Understanding Breast Cancer Images in Art History as a Form of Health Communication.

Can art and visual images meant for public consumption (museums, galleries, social media platforms) serve as a critical form of health communication for breast cancer patients? For their clinicians? For the population at large? Art history research methods are applied to a range of breast cancer images in western art in order to understand what the images communicate to us about patient experience, agency, and inequity in health care at the time of their construction. The following is a selective look at western art as it reflects and informs our understanding of breast cancer over time.

Guideline Awareness Disparities in Plastic Surgery: A Survey of American Society of Plastic Surgeons.

The American Society of Plastic Surgeons (ASPS) clinical practice guidelines were constructed to help direct evidence-based surgical management in plastic surgery. Societal member awareness of the recommendations for breast reconstruction has yet to be studied among ASPS members. Methods: Univariate and multivariate analyses were performed using electronic survey data from 243 ASPS members. Characteristics, including respondent demographics, practice distribution, and geographic locations, were correlated to the awareness of autologous and expander/implant-based reconstruction guidelines. Results: Of the respondents, 52% and 35.7% reported awareness for autologous breast reconstruction and expander/implant-based reconstruction guidelines, respectively. Surgeons who performed more general and autologous breast reconstruction were more likely to be aware of autologous breast reconstruction and expander/implant-based guidelines (P = 0.0034 and 0.032). Autologous breast reconstruction guideline awareness was geographically disparate (P = 0.031), with greater awareness in the Northeast (OR, 4.5; 95% CI, 1.63-12.53; P = 0.01) and Southwest (OR, 3.91; 95% CI, 1.18-13.83; P = 0.01). Respondents with larger practice percentages of breast reconstruction and those with higher annual academic meeting attendance reported greater awareness of expander/implant-based guidelines (P = 0.044 and 0.040). Meeting attendance (OR, 2.14; 95% CI, 1.15-8.91; P = 0.022) and practice-based (OR, 3.14; 95% CI, 1.52-8.91; P = 0.027) awareness disparities were also appreciated on multivariate analysis. Conclusions: Guideline awareness in plastic surgery varies by practice composition and geography. These findings can be used to help inform more targeted educational and implementation strategies in breast reconstruction. Clinical Question/Level of Evidence: Quality Improvement/Level IV.

Extent of tumor fibrosis/hyalinization and infarction following neoadjuvant radiation therapy is associated with improved survival in patients with soft-tissue sarcoma.

INTRODUCTION: Current standard of care for most intermediate and high-grade soft-tissue sarcomas (STS) includes limb-preserving surgical resection with either neoadjuvant radiation therapy (NRT) or adjuvant radiation therapy. To date, there have been a few studies that attempt to correlate histopathologic response to NRT with oncologic outcomes in patients with STS. METHODS: Using our institutional database, we identified 58 patients who received NRT followed by surgical resection for primary intermediate or high-grade STS and 34 patients who received surgical resection without NRT but did receive adjuvant radiation therapy or did not receive any radiation therapy. We analyzed four histologic parameters of response to therapy: residual viable tumor, fibrosis/hyalinization, necrosis, and infarction (each ratiometrically determined). Data were stratified into two binary groups. Unadjusted, 5- and 10-year overall survival, and relapsed-free survival (RFS) were calculated using the Kaplan-Meier method. RESULTS: Analysis of pathologic characteristics showed that patients treated with NRT demonstrate significantly higher tumor infarction, higher tumor fibrosis/hyalinization, and a lower percent viable tumor compared with patients not treated with NRT (p < 0.0001). Based on Kaplan-Meier curve analysis and multivariate cox proportional hazard model for OS and RFS, patients treated with NRT and showing >12.5% tumor fibrosis/hyalinization have significantly higher overall survival and recurrence-free survival at 5 and 10 years. DISCUSSION AND CONCLUSION: We have identified three histopathologic characteristics-fibrosis, hyalinization, and infarction-that may serve as predictive biomarkers of response to NRT for STS patients. Future prospective studies will be needed to confirm this association.

Patient Perspectives on the Financial Costs and Burdens of Breast Cancer Surgery.

