The HAPPE plus Event-Related (HAPPE+ER) software: A standardized preprocessing pipeline for event-related potential analyses.

Event-Related Potential (ERP) designs are a common method for interrogating neurocognitive function with electroencephalography (EEG). However, the traditional method of preprocessing ERP data is manual-editing - a subjective, time-consuming processes. A number of automated pipelines have recently been created to address the need for standardization, automation, and quantification of EEG data pre-processing; however, few are optimized for ERP analyses (especially in developmental or clinical populations). We propose and validate the HAPPE plus Event-Related (HAPPE+ER) software, a standardized and automated pre-processing pipeline optimized for ERP analyses across the lifespan. HAPPE+ER processes event-related potential data from raw files through preprocessing and generation of event-related potentials for statistical analyses. HAPPE+ER also includes post-processing reports of both data quality and pipeline quality metrics to facilitate the evaluation and reporting of data processing in a standardized manner. Finally, HAPPE+ER includes post-processing scripts to facilitate validating HAPPE+ER performance and/or comparing to performance of other preprocessing pipelines in users' own data via simulated ERPs. We describe multiple approaches with simulated and real ERP data to optimize pipeline performance and compare to other methods and pipelines. HAPPE+ER software is freely available under the terms of GNU General Public License at https://www.gnu.org/licenses/#GPL.

Definition of the supraclavicular and infraclavicular nodes: implications for three-dimensional CT-based conformal radiation therapy.

PURPOSE: To delineate with computed tomography (CT) the anatomic regions containing the supraclavicular (SCV) and infraclavicular (IFV) nodal groups, to define the course of the brachial plexus, to estimate the actual radiation dose received by these regions in a series of patients treated in the traditional manner, and to compare these doses to those received with an optimized dosimetric technique. MATERIALS AND METHODS: Twenty patients underwent contrast material-enhanced CT for the purpose of radiation therapy planning. CT scans were used to study the location of the SCV and IFV nodal regions by using outlining of readily identifiable anatomic structures that define the nodal groups. The brachial plexus was also outlined by using similar methods. Radiation therapy doses to the SCV and IFV were then estimated by using traditional dose calculations and optimized planning. A repeated measures analysis of covariance was used to compare the SCV and IFV depths and to compare the doses achieved with the traditional and optimized methods. RESULTS: Coverage by the 90% isodose surface was significantly decreased with traditional planning versus conformal planning as the depth to the SCV nodes increased (P < .001). Significantly decreased coverage by using the 90% isodose surface was demonstrated for traditional planning versus conformal planning with increasing IFV depth (P = .015). A linear correlation was found between brachial plexus depth and SCV depth up to 7 cm. CONCLUSION: Conformal optimized planning provided improved dosimetric coverage compared with standard techniques.

Observations of residual differentiation potential during lineage commitment.

We have recently described a subset of the multipotent progenitor pool that contains a common lymphoid progenitor. This subset of cells is lineage negative and expresses c-kit and Sca-1, but lacks expression of Thy 1.1 (Thyneg). Based on the observation that lethally irradiated mice transplanted with these cells die from anemia unless supported with competitor marrow, we hypothesized that these progenitors lacked erythroid potential. We analyzed the erythroid potential of these cells by transplanting them into mice allelic at the hemoglobin locus and compared their erythroid potential with the Thy-1.1low (Thylow) subset that contains hematopoietic stem cells. We also performed CFU-C assays in methylcellulose containing recombinant cytokines and determined erythroid contribution to colonies using in situ benzidine staining. Donor-derived hemoglobin was observed following transplant of Thyneg cells, even though 19 of 20 of these animals died from anemia. In contrast, recipients of Thylow cells showed complete donor-derived engraftment 30 days following transplant. While approximately 60% of day 4 colonies derived from Thyneg cells expressed hemoglobin, by day 11 less than 5% were hemoglobinized. In contrast, greater than 70% of the Thylow subset contained hemoglobinized cells at the end of the observation period. A similar transient appearance of myeloid progeny was also observed in colonies derived from c-kitlow Thyneg lymphoid progenitor cells. We conclude that these studies demonstrate commitment to the lymphoid lineage at the Thylow-to-Thyneg interface, and that the loss of erythroid and myeloid potential is gradual rather than abrupt. Hemoglobinized colonies may be undergoing apoptosis because of down-regulation of GATA-1 or because of a death signal from surrounding nonerythrocytic cells.

