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A ngiosarcoma of the breast is a rare malignant tumor that often has a nonspecific clinical and radiobogic presentation. beading to a delay in diagnosis. Several studies have now demonstrated that MR imaging can reveal and aid in staging breast cancer with greater sensitivity than mammography [I]. We report a patient in whom MR imaging was used on two separate occasions over a 2-month period to visualize bilateral angiosarcomas. one of which caused only an equivocal finding on physical examination.

Graft-versus-host disease (GVHD) is a major cause of morbidity and mortality following allogeneic hematopoietic stem cell transplantation (HSCT). Advances in molecular typing of major histocompatibility complex (MHC) alleles have decreased but not eliminated the occurrence of acute GVHD. Minor histocompatibility antigen (mHA) disparities between patients and their molecularly HLA-identical donors are likely to represent the residual targets of donor immunity. The majority of mHAs are encoded by SNPs which are disparate between patient and donor. Identification of these immunogenic SNPs would provide both a clinical benefit as well as insight into the biology of GVHD. We used Affymetrix high-density arrays to assess 10,043 SNPs spanning the entire genome. We have examined genomic DNA from 36 patient/donor pairs (21 with acute GVHD grades II-IV and 15 without GVHD). All patients and donors were HLA and sex-matched siblings and all patients received T-cell depleted transplants. T cell depletion is important in this context as it removes the potential pharmacogenomic confounding factor of differential sensitivity to immunosuppressive agents. Because the donors and recipients are related, large areas of the genome are identical by descent. Similarly sized blocks of chromosome are disparately inherited. We hypothesized that genomic regions important to the immunopathogenesis of GVHD would be more likely to be disparately inherited in pairs with GVHD than in pairs without GVHD. As a control of our method we compared the area of chromosome 6 surrounding the MHC complex and demonstrated that there was minimal SNP disparity in either GVHD pairs or asymptomatic pairs. We also focused our attention on the region of chromosome 6 outside the MHC area, hypothesizing that disparities in this area would have to result from recombination events. Interestingly the only major area of disparity on Chr 6 was in the gene GMDS, which has been proposed to play a role in the extravasation of activated lymphocytes. We then examined other chromosomes for evidence of genomic regions that that were selectively disparate in GVHD pairs. We were able to identify several genomic regions that appeared to be associated with this outcome. The Lander-Green algorithm was used to estimate the allele sharing between the siblings for each SNP marker and then the disparity score was defined as the average allele sharing of the GVHD group - average allele sharing of the asymptomatic group. The five genomic regions with the highest disparity scores (ranked in order of score) and the gene closest to the region are: 11q14.3 (gene cysteine and histidine-rich domain (CHORD)-containing, zinc binding protein 1), 9p22.2 (gene SH3GL2), 5p15 (gene KIAA0947), 10p15.1 (gene aldo-keto reductase family 1, member C4), and 9p21.2 (Chr 9 ORF 72). The highly disparate regions ranged between 70 and 2200 kb in size. Interestingly the total number of disparate SNPs was not different between pairs with GVHD and pairs without GVHD, supporting the hypothesis that a limited number of SNPs are important immunologic targets. This technique of genome-wide disparity analysis is a promising addition to our ability to define important mHA.