PURPOSE: Although financial toxicity is a well-documented aspect of cancer care, little is known about how patients narratively characterize financial experiences related to breast cancer treatment. We sought to examine these patient experiences through mixed methods analysis. METHODS: Women (≥ 18 years old) with a history of breast cancer were recruited from the Love Research Army and Sisters Network to complete an 88-item electronic survey including an open-ended response. Quantitative data were used to sort and stratify responses to the open-ended question, which comprised the qualitative data evaluated here. Descriptive statistics and qualitative content analysis were used to evaluate the financial costs and other burdens resulting from breast cancer surgery. RESULTS: In total, 511 respondents completed the survey in its entirety and wrote an open-ended response. Participants reported significant financial burden in different categories including direct payments for medical care and indirect costs such as lost wages and travel expenses. Treatment-related costs burdened participants for years after diagnosis, forming a financial arc for many participants. Discrepancies existed between the degree of financial burden reported on multiple-choice questions and participants' corresponding open-ended descriptions of financial burden. Participants described a lack of communication surrounding costs with their providers and difficulty negotiating payments with insurance. CONCLUSION: Breast cancer care can result in ongoing financial burden years after diagnosis among all patients, even those with adequate insurance patient populations.

Where advocacy meets patient-centered care-cost considerations in breast reconstruction decision-making.

Cancer care in the United States is unquestionably expensive. In 2017, annual costs related to cancer-related treatment reached $180 billion. There is clear evidence that the increased cost of cancer care translates to financial hardship. This hardship is widespread, impacting as many as 75% of patients and their families with associated adverse sequelae. Growing recognition of the negative impact of cancer-related treatment costs on patients and their families led to the creation of the term "financial toxicity". The present editorial is borne out of the need to bring this problem to the attention of practicing surgeons, as to the best of our knowledge is still underreported in our specialties.

Identifying Factors Most Important to Lower Extremity Trauma Patients: Key Concepts from the Development of a Patient-Reported Outcome Instrument for Lower Extremity Trauma, The LIMB-Q.

BACKGROUND: Severe lower extremity injuries are challenging to treat. The aspects of limb salvage and amputation most important to patients are not well-defined. This study's aim is to develop a conceptual framework for a patient-reported outcome instrument for lower extremity trauma patients, by defining issues and concepts most important to this patient population. METHODS: This is an interpretative description of transcripts collected from semistructured qualitative interviews at a single institution. High-energy lower extremity trauma patients were recruited by means of purposeful sampling to maximize variability. Thirty-three participant interviews were needed to reach content saturation. These participants were aged 19 to 79 years; 21 were men (63.6 percent); participation was after reconstruction [n= 15 (45.5 percent)], after amputation [n = 11 (33.3 percent)], or after amputation after failed reconstruction [n = 7 (21.2 percent)]. Interviews were recorded, transcribed, and coded line-by-line. Concepts were labeled with major and minor themes and refined through a process of constant comparison. Analysis led to the development of a conceptual framework and item pool to inform the development of a patient-reported outcome measure. RESULTS: In total, 2430 unique codes were identified and used to generate the conceptual framework covering 10 major themes: appearance, environment, finances, physical, process of care, prosthesis, psychological, sexual, social, and treatment. CONCLUSIONS: This study establishes a comprehensive set of concepts, identifying what is most important to severe lower extremity trauma patients. These findings can be used to inform and focus research and clinical care, and provides the framework to develop a lower extremity trauma-specific patient-reported outcome instrument: the LIMB-Q.

Does facility volume influence survival in patients with primary malignant bone tumors of the vertebral column? A comparative cohort study.

