The effect of loss of immunity on noise-induced sustained oscillations in epidemics.

The effect of loss of immunity on sustained population oscillations about an endemic equilibrium is studied via a multiple scales analysis of a SIRS model. The analysis captures the key elements supporting the nearly regular oscillations of the infected and susceptible populations, namely, the interaction of the deterministic and stochastic dynamics together with the separation of time scales of the damping and the period of these oscillations. The derivation of a nonlinear stochastic amplitude equation describing the envelope of the oscillations yields two criteria providing explicit parameter ranges where they can be observed. These conditions are similar to those found for other applications in the context of coherence resonance, in which noise drives nearly regular oscillations in a system that is quiescent without noise. In this context the criteria indicate how loss of immunity and other factors can lead to a significant increase in the parameter range for prevalence of the sustained oscillations, without any external driving forces. Comparison of the power spectral densities of the full model and the approximation confirms that the multiple scales analysis captures nonlinear features of the oscillations.

Stochastic phase dynamics: multiscale behavior and coherence measures.

A multiscale approach is used to derive stochastic amplitude and phase dynamics for a canonical noise-sensitive model exhibiting coherence resonance. Explicit expressions for the dependence on noise levels and model type are compared with computational coherence measures.

Workshop on partial breast irradiation: state of the art and the science, Bethesda, MD, December 8-10, 2002.

Breast conserving surgery followed by radiation therapy has been accepted as an alternative to mastectomy in the management of patients with early-stage breast cancer. Over the past decade there has been increasing interest in a variety of radiation techniques designed to treat only the portion of the breast deemed to be at high risk for local recurrence (partial-breast irradiation [PBI]) and to shorten the duration of treatment (accelerated partial-breast irradiation [APBI]). To consider issues regarding the equivalency of the various radiation therapy approaches and to address future needs for research, quality assurance, and training, the National Cancer Institute, Division of Cancer Treatment and Diagnosis, Radiation Research Program, hosted a Workshop on PBI in December 2002. Although 5- to 7-year outcome data on patients treated with PBI and APBI are now becoming available, many issues remain unresolved, including clinical and pathologic selection criteria, radiation dose and fractionation and how they relate to the standard fractionation for whole breast irradiation, appropriate target volume, local control within the untreated ipsilateral breast tissue, and overall survival. This Workshop report defines the issues in relation to PBI and APBI, recommends parameters for consideration in clinical trials and for reporting of results, serves to enhance dialogue among the advocates of the various radiation techniques, and emphasizes the importance of education and training in regard to results of PBI and APBI as they become emerging clinical treatments.

Asymptotic analysis of noise sensitivity in a neuronal burster.

A combination of asymptotic approaches provides a new analysis of the effect of small noise on the bursting cycle of a neuronal burster of elliptic type (type III). The analysis is applied to a stochastic model of an excitable spine, with an activity-dependent stem conductance, that exhibits conditional burst dynamics. First, we give an asymptotic approximation to the probability density for the state of the system. This density is used to compute several quantities which describe the influence of the noise on the transition from the silent to the active phase. Second, we also use a multiscale method to provide a reduced system for analysing the effect of noise on the transition out of the active phase. The combination of these two approaches results in a new framework for a quantitative description of how noise shortens the burst cycle, which measures the significant influence of small noise. For the stochastic spine model, this study suggests that small amplitude noise can significantly influence the activity-dependent morphological plasticity of dendritic spines. The techniques used in this paper combine probabilistic and asymptotic methods, and have been generalized for other noisy nonlinear systems.

Brachytherapy in the treatment of breast cancer.

Whole-breast external-beam radiation therapy (EBRT) involves a 6-week course of fractionated treatments. In contrast, brachytherapy can be completed in a 4- to 5-day treatment course. Because of this shortened time frame, there has been interest in breast brachytherapy as a sole modality after lumpectomy. The American Brachytherapy Society (ABS) has issued guidelines specifically for the use of brachytherapy in breast carcinoma. In these guidelines, the ABS addresses important areas of controversy related to the indications, execution, and evaluation of breast implants when utilized in the following settings: as the sole treatment modality following lumpectomy, as an alternative to a 6-week course of EBRT following lumpectomy, as a boost following whole-breast irradiation, and for the treatment of local recurrences following breast-conservation treatment. The ABS recommends a precise definition and meticulous delineation of the clinical target volume. In addition, the Society recommends the routine use of dose-volume histograms and a dose-homogeneity index as tools to ensure reproducible brachytherapy and to allow interinstitutional comparisons. Brachytherapy as a sole modality is currently considered investigational and should be performed in the context of a controlled clinical trial. Practitioners and cooperative groups are encouraged to use these guidelines to formulate treatment and dose-reporting policies, but responsibility for medical decisions ultimately rests with the treating radiation oncologist.

