PARP (Poly ADP-Ribose Polymerase) inhibitors for locally advanced or metastatic breast cancer.

BACKGROUND: Locally advanced and metastatic breast cancer remains a challenge to treat. With emerging study results, it is important to interpret the available clinical data and apply the evidence offering the most effective treatment to the right patient. Poly(ADP Ribose) Polymerase (PARP) inhibitors are a new class of drug and their role in the treatment of locally advanced and metastatic breast cancer is being established. OBJECTIVES: To determine the efficacy, safety profile, and potential harms of Poly(ADP-Ribose) Polymerase (PARP) inhibitors in the treatment of patients with locally advanced or metastatic breast cancer. The primary outcome of interest was overall survival; secondary outcomes included progression-free survival, tumour response rate, quality of life, and adverse events. SEARCH METHODS: On 8 June 2020, we searched the Cochrane Breast Cancer Group Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE via OvidSP, Embase via OvidSP, World Health Organization International Clinical Trials Registry Platform (WHO ICTRP) search portal and ClinicalTrials.gov. We also searched proceedings from the major oncology conferences as well as scanned reference lists from eligible publications and contacted corresponding authors of trials for further information, where needed. SELECTION CRITERIA: We included randomised controlled trials on participants with locally advanced or metastatic breast cancer comparing 1) chemotherapy in combination with PARP inhibitors, compared to the same chemotherapy without PARP inhibitors or 2) treatment with PARP inhibitors, compared to treatment with other chemotherapy. We included studies that reported on our primary outcome of overall survival and secondary outcomes including progression-free survival, tumour response rate, quality of life, and adverse events. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures defined by Cochrane. Summary statistics for the endpoints used hazard ratios (HR) with 95% confidence intervals (CI) for overall survival and progression-free survival, and odds ratios (OR) for response rate (RR) and toxicity. MAIN RESULTS: We identified 49 articles for qualitative synthesis, describing five randomised controlled trials that were included in the quantitative synthesis (meta-analysis). A sixth trial was assessed as eligible but had ended prematurely and no data were available for inclusion in our meta-analysis. Risk of bias was predominately low to unclear across all studies except in regards to performance bias (3/5 high risk) and detection bias for the outcomes of quality of life (2/2 high risk) and reporting of adverse events (3/5 high risk). High-certainty evidence shows there may be a small advantage in overall survival (HR 0.87, 95% CI 0.76 to 1.00; 4 studies; 1435 patients). High-certainty evidence shows that PARP inhibitors offer an improvement in PFS in locally advanced/metastatic HER2-negative, BRCA germline mutated breast cancer patients (HR 0.63, 95% CI 0.56 to 0.71; 5 studies; 1474 patients). There was no statistical heterogeneity for these outcomes. Subgroup analyses for PFS outcomes based on trial level data were performed for triple-negative breast cancer, hormone-positive and/or HER2-positive breast cancer, BRCA1 and BRCA2 germline mutations, and patients who had received prior chemotherapy for advanced breast cancer or not. The subgroup analyses showed a persistent PFS benefit regardless of the subgroup chosen. Pooled analysis shows PARP inhibitors likely result in a moderate improvement in tumour response rate compared to other treatment arms (66.9% vs 48.9%; RR 1.39, 95% CI 1.24 to 1.54; 5 studies; 1185 participants; moderate-certainty evidence). The most common adverse events reported across all five studies included neutropenia, anaemia and fatigue. Grade 3 or higher adverse events probably occur no less frequently in patients receiving PARP inhibitors (59.4% for PARP arm versus 64.5% for non-PARP arm, RR 0.98, 95% CI 0.91 to 1.04; 5 studies; 1443 participants; moderate-certainty evidence). Only two studies reported quality of life outcomes so this was not amenable to meta-analysis. However, both studies that did assess quality of life showed PARP inhibitors were superior compared to physician's choice of chemotherapy in terms of participant-reported outcomes. AUTHORS' CONCLUSIONS: In people with locally advanced or metastatic HER2-negative, BRCA germline mutated breast cancer, PARP inhibitors offer an improvement in progression-free survival, and likely improve overall survival and tumour response rates. This systematic review provides evidence supporting the use of PARP inhibitors as part of the therapeutic strategy for breast cancer patients in this subgroup. The toxicity profile for PARP inhibitors is probably no worse than chemotherapy but more information is required regarding quality of life outcomes, highlighting the importance of collecting such data in future studies. Future studies should also be powered to detect clinically important differences in overall survival and could focus on the role of PARP inhibitors in other relevant breast cancer populations, including HER2-positive, BRCA-negative/homologous recombination repair-deficient and Programmed Death-Ligand 1 (PDL1) positive.

