Recurrence and Survival Rates for 1400 Early Breast Tumors Treated with Intraoperative Radiation Therapy (IORT).

INTRODUCTION: Intraoperative radiotherapy (IORT) permits accurate delivery of radiation therapy directly to the tumor bed. We report local, regional, and distant recurrence data along with overall and breast cancer-specific survival for 1400 tumors treated with x-ray IORT. METHODS: A total of 1367 patients with 1400 distinct tumors were enrolled in a registry trial. All received breast conservation surgery and low-energy 50 kV x-ray IORT. To be eligible for excision plus IORT as the only local treatment, histopathology had to confirm tumor size ≤30 mm, margins ≥2 mm, negative lymph nodes, and no extensive lymphovascular invasion. Patients who failed any parameters were referred for additional surgery and/or whole breast radiation therapy (WBRT). RESULTS: There were 64 ipsilateral local recurrences, 60 were in the IORT only group, 7 axillary recurrences, and 7 distant recurrences. Forty-one local recurrences were within the same quadrant as the index cancer. Twenty-three were in different quadrants. With 62 months of median follow-up, the 5-year Kaplan-Meier probability of any event for all 1400 tumors was 5.27%. For 1175 patients who received IORT only, it was 5.98%. For favorable subtypes, it ranged from 2.41 to 4.31%. Multivariate analysis revealed that biologic subtype luminal A and the addition of WBRT significantly reduced the risk of local recurrence. CONCLUSIONS: The local, regional, and distant recurrence rates observed were comparable to those reported in the literature for IORT but higher than those reported for standard forms of WBRT, hypofractionated treatment, or APBI. IORT benefits include convenience, decreased exposure to medical environments, and low complication rates.

Intraoperative Radiation Using Low-Kilovoltage X-Rays for Early Breast Cancer: A Single Site Trial.

INTRODUCTION: Two prospective, randomized trials, TARGIT-A and ELIOT, have shown intraoperative radiation therapy (IORT) to be a safe alternative to whole breast radiation therapy following breast-conserving surgery for selected low-risk patients. However, minimal data are available about the clinical effectiveness of this modality of treatment using the Xoft® Axxent® Electronic Brachytherapy (eBx®) System®. METHODS: A total of 201 patients with 204 early-stage breast cancers were enrolled in a prospective X-ray IORT trial from June 2010 to September 2013. All tumors were treated with breast-conserving surgery and IORT. Data were collected at 1 week, 1 month, 6 months, 1 year, and yearly thereafter. RESULTS: With a median follow-up of 50 months, there have been seven ipsilateral breast tumor events (IBTE), no regional or distant recurrences, and no breast cancer-related deaths. One IBTE was within the IORT field, four outside of the IORT field but within the same quadrant as the index cancer, and two were new biologically different cancers in different quadrants. Three events were in patients who deviated from the protocol criteria. Kaplan-Meier analysis projects that 2.9% of patients will recur locally at 4 years. CONCLUSIONS: Recurrence rates observed in this trial were comparable to those of the TARGIT-A and ELIOT trials as well as the retrospective TARGIT-R trial. The low complication rates previously reported by our group as well as the low recurrence rates reported in this study support the cautious use and continued study of IORT in selected women with low-risk breast cancer.

Acute and Chronic Complications in Patients with Ductal Carcinoma in Situ Treated with Intraoperative Radiation Therapy.

Intraoperative radiation therapy (IORT) delivers radiation therapy directly to the tumor bed at the time of surgery. Minimal data are available regarding IORT complications in patients diagnosed with ductal carcinoma in situ (DCIS) using the Xoft® Axxent eBx® System. 146 patients with pure DCIS received X-ray based IORT therapy using the Xoft® Axxent eBx® System at Hoag Memorial Hospital Presbyterian between June 2010 to April 2016 and were accrued to an IORT data registry study. The protocols were approved by the institutional review board and met the guidelines of their responsible governmental agency. Data were collected at 1 week, 1 month, 6 months, 1 year, and thereafter yearly. Acute complications were defined as those occurring within the first month. Chronic complications were those that persisted beyond 6 months. Acute complications were observed in 18% of patients and included hematomas that required drainage, an infection treated with antibiotics, and erythema. Chronic complications were observed in 12% of patients and included a seroma, fibrosis and hyperpigmentation. The majority of acute and chronic problems were mild (Grade I). If Grade I erythema, fibrosis, and hyperpigmentation are not included, only 11/146 patients (7.5%) had significant complications. The rate of acute and chronic complications from X-ray IORT in DCIS patients was low compared to historical toxicity rates observed in DCIS patients treated with whole breast irradiation. Our data indicate that X-ray IORT can be utilized safely in patients diagnosed with DCIS.