BACKGROUND CONTEXT: Facility volume has been correlated with survival in many cancers. This relationship has not been established in primary malignant bone tumors of the vertebral column (BTVC). PURPOSE: To investigate whether facility patient volume is associated with overall survival in patients with primary malignant BTVCs. STUDY DESIGN: Retrospective comparative cohort. PATIENT SAMPLE: Adult patients with chordomas, chondrosarcomas, or osteosarcomas of the mobile spine. OUTCOME MEASURES: Five-year survival. METHODS: We retrospectively analyzed 733 patients with primary malignant BTVCs in the national cancer database from 2004 through 2015. Univariate and multivariate analyses were used to correlate specific outcome measures with facility volume. Volume was stratified based on cumulative martingale residuals to determine the inflection point of negative to positive impact on survival based on the patient cohort. Long-term survival was compared between patients treated at high and low volume using the Kaplan-Meier method. Only patients with malignant primary tumors were considered eligible for inclusion; patients with incomplete treatment data or benign tumors were excluded. RESULTS: Patients treated at high-volume centers (HVCs) were younger (p=.0003) and more likely to be insured (p<.0001). There were no significant differences in tumor characteristics. Patients treated at high-volume facilities had improved 5-year survival of 71% versus 58% at low-volume centers (p<.0001). Patients treated at HVCs were more likely to receive surgical treatment (91% vs. 80%, p<.0001); if surgery was performed, they were more likely to undergo an en bloc resection (48% vs. 30%, p<.0001). However, there were no differences in margin status or utilization of radiotherapy or chemotherapy between HVCs and low-volume centers. In a multivariate analysis, facility volume was independently associated with improved survival overall (HR 0.75 [0.58-0.97], p=.03). CONCLUSIONS: Primary malignant BTVCs are rare, even for HVCs. Despite this, patient survival was significantly improved when treatment was performed at HVCs.

Revisiting the Role of Radiation Therapy in Chondrosarcoma: A National Cancer Database Study.

BACKGROUND: Although chondrosarcomas (CS) are mostly considered radioresistant, advancements in radiotherapy have brought attention to its use in these patients. Using the largest registry of primary bone tumors, the National Cancer Database (NCDB), we sought to better characterize the current use of radiotherapy in CS patients and identify any potential survival benefit with higher radiation doses and advanced radiation therapies. METHODS: We retrospectively analyzed CS patients in the NCDB from 2004 to 2015 who underwent radiotherapy. The Kaplan-Meier method with statistical comparisons was used to identify which individual variables related to dosage and delivery modality were associated with improved 5-year survival rates. Multivariate proportional hazards analyses were performed to determine independent predictors of survival. RESULTS: Of 5,427 patients with a histologic diagnosis of chondrosarcoma, 680 received a form of radiation therapy (13%). The multivariate proportional hazards analysis controlling for various patient, tumor, and treatment variables, including RT dose and modality, demonstrated that while overall radiation therapy (RT) was not associated with improved survival (HR 0.96, 95% CI 0.76-1.20), when examining just the patient cohort with positive surgical margins, RT trended towards improved survival (HR 0.81, 95% CI 0.58-1.13). When comparing advanced and conventional RT modalities, advanced RT was associated with significantly decreased mortality (HR 0.55, 95% CI 0.38-0.80). However, advanced modality and high-dose RT both trended only toward improved survival compared to patients who did not receive any RT (HR 0.74, 95% CI 0.52-1.06 and HR 0.93, 95% CI 0.71-1.21, respectively). CONCLUSIONS: Despite the suggested radioresistance of CS, modern radiotherapies may present a treatment option for certain patients. Our results support a role for high-dose, advanced radiation therapies in selected high-risk CS patients with tumors in surgically challenging locations or unplanned positive margins. While there is an associated survival rate benefit, further, prospective studies are needed for validation.

Epidemiologic and survival trends in adult primary bone tumors of the spine.

BACKGROUND CONTEXT: Malignant primary spinal tumors are rare making it difficult to perform large studies comparing epidemiologic, survival, and treatment trends. We investigated the largest registry of primary bone tumors, the National Cancer Database (NCDB), to compare epidemiologic and survival trends among these tumors. PURPOSE: To use the NCDB to describe current epidemiologic trends, treatment modalities, and overall survival rates in patients with chordomas, osteosarcomas, chondrosarcomas, and Ewing sarcomas of the mobile spine. The secondary objective was to determine prognostic factors that impact overall survival rates. STUDY DESIGN: Retrospective study. PATIENT SAMPLE: A total of 1,011 patients with primary bone tumors of the spine (377 chordomas, 223 chondrosarcomas, 278 Ewing sarcomas, and 133 osteosarcomas). OUTCOME MEASURES: Five-year survival. METHODS: We reviewed the records of 1,011 patients in the NCDB from 2004 through 2015 with histologically confirmed primary osteosarcoma, chondrosarcoma, Ewing sarcoma, or chordoma of the spine. Demographic, clinical, and outcomes data were compiled and compared using chi-squared tests and ANOVA. Long-term survival was compared using the Kaplan-Meier method with statistical comparisons based on the log-rank test. Multivariate analysis was performed to determine survival determinants. RESULTS: Surgical resection was the primary mode of treatment for chondrosarcoma (90%), chordoma (84%), and osteosarcoma (80%). The treatment for Ewing sarcoma was multimodal involving chemotherapy, radiation therapy, and surgical resection. Five-year survival rates varied significantly with chordomas and chondrosarcomas having the greatest survival (70% and 69%), osteosarcomas having the worse survival (38%), and Ewing having intermediate 5-year survival at 62% (overall log-rank p<.0001). Multivariate analysis demonstrated significantly improved 5-year survival rates with younger age at diagnosis, private insurance status, lower comorbidity score, lower tumor grade, smaller tumor size, surgical resection, and negative surgical margin. Radiation therapy only improved survival for Ewing sarcoma. CONCLUSIONS: This study provides the most comprehensive description of the epidemiologic, treatment, and survival trends of primary bone tumors of the mobile spine. Second, patient and tumor characteristics associated with improved 5-year survival were identified using a multivariate model.

