Abstract-Allopurinol, an inhibitor of xanthine oxidase, increases myofilament calcium responsiveness and blunts calcium cycling in isolated cardiac muscle. We sought to extend these observations to conscious dogs with and without pacing-induced heart failure and tested the prediction that allopurinol would have a positive inotropic effect without increasing energy expenditure, thereby increasing mechanical efficiency. In control dogs (nϭ10), allopurinol (200 mg IV) caused a small positive inotropic effect; (dP/dt) max increased from 3103Ϯ162 to 3373Ϯ225 mm Hg/s (ϩ8.3Ϯ3.2%; Pϭ0.01), but preload-recruitable stroke work and ventricular elastance did not change. In heart failure (nϭ5), this effect was larger; (dP/dt) max rose from 1602Ϯ190 to 1988Ϯ251 mm Hg/s (ϩ24.4Ϯ8.7%; Pϭ0.03), preload-recruitable stroke work increased from 55.8Ϯ9.1 to 84.9Ϯ12.2 mm Hg (ϩ28.1Ϯ5.3%; Pϭ0.02), and ventricular elastance rose from 6.0Ϯ1.6 to 10.5Ϯ2.2 mm Hg/mm (Pϭ0.03). Allopurinol did not affect myocardial lusitropic properties either in control or heart failure dogs. In heart failure dogs, but not controls, allopurinol decreased myocardial oxygen consumption (-49Ϯ4.6%; Pϭ0.002) and substantially increased mechanical efficiency (stroke work/myocardial oxygen consumption; ϩ122Ϯ42%; Pϭ0.04). Moreover, xanthine oxidase activity was Ϸ4-fold increased in failing versus control dog hearts (387Ϯ125 versus 78Ϯ72 pmol/min ⅐ mg -1 ; Pϭ0.04) but was not detectable in plasma. These data indicate that allopurinol possesses unique inotropic properties, increasing myocardial contractility while simultaneously reducing cardiac energy requirements. The resultant boost in myocardial contractile efficiency may prove beneficial in the treatment of congestive heart failure. (Circ Res. 1999;85:437-445.)

Soft tissue sarcomas in children are relatively rare. Approximately 850 to 900 children and adolescents are diagnosed each year with rhabdomyosarcoma (RMS) or one of the non-RMS soft tissue sarcomas (NRSTS). Of these, 350 are cases of RMS. RMS is the most common soft tissue sarcoma in children 14 years old and younger, and NRSTS is more common in adolescents and young adults. Infants also get NRSTS, but their tumors constitute a distinctive set of histologies, including infantile fibrosarcoma and malignant hemangiopericytoma, not seen in adolescents. Surgery is a major therapeutic modality for all pediatric soft tissue sarcomas, and radiation can play a role in the local therapy for these tumors. RMS is always treated with adjuvant chemotherapy, whereas chemotherapy is reserved for the subset of NRSTS that are high grade or unresectable. This review discusses the etiology, biology, and treatment of pediatric soft tissue sarcomas, including new approaches to therapy aimed at improving the dismal prognosis of patients who have recurrent and metastatic disease. Rhabdomyosarcoma EpidemiologyRMS is the most common soft tissue sarcoma among children less than 15 years old, with an incidence of 4.6 per million per year [1]. This represents 50% of all soft tissue sarcomas in this age range. It is slightly more common in boys than in girls, with a ratio of 1. slightly more common in white children than in black children less than 5 years old (1.1:1) but is more common in black children than in white children 5 years of age or older (1.2:1). Over the past 30 years, the incidence of RMS in the pediatric age group has been constant [1]. EtiologyLittle is known about the etiology of RMS. A few cases are associated with Li-Fraumeni syndrome (caused by germline mutations in p53) [2] or with neurofibromatosis (caused by mutations in NF1) [3]. There also is a weak association with congenital anomalies, especially in boys [4]. These tumors sometimes are seen as second malignant neoplasms after radiation therapy. Molecular and cellular biologyThere are two major histologic variants of RMS-embryonal and alveolar. Other, minor, histologic types include spindle cell, botryoid, and pleomorphic. Embryonal RMS is named for its resemblance to immature skeletal muscle, accounts for 60% of RMS cases in patients less than 20 years of age, and tends to arise in the head and neck region, orbits, and genitourinary region (including bladder and prostate). Alveolar RMS, named for its resemblance to normal lung parenchyma, arises predominantly in the head and neck region and the extremities [3]. Histologically, RMS is a small round blue cell tumor, characterized by expression of muscle-specific antigens, such as desmin and MyoD, and by the presence of eosinophilic rhabdomyoblasts on standard pathologic staining.Alveolar RMS is characterized by the presence of one of two recurrent chromosomal translocations: t(2;13)(q35;q14), seen in 55% of cases, or t(1;13)(p36;q14), seen in 22% of cases [5]. These fuse the FKHR gene on chromosome 13 with...

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