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.

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.

Breast conservation and prolonged chemotherapy for locally advanced breast cancer: the University of Michigan experience.

PURPOSE: To determine whether breast conservation and prolonged neoadjuvant chemotherapy have efficacy in locally advanced breast cancer (LABC), as measured by survival and rate of breast conservation. MATERIALS AND METHODS: Eighty-nine patients with stage III disease were enrolled at the University of Michigan (UM) onto a prospective nonrandomized trial. Patients received nine 21-day cycles of neoadjuvant chemohormonal therapy that consisted of doxorubicin 30 mg/m2 and cyclophosphamide 750 mg/m2 intravenously on day 1, conjugated estrogens 0.625 mg orally twice daily on days 6 to 8, methotrexate 40 mg/m2 and fluorouracil 500 mg/m2 intravenously on day 8, and tamoxifen 10 mg orally twice daily on days 9 to 14. Patients with a negative biopsy received radiation only, while those with residual disease underwent mastectomy and postoperative radiotherapy. Eight more cycles of chemohormonal therapy were administered after local-regional therapy. RESULTS: The clinical response rate to neoadjuvant therapy was 97%, 28% of patients had a complete pathologic response evaluated at biopsy. Five-year overall and disease-free survival probabilities were 54% and 44%, respectively. The median disease-free survival time was 2.4 years. The 5-year actuarial rates of local-regional control with local failure as only first failure were 82% and 78% following radiotherapy, and mastectomy and radiotherapy, respectively (P = .99). CONCLUSION: Prolonged neoadjuvant chemohormonal therapy and biopsy-driven local therapy have efficacy in LABC, with 28% of patients being candidates for breast conservation and a 5-year overall survival rate of 54%.

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.

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.

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.

Pharmacologic erection with intracavernosal injection for men with sexual dysfunction following irradiation: a preliminary report.

Impotence is a possible consequence of treatment of pituitary adenomas and prostatic carcinomas. Following pituitary irradiation, the effect has been attributed to decreased gonadotrophins, while a variety of mechanisms, primarily vascular and neurogenic, have been proposed to explain the impotence following irradiation of prostatic carcinomas. Men with impotence of any etiology have been entered on a program to evaluate prospectively the efficacy of intracavernosal injection of vasoactive compounds in producing a satisfactory erection with pharmacologic means. Ten of these men had developed impotence following therapy for pituitary adenomas (2) or prostatic carcinomas (8). Test doses of 0.1 to 0.5 ml of a phentolamine (1 mg/ml) and papaverine (30 mg/ml) mixture were used; the dose was titrated to produce an erection deemed sufficient for vaginal penetration. All patients achieved a satisfactory response (i.e., tumescence and rigidity) lasting 10 minutes to 3 hours. Seven patients have continued in the pharmacologic erection program, with six patients functioning normally, and the remaining patient noting decreased tumescence after 18 months of treatment, but adequate erections are maintained with supplemental penile ring. Two patients have discontinued intracavernosal injections due to inconvenience, and one patient was lost to follow-up. Recent substitution of prostaglandin E1 (PGE1) has produced similar results and has replaced the phentolamine-papaverine combination. These preliminary results indicate that pharmacologic erection can be achieved in patients with impotence related to the treatment of pituitary and prostatic neoplasms and represents a reasonable alternative to implanted penile prostheses.

Microscopic extracapsular extension in the axilla: is this an indication for axillary radiotherapy?

