Topoisomerase I interactive drugs in children with cancer

Topotecan, irinotecan, and 9-aminocamptothecin (9-AC) are analogs of the plant alkaloid 20(S)-camptothecin (CMT), the prototypical DNA topoisomerase I interactive agent. These agents interact with the topoisomerase I-DNA complex and prevent resealing topoisomerase I-mediated DNA single-strand breaks. This eventual leads to double-strand DNA breaks and apoptosis or cell death. Topotecan, irinotecan, and 9-AC have shown significant activity in mice bearing pediatric solid tumor xenografts; the greatest antitumor responses were found with protracted continuous schedules. Preclinical data also suggest that maintenance of an exposure-duration threshold (EDT) may be required to achieve optimal cytotoxicity. Pediatric Phase I trials have evaluated the toxicity and safety of camptothecin analogs in children with relapsed solid tumors and relapsed acute leukemia. The primary dose-limiting toxicity (DLT) for the CMT analogs in children has been myelosuppression, except for mucositis observed with the 120-hr continuous topotecan infusion schedule. Pharmacodynamic relationships with these analogs have been reported between systemic exposure, and myelosuppression and mucositis. Although not a primary objective of the early Phase I studies, antitumor responses have been reported. In this review, the pharmacokinetics and pharmacodynamics of the CMT analogs studied in children are summarized, and future studies of these agents are discussed. Address for offprints: Clinton F. Stewart, Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, 332 N. Lauderdale, Memphis, TN 38105, USA     

Evaluation of the plain abdominal X-ray in the acute abdomen.

The prognostic value of an erect and supine abdominal X-ray was studied prospectively in 97 patients with an acute abdomen. Although 64 (66%) of the radiographs showed an abnormality, the surgical registrar altered his clinical diagnosis on only seven occasions and changed his management on four. A consultant radiologist was the most accurate at reporting the X-rays even without seeing the patient, whilst junior surgical and radiological staff were as accurate as each other. A surgical registrar, however, was more accurate than junior radiologists in making a diagnosis. The investigation was of immediate clinical value in only 4% of the patients, and its use could probably be limited without detriment to patients.     

Signs of acute carpal instability associated with distal radial fracture

The posteroanterior and lateral wrist radiographs of 52 adults who sustained acute distal radial fractures were reviewed to determine the incidence of radiographic signs of concomitant acute scapholunate ligamentous injury. Three radiographic criteria, either separately or in concert, were used to identify scapholunate ligamentous injury. They are (a) scapholunate angle >60°; (b) widening of the scapholunate space >2 mm; and (c) the cortical ring sign (also called the scaphoid or signet ring sign). Thirty-six of 52 cases (69%; 95% confidence interval =52.1–82.2%) showed evidence of scapholunate ligamentous injury; 16 of 52 cases (31%; 95% confidence interval =16.8–46.6%) showed no evidence of scapholunate ligamentous injury. Statistical analysis suggests that a minimum of 52.1% of all adult distal radial fractures are associated with signs of concurrent acute scapholunate ligamentous injury. The analysis also suggests that independent variables such as age, gender, severity of radius fracture, or mechanism of injury do not significantly alter the incidence of associated carpal ligamentous instability. This study has established a greater than 52.1% incidence of radiographic signs of scapholunate instability in adults with acute distal radial fractures. It is incumbent upon radiologists to search for the signs of scapholunate dissociation in all adult cases of distal radius fracture, regardless of age, gender, severity of radius fracture, or mechanism of injury.     

Atypical white matter volume development in children following craniospinal irradiation

Most children with medulloblastoma (MB), the second most common pediatric brain tumor, have a 70% probability of survival. However, survivors who receive aggressive therapy are at significant risk of cognitive deficits that have been associated with lower volumes of normal-appearing white matter (NAWM). We hypothesized that cranial irradiation inhibited normal brain volume development in these survivors. We retrospectively analyzed 324 MRI studies of 52 patients with histologically proven MB treated with surgery and 35 to 40 Gy craniospinal irradiation, with or without chemotherapy. The volume of NAWM and that of cerebrospinal fluid were quantified from a single index section and compared with those of healthy, age-similar control subjects. A quadratic random coefficient model was used to identify trends in brain volume with increasing age. Patients treated for MB at younger ages demonstrated substantially less development of NAWM volume than did their healthy peers. Younger age at the time of irradiation and the need for a ventricular shunt were significantly associated with reduced NAWM volume. NAWM and craniospinal fluid volume differences between patients who had shunts and those without resolved over a period of four to five years. NAWM volume is known to be associated with neurocognitive test performance, which shows deficiencies after cranial irradiation early in life. Therefore, volumetric monitoring of brain development can be used to guide the care of survivors, assess the toxicity of previous and current clinical trials, and aid in the design of therapies that minimize toxicity.     