Perspectives on the Costs of Cancer Care: A Survey of the American Society of Breast Surgeons.

BACKGROUND: Cancer treatment costs are not routinely addressed in shared decisions for breast cancer surgery. Thus, we sought to characterize cost awareness and communication among surgeons treating breast cancer. METHODS: We conducted a self-administered, confidential electronic survey among members of the American Society of Breast Surgeons from 1 July to 15 September 2018. Questions were based on previously published or validated survey items, and assessed surgeon demographics, cost sensitivity, and communication. Descriptive summaries and cross-tabulations with Chi-square statistics were used, with exact tests where warranted, to assess findings. RESULTS: Of those surveyed (N = 2293), 598 (25%) responded. Surgeons reported that 'risk of recurrence' (70%), 'appearance of the breast' (50%), and 'risks of surgery' (47%) were the most influential on patients' decisions for breast cancer surgery; 6% cited out-of-pocket costs as significant. Over half (53%) of the surgeons agreed that doctors should consider patient costs when choosing cancer treatment, yet the majority of surgeons (58%) reported 'infrequently' (43%) or 'never' (15%) considering patient costs in medical recommendations. The overwhelming majority (87%) of surgeons believed that patients should have access to the costs of their treatment before making medical decisions. Surgeons treating a higher percentage of Medicaid or uninsured patients were more likely to consistently consider costs (p < 0.001). Participants reported that insufficient knowledge or resources (61%), a perceived inability to help with costs (24%), and inadequate time (22%) impeded cost discussions. Notably, 20% of participants believed that discussing costs might impact the quality of care patients receive. CONCLUSIONS: Cost transparency remains rare, however in shared decisions for breast cancer surgery, improved cost awareness by surgeons has the potential to reduce financial hardship.

Decline in Racial Disparities in Postmastectomy Breast Reconstruction: A Surveillance, Epidemiology, and End Results Analysis from 1998 to 2014.

BACKGROUND: Despite increasing emphasis on reducing racial disparities in breast cancer care in the United States, it remains unknown whether access to breast reconstruction has improved over time. The authors characterized contemporary patterns of breast reconstruction by race and ethnicity. METHODS: The Surveillance, Epidemiology, and End Results database was used to identify women undergoing mastectomy for stage 0 to III breast cancer from 1998 to 2014. Multivariable logistic regression was used to estimate the association of demographic factors with likelihood of postmastectomy reconstruction. Multivariable logistic regression was used to predict reconstruction subtype. Patients undergoing reconstruction were grouped by diagnosis year to assess change in the population over time by race and ethnicity. RESULTS: Of 346,418 patients, 21.8 percent underwent immediate reconstruction. Non-Hispanic black race (OR, 0.71) and Hispanic ethnicity (OR, 0.63) were associated with a decreased likelihood of reconstruction (all p < 0.001). Race was predictive of reconstruction type, with non-Hispanic black (OR, 1.52) and Hispanic women (OR, 1.22) more likely to undergo autologous versus implant-based reconstruction (p < 0.001). Although rates of reconstruction increased over time across all races, non-Hispanic black and Hispanic patients had a higher adjusted per-year increase in rate of reconstruction compared with non-Hispanic white patients (interaction p < 0.001). CONCLUSIONS: Rates of postmastectomy reconstruction have increased more quickly over time for minority women compared with white women, suggesting that racial disparities in breast reconstruction may be improving. However, race continues to be associated with differences in types and rates of reconstruction. Further research is necessary to continue to improve access to breast reconstruction in the United States. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, III.

