Rachel A. Greenup

Incidence and risk factors for venous thromboembolism in critically ill children after trauma.

BACKGROUND Venous thromboembolism (VTE) causes major morbidity in adults after trauma, occurring in up to 50% of patients without prophylaxis. The incidence of VTE after trauma is lower in children. No study has measured the incidence of and risk factors for VTE in critically ill children after trauma. METHODS Nested case-control study of children, younger than 18 years, admitted to the pediatric intensive care unit at a level I trauma center. Three controls were selected for each identified VTE case. RESULTS Nine of 144 children admitted to the pediatric intensive care unit after trauma developed VTE (incidence 6.2%, 95% confidence interval [CI] 2.3-10.2), with a median age of 8.6 years (range, 2.3-17.9). VTE was diagnosed at a median of 9 days after admission, with 67% of VTE located at the site of previous or existing central venous line (CVL). Significant risk factors for thrombosis included parenteral nutrition (odds ratio [OR] 20, 95% CI 1.9-227), CVL (OR 19, 95% CI 2-178), deep sedation (OR 13, 95% CI 1.6-48), neuromuscular blockade (OR 10, 95% CI 1.4-70), inotropic support (OR 10, 95% CI 1.7-59), and recombinant factor VIIa administration (p = 0.012, OR not calculable). Logistic analysis found a 7.9-fold increase in the odds of developing VTE for each additional CVL (p = 0.005), a threefold increase with each additional risk factor present (p = 0.009), and a 1.3-fold increase for an increase in injury severity (p = 0.03). VTE was not associated with sepsis, spinal cord injury, fracture, or elevated D-dimer level. CONCLUSIONS VTE is not a rare event in critically ill children after trauma. Most patients developing thrombosis have multiple risk factors, including poor perfusion, immobility, and presence of a CVL.

A mouse-human phase 1 co-clinical trial of a protease-activated fluorescent probe for imaging cancer

A first-in-human phase 1 clinical trial of the PEGylated protease-activated fluorescent probe, LUM015, enables tumor imaging at a safe and tolerable dose in humans. Protease probe tested in humans Cancer cells secrete more of the protease cathepsin than healthy cells, partly as a way to enzymatically remodel their surroundings for tumor growth and metastasis. Whitley et al. developed an imaging probe that could be activated in the presence of these cathepsins, thus allowing surgeons to distinguish tumor margins intraoperatively. Their probe, called LUM015, was able to signal the presence of cancer in vivo in a mouse sarcoma model, and in a so-called “co-clinical trial” in 15 patients, it was safe and cleaved as expected in different types of tumor tissues. With favorable biodistribution and pharmacokinetics also demonstrated, protease-activated probes are now poised for further adaptation to tumor resections, signaling the presence of residual cancer. Local recurrence is a common cause of treatment failure for patients with solid tumors. Intraoperative detection of microscopic residual cancer in the tumor bed could be used to decrease the risk of a positive surgical margin, reduce rates of reexcision, and tailor adjuvant therapy. We used a protease-activated fluorescent imaging probe, LUM015, to detect cancer in vivo in a mouse model of soft tissue sarcoma (STS) and ex vivo in a first-in-human phase 1 clinical trial. In mice, intravenous injection of LUM015 labeled tumor cells, and residual fluorescence within the tumor bed predicted local recurrence. In 15 patients with STS or breast cancer, intravenous injection of LUM015 before surgery was well tolerated. Imaging of resected human tissues showed that fluorescence from tumor was significantly higher than fluorescence from normal tissues. LUM015 biodistribution, pharmacokinetic profiles, and metabolism were similar in mouse and human subjects. Tissue concentrations of LUM015 and its metabolites, including fluorescently labeled lysine, demonstrated that LUM015 is selectively distributed to tumors where it is activated by proteases. Experiments in mice with a constitutively active PEGylated fluorescent imaging probe support a model where tumor-selective probe distribution is a determinant of increased fluorescence in cancer. These co-clinical studies suggest that the tumor specificity of protease-activated imaging probes, such as LUM015, is dependent on both biodistribution and enzyme activity. Our first-in-human data support future clinical trials of LUM015 and other protease-sensitive probes.

Trends in Treatment Patterns and Outcomes for Ductal Carcinoma In Situ.