Postmastectomy radiotherapy: clinical practice guidelines of the American Society of Clinical Oncology.

OBJECTIVE: To determine indications for the use of postmastectomy radiotherapy (PMRT) for patients with invasive breast cancer with involved axillary lymph nodes or locally advanced disease who receive systemic therapy. These guidelines are intended for use in the care of patients outside of clinical trials. POTENTIAL INTERVENTION: The benefits and risks of PMRT in such patients, as well as subgroups of these patients, were considered. The details of the PMRT technique were also evaluated. OUTCOMES: The outcomes considered included freedom from local-regional recurrence, survival (disease-free and overall), and long-term toxicity. EVIDENCE: An expert multidisciplinary panel reviewed pertinent information from the published literature through July 2000; certain investigators were contacted for more recent and, in some cases, unpublished information. A computerized search was performed of MEDLINE data; directed searches based on the bibliographies of primary articles were also performed. VALUES: Levels of evidence and guideline grades were assigned by the Panel using standard criteria. A "recommendation" was made when level I or II evidence was available and there was consensus as to its meaning. A "suggestion" was made based on level III, IV, or V evidence and there was consensus as to its meaning. Areas of clinical importance were pointed out where guidelines could not be formulated due to insufficient evidence or lack of consensus. RECOMMENDATIONS: The recommendations, suggestions, and expert opinions of the Panel are described in this article. VALIDATION: Seven outside reviewers, the American Society of Clinical Oncology (ASCO) Health Services Research Committee members, and the ASCO Board of Directors reviewed this document.

Long-term results of wide-field brachytherapy as the sole method of radiation therapy after segmental mastectomy for T(is,1,2) breast cancer.

BACKGROUND: We hypothesized that wide-field brachytherapy (BRT) after margin negative excision would result in complication rates, local recurrence rates, and cosmesis scores equivalent to external beam radiotherapy (ERT). METHODS: Patients with T(is,1,2) tumors less than or equal to 4 cm, 0 to 3 positive axillary nodes, and negative inked surgical margins were entered prospectively into BRT phase I/II trial. Patients who met the eligibility criteria for BRT but were treated with ERT during the same time period were retrospectively identified as controls. A blinded panel of healthcare professionals graded cosmetic outcome. RESULTS: Fifty patients with 51 breast cancers received BRT from January 1992 to October 1993. We identified 94 patients eligible for BRT but concurrently treated with ERT. At a median follow-up of 75 months, the two groups were similar for grade III treatment toxicities, local/regional recurrence rates, and cosmesis scores. CONCLUSIONS: For selected breast cancer patients undergoing breast-conserving therapy, BRT is an attractive alternative to ERT.

The influence of young age and positive family history of breast cancer on the prognosis of ductal carcinoma in situ treated by excision with or without radiation therapy or by mastectomy.

BACKGROUND: Several recent studies have investigated the influence of family history on the progression of DCIS patients treated by tylectomy and radiation therapy. Since three treatment strategies have been used for DCIS at our institution, we evaluated the influence of family history and young age on outcome by treatment method. METHODS: Between 1/1/82 and 12/31/92, 128 patients were treated for DCIS by mastectomy (n = 50, 39%), tylectomy alone (n = 43, 34%), and tylectomy with radiation therapy (n = 35, 27%). Median follow-up is 8.7 years. Thirty-nine patients had a positive family history of breast cancer; 26 in a mother, sister, or daughter (first-degree relative); and 26 in a grandmother, aunt, or cousin (second-degree relative). Thirteen patients had a positive family history in both first- and second-degree relatives. RESULTS: Six women developed a recurrence in the treated breast; all of these were initially treated with tylectomy alone. There were no recurrences in the mastectomy group or the tylectomy patients treated with postoperative radiation therapy. Patients with a positive family history had a 10.3% local recurrence rate (LRR), vs. a 2.3% LRR in patients with a negative family history (p = 0.05). Four of 44 patients (9.1%) 50 years of age or younger recurred, compared to two of 84 patients (2.4%) over the age of 50 (p = 0.10). Fifteen patients had both a positive family history and were 50 years of age or younger. Among these women, the recurrence rate was 20%. Women in this group treated by lesionectomy alone had a LRR of 38% (3 of 8). CONCLUSION: The most important determinant of outcome was the selection of treatment modality, with all of the recurrences occurring in the tylectomy alone group. In addition to treatment method, a positive family history significantly influenced LRR in patients treated by tylectomy, especially in women 50 years of age or younger. These results suggest that DCIS patients, particularly premenopausal women with a positive family history, benefit from treatment of the entire breast, and raise concerns about treating patients with a possible genetic susceptibility to breast cancer with tylectomy alone.