Estimating the OncotypeDX score: validation of an inexpensive estimation tool.

BACKGROUND: OncotypeDX, a multi-gene expression assay, has been incorporated into clinical practice as a prognostic and predictive tool. However, its use in resource-constrained international healthcare systems is limited. Here we develop and validate a simplified model using clinicopathologic criteria to predict OncotypeDX score. METHODS: Patients with estrogen receptor (ER) and/or progesterone receptor (PR)-positive and HER2-negative invasive ductal carcinoma for whom the OncotypeDX test was successfully performed between 09/2008 and 12/2011 were retrospectively identified. Tumor size, nuclear and histologic grade, lymphovascular invasion, and ER and PR status were extracted from pathology reports. Data were split into a training dataset comprising women tested 09/2008-04/2011, and a validation dataset comprising women tested 04/2011-12/2011. Using the training dataset, linear regression analysis was used to identify factors associated with OncotypeDX score, and to create a simplified risk score and identify risk cutoffs. RESULTS: Estrogen and progesterone receptors, tumor size, nuclear and histologic grades, and lymphovascular involvement were independently associated with OncotypeDX. The full model explained 39% of the variation in the test data, and the simplified risk score and cutoffs assigned 57% of patients in the test data to the correct risk category (OncotypeDX score <18, 18-30, >30). 41% of patients were predicted to have OncotypeDX score <18, of these 83, 16, and 2% had true scores of <18, 18-30, and >30, respectively. CONCLUSIONS: Awaiting an inexpensive test that is prognostic and predictive, our simplified tool allows clinicians to identify a fairly large group of patients (41%) with very low chance of having high-risk disease (2%).

Causes of death in long-term survivors of head and neck cancer.

BACKGROUND: Survivors of head and neck squamous cell carcinoma (HNSCC) face excess mortality from multiple causes. METHODS: We used the population-based Surveillance, Epidemiology, and End Results (SEER) cancer registry data to evaluate the causes of death in patients with nonmetastatic HNSCC diagnosed between 1992 and 2005 who survived at least 3 years from diagnosis (long-term survivors). We used competing-risks proportional hazards regression to estimate probabilities of death from causes: HNSCC, second primary malignancy (SPM) excluding HNSCC, cardiovascular disease, and other causes. RESULTS: We identified 35,958 three-year survivors of HNSCC with a median age at diagnosis of 60 years (range = 18-100 years) and a median follow-up of 7.7 years (range = 3-18 years). There were 13,120 deaths during the study period. Death from any cause at 5 and 10 years was 15.4% (95% confidence interval [CI] = 15.0%-15.8%) and 41.0% (95% CI = 40.4%-41.6%), respectively. There were 3852 HNSCC deaths including both primary and subsequent head and neck tumors. The risk of death from HNSCC was greater in patients with nasopharynx or hypopharynx cancer and in patients with locally advanced disease. SPM was the leading cause of non-HNSCC death, and the most common sites of SPM death were lung (53%), esophagus (10%), and colorectal (5%) cancer. CONCLUSIONS: Many long-term HNSCC survivors die from cancers other than HNSCC and from noncancer causes. Routine follow-up care for HNSCC survivors should expand beyond surveillance for recurrent and new head and neck cancers.

Black race as a prognostic factor in triple-negative breast cancer patients treated with breast-conserving therapy: a large, single-institution retrospective analysis.