PURPOSE: Although the axilla is often treated with radiotherapy (RT) postoperatively when microscopic extracapsular extension (ECE) of lymph nodal metastases is present, little data are available to assess axillary failure in the absence of such treatment. As it has been the practice at this institution to withhold axillary irradiation in the presence of microscopic extracapsular spread, we retrospectively analyzed our results for axillary recurrence, disease-free survival (DFS), and overall survival (OS). METHODS AND MATERIALS: Clinical records were reviewed of 82 women with Stage II node positive breast cancer treated with lumpectomy, axillary dissection, and RT in addition to systemic chemo/hormonal therapy. Axillary surgery consisted of a level I, II, +/- III dissection, with a median of 16.5 nodes removed. Tangential radiotherapy fields were used to treat the breast. All patients were also treated with an abbreviated supraclavicular field with the lateral border medial to the humeral head. Pathological sections were available for review in 72 of the 82 women. RESULTS: Twenty-seven of 72 (37.5%) had evidence of ECE; 45 of 72 (62.5%) had metastatic carcinoma confined within the nodal capsule. Clinical characteristics were comparable between the patients with and without ECE with the exception of (a) pathologic subtype, with a greater percentage of infiltrating ductal tumors associated with ECE (p = 0.044), and (b) number of positive lymph nodes, with 93% of patients without ECE having one to three positive nodes vs. only 56% among patients with ECE (p < 0.001). With a median follow-up of 40 months, 1 of 27 patients (4%) with ECE experienced an axillary failure as a component of first failure compared to 0 of 45 patients without ECE (p = 0.4). There were no isolated axillary failures. Five-year disease-free survival (72% without ECE vs. 57% with ECE, p = 0.12) and overall survival (83% vs. 53%, respectively, p = 0.068) suggested a less favorable outcome for patients with ECE. CONCLUSIONS: Microscopic ECE appears to be associated with increased axillary involvement and decreased survival rather than subsequent axillary failure. Our data suggest that radiotherapy to a dissected axilla may be omitted for the sole indication of microscopic extracapsular disease.

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.

Is c-erb B-2 a predictor for recurrent disease in early stage breast cancer?

PURPOSE: To assess the prognostic importance of c-erb B-2 expression in early stage breast cancer. METHODS AND MATERIALS: Immunohistochemical analysis for c-erb B-2 over-expression was retrospectively performed on 107 paraffin-embedded specimens of women with Stage I or II breast cancer entered in a randomized trial. Results were correlated with known prognostic factors such as pathologic axillary involvement, T-size, estrogen and progesterone receptor status, and nuclear grade. Immunohistochemical staining for c-erb B-2 protein expression was also correlated with breast/chest wall failure as well as survival without evidence of disease (NED) and overall survival. RESULTS: C-erb B-2 overexpression was positive in 21% of the biopsy specimens. A significant association was found between c-erb-2 positivity and lesions containing an intraductal component, with 62% of lesions staining positively for c-erb B-2 having an intraductal component compared to only 36% of lesions with an intraductal component staining negatively for the c-erb B-2 protein (p2 = .031). A significant correlation between c-erb B-2 protein over-expression and axillary nodal status, primary tumor size, nuclear grade, and estrogen and progesterone receptor status was not identified. Cox proportional hazards model did not show a significant effect of c-erb B-2 expression for NED or overall survival. CONCLUSION: Our study did not find over-expression of c-erb B-2 to reliably predict for recurrent disease in early stage breast cancer. This data can be added to other series comparing erb B-2 expression and disease outcome among node-positive and node-negative women with carcinoma 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.

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.

The effect of systemic therapy on local-regional control in locally advanced breast cancer.

One hundred and seven patients with locally advanced breast cancer were prospectively referred for multimodality treatment on protocol using chemohormonal therapy to maximal response followed by local treatment and maintenance therapy. Forty-eight patients (45%) were diagnosed with Stage IIIA disease, 46 (43%) with Stage IIIB inflammatory cancer, and 13 (12%) with Stage IIIB non-inflammatory disease. Induction therapy consisted of cyclophosphamide, doxorubicin, methotrexate, and 5-fluorouracil with hormonal synchronization using tamoxifen and conjugated estrogens. Local treatment was determined by response to chemotherapy. Patients with a clinical parital response underwent mastectomy followed by local-regional radiotherapy while patients with a clinical complete response were biopsied for pathologic correlation. Those with residual disease received mastectomy followed by radiotherapy while those with a pathologic complete response received radiation only to the intact breast and regional nodes. With a median follow-up of 64 months, patients with IIIA disease had a significantly lower local-regional failure rate compared to IIIB inflammatory patients, with the 5-year actuarial local-regional failure rate as only site of first failure 3% for IIIA disease versus 21% for IIIB inflammatory cancer (p = .02), and local-regional failure as any component of first failure 12% versus 36% (p = .01), respectively. When local-regional failure was analyzed by repeat biopsy, 5/31 (16%) patients with a pathologic complete response treated with radiation only developed a local-regional failure versus 2/53 (4%) with residual disease treated with mastectomy and postoperative radiotherapy. The 5-year actuarial local-regional failure rate as first site of failure was 23% for radiation only versus 5% for mastectomy and post-operative radiotherapy (p = .07). The response to chemotherapy did not reliably predict local-regional control. Both relapse-free survival and overall survival were significantly better for IIIA versus IIIB patients; stratification by repeat biopsy did not however, significantly affect either relapse-free or overall survival.