Perioperative Treatment with a Prolyl Hydroxylase Inhibitor Reduces Necrosis in a Rat Ischemic Skin Flap Model.

BACKGROUND: The hypoxia-inducible factor (HIF) pathway, regulated by prolyl hydroxylase, is central to tissue adaptation to ischemia. The authors tested whether the prolyl hydroxylase inhibitor dimethyloxalylglycine reduces skin flap necrosis. METHODS: Dorsal skin flaps were raised on hairless rats, with dimethyloxalylglycine delivered intraperitoneally and/or topically for 7 days before and after surgery. After 14 treatment days, percentage of flap necrosis was compared grossly and tissue perfusion compared with an in vivo imaging system. Angiogenesis was compared using immunohistochemical CD31 staining and enzyme-linked immunosorbent assay for tissue vascular endothelial growth factor. Expression levels of HIF-1α and terminal deoxynucleotidyl transferase-mediated dUDP end-labeling were compared using immunohistochemical staining. Complete blood counts and gross necropsy specimens were obtained to assess systemic toxicity. RESULTS: Dimethyloxalylglycine administration significantly improved postoperative flap viability, with combined topical and intraperitoneal dimethyloxalylglycine administration leading to reduced necrosis on postsurgical day 7 at 6 mg/kg/day, 12 mg/kg/day, 24 mg/kg/day, and 48 mg/kg/day versus controls (all p < 0.05). Compared with controls (unperfused, 39.9 ± 3.8 percent), dimethyloxalylglycine treatment led to a dose-dependent decrease in unperfused tissue at 6 mg/kg/day (11.4 ± 1.7 percent), 12 mg/kg/day (9.4 ± 4.2 percent), 24 mg/kg/day (4.7 ± 2.6 percent), and 48 mg/kg/day (1.4 ± 0.9 percent) (all p < 0.001). Topical dimethyloxalylglycine application alone administered at 48 mg/kg/day was sufficient to improve flap viability (p = 0.005). Dimethyloxalylglycine-treated flaps exhibited higher CD31 staining (p = 0.004), tissue vascular endothelial growth factor (p = 0.007), HIF-1α staining (p < 0.001), and reduced terminal deoxynucleotidyl transferase-mediated dUDP end-labeling staining (p = 0.045). There were no differences in hematocrit or macroscopic organ changes on gross necropsy. CONCLUSION: Topical and systemic targeting of the HIF-1 pathway may be a promising therapeutic approach to improve flap resistance to ischemia.

The Influence of Marital Status on Contemporary Patterns of Postmastectomy Breast Reconstruction.

BACKGROUND: Marital status is known to influence quality of life, survival, and treatment decision-making after breast cancer diagnosis. We aimed to determine whether relationship status impacts contemporary patterns of immediate breast reconstruction. METHODS: Surveillance, Epidemiology, and End Results (SEER)-18 was used to identify females undergoing mastectomy for stage 0-III breast cancer from 1998 to 2014. Multivariate logistic regression was used to estimate the association of relationship status with the likelihood of postmastectomy reconstruction. Patients were grouped by diagnosis year to assess change in the reconstructed population with time. Among younger patients ≤45 years, a generalized logistic model was used to predict reconstruction subtype. RESULTS: Among 346,418 patients, reconstruction after mastectomy was more likely to occur in women with relationship support in the form of a marriage or partner [odds ratio (OR) 1.31; 95% confidence interval (CI), 1.28-1.34; p<0.001]. Women who were separated (OR 0.76), single (OR 0.73), or widowed (OR 0.56) were significantly less likely than married women to undergo reconstruction (all p<0.001). During the 17-year study period, change in reconstruction rates with time varied by relationship status (interaction p=0.02), with reconstruction rates among divorced patients increasing more slowly than those among married and partnered women. Among younger women, subtype patterns varied by relationship status (p=0.004), with divorced women less likely to receive autologous over implant reconstruction (OR 0.87; p = 0.03). CONCLUSION: Relationship status may influence decision-making regarding pursuit and type of postmastectomy reconstruction. Consideration of support networks of patients with breast cancer could facilitate tailored preoperative counseling by reconstructive surgeons.