Triple-negative breast cancer (TNBC) disproportionately affects black women. However, black race as a prognostic factor in TNBC has not been well studied. We evaluated the effect of race, among other variables, on outcomes in women with TNBC. A total of 704 patients with stages I-III TNBC treated with breast-conserving surgery ± adjuvant radiation therapy (RT) and chemotherapy were identified from an institutional database. Competing risk analyses, Kaplan-Meier methods, and Cox proportional hazards models identified associations among clinicopathologic variables on locoregional recurrence (LRR), distant recurrence (DR), and overall survival (OS). LRR was defined as a biopsy proven, triple receptor-negative recurrence in the ipsilateral breast or regional lymph nodes. At a median follow-up of 51 months, there were 55 LRR, 61 DR, and 111 death events. Compared to non-black women, black women had higher disease stage and were more likely to receive axillary lymph node dissection, chemotherapy, and nodal irradiation (all P < 0.05). After adjustment for stage, age, lymphovascular invasion, chemotherapy, and RT on multivariate analysis, black race was prognostic for increased risk of LRR (hazard ratio [HR] = 3.17; 95 % confidence interval: 1.7-5.8; P = 0.0002). The 5-year risk of regional recurrence was higher in black women (10 vs. 2 %, P < 0.0001), but local failures were similar between groups (3.0 vs. 5.3 %, P = 0.15). RT was an independent predictor for decreased LRR and increased OS on multivariate analyses (P = 0.0006 and P = 0.0003, respectively). Black women with TNBC had equivalent local control, but higher risk of regional nodal failure, compared with non-black counterparts. The routine use of comprehensive nodal irradiation may be beneficial for black women with TNBC.

Favorable prognosis in patients with T1a/T1bN0 triple-negative breast cancers treated with multimodality therapy.

BACKGROUND: The authors evaluated the clinical characteristics, natural history, and outcomes of patients who had ≤1 cm, lymph node-negative, triple-negative breast cancer (TNBC). METHODS: After excluding patients who had received neoadjuvant therapy, 1022 patients with TNBC who underwent definitive breast surgery during 1999 to 2006 were identified from an institutional database. In total, 194 who had lymph node-negative tumors that measured ≤1 cm comprised the study population. Clinical data were abstracted, and survival outcomes were analyzed. RESULTS: The median follow-up was 73 months (range, 5-143 months). The median age at diagnosis was 55.5 years (range, 27-84 years). Tumor (T) classification was microscopic (T1mic) in 16 patients (8.2%), T1a in 49 patients (25.3%), and T1b in 129 patients (66.5%). Most tumors were poorly differentiated (n = 142; 73%), lacked lymphovascular invasion (n = 170; 87.6%), and were detected by screening (n = 134; 69%). In total, 129 patients (66.5%) underwent breast-conserving surgery, and 65 patients (33.5%) underwent mastectomy. One hundred thirteen patients (58%) received adjuvant chemotherapy, and 123 patients (63%) received whole-breast radiation. The patients who received chemotherapy had more adverse clinical and disease features (younger age, T1b tumor, poor tumor grade; all P < .05). Results from testing for the breast cancer (BRCA) susceptibility gene were available for 49 women: 19 women had BRCA1 mutations, 7 women had BRCA2 mutations, and 23 women had no mutations. For the entire group, the 5-year local recurrence-free survival rate was 95%, and the 5-year distant metastasis-free survival rate was 95%. There was no difference between patients with T1mic/T1a tumors and patients with T1b tumors in the distant recurrence rate (94.5% vs 95.5%, respectively; P = .81) or in the receipt of chemotherapy (95.9% vs 94.5%, respectively; P = .63). CONCLUSIONS: Excellent 5-year locoregional and distant control rates were achievable in patients with TNBC who had tumors ≤1.0 cm, 58% of whom received chemotherapy. These results identified a group of patients with TNBC who had favorable outcomes after early detection and multimodality treatment.

Prevalence of BRCA1 and BRCA2 mutations in Ashkenazi Jewish families with breast and pancreatic cancer.