Primary soft tissue sarcomas of the breast: local-regional control with post-operative radiotherapy.

PURPOSE: A retrospective analysis was undertaken to determine the efficacy of postoperative radiotherapy in patients with primary sarcoma of the breast. METHODS AND MATERIALS: Ten patients with high-grade nonmetastatic primary sarcoma of the breast were treated at the National Cancer Institute, NIH, between 1979 and 1989 with mastectomy and adjuvant radiotherapy. Chemotherapy was given to three patients as part of a randomized trial. RESULTS: With a median potential followup of 99 months postoperatively, seven patients remain alive and without evidence of disease 142, 119, 82, 48, 45, 28, and 19 months postoperatively. Three patients died of metastatic disease 7, 25, and 29 months, postoperatively. There were no local or regional failures. Actuarial 5-year disease free and overall survival were 68% and 66%, respectively. CONCLUSION: Sarcomas of the breast have a prognosis similar to that of extremity sarcomas. When adjuvant radiotherapy is used, excellent local control may be achieved.

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.

Radiation protection of rat parenchymal hepatocytes with S-2-(3-aminopropylamino)ethylphosphorothioic acid.

The ability to protect parenchymal hepatocytes from ionizing radiation damage with S-2-(3-aminopropylamino)-ethylphosphorothioic acid (WR-2721) was investigated. The clonogenic survival of irradiated hepatocytes was determined with an in vivo transplantation assay system. Injection of WR-2721 (400 mg/kg) immediately after irradiation was without protective effect. In contrast, an intraperitoneal (IP) injection of WR-2721 30 min prior to 60Co irradiation resulted in a significant protection of parenchymal hepatocytes. The mean lethal dose (Do) and extrapolation number (n) of the survival curve for unprotected hepatocytes as 2.9 Gy and 1.8, respectively. The Do and n values for hepatocytes protected with WR-2721 were 5.7 Gy and 1.8, respectively. Thus, WR-2721 at a concentration of 400 mg/kg acted as a dose modifying agent with a dose modifying factor of approximately 2.0. Decreasing the concentration of WR-2721 to 200 mg/kg did not significantly reduce the radioprotective effectiveness of the drug. However, at concentrations less than 200 mg/kg, the radioprotective effect decreased in a dose-response manner with a concentration of 150 mg/kg providing 50% of the maximum effect observed.

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.

Defining the role of post-mastectomy radiotherapy: the new evidence.

In an early meta-analysis of the post-mastectomy radiotherapy trials, the use of obsolete radiotherapy techniques resulted in increased cardiac mortality. With maturation of these data and inclusion of more recent trials, however, a survival advantage is now emerging. This, in concert with the improvement in disease-free and overall survival evident in the larger studies of post-mastectomy radiotherapy with adjuvant chemotherapy, generates a new enthusiasm in support of post-mastectomy radiotherapy. The lessons we have learned from the earlier trials emphasize the importance of precise radiation planning and delivery so that long-term morbidity can be minimized and survival improved by the reduction in breast cancer deaths.

Human bite marks. Differential diagnosis.

Human bite marks are common findings in cases of fights among children, child abuse, sexual abuse, among institutionalized persons, and in a number of homicide cases. Human bites can mimic annular or arciform dermatoses. These are reviewed from both a clinical and histologic viewpoint. An example is presented of a 2 year-old girl with several annular lesions that were clinically mistaken for a dermatophyte infection. Antifungal medications were ineffective. After several days, a dermatologist identified the lesions as human bites. Physicians and other health care workers must be able to differentiate the clinical appearance of bite marks from other dermatologic diseases at an early stage so as to initiate proper therapy and counseling and, if indicated, a search for the perpetrator.