Positive Nipple Margins in Nipple-Sparing Mastectomy: Management of Nipples Containing Cancer or Atypia.

BACKGROUND: Nipple-sparing mastectomy (NSM) is an oncologically safe approach for breast cancer treatment and prevention; however, there are little long-term data to guide management for patients whose nipple margins contain tumor or atypia. METHODS: NSM patients with tumor or atypia in their nipple margin were identified from a prospectively maintained, single-institution database of consecutive NSMs. Patient and tumor characteristics, treatment, recurrence, and survival data were assessed. RESULTS: A total of 3158 NSMs were performed from June 2007 to August 2019. Nipple margins contained tumor in 117 (3.7%) NSMs and atypia only in 164 (5.2%) NSMs. Among 117 nipple margins that contained tumor, 34 (29%) margins contained invasive cancer, 80 (68%) contained ductal carcinoma in situ only, and 3 (3%) contained lymphatic vessel invasion only. Management included nipple-only excision in 67 (57%) breasts, nipple-areola complex excision in 35 (30%) breasts, and no excision in 15 (13%) breasts. Only 23 (24%) excised nipples contained residual tumor. At 67 months median follow-up, there were 2 (1.8%) recurrences in areolar or peri-areolar skin, both in patients with nipple-only excision. Among 164 nipple margins containing only atypia, 154 (94%) nipples were retained. At 60 months median follow-up, no patient with atypia alone had a nipple or areola recurrence. CONCLUSIONS: Nipple excision is effective management for nipple margins containing tumor. No intervention is required for nipple margins containing only atypia. Our results support broad eligibility for NSM with careful nipple margin assessment.

Long-Term Patient-Reported Outcomes Comparing Oncoplastic Breast Surgery and Conventional Breast-Conserving Surgery: A Propensity Score-Matched Analysis.

INTRODUCTION: Oncoplastic breast surgery (OBS) combines plastic surgery techniques with conventional breast-conserving surgery (BCS) and expands BCS eligibility. Limited data are available on patient-reported outcomes (PROs) after OBS. Here we compare long-term PROs after OBS and BCS utilizing the BREAST-Q. PATIENTS AND METHODS: Women undergoing OBS or BCS between 2006 and 2019 who completed ≥ 1 long-term BREAST-Q survey 3-5 years postoperatively were identified. Baseline characteristics were compared between women who underwent OBS/BCS. Women who underwent OBS were paired with those who underwent BCS using 1:2 propensity matching [by age, body mass index (BMI), race, T stage, and multifocality]. BREAST-Q scores were compared preoperatively and 3-5 years postoperatively. RESULTS: A total of 297 patients were included for analysis (99 OBS/198 BCS). Women who underwent OBS were younger (p < 0.001) and had higher BMI (p = 0.005) and multifocal disease incidence (p = 0.004). There was no difference between groups in nodal stage, re-excision rates, axillary surgery, chemotherapy, endocrine therapy, or radiotherapy. After propensity matching preoperatively, women who underwent OBS reported lower psychosocial well-being (63 versus 100, p = 0.039) but similar breast satisfaction and sexual well-being compared with women who underwent BCS; however, only three patients who underwent BCS had preoperative BREAST-Q scores available for review. In long-term follow-up, women who underwent OBS reported lower psychosocial scores (74 versus 93, p = 0.011) 4 years postoperatively, but not at 5 years (76 versus 77, p = 0.83). There was no difference in long-term breast satisfaction or sexual well-being. CONCLUSIONS: Women who undergo OBS present with a larger disease burden and may represent a group of non-traditional BCS candidates; they reported similar long-term breast satisfaction and sexual well-being compared with women who undergo BCS. While women who underwent OBS reported lower psychosocial well-being scores preoperatively and during a portion of the follow-up period, this difference was no longer seen at 5 years postoperatively.

