Julie A. Margenthaler

Whole Genome Analysis Informs Breast Cancer Response to Aromatase Inhibition

To correlate the variable clinical features of oestrogen-receptor-positive breast cancer with somatic alterations, we studied pretreatment tumour biopsies accrued from patients in two studies of neoadjuvant aromatase inhibitor therapy by massively parallel sequencing and analysis. Eighteen significantly mutated genes were identified, including five genes (RUNX1, CBFB, MYH9, MLL3 and SF3B1) previously linked to haematopoietic disorders. Mutant MAP3K1 was associated with luminal A status, low-grade histology and low proliferation rates, whereas mutant TP53 was associated with the opposite pattern. Moreover, mutant GATA3 correlated with suppression of proliferation upon aromatase inhibitor treatment. Pathway analysis demonstrated that mutations in MAP2K4, a MAP3K1 substrate, produced similar perturbations as MAP3K1 loss. Distinct phenotypes in oestrogen-receptor-positive breast cancer are associated with specific patterns of somatic mutations that map into cellular pathways linked to tumour biology, but most recurrent mutations are relatively infrequent. Prospective clinical trials based on these findings will require comprehensive genome sequencing.

Randomized Phase II Neoadjuvant Comparison Between Letrozole, Anastrozole, and Exemestane for Postmenopausal Women With Estrogen Receptor–Rich Stage 2 to 3 Breast Cancer: Clinical and Biomarker Outcomes and Predictive Value of the Baseline PAM50-Based Intrinsic Subtype—ACOSOG Z1031

PURPOSE Preoperative aromatase inhibitor (AI) treatment promotes breast-conserving surgery (BCS) for estrogen receptor (ER)-positive breast cancer. To study this treatment option, responses to three AIs were compared in a randomized phase II neoadjuvant trial designed to select agents for phase III investigations. PATIENTS AND METHODS Three hundred seventy-seven postmenopausal women with clinical stage II to III ER-positive (Allred score 6-8) breast cancer were randomly assigned to receive neoadjuvant exemestane, letrozole, or anastrozole. The primary end point was clinical response. Secondary end points included BCS, Ki67 proliferation marker changes, the Preoperative Endocrine Prognostic Index (PEPI), and PAM50-based intrinsic subtype analysis. RESULTS On the basis of clinical response rates, letrozole and anastrozole were selected for further investigation; however, no other differences in surgical outcome, PEPI score, or Ki67 suppression were detected. The BCS rate for mastectomy-only patients at presentation was 51%. PAM50 analysis identified AI-unresponsive nonluminal subtypes (human epidermal growth factor receptor 2 enriched or basal-like) in 3.3% of patients. Clinical response and surgical outcomes were similar in luminal A (LumA) versus luminal B tumors; however, a PEPI of 0 (best prognostic group) was highest in the LumA subset (27.1% v 10.7%; P = .004). CONCLUSION Neoadjuvant AI treatment markedly improved surgical outcomes. Ki67 and PEPI data demonstrated that the three agents tested are biologically equivalent and therefore likely to have similar adjuvant activities. LumA tumors were more likely to have favorable biomarker characteristics after treatment; however, occasional paradoxical increases in Ki67 (12% of tumors with > 5% increase after therapy) suggest treatment-resistant cells, present in some LumA tumors, can be detected by post-treatment profiling.

Surgical Removal of the Primary Tumor Increases Overall Survival in Patients With Metastatic Breast Cancer: Analysis of the 1988–2003 SEER Data

BackgroundPrimary treatments for stage IV breast cancer are chemotherapy and radiation, with surgery usually reserved for tumor-related complications. We sought to determine whether surgical removal of the primary tumor provides a survival advantage for women with metastatic breast cancer.MethodsWe conducted a retrospective, population-based cohort study by using the 1988–2003 Surveillance, Epidemiology, and End Results (SEER) program data. By use of multivariate Cox regression models, overall survival in women with stage IV disease was compared between women who underwent surgical excision of their breast tumor with women who did not, controlling for potential confounding demographic, tumor- and treatment-related variables, and propensity scores (accounting for variables associated with the likelihood of having surgery).ResultsOf 9734 SEER patients with stage IV breast cancer, 47% underwent breast cancer surgery and 53% did not. Median survival was longer for women who had surgery than for women who did not, both among women who were alive at the end of the study period (36.00 vs. 21.00 months; P < .001) and among women who had died during follow-up (18.00 vs. 7.00 months; P < .001). After controlling for potential confounding variables and propensity scores, patients who underwent surgery were less likely to die during the study period compared with women who did not undergo surgery (adjusted hazard ratio, .63, 95% confidence interval, .60–.66).ConclusionsAnalysis of the 1988–2003 SEER data indicated that extirpation of the primary breast tumor in patients with stage IV disease was associated with a marked reduction in risk of dying after controlling for variables associated with survival.