Surgical Resection of the Primary Tumor in Women With De Novo Stage IV Breast Cancer: Contemporary Practice Patterns and Survival Analysis.

OBJECTIVE: We evaluated patterns of surgical care and their association with overall survival among a contemporary cohort of women with stage IV breast cancer. BACKGROUND: Surgical resection of the primary tumor remains controversial among women with stage IV breast cancer. METHODS: Women diagnosed with clinical stage IV breast cancer from 2003 to 2012 were identified from the American College of Surgeons National Cancer Database. Those with intact primary tumors who were alive 12 months after diagnosis were categorized by treatment sequence: (1) surgery before systemic therapy, (2) systemic therapy before surgery, and (3) systemic therapy alone. Multivariate logistic regression was used to estimate the association of treatment sequence with surgery type. Overall survival was estimated using multivariate Cox proportional hazards models. RESULTS: Among 24,015 women, 56.2% (13,505) underwent systemic therapy alone and 43.8% (10,510) underwent surgical resection. Rates of surgery decreased slightly over time (43.1% in 2003 to 41.9% in 2011). Treatment with systemic therapy before surgery was associated with larger tumor size (median 4.5 vs 3.1 cm, P < 0.001) and receipt of mastectomy (81.4% vs 52.2%, P < 0.001) when compared to those who underwent surgery first. Receipt of surgery, whether before or after systemic therapy (Hazard Ratio, 0.68; 95% confidence interval, 0.62-0.73; Hazard Ratio, 0.56; 95% confidence interval, 0.52-0.61; P < 0.001), was independently associated with improved adjusted overall survival when compared to systemic therapy alone. CONCLUSIONS: Surgical resection of the primary tumor occurs in almost half of women with stage IV breast cancer alive 1 year after diagnosis, and is increasingly occurring after systemic therapy. Coordinated multidisciplinary care remains highly relevant in the setting of metastatic breast cancer, where surgical decisions should be made on an individual basis and may affect survival in select women.

Preoperative radiation therapy in the surgical management of gastric and junctional adenocarcinoma: Should lymph node retrieval guidelines be altered?

BACKGROUND: Although surgery remains the cornerstone of gastric cancer therapy, the use of radiation therapy (RT) is increasingly being employed to optimize outcomes. We sought to assess outcomes following use of RT for the treatment of gastric adenocarcinoma. METHODS: Using the National Cancer Data Base (NCDB) from 1998 to 2012, all patients with resected gastric adenocarcinoma were identified. Patients were stratified into four groups based on preoperative therapy: RT alone, chemotherapy only, chemoradiotherapy (CRT), and no preoperative therapy. Overall survival was estimated using multivariate Cox proportional hazards model. Adjusted secondary outcomes include margin positivity, lymph node harvest, LOS, 30-day readmission and mortality. RESULTS: A total of 10 019 patients met study criteria. In the unadjusted analysis, patients undergoing CRT compared to chemotherapy alone had fewer positive margins (7.9% vs 15.9%; P < 0.001), increased negative LNs (54.6% vs 37.7%; P < 0.001) with reduced LN retrieval (mean: 13.5 vs 19.6; P < 0.01). After multivariate adjustment, there was no survival benefit to any preoperative therapy; however, preoperative RT/CRT remained associated with decreased LN retrieval. CONCLUSIONS: The results support previous reports on preoperative RT resulting in decreased margin positivity. This study highlights the need to reconsider practice guidelines regarding appropriate lymphadenectomy in the setting of preoperative RT given reduced LN retrieval.

The Efficacy of the Interferon Alpha/Beta Response versus Arboviruses Is Temperature Dependent.