Oncologic Safety of Nipple-Sparing Mastectomy for Breast Cancer in BRCA Gene Mutation Carriers: Outcomes at 70 Months Median Follow-Up.

BACKGROUND: Retention of the nipple-areola complex with nipple-sparing mastectomy (NSM) techniques provides a more natural cosmetic result than procedures that sacrifice the nipple. While the oncologic safety of NSM is established by several studies, there is little long-term data on outcomes in BRCA mutation carriers with breast cancer. PATIENTS AND METHODS: BRCA1/2 mutation carriers who underwent NSM and immediate reconstruction from 2008 to 2019 were reviewed and patients with breast cancer on biopsy or final pathology were included. Patient demographics and tumor characteristics, as well as treatment, recurrence, and survival data were collected. RESULTS: A total of 114 therapeutic NSM were performed in 105 BRCA mutation carriers (56 BRCA1, 47 BRCA2, and two women with both mutations). Median age was 45 years. Cancers were 18% stage 0, 52% stage I, 27% stage II, and 3% stage III. Mean invasive tumor size was 1.6 cm and 33 (35%) invasive tumors were triple negative. There were five (4.4%) positive nipple margins on final pathology; all underwent nipple excision. Most patients (80, 76%) received systemic therapy: 65 (62%) received chemotherapy and 48 (46%) received endocrine therapy. At 70 months median follow-up (range 15-150 months), no patient had developed a recurrence in the retained nipple-areola complex or at the site of a nipple excised for a positive margin. The rate of locoregional recurrence outside the nipple was 2.6%, and the rate of distant recurrence was 3.8%. Overall survival was 96%. CONCLUSIONS: NSM is a safe option for BRCA1 and BRCA2 mutation carriers who undergo mastectomy for breast cancer.

Targeted Nipple Areola Complex Reinnervation: Technical Considerations and Surgical Efficiency in Implant-based Breast Reconstruction.

Background: Despite promising pilot study results, adoption of neurotization of immediate implant-based reconstructions has not occurred. Methods: For surgeons interested in adopting breast reinnervation techniques, we present ways to overcome initial barriers by decreasing operative time and maximizing chances of sensory recovery. Results: We discuss the combined experience at two academic teaching hospitals, where neurotization of both immediate tissue expander cases and direct-to-implant reconstructions are performed through varying mastectomy incisions. Conclusion: Initial barriers can be overcome by shortening operative time and providing an individualized reinnervation approach that aims to increase the chance of meaningful sensation.

The Effect of Age on Outcomes After Neoadjuvant Chemotherapy for Breast Cancer.

BACKGROUND: Younger women (age ≤ 40 years) with breast cancer undergoing neoadjuvant chemotherapy (NAC) have higher rates of pathologic complete response (pCR); however, it is unknown whether axillary or breast downstaging rates differ by age. In this study, we compared pCR incidence and surgical downstaging rates of the breast and axilla post NAC, between patients aged ≤ 40, 41-60, and ≥ 61 years. METHODS: We identified 1383 women with stage I-III breast cancer treated with NAC and subsequent surgery from November 2013 to December 2018. pCR and breast/axillary downstaging rates were assessed and compared across age groups. RESULTS: Younger women were significantly more likely to have ductal histology, poorly differentiated tumors, and BRCA mutations; 35% of tumors were hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-), 36% were HER2-positive (HER2+), and 29% were triple negative (TN), with similar subtype distribution across age groups (p = 0.6). Overall, pCR rates did not differ by age, however among patients with TN tumors (n = 394), younger women had higher pCR rates (52% vs. 35% among those aged 41-60 years and 29% among those aged ≥61 years; p = 0.007) and were more likely to have tumors with high tumor-infiltrating lymphocyte (TIL) concentrations (p < 0.001). Downstaging to breast-conserving surgery (BCS) eligibility post NAC among initially BCS-ineligible patients was similar across age groups; younger women chose BCS less often (p < 0.001). Among cN1 patients (n = 813), 52% of women ≤40 years of age avoided axillary lymph node dissection (ALND) with NAC, versus 39% and 37% in the older groups (p < 0.001). CONCLUSIONS: Younger women undergoing NAC for axillary downstaging were more likely to avoid ALND across all subtypes; however, overall pCR rates did not differ by age. Despite equivalent breast downstaging and BCS eligibility rates across age groups, younger women were less likely to undergo BCS.

