Rhabdomyosarcoma (RMS) typically arises from skeletal muscle. Currently, RMS in patients with recurrent and metastatic disease have no successful treatment. The molecular pathogenesis of RMS varies based on cancer sub-types. Some embryonal RMS but not other sub-types are driven by sonic hedgehog (Shh) signaling pathway. However, Shh pathway inhibitors particularly smoothened inhibitors are not highly effective in animals. Here, we show that Shh pathway effectors GLI1 and/or GLI2 are over-expressed in the majority of RMS cells and that GANT-61, a specific GLI1/2 inhibitor dampens the proliferation of both embryonal and alveolar RMS cells-derived xenograft tumors thereby blocking their growth. As compared to vehicle-treated control, about 50% tumor growth inhibition occurs in mice receiving GANT-61 treatment. The proliferation inhibition was associated with slowing of cell cycle progression which was mediated by the reduced expression of cyclins D1/2/3 & E and the concomitant induction of p21. GANT-61 not only reduced expression of GLI1/2 in these RMS but also significantly diminished AKT/mTOR signaling. The therapeutic action of GANT-61 was significantly augmented when combined with chemotherapeutic agents employed for RMS therapy such as temsirolimus or vincristine. Finally, reduced expression of proteins driving epithelial mesenchymal transition (EMT) characterized the residual tumors.

Nontuberculous mycobacteria (NTM) are ubiquitous free living soil and water– borne organisms that cause numerous clinical syndromes including lymphadenitis, skin, soft tissue and pulmonary infections, however disseminated infection is almost exclusively in patient with severe immunocompromise (i.e:HIV, Hematological malignancy, and bone marrow transplant). Mycobacterium avium complex (MAC) is hard to diagnose as it is considered slow grower NTM. We describe a case of disseminated Mycobacterium avium-intracellulare complex infection in teenager with sickle hemoglobinopathy with unique presentation mimicking pRBCs transfusion reaction. Patient presented on three different occasions with tachycardia, hypotension and fever within 2-24 hours following pRBCs pheresis, all three episodes were investigated and were negative for transfusion reactions. Patient had central venous catheter (CVC), frequent admissions for vaso-occlusive painful episode, on hydrocortisone for adrenal insufficiency and off Hydroxyurea for two months. Diagnosis of mycobacterium avium complex bacteremia was confirmed by two positive blood cultures, whole body CT scan showed liver nodules, spleen nodules and lung nodules. Pulmonary dissemination was confirmed by Biopsy and culture, Lymphocyte markers showed severe lymphopenia with absolute CD4 count of 64. Patient underwent treatment with three month of four antibiotics followed by 9 months of three antibiotics with removal of the central line, follow up scan showed decrease size and numbers of nodules, patient started tolerating pheresis within one month of the antibiotics initiation. NTM infection should be added to the list of pathogens in sickle cell patients with CVCs and fever and should be considered in frequent pRBC transfusion like reaction with negative workup. Routine blood culture can identify rapid growing NTM but specific mycobacterial blood culture is required in case of other NTM species (slow grower). As dissemination almost always occurs in those with impaired cellular immunity, HIV testing and lymphocyte markers should be performed Removal of involved CVCs is essential for the treatment as well as appropriate antimicrobial medications. Disclosures No relevant conflicts of interest to declare.