BACKGROUND: Germline mutations in the BRCA2 cancer susceptibility gene are associated with an increased risk of pancreatic cancer (PC). Breast-pancreas cancer families with BRCA1 mutations have also been observed. The influence of a family history (FH) of PC on BRCA mutation prevalence in patients with breast cancer (BC) is unknown. METHODS: A clinical database review (2000-2009) identified 211 Ashkenazi Jewish (AJ) BC probands who 1) underwent BRCA1/2 mutation analysis by full gene sequencing or directed testing for Ashkenazi founder mutations (BRCA1: 185delAG and 5382insC; BRCA2: 6174delT) and 2) had a FH of PC in a first-, second-, or third-degree relative. For each proband, the pretest probability of identifying a BRCA1/2 mutation was estimated using the Myriad II model. The observed-to-expected (O:E) mutation prevalence was calculated for the entire group. RESULTS: Of the 211 AJ BC probands with a FH of PC, 30 (14.2%) harbored a BRCA mutation. Fourteen (47%) of the mutations were in BRCA1 and 16 (53%) were in BRCA2. Patients diagnosed with BC at age ≤ 50 years were found to have a higher BRCA1/2 mutation prevalence than probands with BC who were diagnosed at age > 50 years (21.1% vs 6.9%; P = .003). In patients with a first-, second-, or third-degree relative with PC, mutation prevalences were 15.4%, 15.3%, and 8.6%, respectively (P = .58). In the overall group, the observed BRCA1/2 mutation prevalence was 14.2% versus an expected prevalence of 11.8% (O:E ratio, 1.21; P = .15). CONCLUSIONS: BRCA1 and BRCA2 mutations are observed with nearly equal distribution in AJ breast-pancreas cancer families, suggesting that both genes are associated with PC risk. In this population, a FH of PC was found to have a limited effect on mutation prevalence.

A 10-year trend analysis of sentinel lymph node frozen section and completion axillary dissection for breast cancer: are these procedures becoming obsolete?

BACKGROUND: Recent results from the ACOSOG Z0011 trial question the use of intraoperative frozen section (FS) during sentinel lymph node (SLN) biopsy and the role of axillary dissection (ALND) for SLN-positive breast cancer patients. Here we present a 10-year trend analysis of SLN-FS and ALND in our practice. METHODS: We reviewed our prospective SLN database over 10 years (1997-2006, 7509 SLN procedures) for time trends and variation between surgeons in the use of SLN-FS and ALND in patients with cN0 invasive breast cancer. RESULTS: Use of SLN-FS decreased from 100% to 62% (P < 0.0001) and varied widely by surgeon (66% to 95%). There were no statistically significant trends in the performance of ALND for patients with SLN metastases detected by FS (n = 1370, 99-99%) or routine hematoxylin and eosin (H&E) (n = 333; 69-77%), but only for those detected by serial section H&E with or without immunohistochemistry (n = 438; 73-48%; P = 0.0054) or immunohistochemistry only (n = 294; 48-28%; P < 0.0001). These trends coincided with an increase in the proportion of completion versus immediate ALND (30-40%; P = 0.0710). CONCLUSIONS: Over 10 years, we have observed a diminishing rate of SLN-FS and, for patients with low-volume SLN metastases, fewer ALND, trends that suggest a more nuanced approach to axillary management. If the Z0011 selection criteria had been applied to our cohort, 66% of SLN-FS (4159 of 6327) and 48% of ALND (939 of 1953) would have been avoided, sparing 13% of all patients the morbidity of ALND.

Minimal disease in the sentinel lymph node: how to best measure sentinel node micrometastases to predict risk of additional non-sentinel lymph node disease.

