A single-cell atlas of human and mouse white adipose tissue.

White adipose tissue, once regarded as morphologically and functionally bland, is now recognized to be dynamic, plastic and heterogenous, and is involved in a wide array of biological processes including energy homeostasis, glucose and lipid handling, blood pressure control and host defence1. High-fat feeding and other metabolic stressors cause marked changes in adipose morphology, physiology and cellular composition1, and alterations in adiposity are associated with insulin resistance, dyslipidemia and type 2 diabetes2. Here we provide detailed cellular atlases of human and mouse subcutaneous and visceral white fat at single-cell resolution across a range of body weight. We identify subpopulations of adipocytes, adipose stem and progenitor cells, vascular and immune cells and demonstrate commonalities and differences across species and dietary conditions. We link specific cell types to increased risk of metabolic disease and provide an initial blueprint for a comprehensive set of interactions between individual cell types in the adipose niche in leanness and obesity. These data comprise an extensive resource for the exploration of genes, traits and cell types in the function of white adipose tissue across species, depots and nutritional conditions.

Improving value delivery in living donor kidney transplant through process improvement.

INTRODUCTION: Living donor kidney evaluation has substantial time variations with significant intercenter variation. One-day donor evaluation has shown to be clinically efficient and improve transplant rates. However, patients' perception of 1-day evaluation is unknown. We hypothesized that 1 day LKD evaluation will improve patient satisfaction and improve living donation rates. METHODS: All interested LD candidates from April 2018 to May 2020 were enrolled in the study. Non-directed donors, donors greater than 60 years old, and recipients with more than three donors underwent multi-day evaluation (control group) while the rest underwent 1-day evaluation (intervention group). An anonymous survey was filled by both groups to assess their perceptions on different areas including time, communication, experience, information provided, and their preferences on living donor evaluation. RESULTS: Donor candidates in the 1-day evaluation group selected that the time from the questionnaire to clinic evaluation took "under 1 month" or "less than 3 months" (62.5% vs. 15.8%, p = .002), with "excellent" for both scheduling process (65% vs. 31.6%, p = .03) and communication (82.5% vs. 57.9%, p = .09) when compared to candidates in the multiple-days evaluation group. One-day candidates felt "very satisfied" with the overall experience (95% vs. 68.4%, p = .02) and felt "extremely well" with the information provided regarding the living donor process (87.5% vs. 47.4%, p = .003) when compared to multiple-day evaluation group. Regardless of the group, 53 (89.8%) patients preferred 1-day evaluation. CONCLUSION: We demonstrate 1-day living donor evaluation is efficient, patient preferred, and adds value through improved communication, and better overall patient satisfaction.

Impact of the COVID-19 pandemic on cancer diagnoses, stage and survival in Alberta.

BACKGROUND: The COVID-19 pandemic is suspected to have affected cancer care and outcomes among patients in Canada. In this study, we evaluated the impact of the state of emergency period during the COVID-19 pandemic (Mar. 17 to June 15, 2020) on cancer diagnoses, stage at diagnosis and 1-year survival in Alberta. METHODS: We included new diagnoses of the 10 most prevalent cancer types from Jan. 1, 2018, to Dec. 31, 2020. We followed patients up to Dec. 31, 2021. We used interrupted time series analysis to examine the impact of the first COVID-19-related state of emergency in Alberta on the number of cancer diagnoses. We used multivariable Cox regression to compare 1-year survival of the patients who received a diagnosis during 2020 after the state of emergency with those who received a diagnosis during 2018 and 2019. We also performed stage-specific analyses. RESULTS: We observed significant reductions in diagnoses of breast cancer (incidence rate ratio [IRR] 0.67, 95% confidence interval [CI] 0.59-0.76), prostate cancer (IRR 0.64, 95% CI 0.56-0.73) and colorectal cancer (IRR 0.64, 95% CI 0.56- 0.74) and melanoma (IRR 0.57, 95% CI 0.47-0.69) during the state of emergency period compared with the period before it. These decreases largely occurred among early-stage rather than late-stage diagnoses. Patients who received a diagnosis of colorectal cancer, non-Hodgkin lymphoma and uterine cancer in 2020 had lower 1-year survival than those diagnosed in 2018; no other cancer sites had lower survival. INTERPRETATION: The results from our analyses suggest that health care disruptions during the COVID-19 pandemic in Alberta considerably affected cancer outcomes. Given that the largest impact was observed among early-stage cancers and those with organized screening programs, additional system capacity may be needed to mitigate future impact.