Mammographically detected ductal carcinoma in situ of the breast treated with breast-conserving surgery and definitive breast irradiation: long-term outcome and prognostic significance of patient age and margin status.

PURPOSE: This study was performed to determine the long-term outcome for women with mammographically detected ductal carcinoma in situ (DCIS; intraductal carcinoma) of the breast treated with breast-conserving surgery followed by definitive breast irradiation. METHODS AND MATERIALS: An analysis was performed of 422 mammographically detected intraductal breast carcinomas in 418 women from 11 institutions in North America and Europe. All patients were treated with breast-conserving surgery followed by definitive breast irradiation. The median follow-up time was 9.4 years (mean, 9.4 years; range, 0.1-19.8 years). RESULTS: The 15-year overall survival rate was 92%, and the 15-year cause-specific survival rate was 98%. The 15-year rate of freedom from distant metastases was 94%. There were 48 local failures in the treated breast, and the 15-year rate of any local failure was 16%. The median time to local failure was 5.0 years (mean, 5.7 years; range, 1.0-15.2 years). Patient age at the time of treatment and final pathology margin status from the primary tumor excision were both significantly associated with local failure. The 10-year rate of local failure was 31% for patient age < or = 39 years, 13% for age 40-49 years, 8% for age 50-59 years, and 6% for age > or = 60 years (p = 0.0001). The 10-year rate of local failure was 24% when the margins of resection were positive, 9% when the margins of resection were negative, 7% when the margins of resection were close, and 12% when the margins of resection were unknown (p = 0.030). Patient age < or = 39 years and positive margins of resection were both independently associated with an increased risk of local failure (p = 0.0006 and p = 0.023, respectively) in the multivariable Cox regression model. CONCLUSIONS: The 15-year results from the present study demonstrated high rates of overall survival, cause-specific survival, and freedom from distant metastases following the treatment of mammographically detected ductal carcinoma in situ of the breast using breast-conserving surgery and definitive breast irradiation. Younger age and positive margins of resection were both independently associated with an increased risk of local failure. The 15-year results in the present study serve as an important benchmark for comparison with other treatment modalities. These results support the use of breast-conserving surgery and definitive breast irradiation for the treatment of appropriately selected patients with mammographically detected ductal carcinoma in situ of the breast.

Salvage treatment for local recurrence after breast-conserving surgery and radiation as initial treatment for mammographically detected ductal carcinoma in situ of the breast.

BACKGROUND: The purpose of the current study is to evaluate the outcome of salvage treatment for local recurrence after breast-conserving surgery and radiation as initial treatment for mammographically detected ductal carcinoma in situ (DCIS; intraductal carcinoma) of the breast. METHODS: An analysis was performed of 42 patients with local only first failure (n = 41) or local-regional only first failure (n = 1) after breast-conserving surgery and radiation treatment had been given for DCIS of the breast. Surgical treatment at the time of local recurrence included mastectomy (n = 37; 88%) or excision (n = 5; 12%). Adjuvant systemic therapy at the time of local recurrence was chemotherapy (n = 3; 7%), tamoxifen (n = 8; 19%), both (n = 1; 2%), none (n = 29; 69%), or unknown (n = 1; 2%). The median interval from the time of initial treatment to local recurrence was 4.8 years (range = 1.0-15.2 yrs). The median follow-up after salvage treatment was 4.5 years (range = 0.2-12.8 yrs). RESULTS: At the time of the local recurrence, 22 patients (52%) had invasive ductal carcinoma, 18 patients (43%) had DCIS, 1 patient (2%) had invasive lobular carcinoma, and 1 patient (2%) had angiosarcoma. After salvage treatment, the rate of overall survival and the rate of cause specific survival for all 42 patients were 92% at both 5- and 8-years after treatment. The rate of freedom from distant metastases was 89% at 5 and 8 years. Favorable prognostic factors after salvage treatment were DCIS as the histology of the local recurrence and mammography only as the method of detection of the local recurrence. CONCLUSIONS: The results of salvage treatment in the current study demonstrated that local recurrences were salvaged with high rates of survival and freedom from distant metastases. These results support the use of breast-conserving surgery and radiation for initial management of DCIS of the breast.

