Phase II clinical trial of carboplatin and docetaxel in patients with metastatic ovarian cancer: active combination with low incidence of peripheral neuropathy.

During the past 2 decades there have been chemotherapeutic advances in the management of patients with advanced epithelial ovarian cancer. Nevertheless, new drug combinations aimed at increasing response and survival and decreasing toxicities are under investigation. The aim of this phase II study is to determine the feasibility, efficacy and toxicity of docetaxel at a dose of 75 mg/m2 in combination with Carboplatin at an area under the curve (AUC) of 6, as first line treatment in patients with advanced ovarian cancer. 37 patients with stage III-IV epithelial ovarian cancer were entered, and are currently evaluable for response and toxicity. Treatment was well tolerated. The most common grade III and IV toxicities were leukopenia and neutropenia. The incidence of febrile neutropenia was 16.2%. Grade II and III sensory peripheral neuropathy occurred in 8.1% of patients. Peripheral neuropathy resolved in two patients and persisted for more than 10 months in one patient. An overall clinical response of 89% was documented (95% CI 74.5% to 96.9%). Carboplatin and docetaxel administered according to our protocol is an effective alternative to other existing platinum-taxane based combinations. This treatment is associated with low incidence of sensory peripheral neuropathy, which is generally associated with better patient compliance and quality of life.

Current treatment options for malignant melanoma.

The incidence of malignant melanoma has increased at an alarming rate over the past few decades. Indications are that it will continue to rise in the foreseeable future. Primary prevention of malignant melanoma through education of the general public regarding the hazards of sun exposure is important in an attempt to reduce the incidence of the disease in the future. It can, however, be expected to take many years before a decrease in the number of cases of this disease is seen. Until such time, the medical oncologist will be faced with an increasing number of referrals for both adjuvant therapy and treatment of metastatic disease. Many agents have been investigated as possible postsurgical adjuvant therapies in patients with malignant melanoma. To date, inteferon-alpha (IFN-alpha) given initially intravenously in high doses followed by subcutaneous therapy for 1 year, is the only treatment that has been shown to increase disease-free and overall survival in patients with high-risk melanomas. Patients falling into this group should still, wherever possible, be enrolled in prospectively randomised clinical trials. Although the prognosis for patients with metastatic melanoma remains poor, some progress in the management of this disease has been made. It has not yet been conclusively proven that combination chemotherapy yields superior results to single agent dacarbazine (DTIC) [which has for many years formed the cornerstone of therapy]. Immunotherapy involving IFNs and interleukin-2 (IL-2) alone or in combination has yielded similar results to those achieved with chemotherapy alone. The combination of chemotherapy plus immunotherapy appears to hold promise, with high response rates and often durable remissions reported, albeit at the expense of considerable treatment-related toxicity. Novel therapies including tumour vaccines and gene therapy also hold promise for the future management of this disease.

Mitomycin C, epirubicin and cisplatin versus mitomycin C alone as therapy for carcinoma of unknown primary origin.

Carcinoma of unknown primary (CUP) site accounts for approximately 6.5% of all cancers. Optimal therapy for patients with CUP has not yet been delineated. The current study was undertaken to evaluate response, time to treatment failure and survival in patients with CUP treated with a combination regimen comprising mitomycin C, epirubicin and cisplatin (MEP) versus mitomycin C alone (MITOC). Eighty-four patients with CUP were randomised to receive either the combination (MEP) or MITOC. Both treatment arms were well matched for age, gender, performance status, dominant site and number of disease sites. Eighty of the above patients were evaluable. Twenty patients (50%) treated with MEP responded to treatment compared with 7 (17%) who received MITOC. Grade III-IV hemopoietic toxicity was documented in 2 patients treated with MEP and no patients treated with MITOC. A single patient treated with MEP developed grade I peripheral neuropathy. Median time to treatment failure was 4.5 months for patients receiving MEP as opposed to 2 months for those receiving MITOC (p = 0.05). Median survival was 9.4 months in patients treated with MEP compared to 5.4 months in those receiving MITOC (p = 0.05). This study indicates that the addition of cisplatin and epirubicin to MITOC results in a significant improvement in the response rate, time to treatment failure and survival in patients with adenocarcinoma of unknown primary site.