BACKGROUND: Volume of disease in the sentinel lymph node (SLN) is a significant predictor of additional nodal metastasis. This study assesses incidence of residual non-SLN disease in a large cohort of women with minimal SLN metastases and compares three methods of SLN micrometastasis volume measurement to determine which best predicts residual disease on completion axillary lymph node dissection (cALND). METHODS: A total of 505 patients with invasive breast cancer and minimal SLN metastasis (pN1mi or pN0(i+)) underwent cALND and had complete data. All SLNs were evaluated by three measurement methods for volume of metastasis: (1) method of detection (frozen section, routine hematoxylin and eosin, serial hematoxylin and eosin, immunohistochemistry), (2) American Joint Committee on Cancer's AJCC Cancer Staging Manual, 7th edition, N category, and (3) number of metastatic cells (1-100, 101-999, ≥1000). Multivariable logistic regression models were used to predict the presence of additional non-SLN disease. RESULTS: A total of 251 patients (50%) had pN0(i+) and 254 patients (50%) had pN1mi disease. Twelve percent of those with pN0(i+) and 20% with pN1mi had additional non-SLN disease. On multivariate analyses including eight variables, only lymphovascular invasion (odds ratio >2.2, P < 0.01) and volume of nodal metastasis as assessed by any method of measurement (method of detection, AJCC, and cell count) were significantly correlated with additional non-SLN disease (P = 0.04, 0.03, and 0.02, respectively). All three models had similar goodness of fit and discrimination (Akaike information criterion = 442, 442, 441; -2log likelihood = 416, 420, 417; concordance index = 0.680, 0.675, 0.676, respectively). CONCLUSIONS: A significant proportion of women with minimal SLN metastases have additional non-SLN disease at cALND. Assessments of SLN volume of disease by three different methods of measurement are equivalent for prediction of additional non-SLN metastases.

Squamous cell carcinoma of the anal canal: patterns and predictors of failure and implications for intensity-modulated radiation treatment planning.

PURPOSE: Intensity-modulated radiation treatment (IMRT) is increasingly used in the treatment of squamous cell carcinoma of the anal canal (SCCAC). Prevention of locoregional failure (LRF) using IMRT requires appropriate clinical target volume (CTV) definition. To better define the CTV for IMRT, we evaluated patterns and predictors of LRF in SCCAC patients given conventional radiation treatment. METHODS AND MATERIALS: We reviewed records of 180 SCCAC patients treated with conventional radiation with or without chemotherapy at our institution between January 1990 and March 2007. All patients received radiation; the median primary tumor dose was 45 Gy. A total of 173 patients also received mitomycin-based chemotherapy. RESULTS: Median follow-up was 40 months. Actuarial 3-year colostomy-free survival was 89% and overall survival (OS) 88%. Actuarial 3-year LRF was 23%. A total of 45 patients had LRF, with 35 (78%) occurring locally in the primary site (25 local only, 10 local and regional); however, 20 (44%) had regional components of failure within the pelvis or inguinal nodes (10 regional only, 10 local and regional). Cumulative sites of LRF (patients may have one or more site of failure) were as follows: primary, 35; inguinal, 8; external perianal, 5; common iliac, 4; presacral, 3; distal rectum, 2; external iliac, 2; and internal iliac, 2. All patients with common iliac failure had cT3 or N+ disease. CONCLUSIONS: The observed patterns of failure support inclusion of the inguinal and all pelvic nodal groups in the CTV for IMRT. In patients with advanced tumor or nodal stage, common iliac nodes should also be included in the CTV.

Predictors of completion axillary lymph node dissection in patients with immunohistochemical metastases to the sentinel lymph node in breast cancer.

BACKGROUND: Axillary lymph node dissection (ALND) in patients with immunohistochemistry (IHC)-determined metastases to the sentinel lymph node (SLN) is controversial. The goal of this study was to examine factors associated with ALND in IHC-only patients. METHODS: Retrospective review of an institutional SLN database from July 1997 to July 2003 was performed. We compared sociodemographic, pathologic, and therapeutic variables between IHC-only patients who had SLN biopsy alone and those that had ALND. RESULTS: Our study group consisted of 171 patients with IHC-only metastases to the SLN. Young age, estrogen receptor negative status, high Memorial Sloan-Kettering Cancer Center nomogram score, and chemotherapy were associated with ALND. Among patients who had ALND (n = 95), 18% had a positive non-SLN. Rates of systemic therapy were similar between those with and without positive non-SLNs at ALND. No axillary recurrences were observed in this series with a median follow-up of 6.4 years. The percentage of patients who were recurrence-free after 5 years was 97% (95% confidence interval, 92.1-98.6). CONCLUSIONS: On the basis of our findings and the lack of prospective randomized data, the practice of selectively limiting ALND to IHC-only patients thought to be at high risk and to patients for whom the identification of additional positive nodes may change systemic therapy recommendations seems to be a safe and reasonable approach.

