Phase I evaluation of 773U82-HCl in a two-hour infusion repeated daily for three days

One of a novel series of compounds (AMAPS or arylmethylaminopropanediols), 773U82-HCl has shown significant antitumor activity inin vitro and inin vivo tumor systems, but has less animal CNS toxicity than the lead compound in the same series (crisnatol). This study was designed to evaluate the pharmacokinetics, qualitative and quantitative toxicities of 773U82-HCl and to determine the recommended phase II dose (MTD) of 773U82-HCl given as a short infusion daily for 3 days every 3 weeks. Twenty-nine patients with refractory malignancies received 79 courses over 9 dose levels during this study. Doses ranged from 50 to 1060 mg/m²d×3 days. Due to the possibility of local hemolysis with concentrations > 1.5 mg/ml, drug was administered in solutions containing 1.5 mg/ml. Because large volumes were needed at the higher dose levels, the infusion duration was increased from 2 hours to 4 hours. Mild to moderate nausea, vomiting, fatigue, dizziness and headaches were observed. Myelosuppression was the dose limiting toxicity. The recommended phase II dose and schedule was determined to be 800 mg/m²d×3d every 3 weeks. 773U82-HCl plasma concentration-time data were analyzed using a two-compartment pharmacokinetic model. The t1/2 averaged 6 hours and the total body clearance was 75.9 L/hr/m². The volume of distribution (Vdss) was large, averaging 470 L/m².Abbreviations ECG electrocardiogram - t^1/2 half-life - Vdss volume of distribution - HPLC highperformance liquid chromatography - Vd_ss steady-state volume of distribution - AUC area under the concentration × time curve - CL total body clearance - C_max peak plasma level - V_c central volume of distribution     

A phase I study of 5-fluorouracil, leucovorin and levamisole

 Purpose: The activity of 5-fluorouracil (5-FU) against colon cancer is enhanced by leucovorin and the combination of 5-FU and levamisole has activity in the adjuvant treatment of colonic malignancies. The combination of 5-FU with both leucovorin and levamisole may provide additional benefit in the treatment of colon cancer. Methods: A phase I study to assess qualitative and quantitative toxicities of this three-drug combination and to determine a dose for further phase II testing was undertaken. The role of levamisole as an immunomodulator was also assessed. Results: A group of 38 patients with incurable etastatic malignancies received 119 cycles of treatment at eight dose levels. 5-FU (375 mg/m² per day) and leucovorin (200 mg/m² per day) were administered intravenously (days 1–5). Levamisole was administered orally (days 1–3 and 15–17) at doses from 30 to 470 mg/m² per day. Patients received both 5FU/leucovorin and 5-FU/leucovorin/levamisole in random order for their initial two cycles. All subsequent treatments were with the three-drug combination. Toxicities included nausea, vomiting, stomatitis, thrombocytopenia and granulocytopenia. Diarrhea was the dose-limiting toxicity at 470 mg/m² per day levamisole. The addition of levamisole resulted in more toxicity than 5-FU and leucovorin alone. No clinical responses were seen with this regimen. The addition of levamisole resulted in more immunomodulation than 5-FU and leucovorin alone as evidenced by release of neopterin from monocytes. Conclusion: With this schedule and dose of 5-FU and leucovorin, the maximum tolerated dose of levamisole was 354 mg/m². However, given the lack of response and the absence of dose-dependent immunomodulation, this may not be the appropriate dose for further phase 11 studies. Received: 20 October 1995 / Accepted: 16 June 1996     

Splenectomy during primary and secondary cytoreductive surgery for epithelial ovarian carcinoma

