020, and January 17, 2021. Main Outcomes and Measures: Recordings from semi-structured interviews were transcribed and deidentified. Thematic analysis was used to identify emergent themes. Results: Among 29 physicians (16 women [55.2%] and 13 men [44.8%]) who participated in interviews, 16 were surgical oncologists, 6 were medical oncologists, and 7 were radiation oncologists. Data on race and ethnicity were not collected. Participants had a range of experience (median [range] years in practice, 12.0 [0.5-30.0]) and practice types (14 academic [48.3%], 7 community [24.1%], and 8 hybrid [27.6%]). Interviews revealed that the decision to omit SLNB was based on nuanced patient- and disease-level factors. Wide variation was observed in oncologists' perspectives on SLNB omission recommendations and supporting data. In addition, participants' statements suggested that the multidisciplinary nature of cancer care may increase oncologists' anxiety regarding SLNB omission. Conclusions and Relevance: In this study, findings from interviews revealed that oncologists' perspectives may have implications for the largely unsuccessful deimplementation of SLNB in women 70 years and older with cT1N0 HR-positive, ERBB2-negative breast cancer. Interventions aimed at educating physicians, improving patient-physician communication, and facilitating preoperative multidisciplinary conversations may help to successfully decrease SLNB rates in this patient population.

Autologous Posterior Rectus Sheath as a Vascularized Onlay Flap: a Novel Approach to Hiatal Hernia Repair.

INTRODUCTION: Complex and recurrent paraesophageal hernia repairs are a challenge for surgeons due to their high recurrence rates despite the use of various prosthetic and suturing techniques. METHODS: Here we describe the use of vascularized fascia harvested from the posterior rectus sheath with peritoneum during robotic hiatal hernia repair in two patients with large complex diaphragmatic defects. RESULTS: Successful harvesting and onlay of the right posterior rectus sheath based on a falciform vascular pedicle was achieved robotically by rotating and securing the flap to the diaphragmatic hiatus as an onlay flap following cruroplasty of the hiatal defect. CONCLUSIONS: In patients with difficult to repair large paraesophageal hernias, we demonstrate a promising new technique to restore the dynamic hiatal complex with the tensile strength of autologous vascularized fascia and peritoneum.

Variation in Use of Surgical Care During the COVID-19 Pandemic by Surgical Urgency and Race and Ethnicity.

Importance: The extent of the disruption to surgical care during the COVID-19 pandemic has not been empirically characterized on a national level. Objective: To characterize the use of surgical care across cohorts of surgical urgency during the COVID-19 pandemic, and to assess for racial and ethnic disparities. Design Setting and Participants: This was a retrospective observational study using the geographically diverse, all payer data from 767 hospitals in the Premier Healthcare Database. Procedures were categorized into 4 cohorts of surgical urgency (elective, nonelective, emergency, and trauma). A generalized linear regression model with hospital-fixed effects assessed the relative monthly within-hospital reduction in surgical encounters in 2020 compared with 2019. Main Outcomes and Measures: Outcomes were the monthly relative reduction in overall surgical encounters and across surgical urgency cohorts and race and ethnicity. Results: The sample included 13 175 087 inpatient and outpatient surgical encounters. There was a 12.6% relative reduction in surgical use in 2020 compared to 2019. Across all surgical cohorts, the most prominent decreases in encounters occurred during Spring 2020 . For example, elective encounters began falling in March, reached a trough in April, and subsequently recovered but never to prepandemic levels (March: -26.8%; 95% CI, -29.6% to -23.9%; April: -74.6%; 95% CI, -75.5% to -73.5%; December: -13.3%; 95% CI, -16.6%, -9.8%). Across all operative surgical urgency cohorts, White patients had the largest relative reduction in encounters. Conclusions and Relevance: As shown by this cohort study, the COVID-19 pandemic resulted in large disruptions to surgical care across all categories of operative urgency, especially elective procedures. Racial and ethnic minority groups experienced less of a disruption to surgical care than White patients. Further research is needed to explore whether the decreased surgical use among White patients was owing to patient discretion and to document whether demand for surgical care will rebound to baseline levels.

Toward Autonomy and Conditional Independence: A Standardized Script Improves Patient Acceptance of Surgical Trainee Roles.

BACKGROUND: Progressive autonomy leading to conditional independence is necessary to achieve competence in surgical skills and decision making. Trust and transparency are ethical imperatives, but practices vary regarding the extent of disclosure of specific resident roles. We tested whether a standardized preoperative script would improve patient acceptance of resident involvement in perioperative care. METHODS: Patients admitted to a resident-run acute care general surgery service between October 2017 and October 2018 were enrolled in an IRB-approved study. During the first half of the rotation (control), operative consent was obtained according to individual practice without specified explanation of resident roles. During the second half (intervention), the senior resident read a short semistructured script specifically explaining team roles and responsibilities, including the degree of resident independence and supervision by attendings. On postoperative day 3, patients completed a survey assessing understanding of their surgical care. RESULTS: Sixty-two patients under the care of 10 rotating chief residents were enrolled; 46 patients completed the survey, 23 in each arm (74% response rate). Ten patients in the control arm (43%) compared to only 3 (13%) in the intervention arm indicated that residents should not be allowed to perform portions of operations (odds ratio 4.94, p = 0.047). Patients in the intervention arm felt that care team roles were more adequately explained to them before their operation (p = 0.002). There was no difference in the number of patients naming a resident as "their doctor." CONCLUSIONS: Use of a short script specifying resident roles improves patient acceptance of trainee participation in perioperative care.