The therapeutic potential of vasopressin receptor antagonists in congestive heart failure

Hospitalisation of patients presenting with deteriorating congestive heart failure is occurring with increasing frequency and is associated with significant morbidity and mortality. Diuretic use, the mainstay therapy for congestion, is associated with electrolyte abnormalities and deteriorating renal function. In a recent randomised study, tolvaptan, a novel vasopressin antagonist, in addition to standard therapy including diuretics, increased net fluid loss resulting in decreased body weight more effectively than standard therapy alone in patients hospitalised for heart failure. This desirable effect was achieved without adversely affecting blood pressure, heart rate, electrolyte levels, or renal function. Although tolvaptan did not reduce the rate of deteriorating heart failure after discharge, post hoc analysis suggested that mortality might be reduced in high-risk patients treated with tolvaptan. These results make an important contribution to heart failure research, and offer an insight into the future role of vasopressin antagonism in the treatment of congestive heart failure.     

Sarcomas of the small intestine

Sarcomas of the small intestine are rare, clearly differentiated, malignant, mesenchymatous tumours that can be of smooth muscle, Schwann cell or fibroblastic origin. From a clinical point of view, the pain and abdominal mass are the 2 types of symptoms that frequently reveal the disease. In rare cases, sarcomas of the small intestine are manifested by an acute complication. No imaging method can clearly confirm the diagnosis. Before immunohistochemistry, differential diagnosis was made on undifferentiated mesenchymatous "stromal" tumours, which are also rare. Exeresis must be complete and without perforation of the tumour because of the risk of locoregional relapse. The benefits provided by chemotherapy and radiotherapy are limited because of the low mitotic activity of the tumour cells and its weak vascularisation. Long-term survival is limited by poor prognosis criteria: high grade malignancy, size greater than 5 cm, tumour extension, perforation of the tumour, quality of surgical resection and histological type.     

Impact of prostate size and body mass index on perioperative morbidity after laparoscopic radical prostatectomy

PURPOSE: We prospectively evaluated the impact of body mass index (BMI) and prostate gland size on operative time, estimated blood loss (EBL) and hospital stay (LOS) in patients undergoing laparoscopic radical prostatectomy at our institution. MATERIALS AND METHODS: A total of 70 consecutive laparoscopic radical prostatectomies were performed at our institution from May 2002 to April 2003. Patients who had pelvic lymphadenectomy were excluded. A total of 62 cases were available for analysis. Two cases were converted to open surgery. Perioperative data on each group were recorded, including patient age, height, weight, American Society of Anesthesiologists score, prostate specific antigen, operative time, EBL, time to regular diet and LOS. Pathology data, including specimen weight, Gleason score and the margin status, were reviewed. Patients were grouped into 3 categories based on obesity, as measured by BMI (25 or less, 26 to 29 and greater than 29 kg/m) and prostatic gland size (less than 30, 30 to 50 g, and greater than 50 gm). Furthermore, an analysis of our initial 20, middle 20 and last 22 cases was also performed. RESULTS: Mean patient age was 63 years and mean American Society of Anesthesiologists score was 2.4. Mean operative time was 247 minutes and average EBL was 413 cc. The average LOS in all groups was 2.2 days. There were no statistically significant differences in operative parameters (operative time, EBL or LOS) among the ideal body weight (BMI 25 kg/m or less), overweight (BMI 26 to 29) and obese (BMI greater than 29) groups. The initial 20 cases, the second 20 and the last 22 had similar operative time, EBL and LOS. The surgical margin positive rate in our series was 17.7% for all stages. Of the patients 82% were completely dry at 6 months. CONCLUSIONS: In our cohort of patient body mass index (25 or less, 26 to 29 and greater than 29 kg/m) did not have a significant impact on operative or postoperative morbidity. However, a positive correlation between prostate gland size (greater than 50 gm) and EBL approached but did not achieve statistical significance. Laparoscopic prostatectomy can be performed safely in obese patients and patients with a large prostate gland.