Complications and patient satisfaction following expander/implant breast reconstruction with and without radiotherapy.

PURPOSE: To compare the rates of complications and patient satisfaction among breast cancer patients treated with mastectomy and tissue expander/implant reconstruction with and without radiotherapy. METHODS AND MATERIALS: As part of the Michigan Breast Reconstruction Outcome Study (MBROS), breast cancer patients undergoing mastectomy with reconstruction were prospectively evaluated with respect to complications, general patient satisfaction with reconstruction, and esthetic satisfaction. Included in this study was a cohort of women who underwent breast reconstruction using an expander/implant (E/I). A subset of these patients also received radiotherapy (RT). At 1 and 2 years postoperatively, a survey was administered which included 7 items assessing both general satisfaction with their reconstruction and esthetic satisfaction. Complication data were also obtained at the same time points using hospital chart review. Radiotherapy patients identified in the University of Michigan Radiation Oncology database that underwent expander/implant reconstruction but not enrolled in the MBROS study were also added to the analysis. RESULTS: Eighty-one patients underwent mastectomy and E/I reconstruction. Nineteen patients received RT and 62 underwent reconstruction without RT. The median dose delivered to the reconstructed breast/chest wall, including boost, was 60.4 Gy (range, 50.0-66.0 Gy) in 1.8- to 2.0-Gy fractions. With a median follow-up of 31 months from the date of surgery, complications occurred in 68% (13/19) of the RT patients compared to 31% (19/62) in the no RT group (p = 0.006). Twelve of 81 patients (15%) had a breast reconstruction failure. Reconstruction failure was significantly associated with experiencing a complication (p = 0.0001) and the use of radiotherapy (p = 0.005). The observed reconstruction failure rates were 37% (7/19) and 8% (5/62) for patients treated with and without radiotherapy, respectively. Tamoxifen was associated with a borderline risk of complications (p = 0.07) and a significant risk of reconstruction failure (p = 0.01). Sixty-six patients of the study group completed the satisfaction survey; 15 patients did not. To offset potential bias for patients not completing the survey, we analyzed satisfaction data assuming "dissatisfaction" scores for surveys not completed. In the analysis of patients with unilateral E/I placement, reconstruction failure was significantly associated with a lower general satisfaction (p = 0.03). Ten percent of patients experiencing a reconstruction failure were generally satisfied compared to 23% who completed E/I reconstruction. In addition, tamoxifen use was associated with a significantly decreased esthetic satisfaction (p = 0.03). Radiotherapy was not associated with significantly decreased general or esthetic satisfaction. CONCLUSION: Irradiated patients had a higher rate of expander/implant reconstruction failure and complications than nonirradiated patients. Despite these differences, our pilot data suggest that both general satisfaction and patient esthetic satisfaction were not significantly different following radiotherapy compared to patients who did not receive RT. Although statistical power was limited in the present study and larger patient numbers are needed to validate these results, this study suggests comparable patient assessment of cosmetic outcome with or without radiotherapy in women who successfully complete expander/implant reconstruction.

Phenotypic distinction and functional characterization of pro-B cells in adult mouse bone marrow.

A lymphoid-committed progenitor population was isolated from mouse bone marrow based on the cell surface phenotype Thy-1.1(neg)Sca-1(pos)c-Kit(low)Lin(neg). These cells were CD43(pos)CD24(pos) on isolation and proliferated in response to the cytokine combination of steel factor, IL-7, and Flt3 ligand. Lymphoid-committed progenitors could be segregated into more primitive and more differentiated subsets based on expression of AA4.1. The more differentiated subset generated only B lymphoid cells in 92% of total colonies assayed, lacked T lineage potential, and expressed Pax5. These studies have therefore defined and isolated a B lymphoid-committed progenitor population at a developmental stage corresponding to the initial expression of CD45R.

Treatment guidelines and techniques in delivery of postmastectomy radiotherapy in management of operable breast cancer.