An Algorithmic Approach to the Surgical Management of Sternal Dehiscence: A Single-Center Experience.

BACKGROUND: Deep sternal wound complications following sternotomy represent a complex challenge. Management can involve debridement, flap reconstruction, and rigid sternal fixation (RSF). We present our 11-year experience in the surgical treatment of deep sternal wound dehiscence using a standardized treatment algorithm. METHODS: A retrospective review was conducted of all 134 cardiac patients who required operative debridement after median sternotomy at a single institution between October 2007 and March 2019. Demographics, perioperative covariates, and outcomes were recorded. Univariate and subgroup analyses were performed. RESULTS: One-hundred twelve patients (83.5%) with a deep sternal dehiscence underwent flap closure and 56 (50%) RSF. Of the patients who underwent flap closure, 87.5% received pectoralis advancement flaps. A 30-day mortality following reconstruction was 3.9%. Median length of stay after initial debridement was 8 days (interquartile range: 5-15). Of patients with flaps, 54 (48%) required multiple debridements prior to closure, and 30 (27%) underwent reoperation after flap closure. Patients who needed only a single debridement were significantly less likely to have a complication requiring reoperation (N = 10/58 vs. 20/54, 17 vs. 37%, p = 0.02), undergo a second flap (N = 6/58 vs. 17/54, 10 vs. 32%, p < 0.001), or, if plated, require removal of sternal plates (N = 6/34 vs. 11/22, 18 vs. 50%, p = 0.02). CONCLUSION: Although sternal dehiscence remains a complex challenge, an aggressive treatment algorithm, including debridement, flap closure, and consideration of RSF, can achieve good long-term outcomes. In low-risk patients, RSF does not appear to increase the likelihood of reoperation. We hypothesize that earlier surgical intervention, before the development of systemic symptoms, may be associated with improved outcomes.

Longitudinal variance of Donor-Derived Cell-Free DNA (dd-cfDNA) in Stable Kidney Transplant (KTx) patients are influenced by donor/recipient variables.

BACKGROUND: The longitudinal time-course of dd-cfDNA after kidney transplant (KTx) is not well-described. The cut off values of dd-cfDNA in KTx derive from biopsy-coupled single measurements. Meaningful interpretation necessitates understanding of: (1) time variance of dd-cfDNA levels post-KTx, (2) factors determining biologic variability, and (3) relationship to donor and recipient characteristics. We hypothesized that an understanding of the aforementioned factors would better inform clinical decision-making using dd-cfDNA. METHODS: One hundred and twenty five KTx patients with dd-cfDNA obtained longitudinally were included. Univariate analyses were directed at inter-patient variability and intra-patient inter-occasion variability of dd-cfDNA. Multivariate linear regression was used in analyses accounting for repeat measures. RESULTS: At 1-month post KTx median dd-cfDNA: (1) were higher in repeat KTx (.57%, P < .001), and dual KTx (1.10%, P = ns) versus a first KTx (.31%); (2) showed a significant difference in donor after cardiac death (DCD [.45%]) versus living related (LRD [.27%]) donors (P = .036). Longitudinal (1-3 months) dd-cfDNA measurements showed a significant downtrend for all donor types. Panel-reactive antibodies (PRA) were positively correlated with dd-cfDNA. CONCLUSIONS: Repeat Tx, dual Tx, DCD, and PRA are associated with a higher dd-cfDNA. Incorporation of donor/recipient variables and time down post transplant is material for rational interpretation of dd-cfDNA.

Oncoplastic breast surgery: Achieving oncological and aesthetic outcomes.