The role of postmastectomy radiation in the treatment of early stage breast cancer: back to the future.

Oncologists once downplayed the adjuvant role of radiotherapy after mastectomy. A decade ago, lacking a survival benefit, studies demonstrating late fatal myocardial infarctions nearly put a stop to any referrals of postoperative high-risk women to radiation oncology. The potential survival benefits of adjuvant radiotherapy may be overshadowed by inadequate technique leading to late cardiac deaths. Is it possible to cover the chest wall, internal mammary lymph chain, supraclavicular, and, where indicated, the axillary nodes and keep the dose to the coronary arteries and the lung to well within tolerance? A modern five-field comprehensive technique can deliver less cardiac and lung irradiation than the standard three-field technique, i.e. supraclavicular field matched to broad tangential fields. Linear accelerators with 4 megavolt (MV) to 6 MV photons, a full spectrum (6 MV to 20 MV) of electron energies, and meticulous computerized treatment planning based on multiple computed tomography planes allow an experienced physics/dosimetry team to treat all target sites while wrapping the dose around critical normal tissues.Whether to offer postmastectomy radiation to women with one to three positive nodes after adjuvant chemotherapy treatment has been the subject of intense discussion since the publication of two major randomized prospective trials. Although before these studies radiotherapy after mastectomy was an established treatment for women with four or more positive axillary nodes, existing data did not justify its use in patients with less extensive nodal involvement. Now, with results from these studies showing improved survival after radiotherapy in all node-positive premenopausal and perimenopausal women, with perhaps its greatest benefit in women with 1-3 positive nodes, practice patterns are again shifting toward strong consideration of treatment in women with less tumor nodal involvement.

Breast brachytherapy.

The benefits and problems of applying brachytherapy to breast cancer management are examined in this article. A history of breast brachytherapy is provided before the uses of brachytherapy in breast cancer are discussed, using several trials as examples. Techniques and tips for implementing brachytherapy are provided and dosimetry is discussed.

Adjuvant irradiation after mastectomy in women with one to three positive axillary nodes: then no; now yes.

The decision whether to offer women with one to three positive nodes postmastectomy radiation after adjuvant chemotherapy has been the subject of intense discussion since the publication of two major randomized prospective trials. Although radiotherapy after mastectomy was an established treatment for women with four or more positive axillary nodes, before these studies, existing data did not justify its use in patients with less extensive nodal involvement. Now with results from these studies showing improved survival after radiotherapy in all node-positive premenopausal and perimenopausal women, with perhaps its greatest benefit in women with one to three positive nodes, practice patterns are again shifting toward strong consideration of treatment in women with less tumor involvement. The arguments supporting this new treatment philosophy are presented.

Image-guided core-needle breast biopsy is an accurate technique to evaluate patients with nonpalpable imaging abnormalities.

OBJECTIVE: The goal was to evaluate one institution's experience with image-guided core-needle breast biopsy (IGCNBB) and compare the pathologic results with wire-localized excisional breast biopsy (WLEBB) for patients with positive cores and the mammographic surveillance results for patients with negative cores. SUMMARY BACKGROUND DATA: IGCNBB is becoming a popular, minimally invasive alternative to WLEBB in the evaluation of patients with nonpalpable abnormalities. METHODS: This study includes all patients with nonpalpable breast imaging abnormalities evaluated by IGCNBB from July 1993 to February 1997. Patients with positive cores (atypical hyperplasia, carcinoma in situ, or invasive carcinoma) were evaluated by WLEBB. Patients with negative cores (benign histology) were followed with a standard mammographic protocol. IGCNBB results were compared with WLEBB results to determine the sensitivity and specificity for each IGCNBB pathologic diagnosis. RESULTS: Of 1440 IGCNBBs performed during the study period, 1106 were classified as benign, and during surveillance follow-up only a single patient was demonstrated to have a carcinoma in the index part of the breast evaluated by IGCNBB (97.3% sensitivity, 99.7% specificity). IGCNBB demonstrated atypical hyperplasia in 72 patients, 5 of whom refused WLEBB. The remaining 67 patients were evaluated by WLEBB: nonmalignant findings were found in 31, carcinoma in situ was found in 25, and invasive carcinoma was found in 11 (100% sensitivity, 88.8% specificity). IGCNBB demonstrated carcinoma in situ in 84 patients; WLEBB confirmed carcinoma in situ in 54 and invasive carcinoma in 30 (65.4% sensitivity, 97.7% specificity). IGCNBB demonstrated invasive carcinoma in 178 patients. Three were lost to follow-up. On WLEBB, 173 of the remaining 175 had invasive carcinoma; the other 2 patients had carcinoma in situ (80.8% sensitivity, 99.8% specificity). CONCLUSIONS: An IGCNBB that demonstrates atypical hyperplasia or carcinoma in situ requires WLEBB to define the extent of breast pathology. Mammographic surveillance for a patient with a benign IGCNBB is supported by nearly 100% specificity. An IGCNBB diagnosis of invasive carcinoma is also associated with nearly 100% specificity; therefore, these patients can have definitive surgical therapy, including axillary dissection or mastectomy, without waiting for the pathologic results of a WLEBB. Based on the authors' findings, IGCNBB can safely replace WLEBB in evaluating patients with nonpalpable breast abnormalities.