Presenting features of breast cancer differ by molecular subtype.

BACKGROUND: Gene expression profiling of breast cancers identifies distinct molecular subtypes that affect prognosis. Our goal was to determine whether presenting features of tumors differ among molecular subtypes. METHODS: Subtypes were classified by immunohistochemical surrogates as luminal A (estrogen receptor [ER] and/or progesterone receptor [PR] positive, HER-2-), luminal B (ER and/or PR+, HER-2+), HER-2 (ER and PR-, HER-2+), or basal (ER, PR, HER-2-). Data were obtained from an established, registered database of patients with invasive breast cancer treated at our institution between January 1998 and June 2007. A total of 6,072 tumors were classifiable into molecular subtypes. The chi(2) test, analysis of variance, and multivariate logistic regression analysis were used to determine associations between subtype and clinicopathologic variables. RESULTS: The distribution of subtypes was luminal A, 71%; luminal B, 8%; HER-2, 6%; and basal, 15%. Marked differences in age, tumor size, extent of lymph node involvement, nuclear grade, multicentric/multifocal disease, lymphovascular invasion (LVI), and extensive intraductal component were observed among subtypes. When compared with luminal A tumors, those overexpressing HER-2 (luminal B, HER-2) were significantly more likely to manifest nodal involvement, multifocal, extensive intraductal component, and LVI (P < 0.0001). On multivariate analysis, after controlling for patient age, tumor size, LVI, and nuclear grade, HER-2 subtype tumors were 2.0 times more likely to have four or more metastatic lymph nodes (P < 0.0001) and 1.6 times more likely to have multifocal disease (P < 0.0001) compared with patients with luminal A. CONCLUSIONS: Tumor presentation varies among molecular subtypes; this information may be useful in selecting local therapy. Neoadjuvant therapy and lymph nodes evaluation before surgery or neoadjuvant therapy are likely to be beneficial in HER-2-overexpressing tumors.

Sentinel lymph node biopsy is successful and accurate in male breast carcinoma.

BACKGROUND: Men and women with breast cancer have similar risks of morbidity related to axillary lymph node dissection (ALND). Sentinel lymph node (SLN) biopsy minimizes this risk. We report results from the largest series of SLN biopsies for male breast cancer and compare this experience with that of female counterparts treated concurrently. STUDY DESIGN: The Memorial Sloan-Kettering Cancer Center SLN biopsy database showed that 7,315 SLN biopsy procedures were performed for primary breast cancer from September 1996 to July 2005. Of these, 78 (1.0%) procedures were performed in men. Followup data were obtained from medical record review. RESULTS: SLN biopsy was successful in 76 of 78 (97%) patients. Negative SLNs were found in 39 of 76 (51%) patients. In 3 (8%) patients with negative SLNs, a positive non-SLN was found, identified by intraoperative palpation. Positive SLNs were found in 37 of 76 (49%) patients. In 22 of 37 (59%), node positivity was determined intraoperatively, prompting immediate ALND. In 15 of 37 (41%) patients with positive SLNs, node positivity was determined postoperatively. Of these 15, 9 (60%) underwent completion ALND. In the 2 of 78 (3%) patients with failed SLN biopsy procedures, ALND was performed and yielded positive nodes. At a median followup of 28 months (range 5 to 96 months), there were no axillary recurrences. Compared with their female counterparts, men with breast cancer had larger tumors and were more likely to have positive nodes. CONCLUSIONS: SLN biopsy is successful and accurate in male breast cancer patients. Although a larger proportion of men have positive nodes, for men with negative nodes, SLN biopsy may reduce morbidity related to ALND.

Influence of frozen-section analysis of sentinel lymph node and lumpectomy margin status on reoperation rates in patients undergoing breast-conservation therapy.