BACKGROUND AND OBJECTIVES: Oncoplastic reconstruction allows more patients to become candidates for breast-conserving surgery (BCS). Oncologic resection of a breast lesion is combined with plastic surgical techniques to improve aesthetic results. Choosing the best oncoplastic method is essential to optimize outcomes, improve cosmesis, and minimize postoperative complications. The aim of this study is to present a treatment algorithm incorporating oncoplastic techniques based on diagnosis, tumor size, tumor location, and breast size and shape. METHODS: A retrospective pilot study of a prospectively collected database was conducted in patients undergoing immediate oncoplastic surgery from 2010 to 2015 at our institution. Oncoplastic surgical techniques were defined as complex layered closure, local tissue rearrangement, pedicled flap, mastopexy, bilateral reduction, or implant placement. Clinical, demographic, and histopathologic data were extracted from electronic patient records. Patient satisfaction was measured by the BREAST-Q questionnaire. RESULTS: A total of 42 women and 46 breasts were included. An algorithm was formulated to assist in selecting an optimal oncoplastic reconstruction plan after BCS. Additionally, patient satisfaction with good aesthetic results was reported. CONCLUSION: In this study, the authors present a reconstructive algorithm describing various oncoplastic approaches aimed to provide a guideline in clinical practice when employing oncoplastic surgery.

Novel Stratification of Mortality Risk by Kidney Disease Stage.

BACKGROUND: Chronic kidney disease (CKD) is a common disorder with a variable clinical course and it is associated with increased mortality. The Intermountain Risk Score (IMRS) is an electronic risk calculator that utilizes complete blood count (CBC) and basic metabolic panel (BMP) values to predict mortality in various healthcare populations. We hypothesized that IMRS would predict mortality in patients with CKD even with adjustment for serum phosphate and urinary albumin. METHODS: Three thousand eight hundred seventy-two patients with CKD classes IIIA-V had IMRS calculated retrospectively and survival analysis was performed investigating 1- and 5-year mortality. Kaplan-Meier survival curves were generated for predefined IMRS groups of low, medium and high risk for CKD patients overall and by sex and CKD stage. Serum phosphate and urinary albumin/creatinine ratios were modeled in multivariate Cox-proportional hazard models. Receiver operator characteristic curves were used to determine c-statistics for mortality. RESULTS: For all patients with CKD, mortality was significantly greater for those with medium- or high-risk compared to low-risk IMRS categories, among each CKD stage. Overall, IMRS was predictive of mortality at both 1 and 5 years, even when adjusted for CKD stage and predicted mortality more accurately than CKD stage alone. Albuminuria was not independently associated with mortality and serum phosphate weakly predicted mortality. CONCLUSION: IMRS is a strong predictor of mortality in patients with CKD and is robustly complementary to CKD stage in refining risk prediction. Given the universal availability and low cost of the CBC and BMP, IMRS may be of a substantial value in CKD risk assessment and management.

Delayed hypersensitivity reaction to acellular dermal matrix in breast reconstruction: the red breast syndrome?

BACKGROUND: Acellular dermal matrix (ADM) has become a valuable tool in reconstructive breast surgery, in part because it has been considered to be a non-reactive and non-immunogenic entity. However, some patients who undergo breast reconstruction with ADMs develop postoperative erythema overlying their ADM grafts. The etiology of this phenomenon is poorly understood. METHODS: In this article, we summarize clinical cases in which patients developed localized breast erythema following reconstruction with ADMs. We review what is known about postoperative breast erythema after ADM-based breast reconstructions and the possible antigenicity of biologic mesh implants. RESULTS: We report 4 implant-based breast reconstruction patients who developed erythematous reactions overlying the region where ADM was placed: one demonstrated a delayed-type hypersensitivity reaction on punch biopsy of the affected skin, leading to removal of the biologic product; 2 others had a similar clinical presentation that responded to corticosteroids without removal of the biologic material, with 1 patient experiencing recrudescence of erythema that responded fully to a second course of corticosteroids; and a fourth showed erythema that was only moderately responsive to antibiotic therapy but which improved consistently after the patient initiated chemotherapy. CONCLUSION: We propose that the etiology of erythema overlying ADM grafts, and the so-called red breast syndrome, may in some patients be a delayed-type hypersensitivity reaction to the ADM product. Affected patients may benefit from treatment with corticosteroids or similar medications, and that such treatment may, in some cases, enable patients to retain the ADM grafts and enable salvage of the reconstructed breast.

AeroForm patient controlled tissue expansion and saline tissue expansion for breast reconstruction: a randomized controlled trial.