Interferon alpha/beta (IFN-α/ß) is a critical mediator of protection against most viruses, with host survival frequently impossible in its absence. Many studies have investigated the pathways involved in the induction of IFN-α/ß after virus infection and the resultant upregulation of antiviral IFN-stimulated genes (ISGs) through IFN-α/ß receptor complex signaling. However, other than examining the effects of genetic deletion of induction or effector pathway components, little is known regarding the functionality of these responses in intact hosts and whether host genetic or environmental factors might influence their potency. Here, we demonstrate that the IFN-α/ß response against multiple arthropod-vectored viruses, which replicate over a wide temperature range, is extremely sensitive to fluctuations in temperature, exhibiting reduced antiviral efficacy at subnormal cellular temperatures and increased efficacy at supranormal temperatures. The effect involves both IFN-α/ß and ISG upregulation pathways with a major aspect of altered potency reflecting highly temperature-dependent transcription of IFN response genes that leads to altered IFN-α/ß and ISG protein levels. Discordantly, signaling steps prior to transcription that were examined showed the opposite effect from gene transcription, with potentiation at low temperature and inhibition at high temperature. Finally, we demonstrate that by lowering the temperature of mice, chikungunya arbovirus replication and disease are exacerbated in an IFN-α/ß-dependent manner. This finding raises the potential for use of hyperthermia as a therapeutic modality for viral infections and in other contexts such as antitumor therapy. The increased IFN-α/ß efficacy at high temperatures may also reflect an innate immune-relevant aspect of the febrile response.IMPORTANCE The interferon alpha/beta (IFN-α/ß) response is a first-line innate defense against arthropod-borne viruses (arboviruses). Arboviruses, such as chikungunya virus (CHIKV), can infect cells and replicate across a wide temperature range due to their replication in both mammalian/avian and arthropod hosts. Accordingly, these viruses can cause human disease in tissues regularly exposed to temperatures below the normal mammalian core temperature, 37°C. We questioned whether temperature variation could affect the efficacy of IFN-α/ß responses against these viruses and help to explain some aspects of human disease manifestations. We observed that IFN-α/ß efficacy was dramatically lower at subnormal temperatures and modestly enhanced at febrile temperatures, with the effects involving altered IFN-α/ß response gene transcription but not IFN-α/ß pathway signaling. These results provide insight into the functioning of the IFN-α/ß response in vivo and suggest that temperature elevation may represent an immune-enhancing therapeutic modality for a wide variety of IFN-α/ß-sensitive infections and pathologies.

The Effect of Hospital Volume on Breast Cancer Mortality.

OBJECTIVE: The aim of this study was to determine whether hospital volume was associated with mortality in breast cancer, and what thresholds of case volume impacted survival. BACKGROUND: Prior literature has demonstrated improved survival with treatment at high volume centers among less common cancers requiring technically complex surgery. METHODS: All adults (18 to 90 years) with stages 0-III unilateral breast cancer diagnosed from 2004 to 2012 were identified from the American College of Surgeons National Cancer Data Base (NCDB). A multivariable Cox proportional hazards model with restricted cubic splines was used to examine the association of annual hospital volume and overall survival, after adjusting for measured covariates. Intergroup comparisons of patient and treatment characteristics were conducted with X and analysis of variance (ANOVA). The log-rank test was used to test survival differences between groups. A multivariable Cox proportional hazards model was used to estimate hazard ratios (HRs) associated with each volume group. RESULTS: One million sixty-four thousand two hundred and fifty-one patients met inclusion criteria. The median age of the sample was 60 (interquartile range 50 to 70). Hospitals were categorized into 3 groups using restricted cubic spline analysis: low-volume (<148 cases/year), moderate-volume (148 to 298 cases/year), and high-volume (>298 cases/year). Treatment at high volume centers was associated with an 11% reduction in overall mortality for all patients (HR 0.89); those with stage 0-I, ER+/PR+ or ER+/PR- breast cancers derived the greatest benefit. CONCLUSIONS: Treatment at high volume centers is associated with improved survival for breast cancer patients regardless of stage. High case volume could serve as a proxy for the institutional infrastructure required to deliver complex multidisciplinary breast cancer treatment.

Preoperative or postoperative radiotherapy versus surgery alone for retroperitoneal sarcoma: a case-control, propensity score-matched analysis of a nationwide clinical oncology database.