BACKGROUND: Frozen-section analysis (FS) of the sentinel lymph node (SLN) is performed to avoid reoperation for axillary lymph node dissection (ALND), but it can miss micrometastatic disease, is labor intensive for the pathologist, and does not alter the number of breast-conservation therapy (BCT) patients needing reoperation for positive margins. The purpose of this study was to determine if eliminating FS would change reoperation rates in BCT patients. STUDY DESIGN: Between January 2004 and December 2005, 1,218 patients had simultaneous BCT and SLN biopsy for invasive breast cancer. FS of the SLN was used selectively at the surgeon's discretion. Clinical and pathologic data were collected. RESULTS: Overall, 542 of 1,218 (44%) patients had positive margins. FS of the SLN was performed in 931 of 1,218 (76%) patients. In those having FS, the SLN positivity rate was 33% (306 of 931). FS identified the positive SLN in 170 of 306 (56%) patients with positive nodes, allowing for immediate ALND. But 101 of these 170 patients had positive lumpectomy margins; and FS of the SLN saved 69 of 931 (7%) patients a second operation. Of patients not having FS, 48 of 287 (17%) had a positive SLN on final pathology. Only 18 of 48 (those seen on routine hematoxylin and eosin) might have been seen on FS, potentially sparing reoperation. Half of patients not having FS required reexcision for positive margins. FS would have spared reoperation for only 8 of 287 (3%) patients in this group. Overall, of 354 of 1,218 patients with SLN metastases, 170 had immediate ALND and 98 had delayed ALND. Of those having delayed ALND, 68 of 98 also had positive margins. CONCLUSIONS: Among patients having BCT with SLN biopsy, FS identified the positive SLN in 56% of patients with positive SLNs, allowing immediate ALND, and was false negative in 44%. Margin status remains a frequent indication for reoperation in BCT; routine FS analysis of the SLN ultimately saves only a minority of patients a second operation.

The role of personality characteristics in young adult driving.

BACKGROUND: Motor vehicle injury is the major cause of mortality among young adults. Information about the individual characteristics of those who drive dangerously could enhance traffic safety programs. The goal of this research was to examine the association between various personality-related characteristics and risky driving behaviors. METHODS: Young adults in Michigan, USA (n = 5,362) were surveyed by telephone regarding several personality factors (risk-taking, hostility, aggression, tolerance of deviance, achievement expectations) and driving behaviors (competitive driving, risk-taking driving, high-risk driving, aggressive driving, and drink/driving). Michigan driver records were obtained to examine offenses, serious offenses, driving offense points, crashes and serious crashes in the three pre-interview years. Multivariate regression analyses, adjusting for age, race, and marital status were conducted separately by sex to identify personality factors related to driving. RESULTS: For men and women, greater risk-taking propensity, physical/verbal hostility, aggression, and tolerance of deviance were significant predictors of a competitive attitude toward driving, risk-taking driving, high-risk driving, driving aggression, and drink/driving. Greater risk-taking propensity, physical/verbal hostility, aggression, and to a small degree, expectations for achievement predicted higher numbers of offenses, serious offenses, and points. CONCLUSION: Traffic safety policies and programs could be enhanced through recognition of the role personality factors play in driving behavior and the incorporation of this knowledge into the design and implementation of interventions that modify the behaviors associated with them.

Longitudinal assessment of cardiovascular exercise performance after pediatric heart transplantation.

BACKGROUND: No existing longitudinal data document exercise performance after pediatric heart transplantation. We report the exercise performance findings from the longitudinal study of pediatric heart transplantation patients and the association of aerobic capacity with echocardiographic measures of graft function. METHODS: We performed a retrospective analysis of 28 children after heart transplantation who underwent 87 exercise tests and echocardiograms. Subjects exercised using graded cycle or treadmill protocols. Maximal oxygen consumption (VO2), physical working capacity, peak heart rate, and anaerobic threshold were evaluated. To measure systolic and diastolic function, shortening fraction and mitral valve pressure half-time (PHT) respectively, were obtained by echocardiography. RESULTS: The average age at transplantation was 10.9 +/- 5.6 years, at initial exercise test was 13.8 +/- 5.0 years, and at final exercise test was 15.8 +/- 5.2 years. Percent-predicted values at the initial exercise test were VO2, 59.3%; physical working capacity, 60.2%; and peak heart rate, 75.8%; these remained similarly decreased at the final exercise test. Shortening fraction and PHT were within normal limits, but PHT was significantly greater at final test (p < 0.05). The relationship of VO2% with time was statistically significant, described by a quadratic equation that included initial VO2% and time from heart transplantation. This relationship remained significant when the shortening fraction (p < .05) but not PHT was added as a covariate in the equation. CONCLUSIONS: Exercise performance after pediatric heart transplantation is impaired and, despite an initial improvement, declines over time. This can be explained by increasing diastolic dysfunction independent of donor graft age. If confirmed, these findings point the direction to further research aimed at limiting this aerobic capacity decline after heart transplantation.