Radiation therapy has been shown to statistically significantly reduce the risk of locoregional recurrence in high-risk patients with operable breast cancer following mastectomy and systemic therapy. Recent trials have also demonstrated a significant survival benefit following radiotherapy in high-risk patients. Therefore, it is important to identify the patients who could potentially derive that survival benefit and to not offer treatment to those patients who are not at increased risk for failure. Established risk factors that predict for increased rates of locoregional recurrence include axillary lymph node involvement and T3 (or T4) disease. While treatment-related factors, such as the extent of the axillary dissection and extent of lymph nodal positivity, also undoubtedly affect locoregional recurrence, additional studies are needed to define the magnitude of their risk. Locoregional patterns of failure have identified the chest wall and supraclavicular/infraclavicular regions to be the most common sites of locoregional failure following mastectomy, which justifies treatment to these regions. While long-term complications are uncommon following locoregional radiotherapy, careful treatment planning is critical to minimize cardiac (and pulmonary) toxicity.

Effect of radiotherapy after breast-conserving treatment in women with breast cancer and germline BRCA1/2 mutations.

PURPOSE: Recent laboratory data suggest a role for BRCA1/2 in the cellular response to DNA damage. There is a paucity of clinical data, however, examining the effect of radiotherapy (RT), which causes double-strand breaks, on breast tissue from BRCA1/2 mutation carriers. Thus the goals of this study were to compare rates of radiation-associated complications, in-breast tumor recurrence, and distant relapse in women with BRCA1/2 mutations treated with breast-conserving therapy (BCT) using RT with rates observed in sporadic disease. PATIENTS AND METHODS: Seventy-one women with a BRCA1/2 mutation and stage I or II breast cancer treated with BCT were matched 1:3 with 213 women with sporadic breast cancer. Conditional logistic regression models were used to compare matched cohorts for rates of complications and recurrence. RESULTS: Tumors from women in the genetic cohort were associated with high histologic (P =.0004) and nuclear (P =.009) grade and negative estrogen (P=.0001) and progesterone (P=.002) receptors compared with tumors from the sporadic cohort. Using Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer toxicity scoring, there were no significant differences in acute or chronic morbidity in skin, subcutaneous tissue, lung, or bone. The 5-year actuarial overall survival, relapse-free survival, and rates of tumor control in the treated breast for the patients in the genetic cohort were 86%, 78%, and 98%, respectively, compared with 91%, 80%, and 96%, respectively, for the sporadic cohort (P = not significant). CONCLUSION: There was no evidence of increased radiation sensitivity or sequelae in breast tissue heterozygous for a BRCA1/2 germline mutation compared with controls, and rates of tumor control in the breast and survival were comparable between BRCA1/2 carriers and controls at 5 years. Although additional follow-up is needed, these data may help in discussing treatment options in the management of early-stage hereditary breast cancer and should provide reassurance regarding the safety of administering RT to carriers of a germline BRCA1/2 mutation.

Rapid, B lymphoid-restricted engraftment mediated by a primitive bone marrow subpopulation.

Utilizing multiparameter flow cytometry, we have defined a subset of bone marrow cells containing lymphoid-restricted differentiation potential after i.v. transplantation. Bone marrow cells characterized by expression of the Sca-1 and c-kit Ags and lacking Ags of differentiating lineages were segregated into subsets based on allele-specific Thy-1.1 Ag expression. Although hematopoietic stem cells were recovered in the Thy-1.1low subset as previously described, the Thy-1.1neg subset consisted of progenitor cells that preferentially reconstituted the B lymphocyte lineage after i.v. transplantation. Recipients of Thy-1.1neg cells did not survive beyond 30 days, presumably due to the failure of erythroid and platelet lineages to recover after transplants. Thy-1.1neg cells predominantly reconstituted the bone marrow and peripheral blood of lethally irradiated recipients with B lineage cells within 2 weeks, although a low frequency of myeloid lineage cells was also detected. In contrast, myeloid progenitors outnumbered lymphoid progenitors when the Thy-1.1neg population was assayed in culture. When Thy-1. 1low stem cells were rigorously excluded from the Thy-1.1neg subset, reconstitution of T lymphocytes was rarely observed in peripheral blood after i.v. transplantation. Competitive repopulation studies showed that the B lymphoid reconstitution derived from Thy-1.1neg cells was not sustained over a 20-wk period. Therefore, the Thy-1. 1neg population defined in these studies includes transplantable, non-self-renewing B lymphocyte progenitor cells.