BACKGROUND: Prosthetic reconstruction of the breast, as a 2-staged procedure using tissue expanders followed by placement of permanent implants, offers favorable aesthetic results with minimal additional surgical intervention. However, the current outpatient process to fill saline expanders can be lengthy and onerous, involving months of office visits and discomfort from the bolus saline expansions. We present a new technology (AeroForm Tissue Expansion System), which has the potential to improve the process of breast tissue expansion by providing a method for low-volume incremental filling, eliminating the need for injections and directly involving the patient by allowing her some control over the expansion process. METHODS: The described study is a 2:1 randomized controlled trial of the investigational CO2 expansion system and saline expanders. Of the 82 women receiving expanders, 58 (39 bilateral and 19 unilateral; bilateral rate, 67%) were implanted with CO2 tissue expanders and 24 subjects (15 bilateral and 9 unilateral; bilateral rate, 63%) were implanted with saline expanders. RESULTS: Preliminary validated expansion results were available for 55 women. Available mean time for active expansion in the CO2 group was 18.2 (9.2) days (median, 14.0; range, 5-39; number of expanders, 53), which was less than the mean time for active expansion in the saline group: 57.4 (33.6) days (median, 55; range, 5-137; number of expanders, 33). Available mean time from implant placement to exchange for a permanent prosthesis in the CO2 group was shorter [106.3 (42.9) days; median, 99; range, 42-237; number of expanders, 53] than for the women in the control group [151.7 (62.6) days; median, 140; range, 69-433; number of expanders, 33]. After 2 events--underexpansion (n=1) and erosion (n=1)--in the CO2 group, the internal membrane was redesigned and the expander bulk was decreased to minimize the risk of underexpansion and erosion in subsequent patients. CONCLUSIONS: Preliminary evidence indicates that the CO2-based tissue expansion system performs the same function as saline expansion devices without significantly altering the risk to the patient and that the device has the potential to make the expansion process faster and more convenient for both the patient and the physician.

The use of abdominal wall tissue expansion prior to herniorrhaphy in massive ventral hernia defects.

BACKGROUND: Massive ventral hernias pose a challenging reconstructive problem. In comparison to bridging mesh repair, the primary fascial repair is associated with significantly reduced rates of hernia recurrence. This study will review our experience with massive ventral hernia repairs using tissue expansion and anterior component separation as well as present the largest case series to date. METHODS: A retrospective review was conducted of 61 patients who underwent abdominal wall tissue expansion prior to herniorrhaphy at a single institution between 2011 and 2017. Demographics, perioperative co-variates, and outcomes were recorded. Univariate and subgroup analysis was performed. Kaplan-Meier survival analysis was used to assess the time to recurrence. RESULTS: Sixty-one patients underwent abdominal wall expansion via tissue expanders (TE). Of these, 56 subsequently underwent staged anterior component separation for attempted closure of large ventral hernia. Major complications of TE placement included TE replacement (4,6.6%), TE leak (2,3.3%), and unplanned readmission (3,4.9%). Higher BMI groups were significantly associated with comorbid hypertension (BMI<30 kg/m2, 22.7%; BMI 30-35 kg/m2, 68.7%; BMI>35 kg/m2, 64.7%; P = 0.004). 15 patients (32.6%) had hernia recurrence and 21 patients (34.4%) still required bridging mesh during herniorrhaphy after tissue expansion. CONCLUSION: The use of tissue expansion prior to herniorrhaphy can be effective in achieving durable closure for most massive abdominal wall defects - especially those associated with musculofascial, soft tissue, or skin deficiencies. In this proof-of-concept analysis, we found that the efficacy and safety profile of this technique compares favorably to other methods for massive hernia repair in the literature.

Outpatient Prosthetic-Based Reconstruction during COVID-19 Pandemic Possible in Selected Patients without Increased Complications.

BACKGROUND: Following the reopening of elective surgery, the authors' division transitioned from inpatient admission to same-day discharge for immediate prosthetic breast reconstruction in an effort to decrease the hospital's clinical burden and minimize potential coronavirus disease of 2019 exposure. This study aims to compare complication rates following this acute transition for patients who had inpatient and outpatient mastectomy with immediate alloplastic reconstruction. METHODS: A retrospective chart review was performed on patients who underwent mastectomy with immediate prosthetic reconstruction. The outcome of interest was 30-day morbidity. Descriptive statistics were compared for patients with outpatient and inpatient operations. Odds ratios were calculated to determine whether any preoperative factors increased odds of 30-day complications. RESULTS: A total of 115 patients were included in this study. Twenty-six patients had outpatient surgery and 89 stayed inpatient postoperatively. Same-day discharge did not significantly impact the odds of having one or more 30-day complications (OR, 0.275; 95% CI, 0.047 to 1.618; P = 0.153). Patients with complications had significantly longer median operating times [5.0 hours (interquartile range, 4.0 to 6.0 hours) versus 4.0 hours (interquartile range, 3.0 to 5.0 hours; P = 0.05), and there was a statistically significant association between length of surgery and odds of complication (OR, 1.596; 95% CI, 1.039 to 2.451; P = 0.033). Age was independently associated with increased risk of 30-day complication (OR, 1.062; 95% CI, 1.010 to 1.117; P = 0.020). CONCLUSION: The authors' findings support a continuation of same-day discharge strategy, which could decrease costs for patients and hospitals without increasing complications. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III.