BACKGROUND Impact of contemporary treatment of pre-invasive breast cancer (ductal carcinoma in situ [DCIS]) on long-term outcomes remains poorly defined. We aimed to evaluate national treatment trends for DCIS and to determine their impact on disease-specific (DSS) and overall survival (OS). METHODS The Surveillance, Epidemiology, and End Results (SEER) registry was queried for patients diagnosed with DCIS from 1991 to 2010. Treatment pattern trends were analyzed using Cochran-Armitage trend test. Survival analyses were performed using inverse probability weights (IPW)-adjusted competing risk analyses for DSS and Cox proportional hazard regression for OS. All tests performed were two-sided. RESULTS One hundred twenty-one thousand and eighty DCIS patients were identified. The greatest proportion of patients was treated with lumpectomy and radiation therapy (43.0%), followed by lumpectomy alone (26.5%) and unilateral (23.8%) or bilateral mastectomy (4.5%) with significant shifts over time. The rate of sentinel lymph node biopsy increased from 9.7% to 67.1% for mastectomy and from 1.4% to 17.8% for lumpectomy. Compared with mastectomy, OS was higher for lumpectomy with radiation (hazard ratio [HR] = 0.79, 95% confidence interval [CI] = 0.76 to 0.83, P < .001) and lower for lumpectomy alone (HR = 1.17, 95% CI = 1.13 to 1.23, P < .001). IPW-adjusted ten-year DSS was highest in lumpectomy with XRT (98.9%), followed by mastectomy (98.5%), and lumpectomy alone (98.4%). CONCLUSIONS We identified substantial shifts in treatment patterns for DCIS from 1991 to 2010. When outcomes between locoregional treatment options were compared, we observed greater differences in OS than DSS, likely reflecting both a prevailing patient selection bias as well as clinically negligible differences in breast cancer outcomes between groups.

Diagnostic Value of Ultrasound in Female Patients With Nipple Discharge

OBJECTIVE The purpose of this study was to assess the contribution of ultrasound to the evaluation of patients with pathologic nipple discharge. MATERIALS AND METHODS A retrospective review was conducted of the records of females who presented with nipple discharge between January 1, 2009, and December 31, 2011. Pathologic nipple discharge was defined as discharge with one or more of the following features: unilateral, clear or bloody, and spontaneous. Patients underwent bilateral mammography followed by ultrasound directed at the subareolar portion of the affected breast. Radiologic findings and pathologic results were reviewed. RESULTS Over a 3-year period, 327 females (mean age, 48 years; range, 13-88 years) presented with nipple discharge. Among these patients, 273 (83%) underwent surgical excision or clinical or radiographic follow-up at least 2 years after presentation and composed the study population. Among the 273 patients, 262 (96%) underwent mammography and 246 (90%) underwent sonography. Among 252 patients who had at least one pathologic feature of nipple discharge and underwent surgical excision or at least 2 years of follow-up, a total of 20 (8%) cases of ductal carcinoma in situ (DCIS) or invasive adenocarcinoma were diagnosed. DCIS or invasive adenocarcinoma was diagnosed in eight patients with normal sonographic findings. For the detection of DCIS and invasive adenocarcinoma, the sensitivity and specificity of ultrasound were 56% (10/18) and 75% (170/228); the sensitivity and specificity of mammography were 15% (3/20) and 98% (237/242). CONCLUSION For females presenting with pathologic nipple discharge, ultrasound is a useful diagnostic tool and may be worth including in the routine evaluation.

Management of Positive Sub-areolar/Nipple Duct Margins in Nipple-Sparing Mastectomies

We evaluated management of positive sub‐areolar/nipple duct margins in nipple‐sparing mastectomies (NSM) at our institution. Retrospective chart review of all NSM from January 2007 to April 2012 was performed and patient, tumor, and treatment information was collected. Sub‐areolar/nipple duct margins included ductal tissue from within the nipple. Of 438 NSM, 22 (5%) had positive sub‐areolar/nipple duct margins; 21 of 220 cancer‐bearing breasts (10%) and 1 of 218 prophylactic mastectomies (0.5%). Positive margins included four with invasive lobular carcinoma and 18 with ductal carcinoma in situ (DCIS). Management included removal of eight nipples and nine nipple areola complexes (NAC). Four of 17 nipple/NAC specimens had evidence of residual DCIS and none had residual invasive cancer. The majority of nipple/NAC specimens excised for a positive margin had no residual malignancy. Future studies are needed to determine the extent of NAC tissue removal required for positive margins.

Cost Implications of the SSO-ASTRO Consensus Guideline on Margins for Breast-Conserving Surgery with Whole Breast Irradiation in Stage I and II Invasive Breast Cancer

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A Quantitative Diffuse Reflectance Imaging (QDRI) System for Comprehensive Surveillance of the Morphological Landscape in Breast Tumor Margins

125 billion is spent annually in the United States for cancer treatment. Among women in this country, breast cancer remains the most common nondermatologic cancer diagnosis and the second leading cause of cancerrelated death. In 2010, breast cancer treatment costs were estimated at

Performance and Practice Guideline for the Use of Neoadjuvant Systemic Therapy in the Management of Breast Cancer