Protriptyline, chronic tension-type headaches, and weight loss in women.

Twenty-five women with chronic tension-type headaches were treated with protriptyline for 3 months, with attention paid to days of monthly headaches before and while taking the medication, as well as change in weight and side effects. One patient stopped the medication because of side effects and 2 did not return for follow-up, yielding 22 patients. The typical dose of protriptyline was 20 mg every morning. Eighty-six percent of patients had fewer headaches each month, with the mean dropping from 28.2 to 11.7 days. Seventy-three percent had a 50% or greater reduction in the number of headaches per month. The average weight change was a loss of slightly over 3 pounds during the study period. The advantages and disadvantages of protriptyline in the treatment of chronic tension-type headaches are discussed, as are mechanisms of action.

Vertebral morphometry derived from digital images.

OBJECTIVE: We describe a method for capturing measurement data directly from digitized images using specialized software and high-resolution workstations. We have evaluated the reliability, accuracy, and reproducibility of this method in an international clinical trial involving vertebral morphometry. MATERIALS AND METHODS: Accuracy was determined using clinical radiographs measured with vernier calipers and a film phantom. Intra- and interobserver variabilities were assessed, and longitudinal reproducibility was evaluated. As part of the trial, spinal radiographs were collected from more than 200 international health care facilities and digitized at four screening centers. Digitized images were stored and sent to our central facility for morphometry and archiving. Timeliness and variability of the process were tracked. RESULTS: Relative accuracy was nearly 100%. Correlation with clinical measurements was high (r = .96; p < .05). The mean coefficient of variation for interobserver variability was 2%. Intraobserver variation was 3-5%. The coefficient of variation for longitudinal reproducibility ranged from 4% to 6%. After 9 months of operation, our trial included 9494 patients. Of approximately 36,000 radiographs, 98% passed quality review. Only 1% of vertebral levels were not measurable. Hardware and software problems were minimal. CONCLUSION: The use of digitized images for morphometry is accurate, reproducible, and convenient. When applied to a large-scale clinical trial, it offers unique advantages that may justify the cost and complexity that exceed those of conventional radiographs.

Tick bite fever in black South Africans--a rare disease?

Tick bite fever (Rickettsia conorii) is a disease which occurs commonly in South Africa. Clinical illness in the black African patient is however rare, despite high seroprevalence rates of antibodies against R. conorii reported from other areas of Southern Africa. We present two case reports of clinically apparent tick bite fever occurring in black South Africans, the first to be documented in sub-Saharan Africa, and examine possible explanations for the marked discrepancy between clinical illness and seroprevalence rates.

Concurrent mutations of coding and regulatory sequences of the Ha-ras gene in urinary bladder carcinomas.

This report concerns the study of Ha-ras gene mutations and ras p21 expression in primary tumors of the urinary bladder. Polymerase chain reaction-based techniques and computerized image analysis were used. The data obtained were related to tumor grade, DNA ploidy, and tumor invasion. A point mutation (G-->T) at Ha-ras codon 12 was found in 30 of 67 tumors. The mutation frequency was greater in grade III (65%) than in grade II (44%) tumors; no mutations were observed in grade I tumors. The mutation was observed more often in aneuploid (58%) than in diploid (28%) tumors. No other substitution at codon 12 was seen and no codon 61 mutation was detected. The tumors were also tested for the A-->G mutation at position 2719 of Ha-ras intron D. Concurrent codon 12 and intron D mutations were identified in seven high-grade aneuploid tumors; six were invasive. The levels of the ras gene product p21 were approximately 10 times higher in tumors with intron D mutation than in those without. These findings confirm on human bladder tumors the observations of the effect of synchronous exon-intron mutations reported on the bladder cancer cell line T24. Our results are the first demonstration of Ha-ras intron D alterations in human tumor tissues and suggest that concurrent mutations at codon 12 and intron D of this gene within the same tumor may contribute to the aggressive behavior of human bladder carcinomas.

Tenckhoff catheter replacement or intraperitoneal urokinase: a randomised trial in the management of recurrent continuous ambulatory peritoneal dialysis (CAPD) peritonitis.