The mechanism of tissue injury in chronic GVHD (cGVHD) is unknown, but donor-derived T cells are thought to be the primary effectors. We demonstrated that antibodies against minor histocompatability antigens develop in association with cGVHD, suggesting coordinated B and T cell mediated injury. We therefore began a clinical trial of specific anti-B cell therapy with Rituximab (Rituxan) as therapy for steroid-refractory cGVHD. Methods: Eligible patients had persistent, clinically extensive cGVHD despite a trial of corticosteroids (at least 0.5 mg/kg/day prednisone for 1 month) and were on stable doses of all immunosuppressants, including steroids, for 4 weeks prior to enrollment. cGVHD was diagnosed clincally in most cases. Rituxan (375 mg/m2/wk x 4) was followed by a second course for non- or partial responders 4 weeks later. All patients underwent thorough oral, ocular, rheumatologic and dermatologic examinations by trained sub-specialists prior to therapy and 8 weeks after Rituxan therapy, where indicated. A validated quality of life (QoL) survey was administered before and after Rituxan therapy as well. Results: 16 patients are enrolled and 10 (median age, 43 yrs) have undegone thorough response evaluations to date. At the time of enrollment, 9 were on steroids, either alone (n=3) or in conjunction with one (n=5) or two (n=1) immunosuppressive agents. One patient was on tacrolimus alone. End-organ involvement included skin(7), eye(6), musculoskeletal(6) and oral mucosa(4). Fifteen 4-week courses of Rituxan were administered, at a median of 14.4 months from cGVHD diagnosis (range 3.5 to 82 months). Rituxan was well tolerated in all patients, with 5 grade 3 adverse infectious events (infectious colitis(2), Hepatitis B reactivaton(1), gastroenteritis(1) and conjunctivitis(1)) and one infusion reaction. Nine weeks after Rituxan initiation, CD19+ B cells were undetectable in all peripheral blood samples. Median serum IgG levels fell 16%, from a baseline of 772 to 645 mg/dl. Median IgM levels fell 33%, from 84 to 56 mg/dl. IgG antibody titers for tetanus toxoid and EBV remain unchanged. Median follow-up is 130 days. Objective responses were noted in 5 patients (3 cutaneous responses, 4 rheumatologic responses ), no response was noted in 4 patients and 1 patient had progressive cutaneous cGVHD. No ocular or oral responses were noted. Mean rheumatologic VAS pain scores improved from 5 to 1, and VAS fatigue scores improved from 5 to 1, while grip strength was unchanged in all patients. Mean oral pain scores and ocular Schirmer test times were unchanged. Mean QoL scores improved in 4 patients, were unchanged in 3, worsened in 1 and were unevaluable in 2. Of the 4 patients with improved QoL scores, 3 also had clinical responses. At this time, all patients remain on systemic immunosuppression. Conclusions: Rituxan can be administered safely to patients with cGVHD, although infectious adverse events may occur. Early results suggest that this agent may have activity as therapy for cGVHD, particularly when cutaneous and rheumatologic manifestations are prominent. An evaluation of serologic responses is ongoing.

PURPOSE: Recent studies have suggested that the sentinel lymph node (SLN) biopsy is an accurate alternative staging procedure for women with breast cancer. The goal of this study was to identify a subset of breast cancer patients in whom metastatic disease was confined only to the SLN. MATERIALS AND METHODS: From two institutions, we recruited 222 women with breast cancer for SLN biopsy. A SLN biopsy was performed in each patient, followed by an axillary dissection in 182 patients. Histologic and immunohistochemical cytokeratin stains were used on all SLNs. RESULTS: The SLN was identified in 220 (97.8%) of the 225 biopsies. Evidence of metastatic breast cancer in the SLN was found in 60 (27.0%) of the 222 patients. Of these patients, 32 (53.3%) had evidence of tumor in the SLN only. By multivariate analysis, two factors were found to be significantly associated with a higher likelihood of tumor involvement in the non-SLNs: primary tumor size larger than 2.0 cm (P = .0004) and macrometastasis (> 2.0 mm) in the SLN (P = .002). Additional analysis revealed that none (0%; 95% confidence interval, 0% to 18.5%) of the 18 patients with primary tumors ≤ 2.0 cm and micrometastasis to the SLN had remaining axillary lymph node involvement. CONCLUSION: The primary tumor size and metastasis size in the SLN are independent factors in predicting the incidence of tumor in the non-SLNs. Therefore, the SLN biopsy alone may be adequate for staging and/or therapy decision making in patients with primary breast tumors ≤ 2.0 cm and micrometastasis in the SLN.