The impact of population-based EGFR testing in non-squamous metastatic non-small cell lung cancer in Alberta, Canada.

OBJECTIVES: While Epidermal Growth Factor Receptor (EGFR) Tyrosine Kinase Inhibitors have been shown to be effective in phase III randomized trials, the value of targeted therapies has been challenging to evaluate at the population-level. We examined the impact of population-level EGFR testing and treatment on survival outcomes among non-squamous metastatic Non-Small Cell Lung Cancer (NSCLC) patients. MATERIALS AND METHODS: Real-world, population-level data were collected from all de novo non-squamous metastatic NSCLC patients in Alberta, Canada from 2004 to 2020. EGFR testing data were collected through Alberta Precision Laboratories. Differences in survival rates and overall survival (OS) pre (2004-2012) and post initiation (post) (2013-2019) testing periods were evaluated using interrupted time series analyses. The impact of testing and subsequent treatment was evaluated using multivariable Cox Proportional Hazards models. RESULTS: In total, 4,578 non-squamous metastatic NSCLC patients were diagnosed pre-EGFR testing and 4,457 patients were diagnosed post-EGFR testing (2013-2019). Among patients diagnosed in the pre-EGFR testing period, the 6-month, 1-year, and 2-year survival probabilities were 0.39 (95 % CI: 0.38-0.41), 0.22 (95 % CI: 0.21-0.23), and 0.09 (95 % CI: 0.08-0.10), while the survival probabilities for patients diagnosed in the post-EGFR testing period were 0.45 (95 % CI: 0.43-0.46), 0.29 (95 % CI: 0.27-0.30), and 0.16 (95 % CI: 0.15-0.17), respectively. After adjusting for baseline patient and clinical characteristics, OS in the post-EGFR period was significantly improved compared to the pre-EGFR period (HR: 0.81; 95 % CI: 0.78-0.85). Among patients who were treated with systemic therapy, those tested for an EGFR mutation had significantly greater survival than patients who were not tested HR of 0.81 (95 % CI: 0.70-0.95). CONCLUSION: These results show the considerable impact of population-based molecular testing and subsequent targeted therapies on survival among metastatic NSCLC patients. The estimates here can be used in future studies to evaluate the population-level cost-effectiveness of testing and treatment.

Development of a risk score to predict occurrence of deep sternal dehiscence requiring operative debridement.

OBJECTIVE: Severe deep sternal wound (DSW) complications after cardiac surgery are a source of cost, morbidity, and mortality. Our objective was to develop and validate a clinical risk score for predicting risk of DSW requiring operative bone debridement, the most severe form of sternal dehiscence. METHODS: A retrospective review was conducted of patients who underwent open cardiac surgery at a single institution between October 2007 and March 2019. Primary outcome was DSW requiring sternal bone debridement. Potential risk factors were screened using Least Absolute Shrinkage and Selection Operator (LASSO) and significant covariates were included in a logistic regression prediction model. Interval validation was performed using 10-fold cross-validation. A novel sternal wound dehiscence risk score was derived from the relative parameterization estimates. RESULTS: One hundred thirty-four of 8403 patients (1.6%) were identified as having a DSW. Female sex (odds ratio [OR], 2.75; 95% CI, 2.58-2.93), body mass index (OR, 1.0946; 95% CI, 1.09-1.09), percent glycated hemoglobin (OR, 1.31; 95% CI, 1.28-1.33), peripheral vascular disease (OR, 2.38; 95% CI, 2.2005-2.5752), smoking (OR, 1.66; 95% CI, 1.53-1.79) and elevated creatinine level (OR, 1.20; 95% CI, 1.18-1.22) were independent predictors of DSW. Patients were categorized as minimal risk (0%-1%), low risk (2%-3%), intermediate risk (4%-7%), and high risk (9%-64.0%) on the basis of risk score. CONCLUSIONS: This risk stratification model for DSW requiring operative debridement might provide individualized estimates of risk, and guide counseling and potential risk mitigation strategies.