Sentinel Lymph Nodes in the Rat: Noninvasive Photoacoustic and US Imaging with a Clinical US System

PURPOSE To evaluate in vivo sentinel lymph node (SLN) mapping by using photoacoustic and ultrasonographic (US) imaging with a modified clinical US imaging system. MATERIALS AND METHODS Animal protocols were approved by the Animal Studies Committee. Methylene blue dye accumulation in axillary lymph nodes of seven healthy Sprague-Dawley rats was imaged by using a photoacoustic imaging system adapted from a clinical US imaging system. To investigate clinical translation, the imaging depth was extended up to 2.5 cm by adding chicken or turkey breast on top of the rat skin surface. Three-dimensional photoacoustic images were acquired by mechanically scanning the US transducer and light delivery fiber bundle along the elevational direction. RESULTS Photoacoustic images of rat SLNs clearly help visualization of methylene blue accumulation, whereas coregistered photoacoustic/US images depict lymph node positions relative to surrounding anatomy. Twenty minutes following methylene blue injection, photoacoustic signals from SLN regions increased nearly 33-fold from baseline signals in preinjection images, and mean contrast between SLNs and background tissue was 76.0 +/- 23.7 (standard deviation). Methylene blue accumulation in SLNs was confirmed photoacoustically by using the optical absorption spectrum of the dye. Three-dimensional photoacoustic images demonstrate dynamic accumulation of methylene blue in SLNs after traveling through lymph vessels. CONCLUSION In vivo photoacoustic and US mapping of SLNs was successfully demonstrated with a modified clinical US scanner. These results raise confidence that photoacoustic and US imaging can be used clinically for accurate, noninvasive imaging of SLNs for axillary lymph node staging in breast cancer patients.

Elevated Breast Cancer Mortality in Women Younger than Age 40 Years Compared with Older Women Is Attributed to Poorer Survival in Early-Stage Disease

BACKGROUND We investigated differences in breast cancer mortality between younger (younger than 40 years of age) and older (40 years of age and older) women by stage at diagnosis to identify patient and tumor characteristics accounting for disparities. STUDY DESIGN We conducted a retrospective study of women diagnosed with breast cancer in the 1988 to 2003 Surveillance, Epidemiology, and End Results Program data. Multivariate Cox regression models calculated adjusted hazard ratios (aHR) and 95% confidence intervals to compare overall and stage-specific breast cancer mortality in women younger than 40 years old and women 40 years and older, controlling for potential confounding variables identified in univariate tests. RESULTS Of 243,012 breast cancer patients, 6.4% were younger than 40 years old, and 93.6% were 40 years of age or older. Compared with older women, younger women were more likely to be African American, single, diagnosed at later stages, and treated by mastectomy. Younger women had tumors that were more likely to be higher grade, larger size, estrogen receptor/progesterone receptor-negative, and lymph-node positive (p < 0.001). Younger women were more likely to die from breast cancer compared with older women (crude HR = 1.39; CI, 1.34 to 1.45). Controlling for confounders, younger women were more likely to die compared with older women if diagnosed with stage I (aHR = 1.44; CI, 1.27 to 1.64) or stage II (aHR = 1.09; CI, 1.03 to 1.15) disease and less likely to die if diagnosed with stage IV disease (aHR = 0.85; CI, 0.76 to 0.95). CONCLUSIONS Higher breast cancer mortality in younger women was attributed to poorer outcomes with early-stage disease. Additional studies should focus on specific tumor biology contributing to the increased mortality of younger women with early-stage breast cancer.

Noninvasive photoacoustic identification of sentinel lymph nodes containing methylene blue in vivo in a rat model

Sentinel lymph node biopsy (SLNB) has become the standard method of axillary staging for patients with breast cancer and clinically negative axillae. Even though SLNB using both methylene blue and radioactive tracers has a high identification rate, it still relies on an invasive surgical procedure with associated morbidity. Axillary ultrasound has emerged as a diagnostic tool to evaluate the axilla, but it can only assess morphology and cannot specifically identify sentinel lymph nodes (SLNs). In this pilot study, we propose a noninvasive photoacoustic SLN identification system using methylene blue injection in a rat model. We successfully image a SLN with high optical contrast (146+/-41, standard deviation) and good ultrasonic resolution (approximately 500 microm) in vivo. We also show potential feasibility for clinical applications by imaging 20- and 31-mm-deep SLNs in 3-D and 2-D, respectively. Our results suggest that this technology would be a useful clinical tool, allowing clinicians to identify SLNs noninvasively in vivo.