Genetic testing and surgical treatment after breast cancer diagnosis: Results from a national online cohort.

BACKGROUND: Genetic testing for hereditary breast cancer has implications for breast cancer decision-making. We examined genetic testing rates, factors associated with testing, and the relationship between genetic testing and contralateral prophylactic mastectomy (CPM). METHODS: Patients with breast cancer (2000-2015) from The Health of Women Study were identified and categorized as low, moderate, or high-likelihood of the genetic mutation using a previously published scale based on period-relevant national guidelines incorporating age and family history. Genetic testing and CPM rates were compared using univariate and multivariate logistic regression. RESULTS: Among 4170 patients (median age 56-years), 38% were categorized as high-likelihood of having a genetic mutation. Among high-likelihood women, 67% underwent genetic testing, the odds of which were increased among women of higher-education and White-race (p < .001). Among 2028 patients reporting surgical treatment, 385 (19%) chose CPM. CPM rate was highest among mutation-positive women (41%), but 26% of women with negative tests still underwent CPM. Independent of test result, genetic testing increased the odds of CPM on multivariate analysis (adjusted-OR: 1.69; 95% CI: 1.29-2.22). CONCLUSIONS: Genetic testing rates were higher among women at high-likelihood of mutation carriage, but one-third of these women were not tested. Racial disparities persisted, highlighting the need to improve testing in non-White populations. CPM rates were associated with mutation-carriage and genetic testing, but many women chose CPM despite negative testing, suggesting that well-educated women consider factors other than cancer mortality in selecting CPM.

Use of post-discharge heparin prophylaxis and the risk of venous thromboembolism and bleeding following bariatric surgery.

INTRODUCTION: Venous thromboembolism (VTE) is a significant cause of morbidity and mortality after bariatric surgery. Roughly 80% of VTEs occur post-discharge. The frequency of post-discharge heparin (PDH) prophylaxis use is unknown, and evidence about benefits and risks is limited. We aimed to determine the rate of use of PDH prophylaxis and evaluate its relationship with VTE and bleeding events. METHODS: Using the Truven Health MarketScan® database, we performed a retrospective cohort study (2007-2015) of adult patients who underwent sleeve gastrectomy or gastric bypass. We determined PDH prophylaxis from outpatient pharmacy claims, and post-discharge 90-day VTE and bleeding events from outpatient and inpatient claims. We used propensity score-adjusted regression models to mitigate confounding bias. RESULTS: Among 43,493 patients (median age 45 years; 78% women; 77% laparoscopic gastric bypass, 17% laparoscopic sleeve gastrectomy, 6% open gastric bypass), 6% received PDH prophylaxis. Overall, 224 patients (0.52%) experienced VTEs, and 806 patients (1.85%) experienced bleeding. The unadjusted VTE rate did not differ between patients who did and did not receive PDH prophylaxis (0.39% vs. 0.52%, respectively; p = 0.347). The unadjusted bleeding rate was higher for the PDH prophylaxis group (2.74% vs. 1.80%, p < 0.001). In our adjusted analysis, a 23% lower risk of VTE in the PDH prophylaxis group was not statistically significant (odds ratio [OR] 0.77, 95% confidence interval [CI] 0.41 to 1.46), whereas the 47% higher risk of bleeding was statistically significant (OR 1.47, 95% CI 1.14 to 1.88). CONCLUSIONS: PDH prophylaxis after bariatric surgery is uncommon. In our analysis, use was not associated with a lower VTE risk but was associated with a higher bleeding risk.