Technique of Abdominal Wall Tissue Expansion for the Treatment of Massive Complicated Ventral Hernias.

Abdominal wall tissue expansion is a unique technique that seeks to augment and expand both the fascial and subcutaneous tissues/skin layers to achieve durable closure of otherwise challenging ventral hernias. In addition to allowing primary fascial closure in a majority of cases, this technique enables reduced tension on the closure, potentially decreasing the recurrence rate. This article describes the senior author's surgical technique for abdominal wall tissue expansion in massive complicated ventral hernias. The plastic surgeon is at a unique advantage to assist with the repair of massive complicated ventral hernias given their comfort with complex tissue handling and expandable devices. This specialized technique thus provides an opportunity for plastic surgeons to serve as expert co-surgeons with general surgery colleagues to help achieve superior outcomes in patients with these challenging hernias.

Neurotensin is an anti-thermogenic peptide produced by lymphatic endothelial cells.

The lymphatic vasculature plays important roles in the physiology of the organs in which it resides, though a clear mechanistic understanding of how this crosstalk is mediated is lacking. Here, we performed single-cell transcriptional profiling of human and mouse adipose tissue and found that lymphatic endothelial cells highly express neurotensin (NTS/Nts). Nts expression is reduced by cold and norepinephrine in an α-adrenergic-dependent manner, suggesting a role in adipose thermogenesis. Indeed, NTS treatment of brown adipose tissue explants reduced expression of thermogenic genes. Furthermore, adenoviral-mediated overexpression and knockdown or knockout of NTS in vivo reduced and enhanced cold tolerance, respectively, an effect that is mediated by NTSR2 and ERK signaling. Inhibition of NTSR2 promoted energy expenditure and improved metabolic function in obese mice. These data establish a link between adipose tissue lymphatics and adipocytes with potential therapeutic implications.

Breast reduction in the irradiated breast: evidence for the role of breast reduction at the time of lumpectomy.

Given the high incidence of breast cancer in our society, it is common to encounter patients with macromastia who desire breast reduction after breast-conserving therapy by lumpectomy and radiation. We hypothesize that radiation leads to a significant increase in postoperative complications after breast reduction. All patients with a history of unilateral breast lumpectomy and radiation who subsequently underwent bilateral breast reduction by a single surgeon from 2004 to 2008 were retrospectively reviewed. Outcomes including cellulitis, wound breakdown, seroma, and need for repeat operations were compared between the radiated and nonradiated breast. The Fisher's exact test was used for statistical analysis. Twelve patients (mean age, 57 years) underwent bilateral breast reduction a mean of 86 months after unilateral lumpectomy and radiation. The nonradiated breasts had no complications postoperatively. The radiated breasts had a significant increase in complications with a total of five breasts (42%, p<0.04) having postoperative complications including cellulitis in two breasts, seroma requiring drainage in five breasts, two cases of fat necrosis, and one case of wound dehiscence. This resulted in two admissions for intravenous antibiotics and two repeat operative procedures. Additionally, three patients had significant breast asymmetry or contour deformities after reduction requiring operative revisions. Breast reduction after radiation leads to a significant increase in complications. Given this data, patients with macromastia undergoing breast conservation therapy for cancer should be considered for reduction at the time of lumpectomy and prior to radiation.

Combined CCNE1 high-level amplification and overexpression is associated with unfavourable outcome in tubo-ovarian high-grade serous carcinoma.