Factor VIII gene variants and inhibitor risk in African American hemophilia A patients.

African American hemophilia A (HA) patients experience a higher incidence of neutralizing anti-factor VIII (FVIII) antibodies ("inhibitors") vis-à-vis white patients. Nonsynonymous single-nucleotide polymorphisms (ns-SNPs) in the F8 gene encoding FVIII-H484, FVIII-E1241, and FVIII-V2238 are more prevalent in African Americans. This study tested the hypothesis that immune responses to these sites provoke inhibitors. Blood samples were obtained from 174 African American and 198 white HA subjects and their F8 gene sequences determined. Major histocompatibility complex class II binding and T-cell recognition of polymorphic sequences were evaluated using quantitative binding assays and HLA-DRB1 tetramers. Peptides corresponding to 4 common ns-SNPs showed limited binding to 11 HLA-DRB1 proteins. CD4 T cells from 22 subjects treated with FVIII products having sequences at residues FVIII-484, 1241, and 2238 differing from those of putative proteins encoded by their F8 genes did not show high-avidity tetramer binding, whereas positive-control staining of tetanus-specific CD4 T cells was routinely successful. African Americans with an intron-22 inversion mutation showed a 2-3 times-higher inhibitor incidence than whites with the same mutation (odds ratio = 2.3 [1.1-5.0, P = .04]), but this did not correlate with any of the ns-SNPs. We conclude that immune responses to "sequence-mismatched" FVIII products are unlikely to contribute appreciably to the inhibitor incidence in African Americans.

Phenotypes of allo- and autoimmune antibody responses to FVIII characterized by surface plasmon resonance.

Evidence of antibody isotype/subtype switching may provide prognostic value regarding the state of immune responses to therapeutic proteins, e.g. anti-factor VIII (FVIII) antibodies that develop in many hemophilia A patients, clinically termed "inhibitors". A sensitive, high- information-content surface plasmon resonance (SPR) assay has been developed to quantify IgG subtype distributions and the domain specificity of anti-drug antibodies. Plasma samples from 22 subjects with an allo- or auto-immune reaction to FVIII were analyzed. Pre-analytical treatment protocols were developed to minimize non-specific binding and specific matrix interference due to von Willebrand factor-FVIII interactions. The dynamic range for IgG quantification was 0.2-5 µg/ml (∼1-33 nM), allowing characterization of inhibitor-positive samples. Subtype-specific monoclonal antibodies were used to quantify the IgG subtype distribution of FVIII-specific antibodies. Most samples obtained from multiply-infused inhibitor subjects contained IgG4 antibodies. Several distinct phenotypes were assigned based on the IgG subtype distribution: IgG1, IgG4, IgG1 & IgG4, and IgG1, IgG2 & IgG4. An IgG1-only response was found in mild/moderate HA subjects during early FVIII infusions, and analysis of serial samples followed antibody class switching as several subjects' immune responses developed. Competition studies utilizing a recombinant FVIII-C2 domain indicated 40-80% of FVIII-specific antibodies in most samples were directed against this domain.

Local control in ductal carcinoma in situ treated by excision alone: incremental benefit of larger margins.

BACKGROUND: Margin width has been shown previously to be the most important predictor of local treatment failure after breast conservation for ductal carcinoma in situ (DCIS). METHODS: Five variables thought to be associated with local recurrence were evaluated by univariate and multivariate analysis in 455 nonrandomized patients with DCIS treated with excision alone. RESULTS: Multivariate analysis showed that margin width, age, nuclear grade, and tumor size all were independent predictors of local recurrence, with margin width as the single most important predictor. After adjusting for all other predictors the likelihood of local recurrence for patients with margins less than 10 mm was 5.39 times as much as that for patients with margins of 10 mm or more (95% confidence interval, 2.68-10.64). CONCLUSIONS: Margin width, the distance between DCIS and the closest inked margin, was the single most important predictor of local recurrence. As margin width increases, the risk for local recurrence decreases.