Multidisciplinary Team-Based Management of Incidentally Detected Lung Nodules.

BACKGROUND: Each year, > 1.5 million Americans are diagnosed with an incidentally detected lung nodule. Practice guidelines attempt to balance the benefit of early detection of lung cancer with the risks of diagnostic testing, but adherence to guidelines is low. The goal of this study was to determine guideline adherence rates in the setting of a multidisciplinary nodule clinic and describe reasons for nonadherence as well as associated outcomes. METHODS: This cohort study included 3 years of follow-up of patients aged ≥ 35 years with an incidentally detected lung nodule evaluated in a multidisciplinary clinic that used the 2005 Fleischner Society Guidelines. RESULTS: Among 113 patients, 67% (95% CI, 58-76) were recommended a guideline-concordant nodule evaluation; 7.1% (95% CI, 3.1-13) and 26% (95% CI, 18-25) were recommended less or more intense evaluation, respectively. In contrast, 58% (95% CI, 48-67), 22% (95% CI, 18-25), and 23% (95% CI, 16-32) received a guideline-concordant, less intense, or more intense evaluation. The most common reason for recommending guideline-discordant care was concern for two different diagnoses that would each benefit from early detection and treatment. A majority of lung cancer diagnoses (88%) occurred in patients who received guideline-concordant care. There were no lung cancer cases in those who received less intense nodule care. CONCLUSIONS: A multidisciplinary nodule clinic may serve as a system-level intervention to promote guideline-concordant care, while also providing a multidisciplinary basis by which to deviate from guidelines to address the needs of a heterogeneous patient population.

Safety and Costs of Endobronchial Ultrasound-Guided Nodal Aspiration and Mediastinoscopy.

BACKGROUND: There remains debate over the best invasive diagnostic modality for mediastinal nodal evaluation. Prior studies have limited generalizability and insufficient power to detect differences in rare adverse events. We compared the risks and costs of endobronchial ultrasound (EBUS)-guided nodal aspiration and mediastinoscopy performed for any indication in a large national cohort. METHODS: We conducted a retrospective study (2007-2015) with MarketScan, a claims database of individuals with employer-provided insurance in the United States. Patients who underwent multimodality mediastinal evaluation (n = 1,396) or same-day pulmonary resection (n = 2,130) were excluded. Regression models were used to evaluate associations between diagnostic modalities and risks and costs while adjusting for patient characteristics, year, concomitant bronchoscopic procedures, and lung cancer diagnosis. RESULTS: Among 30,570 patients, 49% underwent EBUS. Severe adverse events-pneumothorax, hemothorax, airway/vascular injuries, or death-were rare and invariant between EBUS and mediastinoscopy (0.3% vs 0.4%; P = .189). The rate of vocal cord paralysis was lower for EBUS (1.4% vs 2.2%; P < .001). EBUS was associated with a lower adjusted risk of severe adverse events (OR, 0.42; 95% CI, 0.32-0.55) and vocal cord paralysis (OR, 0.57; 95% CI, 0.54-0.60). The mean cost of EBUS was $2,211 less than mediastinoscopy ($6,816 vs $9,023; P < .001). After adjustment this difference decreased to $1,650 (95% CI, $1,525-$1,776). CONCLUSIONS: When performed as isolated procedures, EBUS is associated with lower risks and costs compared with mediastinoscopy. Future studies comparing the effectiveness of EBUS vs mediastinoscopy in the community at large will help determine which procedure is superior or if trade-offs exist.

Prediction Model for Nodal Disease Among Patients With Non-Small Cell Lung Cancer.