Objective: Transmyocardial laser revascularization is an investigational technique for revascularizing ischemic myocardium in patients with inoperable coronary arterial disease. This study tests the hypothesis that laser revascularization prevents left ventricular functional deterioration and aneurysm formation after acute anteroapical myocardial infarction. Methods: An ultrasonic ascending aortic flow probe and snares around the distal left anterior descending and second diagonal coronary arteries were placed in 26 Dorsett hybrid sheep. Ten to 14 days later, snared arteries were occluded to produce an anteroapical infarction of 23% of left ventricular mass. Before infarction 14 animals had 34 ± 4 transmyocardial perforations in the area of the anticipated infarction made with a carbon dioxide laser. Twelve animals served as controls. Hemodynamic measurements and transdiaphragmatic quantitative echocardiograms were obtained before, immediately after, and 2, 5, and 8 weeks after infarction. Eighteen sheep completed the protocol. Results: All animals had large anteroapical left ventricular aneurysms with massive ventricular enlargement. Immediately after infarction the anterior wall became thinner and dyskinetic in all sheep. At 8 weeks aneurysmal size and shape were indistinguishable between groups. Two days after infarction, laser holes were filled with fibrin. At 5 and 8 weeks the infarct consisted of dense collagen, fibroblasts, scattered calcifications, myocyte fragments, neutrophils, macrophages, and no laser holes. There were no significant differences at any time between groups for cardiac pressures or output, ventricular volumes, ejection fraction, stroke work, and the stroke work–left ventricular end-diastolic pressure index. Conclusion: Transmyocardial laser perforations do not revascularize acute myocardial infarction in sheep. (J Thorac Cardiovasc Surg 1998;116:752-62)

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Background: p16 is a nuclear protein encoded by the p16INK4a gene that regulates the G1-S cell cycle checkpoint. Its overexpression could reflect normal proliferative arrest, but also the evolution of carcinogenic processes that have overcome the p16 block, with progression from hyperplasic lesions to invasive breast cancer. Our aim with this study was to correlate p16 expression, both individually and in combination with expression of COX-2 and Ki67, with subsequent risk of breast cancer among women with atypical hyperplasia. Methods: p16 expression was assessed by immunohistochemical assays in archival paraffin-embedded, formalin-fixed sections from 233 women with atypia whose biopsy specimens were obtained via surgical excision at the Mayo Clinic from January 1, 1967, through December 31, 1991. p16 expression was scored as percent of cells positive and intensity of staining. Risk factor information and follow-up for breast cancer events were obtained via study questionnaire and the medical records. Standardized incidence ratios (SIRs) were used to compare observed numbers of breast cancer events to population-based expected counts, both at 10 years and over the entire course of follow-up. Results: Forty-seven patients (20%) developed breast cancer with a mean follow-up of 14.3 (SD=6.96) years. The overall risk of developing breast cancer was not modified by increasing p16 overexpression (low percent of staining with RR=3.89, 95% CI=2.72 to 5.56; high percent of staining with RR=3.91, 95% CI=2.43 to 6.28; similar results for intensity of staining). However, overexpression of both p16 and COX2 conveyed a stronger risk of breast cancer (SIR=4.01, 95% CI 2.28 to 7.07) as compared to dual low expression (SIR 1.78, 95% CI 0.67-4.74). Moreover, overexpression of both Ki67 and p16 was related to a higher 10-year breast cancer risk (SIR 6.25, 95% CI 2.35-16.6) as compared to low expression of both markers (SIR 0.87, 95% CI 0.22-3.49). Conclusions: although single expression of p16 does not stratify breast cancer risk, its overexpression in concert with biomarkers that reflect other carcinogenic processes (e.g. Ki67 and COX2) could help to define risk of tumor development. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 910.

The authors present six cases of benign tumors of the breast with numerous multinucleated stromal giant cells (MSGC). All six patients were women aged 37-70 years (mean 48 years), presenting clinically with a breast mass 1.0-3.8 cm in size (mean 1.9 cm; median 1.5 cm). By standard H&E examination, all cases showed the presence of numerous MSGC haphazardly dispersed within the tumor stroma. Three cases revealed MSGC merging into the surrounding adipose tissue simulating infiltrative growth. The MSGC appeared to have multiple nuclei (5 to 25) with fine chromatin and sporadic small nucleoli. Their cytoplasm was inconspicuous. The MSGC expressed vimentin only and to lesser extent CD34. These cells were negative for muscle markers, keratins, S-100 protein, vascular markers, CD68 and hormone receptors. Interestingly, the majority of MSGC and mononuclear stromal cells showed reactivity for p53 protein and Ki-67 proliferation antigen. All patients were treated by simple excision and remain free of recurrence (mean 70 months, median 48 months.). The reactivity of p53 in MSGC and mononuclear stromal cells may play a key role in linking these two cell types. Nonetheless, the presence of MSGC does not alter prognosis of otherwise typical benign lesions.