Handheld array-based photoacoustic probe for guiding needle biopsy of sentinel lymph nodes

By modifying a clinical ultrasound array system, we develop a novel handheld photoacoustic probe for image-guided needle biopsy. The integration of optical fiber bundles for pulsed laser light delivery enables photoacoustic image-guided insertion of a needle into rat axillary lymph nodes with accumulated indocyanine green (ICG). Strong photoacoustic contrast of the needle is achieved. After subcutaneous injection of the dye in the left forepaw, sentinel lymph nodes are easily detected, in vivo and in real time, beneath 2-cm-thick chicken breast overlaying the axillary region. ICG uptake in axillary lymph nodes is confirmed with fluorescence imaging both in vivo and ex vivo. These results demonstrate the clinical potential of this handheld photoacoustic system for facile identification and needle biopsy of sentinel lymph nodes for cancer staging and metastasis detection in humans.

Blunt renal trauma in children: Experience with conservative management at a pediatric trauma center

BACKGROUND The authors reviewed the outcome for children with blunt renal injury managed with a nonoperative protocol at their pediatric trauma center. METHODS Fifty-five consecutive children aged 0.5 to 17 years with blunt renal injury managed over a 14-year period were reviewed. All patients were evaluated with computed tomographic scanning. Injuries were graded according to the American Association for the Surgery of Trauma Organ Injury Scale. RESULTS Forty-eight of 55 children (87%) were successfully managed nonoperatively. Overall, there were 5 grade I, 13 grade II, 18 grade III, 14 grade IV, and 5 grade V injuries. All children with grades I and III injuries were successfully managed nonoperatively. Two (6%) of these children required transfusion. Only four (29%) children with grade IV and three (60%) with grade V injuries required surgical interventions (one nephrostomy, six nephrectomies). Excluding patients with continuing hemorrhage, only 2 (14%) of 14 with high-grade injuries required surgical intervention (1 nephrostomy, 1 nephrectomy). Clearance of gross hematuria correlated with severity of injury and was prolonged in grade IV and V compared with grade I to III injuries (6.8 +/- 2.7 vs. 3.2 +/- 2.1 days, respectively; p < 0.05). Fifty-one children (93%) available for follow-up were normotensive with normal renal function. CONCLUSION These data support the use of conservative management for all grades in stable children with blunt renal injury. Transfusion requirements, operative rates, and outcome are consistent with other pediatric solid organ injuries.

Risk Factors for Adverse Outcomes After the Surgical Treatment of Appendicitis in Adults

Objective To define risk factors that predict adverse outcomes after the surgical treatment of appendicitis in Department of Veterans Affairs Medical Centers. Summary Background Data Risk factors for adverse outcomes after the surgical treatment of appendicitis in adults are poorly defined. Accurate presurgical assessment of the risk of perioperative complications and death is important in planning surgical therapy. Methods The VA National Surgical Quality Improvement Program contains prospectively collected and extensively validated data on ∼1,000,000 major surgical operations. All patients undergoing surgical intervention for appendicitis from 1991 to 1999 registered in this database were selected for study. Independent variables examined included 68 putative preoperative risk factors and 12 intraoperative process measures. Dependent variables were 21 specific adverse outcomes, including death. Stepwise logistic regression analysis was used to construct models predicting 30-day morbidity rate and the 30-day postoperative mortality rate. Results There were 4163 patients identified. The mean age was 50 years; 96% were male. Sixteen percent of patients had 1 or more complications after surgical intervention. Prolonged ileus, failure to wean from the ventilator, pneumonia, and both superficial and deep wound infection were the most frequently reported complications, accounting for the majority of the morbidity. The 30-day mortality rate was 1.8% (74 deaths). For >50% of the complications reported, the 30-day mortality rates were significantly higher (P < 0.01) for patients with complications than for those without. Thirty-day mortality rates for several complications exceeded 30%, including cardiac arrest, coma >24 hours, myocardial infarction, acute renal failure, bleeding requiring >4 units of red cells, and systemic sepsis. Four preoperative factors predicted a high risk of 30-day mortality in the logistic regression analysis: “completely dependent” functional status, bleeding disorder, steroid usage, and current pneumonia. “Threat to life” or “moribund” American Society of Anesthesiologists classification and more than a 10% weight loss in the 6 months before surgery were associated with a high risk of complications. Conclusions Morbidity and mortality rates after the surgical treatment of appendicitis in VA hospitals are comparable with those reported in other large series. Most postsurgical complications are associated with an increased 30-day mortality rate. The models presented here are the most robust available in predicting 30-day morbidity and mortality for VA patients with appendicitis. Furthermore, they provide a starting point for the design of similar models to evaluate non-VA patients with appendicitis using the data the National Surgical Quality Improvement Program is currently gathering from private hospitals.

Patient and tumor characteristics associated with increased mortality in young women (≤40 years) with breast cancer

The goal of the current study is to identify predictors responsible for mortality disparities between young (≤40 years) and older (>40 years) women with breast cancer.