Rhabdomyosarcoma (RMS) is the most common paediatric soft-tissue sarcoma including two major subtypes, alveolar rhabdomyosarcoma (ARMS) and embryonal rhabdomyosarcoma (ERMS). Increasing evidence suggests that oncogenesis of RMS involves multistages of signalling protein dysregulation which may include prolonged activation of serine/threonine kinases such as phosphoinositide-dependant kinase-1 (PDK-1) and AKT. To date, whether PDK-1/AKT pathway is activated in RMS is unknown. This study was to examine phosphorylation status of AKT and to evaluate a novel small molecular inhibitor, OSU-03012 targeting PDK-1 in RMS. We examined phosphorylation levels of AKT using ARMS and ERMS tissue microarray and immunohistochemistry staining. Our results showed phospho-AKT Thr308 level is elevated 42 and 35% in ARMS and ERMS, respectively. Phospho-AKT Ser473 level is also increased 43% in ARMS and 55% in ERMS. Furthermore, we showed that OSU-03012 inhibits cell viability and induces apoptosis in ARMS and ERMS cell lines (RH30, SMS-CTR), which express elevated phospho-AKT levels. Normal cells are much less sensitive to OSU-03012 and in which no detectable apoptosis was observed. This study showed, for the first time, that PDK-1/AKT pathway is activated in RMS and may play an important role in survival of RMS. PDK-1/AKT pathway may be an attractive therapeutic target for cancer intervention in RMS using OSU-03012.

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We describe new pathologic findings in two sibs with Farber lipogranulomatosis. The first child, a 3‐month‐old boy, presented with only hepatosplenomegaly and had a fulminant clinical course suggestive of malignant histiocytosis. The second child, a 5 1/2‐month‐old girl, had the typical clinical presentation of Farber disease, with hoarseness and painful swollen joints. At autopsy, storage material was demonstrated in the second child at laryngeal and periarticular subcutaneous sites. Visceral involvement was prominent in both sibs, although not typical of the disease, and included a newly described nephropathy with elevated urine ceramide levels. Liver and spleen contained massive histiocytic infiltrates in association with elevated ceramide levels. Lymph nodes also contained histiocytic infiltrates but without the sinusoidal involvement typical of proliferative histiocytic disorders. These two cases demonstrate new pathologic anomalies in Farber disease, indicating that biochemical analyses of biopsy specimens may be necessary to establish the diagnosis of Farber disease when atypical clinical and morphologic anomalies are present.

We examined full-thickness rectal biopsies from 30 children who had chronic constipation, including 5 children with constipation associated with clinical symptoms of intestinal pseudo-obstruction. Biopsies from 9 patients who required colonic interposition and from 7 with Hirschsprung's disease were used as controls. Tissues were evaluated for muscularis mucosae thickness (in mm), for absolute circular and longitudinal muscle layer thicknesses and their ratio, and for the intensity of neural vasoactive intestinal peptide (VIP) immunohistochemical staining. Atrophy of the rectal musculature with focal muscle fiber vacuolation or muscle fiber disappearance was found in all children with chronic constipation. Muscularis mucosae thickness was increased (P < .01) and the circular-to-longitudinal muscle ratio was decreased in the constipation group, with the greatest degree of atrophy being demonstrated in the circular layer. Two of the patients had additional biopsies up to 9 years after the first that illustrate progressive myopathic changes over time. This study demonstrates muscular atrophy in the rectum of children with chronic constipation. Besides primary idiopathic disease, potential etiologies include chronic distention, denervation, functional obstruction from obstipation, alteration in gut hormones, and toxic, ischemic, or neural injury.