Significance of SF3B1 Mutations in Myeloid Neoplasms.

Myelodysplastic neoplasm with low blasts and SF3B1 mutation (MDS-LB-SF3B1) has undergone significant classification changes in the past year with the publication of the 5th edition of the World Health Organization Classification of Tumors of Haematopoietic and Lymphoid Tissues and the International Consensus Classification. This article reviews the basic biology of SF3B1, iron metabolism, and dysfunction that leads to the formation of ring sideroblasts. It highlights neoplastic and non-neoplastic considerations to the differential diagnoses. Finally, a review on the evolution of the prognostic scoring system and treatment regimens that are available to patients with a diagnosis of MDS is presented.

Probability of malignancy as determined by ThyroSeq v3 genomic classifier varies according to the subtype of atypia.

BACKGROUND: ThyroSeq assesses the probability of malignancy (POM) in thyroid fine-needle aspiration cytology specimens diagnosed as atypia of undetermined significance (AUS). The authors investigated whether defined AUS subcategories are associated with specific molecular alterations, the molecular-derived risk of malignancy (MDROM), and the risk of malignancy (ROM). METHODS: Fine-needle aspiration cytology reports of AUS and corresponding results from the ThyroSeq version 3 genomic classifier results were retrieved and subcategorized as follicular cells with either cytologic atypia (FC-C), architectural atypia (FC-A), both cytologic and architectural atypia (FC-CA), or a predominance of Hurthle cells (PHC). The MDROM, ROM, and frequency of molecular alterations by subcategory were computed and analyzed, and p < .05 was considered significant. RESULTS: The final analysis included 541 cases subdivided into 233 with FC-A, 104 with FC-C, 116 with FC-CA, and 88 with PHC. The benign call rate and positive call rate for the AUS category were 72% and 28%, respectively, which varied between AUS subcategories. The MDROM by subcategory was 15.9% FC-A, 20.5% FC-C, 33.8% FC-CA, and 14.4% PHC. Histologic follow-up was available for 155 (28%) AUS cases with a follow-up period ≥12 months. The 95% confidence intervals of the MDROMs overlapped with the ROMs. The highest MDROM and ROM were in the FC-CA subcategory. RAS mutations were present in all subcategories. BRAF V600E mutations and papillary thyroid carcinoma were most frequent in the FC-CA subcategory. Noninvasive follicular thyroid neoplasm with papillary-like nuclear features was significantly more frequent in the FC-C subcategory. CONCLUSIONS: The current results demonstrated that AUS subcategories are associated with specific genetic alterations, the MDROM, and the ROM. Molecular results and an awareness of various cancer probabilities within AUS subcategories can allow for a more tailored management.

Primary gastrointestinal liposarcoma-a clinicopathological study of 8 cases of a rare entity.

Primary gastrointestinal liposarcoma is rare, and information regarding this entity is largely based on single case studies. We report on 8 patients with primary liposarcoma of the gastrointestinal tract and review the pertinent literature. The cohort includes 6 men and 2 women who ranged in age from 51 to 81 years (median 68.5). Two tumors arose in the stomach, 4 in the small intestine, and 2 in the large intestine. Tumors ranged in size from 2.5 to 14.5 cm (median 7 cm), originated in the submucosa or muscularis propria of the intestinal wall, and frequently protruded into the bowel lumen, resulting in mucosal ulceration and luminal obstruction. Six tumors were dedifferentiated liposarcomas, and 2 were well-differentiated liposarcoma. Surgical excision was performed on all tumors except for 1 case of dedifferentiated liposarcoma. On follow-up, 1 patient with dedifferentiated liposarcoma developed a lytic sacral lesion suspicious for metastasis 4 months after resection of the primary, and another underwent marginal resection and presented with recurrence 4 years later, had tumor re-resection, and was considered disease-free at 6 weeks postsurgery. A third patient with dedifferentiated liposarcoma was alive with unknown disease status at 17 months following surgery, and another patient with dedifferentiated liposarcoma was alive without evidence of disease at 30 months following surgery. No follow-up information on the remaining patients is available. Overall, liposarcomas of the intestinal tract are most frequently high-grade dedifferentiated tumors that are biologically aggressive and require surgical excision with widely negative margins to help reduce the risk of local recurrence and dissemination. Important in the differential diagnosis is malignant gastrointestinal stromal tumor. Care must be taken not to misdiagnose one entity for the other because the correct diagnosis carries important therapeutic implications.

