A retrospective clinicopathologic evaluation of 42 patients with cystosarcoma phyllodes was undertaken to determine if tumor size, contour, degree of stromal atypia and mitotic activity were reliable indicators of clinical behavior. Excluding size, the latter three determinants showed a positive correlation with prognosis and served as the basis of a classification in which 18 benign, 5 borderline and 19 malignant cystosarcomas were diagnosed. The tumors occurred in women averaging 44.3 years of age who most often presented with a palpable occasionally painful mass with a median diameter of 5 cm. Excision or simple mastectomy were the more frequent forms of therapy. Local recurrences were experienced by 6 patients and occurred in all 3 categories of tumor. Only malignant neoplasms developed systemic metastases which was observed in 4

The clinical and pathologic features of ten mammary sarcomas are discussed. Tumor size, contour, degree of cellular atypia, and mitotic activity were specifically evaluated to determine if they are important indiced of clinical behavior. Results indicate that infiltrating margins, 2-3+ stromal atypia, and eight or more mitoses per 10 HPF are characteristics of neoplasms associated with a poor prognosis. Tumor size was an unreliable criterion. A classification of breast sarcomas is presented with an appeal to avoid use of the term "stromal sarcoma" as a specific pathologic diagnosis. Since a diagnosis based upon cell of origin and correlated with the above morphologic features is fundamental to an intelligent therapeutic approach to this rare group of neoplasms, future reports dealing with this subject should include these details.

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Hereditary inclusion body myopathy (HIBM) is a young-adult onset autosomal recessive disorder caused by a hypomorphic rate limiting enzyme of sialic acid biosynthesis. The enzyme is UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase, and is encoded by the GNE gene. HIBM causes slowly progressive muscle weakness and atrophy. Patients are typically diagnosed at 20-30 years of age, and most patients are incapacitated and wheelchair-confined by 30-50 years of age. Some sialic acid containing glycoproteins, including neural cell adhesion molecule (NCAM), are hyposialylated in HIBM muscle biopsy samples. We developed a method to allow detection of serum NCAM sialylation using Western blot, and tested serum samples from several patients and a HIBM mouse model. Preliminary results showed a clear difference in polysialylated and hyposialylated forms of NCAM extracted from serum, and showed NCAM is hyposialylated in HIBM serum samples. This initial finding may prove useful in reducing the need for serial muscle biopsies in HIBM treatment trials. Additional studies are underway to further validate this finding and to evaluate the specificity, reliability, and robustness of this potential serum biomarker for HIBM.

Hereditary Inclusion Body Myopathy (HIBM, IBM2, MIM:600737) is an autosomal recessive adult onset progressive muscle wasting disorder. It is associated with the degeneration of distal and proximal muscles, while often sparing the quadriceps. The bifunctional enzyme UDP-GlcNAc 2-epimerase/ManNAc kinase (GNE/MNK), encoded by the GNE gene, catalyzes the first two committed, rate-limiting steps in the biosynthesis of N-acetylneunaminic acid (sialic acid). Affected individuals have been identified with mutations in the GNE gene. In the present study, the GNE coding region of 136 symptomatic patients were sequenced. A total of 41 patients were found to have GNE mutations. Eight novel mutations were discovered among seven patients. Of the eight novel mutations, seven were missense (p.I150V, p.Y186C, p.M265T, p.V315T, p.N317D, p.G669R, and p.S699L) and one was nonsense (p.W495X), all of which span the epimerase, kinase, and allosteric domains of GNE. In one patient, one novel mutation was found in the allosteric region and kinase domain of the GNE gene. Mutations in the allosteric region lead to a different disease, sialuria; however, this particular mutation has not been described in patients with sialuria. The pathological significance of this variation with GNE function remains unknown and further studies are needed to identify its connection with HIBM. These findings further expand the clinical and genetic spectrum of HIBM.

Forty-seven patients with various connective tissue disorders were studied to evaluate the spontaneous release of lymphocyte factors affecting the in vitro migration of guinea pig macrophages. In the assay used the lymphocytes from 8 patients produced an excessive amount of factors inhibiting macrophage migration while the lymphocytes from 12 patients produced an enhancement of migration. There were no differences in the delayed hypersensitivity skin test responses between the 2 groups of patients. The data are consistent with either an abnormality of suppressor lymphocyte function or an altered lymphocyte subpopulation relationship as a factor in this in vitro abnormality.

The 5,10-methylenetetrahydrofolate reductase gene (MTHFR) 677C>T polymorphism produces an elevation in plasma homocysteine concentrations when present in the homozygous state. Increased homocysteine levels have been associated with a greater risk for vascular diseases, including cardiovascular disease and ischemic stroke. In this study, we genotyped 42 nucleic acid samples for the C677T allele from our database of Middle Eastern patients as routine validation of the MTHFR 677C>T assay. Our study is the first to evaluate MTHFR C677T genotype frequency in a population of Middle Eastern patients residing in the United States. Among the patients, 47.6% were wild type, 40.5% were heterozygous, and 11.9% were homozygous for the C677T variant. Although C677T genotype frequency in our patient population is slightly higher than that reported by Golbahar et al. (2005), statistical analysis showed no statistically significant difference beyond chance in genotype profiles (chi(2) = 1.54, df = 2, p = 0.1675). However, our findings implicate the need for a larger sample size to explore the need to implement standard clinical screening of MTHFR 677C>T. We also highlight the robust, reliable, and reproducible assay afforded by the use of anchor and sensor hybridization probes within the LightCycler platform to perform amplification and melting curve analysis protocols. Melting curve profiles that are produced display distinct and robust T(m) peaks based on the degree of anchor and sensor hybridization to amplicons produced from template DNA that is either wild-type, heterozygous, or a homozygous variant at the MTHFR 677C>T locus. A 10 degrees C gap between T(m) peaks allows for rapid and accurate qualitative identification of genotype.

Hereditary inclusion body myopathy/distal myopathy with rimmed vacuoles is an adult onset autosomal recessive muscle-wasting disease common in people of Iranian-Jewish descent, due to the founder allelic variant GNE:p.M712T. High correlation of disease susceptibility with GNE:p.M712T allows its use as a molecular marker for diagnosis. In this study, we applied and validated the use of melting curve analysis using SimpleProbe technology for detection of this mutation using specimens obtained by mouthwash, buccal swab, and whole blood. The assay was then applied to 43 clinical specimens, and results were validated by additional methods. A probe spanning this mutation in exon 12 accurately discerns two Tm corresponding to its hybridization to wild-type and M712T-derived amplicons. A 10 degrees C divergence in Tm allowed rapid single-tube genotyping of reference and patient samples with 100% accuracy. Distal myopathy constitutes a large heterogeneous group of pathologies with similar physiological manifestations and little molecular markers for distinguishing subtypes. Application of SimpleProbes for detection of GNE:p.M712T on genomic DNA obtained from buccal epithelial cells allows accurate, rapid, and cost-effective identification of this allele in individuals at risk. This procedure is amenable to automated high-throughput applications and can be extended to both clinical and research applications.