Chemopreventive effects and associated mechanisms of Withaferin A (WA) against intestinal and colon carcinogenesis remain unknown. We investigated the chemopreventive effect of WA on transgenic mouse APCMin/+ and chemically induced azoxymethane/dextran sodium sulfate (AOM/DSS) models of intestinal and colon carcinogenesis. Oral WA administration (4 mg/kg and 3mg/kg) inhibited tumor initiation and progression of intestinal polyp formation in APCMin/+ mice and colon carcinogenesis in the AOM/DSS mouse model. WA-administered mice showed a significant reduction in both number (duodenum, 33% (p>0.05); jejunum, 32% (p<0.025); ileum, 43% (p<0.001); and colon 59% (p<0.01) and size of polyps in APCMin/+ mice compared to the respective controls. Similarly, tumor multiplicity was significantly reduced (p<0.05) in the colon of WA-administered AOM/DSS mice. Pathological analysis showed reduced adenomas and tissue inflammation in WA-administered mouse models. Molecular studies suggested that WA inhibited the expression of inflammatory (IL-6, TNFα and COX2), pro-survival (pAKT, Notch1, and NF-κB), markers in APCMin/+ and AOM/DSS models. The results suggest that WA is a potent agent for preventing colon carcinogenesis and further investigation is required to show clinical utility of the agent.

Chronic myeloid leukemia (CML) is the most common chronic myeloproliferative disorder, which was the first to be described and understood at a molecular level. Marked basophilia can be seen in CML and other neoplastic and reactive processes. Tryptase is a serine protease that is mainly expressed in mast cells, whereas basophils express only trace amounts of the enzyme. Therefore, it has always been regarded as a specific marker for mast cells. We report a case of a 41-year-old male who had been diagnosed with CML eight years ago, and, interestingly, his most recent bone marrow biopsy demonstrated an accelerated phase of the disease with a significant increase of basophils count. These basophils were immunoreactive with tryptase along with CD123. In the literature, this phenomenon of tryptase immunoreactivity by basophils has been described in association with CML, primary myelofibrosis, and myelodysplastic syndrome. Therefore, our finding supports these data and suggests that tryptase should not be regarded as a specific marker for mast cells when approaching various myeloid neoplasms including CML.

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Primary mediastinal germ cell tumors (GCTs) account for a small subset of all GCTs. Teratoma is the most common GCT of the mediastinum and usually occurs in adults from 20 to 40 years of age. Malignant somatic transformation is a rare phenomenon that has been described in both primary and metastatic mediastinal GCTs. The most common types of malignant somatic transformation described in mediastinal GCTs are sarcomas and carcinomas, with very few cases of melanoma found in the literature. We report the case of a 21-year-old male patient who presented with anterior mediastinal mass that on initial biopsy and workup revealed a mediastinal mixed GCTwith teratoma and yolk sac components. Following chemotherapy, the resected mass demonstrated residual teratoma with malignant transformation into melanocytic, neuroectodermal, and undifferentiated sarcomatous elements. The patient rapidly developed metastases to the lung, liver, spleen, and spine. Biopsy of the bone marrow and liver confirmed metastatic dissemination by melanocytic transformed GCT. Molecular analysis for BRAF mutation was negative. The rapid multiorgan pattern of metastatic spread indicates a very aggressive phenotype. This case represents the second reported case of malignant melanocytic tumor as part of multilineage malignant differentiation arising from mediastinal GCT.