A Case Report of Heel Pain Mimicking Plantar Fasciitis and Osteosarcoma: A Unique Presentation of a Nora's Lesion.

Bizarre parosteal osteochondromatous proliferation, otherwise known as "Nora's lesion," is a rare benign neoplasm first described by Nora in 1983. The exact etiology of this neoplasm remains unknown, and its presentation in the lower extremity presents a diagnostic challenge, as both clinical and radiologic features cannot fully differentiate it from other neoplasms. We present the case of a 48-year-old female with plantar heel pain secondary to Nora's lesion mimicking plantar fasciitis and periosteal osteosarcoma. Following bone biopsy for histopathologic analysis, the patient's symptoms spontaneously resolved, and she returned to activity with complete resolution of symptoms 18 months post biopsy. Bizarre parosteal osteochondromatous proliferation as an etiology for plantar heel pain has not been previously described in the literature. Although rare, it should be considered in the differential diagnosis for patients presenting with plantar heel pain, especially after failed conservative treatment. Following diagnostic confirmation by histopathology, complete surgical excision is the treatment of choice.

Possible Genetic Origin of Limb-Body Wall Complex.

Limb body wall complex (LBWC) is characterized by multiple severe congenital malformations including an abdominal and/or thoracic wall defect covered by amnion, a short or absent umbilical cord with the placenta almost attached to the anterior fetal wall, intestinal malrotation, scoliosis, and lower extremity anomalies. There is no consensus about the etiology of LBWC and many cases with abnormal facial cleft do not meet the requirements for the true complex. We describe a series of four patients with LBWC and other malformations in an attempt to explain their etiology. There are several reports of fetuses with LBWC and absent gallbladder and one of our patients also had polysplenia. Absent gallbladder and polysplenia are associated with laterality genes including HOX, bFGF, transforming growth factor beta/activins/BMP4, WNT 1-8, and SHH. We postulate that this severe malformation may be due to abnormal genes involved in laterality and caudal development.

Epigenetic reprogramming induces the expansion of cord blood stem cells.

Cord blood (CB) cells that express CD34 have extensive hematopoietic capacity and rapidly divide ex vivo in the presence of cytokine combinations; however, many of these CB CD34+ cells lose their marrow-repopulating potential. To overcome this decline in function, we treated dividing CB CD34+ cells ex vivo with several histone deacetylase inhibitors (HDACIs). Treatment of CB CD34+ cells with the most active HDACI, valproic acid (VPA), following an initial 16-hour cytokine priming, increased the number of multipotent cells (CD34+CD90+) generated; however, the degree of expansion was substantially greater in the presence of both VPA and cytokines for a full 7 days. Treated CD34+ cells were characterized based on the upregulation of pluripotency genes, increased aldehyde dehydrogenase activity, and enhanced expression of CD90, c-Kit (CD117), integrin α6 (CD49f), and CXCR4 (CD184). Furthermore, siRNA-mediated inhibition of pluripotency gene expression reduced the generation of CD34+CD90+ cells by 89%. Compared with CB CD34+ cells, VPA-treated CD34+ cells produced a greater number of SCID-repopulating cells and established multilineage hematopoiesis in primary and secondary immune-deficient recipient mice. These data indicate that dividing CB CD34+ cells can be epigenetically reprogrammed by treatment with VPA so as to generate greater numbers of functional CB stem cells for use as transplantation grafts.

Thymosin ß4 and cardiac regeneration: are we missing a beat?

Epicardial resident stem cells are known to differentiate into cardiomyocytes during cardiac development, amongst other cell types. Whether epicardium-derived progenitor cells (EPDCs) retain this plasticity in the adult heart has been the topic of heated scientific debate. Priming with thymosin beta 4, a peptide which has been suggested to be critical for cardiac development and to have cardio-protective properties, was recently shown to induce differentiation of EPDCs into cardiomyocytes in a small animal model of myocardial infarction. This finding is in stark contrast to another recent study in which thymosin beta 4 treatment following myocardial infarction did not induce cardiomyocyte differentiation of EPDCs. While EPDCs seem to exhibit overall cardio-protective effects on the heart following myocardial infarction, they have not been shown to differentiate into cardiomyocytes in a clinically relevant setting. It will be important to understand why the ability of one therapeutic agent to induce cardiomyocyte differentiation of EPDCs seemingly depends on a single variable, i.e. the time of administration. Furthermore, in light of a recent report, it appears that thymosin beta 4 may be dispensable for cardiac development.