Expression of CD27 on murine hematopoietic stem and progenitor cells.

Hematopoietic stem cells (HSC) are defined by self-renewal and multilineage differentiation potentials. In order to uncover the genetic program of HSC, we utilized high-density arrays to compare gene expression in highly purified mouse HSC and their mature progeny. One molecule specifically expressed in immature cells is CD27, a member of the TNF receptor family previously shown to play roles in lymphoid proliferation, differentiation, and apoptosis. We show here that the CD27 protein is expressed by about 90% of cells in a purified HSC population. Interestingly, the CD27pos cells are enriched for cells with short-term hematopoietic activities (colony forming potential in vivo and in vitro), while the minority CD27neg population is more effective in clonal long-term transplantation.

Cost-effectiveness of adding an electron-beam boost to tangential radiation therapy in patients with negative margins after conservative surgery for early-stage breast cancer.

PURPOSE: Electron-beam boosts (EBB) are routinely added after conservative surgery and tangential radiation therapy (TRT) for early-stage breast cancer. We performed an incremental cost-utility analysis to evaluate their cost-effectiveness. METHODS: A Markov model examined the impact of adding an EBB to TRT from a societal perspective. Outcomes were measured in quality-adjusted life years (QALYs). On the basis of the Lyon trial, the EBB was assumed to reduce local recurrences by approximately 2% at 10 years but to have no impact on survival. Patients' utilities were used to adjust for quality of life. Given the small absolute benefit of the EBB, baseline utilities were assumed to be the same with or without it, an assumption evaluated by Monte Carlo simulation. Direct medical, time, and travel costs were considered. RESULTS: Adding the EBB led to an additional cost of $2,008, an increase of 0.0065 QALYs and, therefore, an incremental cost-effectiveness ratio of over $300,000/QALY. In a sensitivity analysis, the ratio was moderately sensitive to the efficacy and cost of the EBB and highly sensitive to patients' utilities for treatment without it. Even if patients do value a small risk reduction, the mean cost-effectiveness ratio estimated by the Monte Carlo simulation remains high, at $70,859/QALY (95% confidence interval, $53,141 to $105,182/QALY). CONCLUSION: On the basis of currently available data, the cost-effectiveness ratio for the EBB is well above the commonly cited threshold for cost-effective care ($50,000/QALY). The EBB becomes cost-effective only if patients place an unexpectedly high value on the small absolute reduction in local recurrences achievable with it.

Late effects of dose fractionation on the mechanical properties of breast skin following post-lumpectomy radiotherapy.

PURPOSE: Late radiation-induced skin effects were studied in a multicenter project using our new sensitive noninvasive viscoelasticity skin analyzer (VESA). METHODS AND MATERIALS: Skin viscoelasticity and anisotropy were examined quantitatively in symmetric areas of both breasts in healthy women and in 110 breast cancer patients who underwent lumpectomy and radiotherapy. These parameters were evaluated by the VESA measurement of the speed of elastic wave propagation in the skin; higher VESA readings correspond to higher skin stiffness. Effect of radiation was estimated by comparison of the data recorded in the irradiated versus nonirradiated breast of the same patient. RESULTS: Skin viscoelasticity and anisotropy were similar in contralateral areas of the breasts in healthy controls as well as in the nonirradiated breasts of the patients. With age, skin viscoelasticity decreased and anisotropy increased similarly in both breasts. Radiotherapy, by a total radiation dose in the range of 45-50 Gy given with 1.8 Gy/fraction (fx) resulted in a similar minor, but still statistically significant, increase of skin stiffness relative to control. The effect was more pronounced when a dose of 50 Gy was given in a higher dose/fraction of 2.5 Gy. CONCLUSION: We found that the increase in dose of radiation per fraction had much more impact on the development of late skin effects than elevation in the total dose given.

Postmastectomy radiotherapy: future directions.