A randomised trial, comparing Tenckhoff catheter replacement as a one-stage procedure and i.p. urokinase, was undertaken in the management of recurrent continuous ambulatory peritoneal dialysis (CAPD) peritonitis. In addition to appropriate i.p. antibiotic treatment, 17 patients received i.p. urokinase (5000 i.u.) on the second and fourth days of antibiotic treatment, and 14 patients underwent CAPD catheter replacement. An additional six patients also underwent catheter replacement following the recurrence of peritonitis after urokinase treatment. The subsequent recurrence rate of peritonitis following CAPD catheter replacement (5%) was significantly less than after urokinase (41%) (p less than 0.001). Fourteen patients remained free of peritonitis for at least three months after catheter replacement, and five patients were peritonitis-free following urokinase for this period.

A method for demonstrating subclinical inguinal herniae in patients undergoing peritoneal dialysis: the isotope 'peritoneoscrotogram'.

We report six patients who presented with genital oedema associated with continuous ambulatory peritoneal dialysis (CAPD) who had no clinically detectable inguinal hernia at the time of initial presentation. In the absence of conventional clinical signs of an inguinal hernia, isotope imaging of the pelviscrotal region after introducing technetium-labelled tin colloid through the dialysis tube has proved to be an accurate guide to localisation of the hernia, has avoided unnecessary bilateral explorations, and has facilitated early repair of the hernia, thus allowing reinstitution of CAPD.

Critical spatial requirement within the origin of simian virus 40 DNA replication.

We inserted a single base pair into the center of a 27-base-pair palindrome within the replication origin of simian virus 40. The mutation did not directly alter the symmetry of the palindrome or the protein-binding sequences within the palindrome. DNA binding studies showed that subunits of the simian virus 40 A protein (T antigen) bound to each of the four recognition pentanucleotides in the origin palindrome but did so with reduced affinity in comparison with wild-type origins. The mutant origin cloned in a plasmid DNA failed to replicate in COS cells. Thus, precise spatial interactions among subunits of A protein are necessary for stable origin binding and are crucial for subsequent steps in the initiation of DNA replication. Furthermore, any possible functional interactions of the simian virus 40 A protein with cellular DNA would require a great fidelity of protein binding arrangements to initiate cellular DNA replication.

The effect of brief episodes of diminished uterine blood flow on breathing movements, sleep states and heart rate in fetal sheep.

Responses to brief episodes of occlusion of the middle uterine artery were examined in six fetal sheep in utero between 122 and 140 days of gestation. Continuous recordings were made of fetal breathing movements, electro-cortical (ECoG) and electro-ocular (EOG) activity, arterial pressure and heart rate. Five minutes of unilateral or bilateral arterial occlusion caused fetal hypoxaemia while changes in mean arterial PCO2 and pH were not statistically significant. Occlusions usually led to a cessation of rapid eye movements (REM) and respiratory activity (86% of trials), to the appearance of high-voltage slow waves in the ECoG (84% of trials) and to a fall in heat rate of more than 10% (81% of trials). With the exception of the changes in heart rate, these responses resemble those which frequently occur during non-labour contractions of the uterus. We conclude that the cessation of fetal breathing movements and rapid eye movements and the onset of slow waves in the ECoG seen in association with uterine contractions may be due to the mild hypoxaemia which accompanies them.

Binding of cis- and trans-dichlorodiammineplatinum(II) to DNA: evidence for unwinding and shortening of the double helix.

The antitumor drug cis-dichlorodiammineplatinum(II) (cis-DDP) and the inactive trans isomer bind and produce cooperative changes in closed and nicked circular duplex DNA's. Covalent binding of both platinum complexes to the closed circular DNA alters the degree of supercoiling, presumably by disrupting and unwinding the double helix. Electron micrographs show the platinated DNA's to be shortened by up to 50 percent of their original length. At similar ratios of bound platinum per nucleotide, the electrophoretic mobilities of the DNA's in gels containing the dye ethidium bromide are the same for both isomers. The only detectable difference in the binding of the two platinum isomers is an increase in the electrophoretic mobility in nondye gels of closed circular DNA having small amounts of bound cis-DDP that is not apparent for the trans complex.