16.5 billion, comprising 13 % of the burden of total cancer-related costs. Health care spending varies throughout the phases of breast cancer treatment, with *23 % of total expenditures allocated during the initial episode of treatment (diagnosis and management during the first year), 41 % during continuing care, and 36 % during the last year of life. It has been estimated that surgical costs account for 25 % of breast cancer treatment expenditure among Medicare patients. An important contributor to health care costs includes deviations from the standard of care and variations in clinical practice that are not supported by evidence. Moreover, dramatic regional variations in health care spending are not associated with the quality of delivered care or with improved patient outcomes. In contrast, studies have consistently shown that adherence to clinical pathways and guidelines, and reductions in unintended practice variations are linked to improvement in clinical outcomes at lower costs. In the current treatment of early-stage breast cancer, management of surgical margins after lumpectomy is a prime example of wide variation in clinical practice. Consensus exits on the importance of removing all microscopically evident disease; however, there has historically been little agreement on what constitutes a pathologically acceptable distance from tumor cells to ink. Definitions of margin adequacy have ranged from ‘‘no tumor on ink’’ in the original NSABP B-06 trial, to the Milan trials requiring quadrantectomy with 2–3 cm of grossly normal tissue around the tumor including overlying skin and underlying fascia. Taghian et al. demonstrated this lack of consensus in defining close and negative margins in a survey of North American and European practicing radiation oncologists, with only 46 % of North American respondents considering ‘‘no tumor on ink’’ as adequately negative margins. A survey of surgeons treating breast cancer again demonstrated wide variation in defining margin adequacy, with only 3 % endorsing ‘‘no tumor on ink’’ as negative margins. The debate of what constitutes a negative margin has continued at a national level and has widespread implications for patients and cancer-related treatment costs. The meta-analysis included in this issue by Moran et al. may finally put rest to this issue. In the United States, 60–75 % of women diagnosed with early-stage breast cancer are treated with breast-conservation therapy (lumpectomy and radiotherapy) based on long-term followup and contemporary data demonstrating equivalent survival to mastectomy. The ‘‘SSO-ASTRO consensus guidelines on margins for breast-conserving surgery with whole breast irradiation in stage I–II invasive breast cancer’’ included 33 studies with 28,162 patients reviewed by an expert panel. Evidence-based consensus guidelines on Society of Surgical Oncology 2014Over

Oncologic Safety of Prophylactic Nipple-Sparing Mastectomy in a Population With BRCA Mutations: A Multi-institutional Study

125 billion is spent annually in the United States for cancer treatment. Among women in this country, breast cancer remains the most common nondermatologic cancer diagnosis and the second leading cause of cancerrelated death. In 2010, breast cancer treatment costs were estimated at

ReCAP: Physician Experience and Attitudes Toward Addressing the Cost of Cancer Care

16.5 billion, comprising 13 % of the burden of total cancer-related costs. Health care spending varies throughout the phases of breast cancer treatment, with *23 % of total expenditures allocated during the initial episode of treatment (diagnosis and management during the first year), 41 % during continuing care, and 36 % during the last year of life. It has been estimated that surgical costs account for 25 % of breast cancer treatment expenditure among Medicare patients. An important contributor to health care costs includes deviations from the standard of care and variations in clinical practice that are not supported by evidence. Moreover, dramatic regional variations in health care spending are not associated with the quality of delivered care or with improved patient outcomes. In contrast, studies have consistently shown that adherence to clinical pathways and guidelines, and reductions in unintended practice variations are linked to improvement in clinical outcomes at lower costs. In the current treatment of early-stage breast cancer, management of surgical margins after lumpectomy is a prime example of wide variation in clinical practice. Consensus exits on the importance of removing all microscopically evident disease; however, there has historically been little agreement on what constitutes a pathologically acceptable distance from tumor cells to ink. Definitions of margin adequacy have ranged from ‘‘no tumor on ink’’ in the original NSABP B-06 trial, to the Milan trials requiring quadrantectomy with 2–3 cm of grossly normal tissue around the tumor including overlying skin and underlying fascia. Taghian et al. demonstrated this lack of consensus in defining close and negative margins in a survey of North American and European practicing radiation oncologists, with only 46 % of North American respondents considering ‘‘no tumor on ink’’ as adequately negative margins. A survey of surgeons treating breast cancer again demonstrated wide variation in defining margin adequacy, with only 3 % endorsing ‘‘no tumor on ink’’ as negative margins. The debate of what constitutes a negative margin has continued at a national level and has widespread implications for patients and cancer-related treatment costs. The meta-analysis included in this issue by Moran et al. may finally put rest to this issue. In the United States, 60–75 % of women diagnosed with early-stage breast cancer are treated with breast-conservation therapy (lumpectomy and radiotherapy) based on long-term followup and contemporary data demonstrating equivalent survival to mastectomy. The ‘‘SSO-ASTRO consensus guidelines on margins for breast-conserving surgery with whole breast irradiation in stage I–II invasive breast cancer’’ included 33 studies with 28,162 patients reviewed by an expert panel. Evidence-based consensus guidelines on Society of Surgical Oncology 2014