BACKGROUND: Recruitment into clinical trials for retroperitoneal sarcoma has been challenging, resulting in termination of the only randomised multicentre trial in the USA investigating perioperative radiotherapy. Nonetheless, use of radiotherapy for retroperitoneal sarcoma has increased over the past decade, substantiated primarily by its established role in extremity sarcoma. In this study, we used a nationwide clinical oncology database to separately compare overall survival for patients with retroperitoneal sarcoma who had surgery and preoperative radiotherapy or surgery and postoperative radiotherapy versus surgery alone. METHODS: We did two case-control, propensity score-matched analyses of the National Cancer Data Base, which included adult patients with retroperitoneal sarcoma who were diagnosed from 2003 to 2011. Patients were included if they had localised, primary retroperitoneal sarcoma. Patients were classified into three groups based on use of radiotherapy: preoperative radiotherapy, postoperative radiotherapy, and no radiotherapy (surgery alone). Patients were excluded if they received both preoperative radiotherapy and postoperative radiotherapy, or if they received intraoperative radiotherapy. Parallel propensity score-matched datasets were created for patients who received preoperative radiotherapy versus those who received no radiotherapy and for patients who received postoperative therapy versus those who received no radiotherapy. Propensity scores were calculated with logistic regression, with multiple imputation and backwards elimination, with a significance level to stay of 0·05. Matching was done with a nearest-neighbour algorithm and matched 1:2 for the preoperative radiotherapy dataset and 1:1 for the postoperative radiotherapy dataset. The primary objective of interest was overall survival for patients who received preoperative radiotherapy or postoperative radiotherapy compared with those who received no radiotherapy within the propensity score-matched datasets. FINDINGS: 9068 patients were included in this analysis: 563 in the preoperative radiotherapy group, 2215 in the postoperative radiotherapy group, and 6290 in the no radiotherapy group. Matching resulted in two comparison groups (preoperative radiotherapy vs no radiotherapy, and postoperative radiotherapy vs no radiotherapy) with negligible differences in all demographic, clinicopathological, and treatment-level variables. In the matched case-control analysis for preoperative radiotherapy median follow-up time was 42 months (IQR 27-70) for the preoperative radiotherapy group versus 43 months (25-64) for the no radiotherapy group; median overall survival was 110 months (95% CI 75-not estimable) versus 66 months (61-76), respectively. In the matched case-control analysis for postoperative radiotherapy median follow-up time was 54 months (IQR 32-79) for patients in the postoperative radiotherapy group and 47 months (26-72) for patients in the no radiotherapy group; median overall survival was 89 months (95% CI 79-100) versus 64 months (59-69), respectively. Both preoperative radiotherapy (HR 0·70, 95% CI 0·59-0·82; p<0·0001) and postoperative radiotherapy (HR 0·78, 0·71-0·85; p<0·0001) were significantly associated with improved overall survival compared with surgery alone. INTERPRETATION: To the best of our knowledge, this is the largest study to date of the effect of radiotherapy on overall survival in patients with retroperitoneal sarcoma. Radiotherapy was associated with improved overall survival compared with surgery alone when delivered as either preoperative radiotherapy or postoperative radiotherapy. Together with the results from the ongoing randomised EORTC trial (62092-22092; NCT01344018) investigating preoperative radiotherapy for retroperitoneal sarcoma pending, these data might provide additional support for the increasing use of radiotherapy for patients with retroperitoneal sarcoma undergoing surgical resection. FUNDING: Department of Surgery, Duke University School of Medicine.

Analysis of perioperative radiation therapy in the surgical treatment of primary and recurrent retroperitoneal sarcoma.

BACKGROUND: Radiation therapy (RT) is increasingly utilized in conjunction with surgery for the treatment of retroperitoneal soft tissue sarcomas (RPS). Despite multiple theoretical advantages of RT, its role in the surgical management of this disease remains ill defined. METHODS: Patients undergoing surgery for RPS from 1990 to 2011 were identified. Patients were classified as having primary or recurrent disease, and then further stratified by the use of perioperative RT. Primary outcomes, including overall survival (OS) and recurrence-free survival (RFS), were estimated using the Kaplan-Meier method with comparisons based on the log rank test. Cox-proportional hazards modeling was used to estimate the independent effect of RT on survival. RESULTS: Ninety-four patients met final inclusion criteria. After adjusting for confounding variables, perioperative RT remained independently associated with a reduced risk of recurrence (HR 0.34, P < 0.01) and death (HR 0.30, P = 0.02). CONCLUSIONS: In this retrospective series, perioperative RT is an independent predictor of improved OS and RFS. These results provide additional support for the use of RT in the multimodality treatment of retroperitoneal sarcoma.