BACKGROUND: We characterized the performance characteristics of guideline-recommended invasive mediastinal staging (IMS) for lung cancer and developed a prediction model for nodal disease as a potential alternative approach to staging. METHODS: We conducted a prospective cohort study of adults with suspected/confirmed non-small cell lung cancer without evidence of distant metastatic disease (by computed tomography/positron emission tomography) who underwent nodal evaluation by IMS and/or at the time of resection. The true-positive rate was the proportion of patients with true nodal disease selected to undergo IMS based on guideline recommendations, and the false-positive rate was the proportion of patients without true nodal disease selected to undergo IMS. Logistic regression was used to predict nodal disease using radiographic predictors. RESULTS: Among 123 eligible subjects, 31 (25%) had pathologically confirmed nodal disease. A guideline-recommended invasive staging strategy had a true-positive rate and false-positive rate of 100% and 65%, respectively. The prediction model fit the data well (goodness-of-fit test, p = 0.55) and had excellent discrimination (optimism corrected c-statistic, 0.78; 95% confidence interval, 0.72 to 0.89). Exploratory analysis revealed that use of the prediction model could achieve a false-positive rate of 44% and a true-positive rate of 97%. CONCLUSIONS: A guideline-recommended strategy for IMS selects all patients with true nodal disease and most patients without nodal disease for IMS. Our prediction model appears to maintain (within a margin of error) the sensitivity of a guideline-recommended invasive staging strategy and has the potential to reduce the use of invasive procedures.

The Safety of Expectant Management for Adhesive Small Bowel Obstruction: A Systematic Review.

BACKGROUND: Surgical training has long been to "never let the sun set on a bowel obstruction" without an operation to rule out and/or treat compromised bowel. However, advances in diagnostics have called into question the appropriate timing of non-emergent operations and expectant management is increasingly used. We performed a systematic review to evaluate the safety and effectiveness of expectant management for adhesive small bowel obstruction (aSBO) compared to early, non-emergent operation. MATERIALS & METHODS: We queried PubMed, EMBASE, and Cochrane databases for studies (1990-present) comparing early, non-emergent operations and expectant management for aSBO (PROSPERO #CRD42017057676). RESULTS: Of 4873 studies, 29 cohort studies were included for full-text review. Four studies directly compared early surgery with expectant management, but none excluded patients who underwent emergent operations from those having early non-emergent surgery, precluding a direct comparison of the two treatment types of interest. When aggregated, the rate of bowel resection was 29% in patients undergoing early operation vs. 10% in those undergoing expectant management. The rate of successful, non-operative management in the expectant group was 58%. There was a 1.3-day difference in LOS favoring expectant management (LOS 9.7 vs. 8.4 days), and the rate of death was 2% in both groups. CONCLUSION: Despite the shift towards expectant management of aSBO, no published studies have yet compared early, non-emergent operation and expectant management. A major limitation in evaluating the outcomes of these approaches using existing studies is confounding by indication related to including patients with emergent indications for surgery on admission in the early operative group. A future study, randomizing patients to early non-emergent surgery or expectant management, should inform the comparative safety and value of these approaches.

Demographic changes in breast cancer incidence, stage at diagnosis and age associated with population-based mammographic screening.

BACKGROUND: Breast cancer incidence and mortality are influenced by early-detection methods, including mammographic screening. Demographic changes in US statistics serve as a model for changes that can be anticipated in countries where mammographic screening has not been implemented. METHODS: SEER statistics (1973-2013) for breast cancer mortality, incidence, stage at diagnosis, and age at diagnosis were examined. Temporal associations between screening changes and breast cancer demographics in the US were documented. FINDINGS: Before 1982 (pre-screening), breast cancer incidence in the US remained stable, with similar incidence of localized and regional cancers, and with in-situ disease comprising <2% of diagnosed disease.1 During the transitional phase of mammographic screening, breast cancer incidence increased. In 1991, breast cancer age-adjusted mortality rates began decreasing and have continued to decrease. In the post-screening phase, stage distribution stabilized, but now with localized and in-situ disease representing the majority of diagnosed cases. The median age at diagnosis has increased to 61 years. DISCUSSION: Mammographic screening increases breast cancer incidence, shifts the stage distribution toward earlier stage disease, and in high-income countries, is associated with improved survival. Whether similar improvement in breast cancer survival can be achieved in the absence of mammographic screening has yet to be conclusively demonstrated.