With careful interpretation of existing studies of postmastectomy radiotherapy, much has been learned about the ability of radiotherapy to significantly reduce local failure and potentially impact on survival. With this knowledge, however, has come additional questions about the mechanisms by which radiotherapy could affect systemic control and the extent of that benefit. Therefore, these questions need to be investigated in well-designed, randomized trials that incorporate aggressive surgical techniques and contemporary chemotherapy regimens into the clinical plan. A trial that is currently in progress should give additional insight into whether regional irradiation in the modern era, which incorporates the internal mammary nodes in the radiotherapy field, impacts systemic control. An upcoming trial will investigate whether women at moderate risk for locoregional failure will benefit from comprehensive radiotherapy after aggressive surgery and chemotherapy. And, although no national studies are currently planned to test the optimal sequencing of radiotherapy and chemotherapy, consideration should be given to studying this issue in large, randomized trials.

Conservative surgery and radiotherapy for early-stage breast cancer using a lung density correction: the University of Michigan experience.

PURPOSE: Although an abundance of reports detail the successful use of definitive radiotherapy of the breast in the treatment in Stage I or II breast cancer, little data have been published concerning the use of lung density correction and its effect upon long-term outcome. As it has been the practice at the University of Michigan to routinely use lung density correction in the dose calculations to the breast, we retrospectively analyzed our results for local control, relapse-free, and overall survival. METHODS AND MATERIALS: Clinical records were reviewed of 429 women with Stage I or II breast cancer treated with lumpectomy, axillary dissection, and breast irradiation with or without systemic chemo/hormonal therapy. Tangential radiotherapy fields delivering 45 to 50 Gy were used to treat the entire breast. A boost was delivered in 95% of cases for a total tumor bed dose of 60 to 66 Gy. All treatment plans were calculated using a lung density correction. RESULTS: With a median follow up of 4.4 years, the 5-year actuarial rate of local control with local failure as the only site of first failure was 96% (95% CI 94-98%). Univariate analysis for local failure as only first failure found the following factors to statistically predict for increased risk of breast recurrence: young age (< or =35 years old), premenopausal status, tumor size >2 cm, positive family history, and positive microscopic margins. Multivariate analysis revealed young age and margin status to be the only factors remaining significant for local failure. The 5-year actuarial relapse-free survival was 85% (95% CI 81-89%); overall survival at 5 years was 90% (95% CI 87-94%). CONCLUSIONS: Lung density correction results in rates of local control, disease-free, and overall survival at 5 years that compare favorably with series using noncorrected unit density calculations. While we will continue to update our results with increasing follow-up, our 5-year data indicate that the use of lung-density correction for dosimetric accuracy does not compromise local control.

The conservative management of Paget's disease of the breast with radiotherapy.

BACKGROUND: The purpose of this study was to evaluate the feasibility of breast-conserving therapy involving limited surgery and definitive radiotherapy as a treatment for Paget's disease, and to determine the disease free and overall survival associated with this approach. METHODS: The authors retrospectively reviewed the charts of all patients treated during the period 1980-1994 for Paget's disease of the breast who did not present with a palpable mass or mammographic density. Through a collaborative review, 30 cases were identified. A biopsy confirming the presence of typical Paget's cells was performed on all patients. All patients received external beam radiotherapy to the breast, with a median dose of 50 gray (Gy). Ninety-seven percent received a boost to the remaining nipple or tumor bed, with a median dose to the tumor bed of 61.5 Gy. RESULTS: The median follow-up for surviving patients was 62 months. Three patients (10%) developed a recurrence in the breast as the only site of first failure, and 2 additional patients (7%) experienced failure in the breast as a component of first failure. The median time to local failure was 69 months. The 5- and 8-year actuarial estimates of local failure as the only site of first failure were 9% (95% confidence interval [CI], 0-20%) and 16% (95% CI, 0-31%), respectively. Of the 5 patients with local failures, 3 were among 22 patients (14%) who underwent complete resection of the nipple or nipple-areola complex, compared with 2 failures among 6 patients (33%) after partial resection (P = 0.29). There were no failures among 2 patients who had a biopsy only. Four of 5 local failures were salvaged by mastectomy, and 3 of these patients were free of disease after a median follow-up of 52 months. The 5- and 8-year estimates of disease free survival for the overall series were both 95% (95% CI, 87-100%); cause specific overall survival was 100% at 8 years. CONCLUSIONS: Breast-conserving therapy involving complete resection of the nipple-areola complex followed by definitive radiotherapy is a viable alternative to mastectomy in the treatment of Paget's disease. High rates of disease free and cause specific survival, in addition to adequate local control, justify consideration of a conservative approach.