A core breast biopsy diagnosis of invasive carcinoma allows for definitive surgical treatment planning.

BACKGROUND: We reviewed our image-guided core needle breast biopsy (IGCNBB) experience with patients diagnosed with invasive carcinoma (IC) to determine the accuracy of a core biopsy diagnosis of invasion and our ability to perform a single definitive cancer operation. METHODS: All IGCNBBs between July 1993 and July 1997 were reviewed to identify patients diagnosed with IC. Data included initial surgical treatment, surgical pathology, and subsequent surgical treatment. RESULTS: Of the 1,676 biopsies, invasive carcinoma was diagnosed in 208 with follow-up in 204 cases. Invasive carcinoma diagnosis was confirmed in 202 of 204 cases (99%). One hundred ninety-two patients had surgical treatment. Of these 192 patients, 173 (90%) could have achieved definitive surgical treatment with a single operation. CONCLUSIONS: An IGCNBB diagnosis of IC is accurate and allows for definitive breast cancer therapy. The potential impact on patient management is that a single operation can usually accomplish what traditionally has required at least two surgical procedures.

Accelerated hyperfractionation radiation therapy after lumpectomy and axillary lymph node dissection in patients with stage I or II breast cancer: pilot study.

PURPOSE: To prospectively assess tolerance to accelerated hyperfractionation radiation therapy in patients undergoing breast-conservation therapy and to exclude, with 90% confidence, a 20% or greater risk of an acute toxic reaction of at least grade 3 (severe). MATERIALS AND METHODS: Thirty-seven patients (aged 33-80 years) with evaluatable cases received 48 Gy in twice-daily 1.6-Gy fractions to the breast and regional lymph nodes (if three or more lymph nodes were involved) and a boost of 9.6 Gy in twice-daily 1.6-Gy fractions. Acute and late effects were scored by using the Radiation Therapy Oncology Group and European Organization for the Research and Treatment of Cancer radiation morbidity criteria. RESULTS: One patient developed a grade 3 acute skin toxic reaction and another grade 3 (continuous) acute edema. There have been no grade 4 (life-threatening) acute toxic reactions, local recurrences, or cancer- or treatment-related deaths. CONCLUSION: This breast-conservation accelerated hyperfractionation radiation therapy schedule is tolerable. Additional follow-up is necessary to determine long-term morbidity and cosmesis, and further study in a larger patient group is necessary to confirm efficacy.

Phase III double-blind evaluation of an aloe vera gel as a prophylactic agent for radiation-induced skin toxicity.

PURPOSE: Considerable pilot data and clinical experience suggested that an aloe vera gel might help to prevent radiation therapy-induced dermatitis. METHODS AND MATERIALS: Two Phase III randomized trials were conducted. The first one was double blinded, utilized a placebo gel, and involved 194 women receiving breast or chest wall irradiation. The second trial randomized 108 such patients to aloe vera gel vs. no treatment. Skin dermatitis was scored weekly during both trials both by patients and by health care providers. RESULTS: Skin dermatitis scores were virtually identical on both treatment arms during both of the trials. The only toxicity from the gel was rare contact dermatitis. CONCLUSIONS: This dose and schedule of an aloe vera gel does not protect against radiation therapy-induced dermatitis.

Disseminated epidemic Kaposi's sarcoma treated with radiation and chemotherapy.

When a 40-year-old patient with end-stage acquired immunodeficiency syndrome (AIDS) had bloating and abdominal pain, a large epidemic Kaposi's sarcoma (EKS) lesion was found obstructing the pylorus. Treatment consisted of single-agent chemotherapy for the disseminated lesions and external beam irradiation to the obstructing lesion. Within days of radiation therapy, symptoms began to resolve, and by completion of therapy, the patient was virtually asymptomatic. Although EKS is common in homosexual men infected with the AIDS virus, these patients usually succumb to overwhelming opportunistic infections. Nevertheless, palliative courses of radiation, which can produce a complete response in 50% to 100% of treated KS lesions, can substantially improve the quality of life in these patients.