Scarabelli C, Gallo A, Campagnutta E, Carbone A. Splenectomy during primary and secondary cytoreductive surgery for epithelial ovarian carcinoma. Int J Gynecol Cancer 1998; 8 : 215–221.
Splenectomy is occasionally indicated to achieve optimal cytoreduction during surgery for epithelial ovarian cancer. Between January 1989 and December 1996, 40 epithelial ovarian cancer patients underwent splenectomy: 14 patients during primary surgery and 26 during secondary cytoreductive surgery. Splenectomy was performed for tumor reduction in 34 patients (85 %) and for iatrogenic injury in six patients (15%). The spleen was removed because of parenchymal splenic metastases in nine patients (22.5 %), significant hilar and/or capsular disease in 10 patients (25 %), and perisplenic disease in 15 patients (37.5%). The histopathological diagnosis of the resected spleens showed microscopic hilar disease in four patients who had the spleen removed because of iatrogenic injury and no disease in only two patients. Splenectomy could be carried out with an acceptable morbidity. Left-sided pleural effusion was the most frequent complication. The estimated two-year survival rate for patients who underwent splenectomy during primary surgery with no residual disease and <2 cm intraperitoneal residual disease was 83% and 42%, respectively. Nine of these patients (64.3%) had recurrent disease. The median time to recurrence was 11 months (range 5–18). The estimated two-year survival rate for patients who underwent splenectomy during secondary surgery with no residual disease and <2 cm intraperitoneal residual disease was 78% and 24%, respectively. The estimated three-year survival rate was 0% for all these patients. The results of the present study show that splenectomy, if necessary to achieve optimal debulking, should be considered in previously untreated patients with no intraperitoneal residual disease and in patients with late (>1 year) recurrent disease.     

Multifocal Cerebral Hemangio-Endothelioma. Case Report and Review of the Literature

BACKGROUND: Intracranial hemangio-endotheliomas (HE) are rare vascular tumours that present histological features and biological behaviour of an intermediate malignancy. We report the first case of primary HE presenting as multiple intracranial masses. CASE DESCRIPTION: The patient is a 20-year-old female who presented with paresis of the left arm. Magnetic Resonance imaging (MRI) showed multiple lesions in both frontal lobes. Total surgical excision of the tumours was obtained; a histological diagnosis of hemangio-endothelioma was made. Five months later, MRI scan showed new intradiploic skull lesions whereas a scintigraphic study revealed multicentric extracranial bone involvement. Treatment based on interferon-alpha (IFN-alpha) administration was undertaken; this produced partial regression of the lesions. Approximately three years after the first operation, the patient is in good clinical condition. CONCLUSIONS: Surgery continues to play the leading role in the treatment of intracranial HE. However, adjuvant therapy with IFN represents a new and well-tolerated therapeutic method for residual intracranial lesions as well as multicentric extracranial disease.     

Placental growth hormone in Down's syndrome screening.

A number of serum markers have been proposed to improve the sensitivity (and specificity) of the triple test, which, until now, has been the gold standard in second-trimester serum screening for Down's syndrome. Among them, human placental growth hormone (hPGH) has been proposed because of its significantly elevated serum levels in pregnancies affected by chromosomal aneuploidies. Our experience, on maternal serum stored from 32 Down's syndrome-affected pregnancies, confirms a slight but significant increase in hPGH levels compared with controls. These data summarized to that of the previous screening could give a calculated detection rate of 71.9%, better than that of the standard triple test alone (65.6%).     

Medial cortex strain distribution during noncemented total hip arthroplasty

Intraoperative proximal femur fractures are a significant concern during noncemented total hip arthroplasty. The current study was performed to investigate the hypothesis that broaching the femur and inserting the stem without using mallet applied impact loads will reduce the risk of intraoperative fracture. Rosette strain gauges were applied to the medial and anteromedial cortex of six human anatomic specimen femurs to compare the strain distribution for broaching and stem insertion. Eight additional femurs were used to compare the strain distribution for stem insertion using impact loading and constant rate stem insertion. For the impact loading stem insertions, the soft tissues surrounding the femur were modeled. Constant rate stem insertions were performed using a mechanical testing machine. The largest strains measured at the medial and anteromedial sites primarily were aligned with the femur hoop axis. The largest strain magnitude, orientation, and sign (tensile or compressive) varied widely among femurs. The stem insertion strains were significantly larger than the broaching strains (two-way analysis of variance with replication). The impact stem insertion strains were not significantly different from the constant rate stem insertion strains. The results indicate that the femur geometry and material properties have a greater influence on the strain distribution than does the implantation technique.