Emergence of vaccine-related pneumococcal serotypes as a cause of bacteremia.

BACKGROUND: The heptavalent pneumococcal conjugate vaccine (PCV7) has decreased the incidence of invasive pneumococcal disease among children in the United States. In the postlicensure period, the impact of non-PCV7 serotypes against pediatric pneumococcal bacteremia is unknown. METHODS: Episodes of bacteremia due to Streptococcus pneumoniae and other respiratory pathogens (ORP), namely Neisseria meningitidis, Haemophilus influenzae, and Moraxella catarrhalis, were identified in children <18 years old at the Children's Hospital of Philadelphia from January 1999 to May 2005. For pneumococci, serotype distribution and antibiotic resistance were compared. RESULTS: A total of 188 episodes of pneumococcal bacteremia and 55 episodes of ORP bacteremia were identified. By comparing data from 1999-2000 with data from 2001 to May 2005, we found that the incidence of pneumococcal bacteremia decreased by 57%. The incidence of bacteremia caused by ORPs was unchanged; 1.43 episodes (95% confidence interval [CI], 0.84-2.29 episodes) to 1.25 (95% CI, 0.88-1.71) per 10,000 emergency department visits. Vaccine serotypes caused 85% of episodes of bacteremia in 1999-2000, compared with 34% of episodes of bacteremia in 2001 to May 2005 (P<.01). The percentage of isolates nonsusceptible to penicillin increased from 25% to 39% (P<.05). The percentage of episodes of pneumococcal bacteremia caused by vaccine-related serotypes--those of the same serogroup but not of the same serotype as PCV7--increased from 6% of episodes in the prelicensure period to 35% of episodes in the postlicensure period (P<.01). Rates of serotype pneumococcal bacteremia caused by nonvaccine serotypes were not statistically different between the 2 periods. CONCLUSIONS: The overall incidence of pneumococcal bacteremia decreased by 57% after the introduction of PCV7. During the postlicensure period, there were significant decreases in the incidence of pneumococcal bacteremia caused by vaccine serotypes; however, rates of penicillin resistance and bacteremia due to vaccine-related serotypes increased.

Examining trajectories of adolescent risk factors as predictors of subsequent high-risk driving behavior.

PURPOSE: To examine the effects on early high-risk driving behavior of changes over time (trajectories) in adolescent alcohol use, friends' support for drinking, susceptibility to peer pressure, and tolerance of deviance. METHODS: Statewide driving data were obtained for 4813 subjects who had completed at least two previous school-based questionnaires. The self-administered questionnaire data provided predictor measures from 5th through 10th grades. Trajectory information on predictor measures was summarized using each measure's slope over time and level at the 10th grade data collection (last value). Regression models used serious offenses, alcohol-related offenses, serious crashes, and alcohol-related crashes as outcomes, trajectory measures as predictors, and produced parameter estimates adjusted for demographic measures. Probabilities of having a serious offense or serious crash for five sample trajectories on each measure were obtained from the estimated regression models. RESULTS: All four predictor measures were important, particularly in predicting serious offenses, alcohol-related offenses, and alcohol-related crashes. The highest probabilities for young adult high-risk driving were found among those with consistently high or increasingly high trajectories of friends' support for drinking, susceptibility to peer pressure, and tolerance of deviance. CONCLUSIONS: Programs to prevent adolescent risk behavior should take into account environmental and personality influences. Prevention efforts need to emphasize preserving low levels, preventing increases, and promoting decreases over time of adolescent risk factors for unhealthy behaviors, such as high-risk driving.