CCNE1 amplification is a recurrent alteration associated with unfavourable outcome in tubo-ovarian high-grade serous carcinoma (HGSC). We aimed to investigate whether immunohistochemistry (IHC) can be used to identify CCNE1 amplification status and to validate whether CCNE1 high-level amplification and overexpression are prognostic in HGSC. A testing set of 528 HGSC samples stained with two optimised IHC assays (clones EP126 and HE12) was subjected to digital image analysis and visual scoring. DNA and RNA chromogenic in situ hybridisation for CCNE1 were performed. IHC cut-off was determined by receiver operating characteristics (ROC). Survival analyses (endpoint ovarian cancer specific survival) were performed and validated in an independent validation set of 764 HGSC. Finally, combined amplification/expression status was evaluated in cases with complete data (n = 1114). CCNE1 high-level amplification was present in 11.2% of patients in the testing set and 10.2% in the combined cohort. The optimal cut-off for IHC to predict CCNE1 high-level amplification was 60% positive tumour cells with at least 5% strong staining cells (sensitivity 81.6%, specificity 77.4%). CCNE1 high-level amplification and overexpression were associated with survival in the testing and validation set. Combined CCNE1 high-level amplification and overexpression was present in 8.3% of patients, mutually exclusive to germline BRCA1/2 mutation and significantly associated with a higher risk of death in multivariate analysis adjusted for age, stage and cohort (hazard ratio = 1.78, 95 CI% 1.38-2.26, p < 0.0001). CCNE1 high-level amplification combined with overexpression identifies patients with a sufficiently poor prognosis that treatment alternatives are urgently needed. Given that this combination is mutually exclusive to BRCA1/2 germline mutations, a predictive marker for PARP inhibition, CCNE1 high-level amplification combined with overexpression may serve as a negative predictive test for sensitivity to PARP inhibitors.

Nipple-sparing mastectomy: evaluation of patient satisfaction, aesthetic results, and sensation.

The purpose of this study is to describe our experience with nipple-sparing mastectomy and immediate reconstruction, with particular attention to patient satisfaction, aesthetic results, and nipple sensation. Immediate reconstruction was performed on 17 breasts in 10 patients, using either implants or autologous tissue flaps. Assessment of outcomes was performed through patient interviews, a self-reported patient satisfaction survey and review of postoperative photographs. Short-term complications included partial loss of the nipple-areolar complex requiring debridement (n = 3) and removal of the nipple-areolar complex (n = 2) for occult ductal carcinoma in situ. While all patients with completed breast reconstructions were satisfied with their general reconstructive experience, 6 of 9 patients were aesthetically satisfied with their breast reconstruction. Postoperative nipple sensation was reported in 75% of patients, although sensation was low (mean of 2.8 of 10). As nipple-sparing mastectomy is becoming an increasing patient preference, preoperative discussion needs to address expectations, aesthetic satisfaction, and long-term cancer control.

Canadian Cancer Trials Group (CCTG) IND211: A randomized trial of pelareorep (Reolysin) in patients with previously treated advanced or metastatic non-small cell lung cancer receiving standard salvage therapy.

OBJECTIVES: Pelareorep (reolysin), a Dearing strain of reovirus serotype 3, has demonstrated oncolytic activity as single agent and synergy with chemotherapy. We evaluated pelareorep, combined with standard second-line chemotherapy in patients with non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: This randomized phase II trial enrolled patients with advanced or metastatic NSCLC after first line chemotherapy. After a safety run-in, patients were randomized 1:1 to chemotherapy (pemetrexed [500 mg/m2, non-squamous], or docetaxel [75 mg/m2], day 1 every 21 days]) +/- pelareorep (4.5 × 1010 TCID50, days 1-3 every 21 days), stratified by EGFR mutation status. The primary outcome was progression free survival (PFS) of patients randomized to chemotherapy + pelareorep vs. chemotherapy alone. Secondary outcomes included overall survival, objective response rate and exploratory translational analyses. RESULTS: Between October 2012 and August 2015, 166 patients were enrolled (14 to the safety run in). Pelareorep did not improve the PFS vs. single agent chemotherapy (median PFS 3.0 months, 95% confidence interval [CI] 2.6-4.1) vs. 2.8 months (95% CI 2.5-4.0), hazard ratio (HR) 0.90 (95% CI 0.65-1.25), P = 0.53). Neither KRAS or EGFR mutation was associated with improved PFS, but STK11 mutations did appear to have an association with improved PFS (HR 0.29 [0.12-0.67); as did PIK3CA mutation (HR 0.45 [0.22-0.93]). The combination was tolerable, although associated with increased rates of neutropenic fever. CONCLUSION: The addition of pelareorep to second-line chemotherapy did not improve the PFS of patients with NSCLC. The three-day pelareorep schedule was tolerable. Further research is needed to evaluate the potential benefit in molecular subtypes of NSCLC.