Accuracy of fluorodeoxyglucose-positron emission tomography within the clinical practice of the American College of Surgeons Oncology Group Z4031 trial to diagnose clinical stage I non-small cell lung cancer.

BACKGROUND: Fluorodeoxyglucose-positron emission tomography (FDG-PET) is recommended for diagnosis and staging of non-small cell lung cancer (NSCLC). Meta-analyses of FDG-PET diagnostic accuracy demonstrated sensitivity of 96% and specificity of 78% but were performed in select centers, introducing potential bias. This study evaluates the accuracy of FDG-PET to diagnose NSCLC and examines differences across enrolling sites in the national American College of Surgeons Oncology Group (ACOSOG) Z4031 trial. METHODS: Between 2004 and 2006, 959 eligible patients with clinical stage I (cT1-2 N0 M0) known or suspected NSCLC were enrolled in the Z4031 trial, and with a baseline FDG-PET available for 682. Final diagnosis was determined by pathologic examination. FDG-PET avidity was categorized into avid or not avid by radiologist description or reported maximum standard uptake value. FDG-PET diagnostic accuracy was calculated for the entire cohort. Accuracy differences based on preoperative size and by enrolling site were examined. RESULTS: Preoperative FDG-PET results were available for 682 participants enrolled at 51 sites in 39 cities. Lung cancer prevalence was 83%. FDG-PET sensitivity was 82% (95% confidence interval, 79 to 85) and specificity was 31% (95% confidence interval, 23% to 40%). Positive and negative predictive values were 85% and 26%, respectively. Accuracy improved with lesion size. Of 80 false-positive scans, 69% were granulomas. False-negative scans occurred in 101 patients, with adenocarcinoma being the most frequent (64%), and 11 were 10 mm or less. The sensitivity varied from 68% to 91% (p=0.03), and the specificity ranged from 15% to 44% (p=0.72) across cities with more than 25 participants. CONCLUSIONS: In a national surgical population with clinical stage I NSCLC, FDG-PET to diagnose lung cancer performed poorly compared with published studies.

Reappraisal of H2S/sulfide concentration in vertebrate blood and its potential significance in ischemic preconditioning and vascular signaling.

Hydrogen sulfide (H(2)S) is rapidly emerging as a biologically significant signaling molecule. Studies published before 2000 report low or undetectable H(2)S (usually as total sulfide) levels in blood or plasma, whereas recent work has reported sulfide concentrations between 10 and 300 microM, suggesting it acts as a circulating signal. In the first series of experiments, we used a recently developed polarographic sensor to measure the baseline level of endogenous H(2)S gas and turnover of exogenous H(2)S gas in real time in blood from numerous animals, including lamprey, trout, mouse, rat, pig, and cow. We found that, contrary to recent reports, H(2)S gas was essentially undetectable (<100 nM total sulfide) in all animals. Furthermore, exogenous sulfide was rapidly removed from blood, plasma, or 5% bovine serum albumin in vitro and from intact trout in vivo. To determine if blood H(2)S could transiently increase, we measured oxygen-dependent H(2)S production by trout hearts in vitro and in vivo. H(2)S has been shown to mediate ischemic preconditioning (IPC) in mammals. IPC is present in trout and, unlike mammals, the trout myocardium obtains its oxygen from relatively hypoxic systemic venous blood. In vitro, myocardial H(2)S production was inversely related to Po(2), whereas we failed to detect H(2)S in ventral aortic blood from either normoxic or hypoxic fish in vivo. These results provide an autocrine or paracrine mechanism for myocardial coupling of hypoxia to H(2)S in IPC, i.e., oxygen sensing, but they fail to provide any evidence that H(2)S signaling is mediated by the circulation.