Phase I clinical and pharmacokinetic study of high-dose mitoxantrone combined with carboplatin, cyclophosphamide, and autologous bone marrow rescue: high response rate for refractory ovarian carcinoma.

PURPOSE: To develop an active high-dose chemotherapy regimen for the treatment of ovarian carcinoma. Due to the rapid development a drug resistance, conventional chemotherapy cures only 20% of patients with advanced disease. However, in vitro data demonstrate a steep dose-response curve to a variety of agents, most notably mitoxantrone. PATIENTS AND METHODS: A phase I study of escalated bolus mitoxantrone (10 to 25 mg/m2 x 3) and cyclophosphamide (30 to 50 mg/kg x 3) with a 5-day infusion of carboplatin (1,500 mg/m2) and an autologous bone marrow transplant (ABMT) was performed. Mitoxantrone pharmacokinetics were performed to document levels required to kill platinum-resistant ovarian carcinoma in vitro. RESULTS: We treated 25 patients; the maximum-tolerated total doses (MTD) were 75 mg/m2 for mitoxantrone, 120 mg/kg for cyclophosphamide, and 1,500 mg/m2 for carboplatin. The dose-limiting toxicity was gastrointestinal, with severe diarrhea, ileus, and resulting sepsis. Transient partial deafness was seen in four patients, and acute renal failure (ARF) occurred in one patient at the first dose level, but was eliminated in subsequent patients with aggressive hydration. There were four early deaths due to ARF (n = 1), Legionella pneumonia (n = 1), and sepsis (n = 2). Peak mitoxantrone levels at the MTD were 623 to 2,810 ng/mL, and the area under the curve (AUC) values of the concentration versus time measurements were 560 to 1,700 ng/mL/h. Of 20 assessable patients, 65% responded, with a 45% complete remission (CR) rate. All six of the assessable patients with ovarian cancer responded: CR in five (83%) and partial remission (PR) in one (17%); the CRs have lasted 7 to 30+ months. Responses were also seen in testicular and breast carcinoma. CONCLUSION: This regimen was well tolerated at the MTD and appears promising for relapsed/refractory ovarian carcinoma, with mitoxantrone levels achieved that are active in vitro against platinum-resistant ovarian carcinoma cells.

Lectin binding to common epithelial tumors of the ovaries.

Binding sites of peanut agglutinin (PNA), Ulex europaeus (UEA-1), wheat germ agglutinin, concanavalin A, and Ricinus communis were localized in 46 common epithelial ovarian tumors. Binding pattern of serous cystadenomas showed significant similarity with the pattern seen in the epithelium of fallopian tubes. Lectin affinity of endometriosis and endometrioid tumors was similar to normal endometrium in secretory phase. Binding pattern of clear cell carcinomas was similar to gestational endometrium, with PNA and UEA-1 showing strong affinity. This pattern is in contrast to clear cell carcinomas of the kidney, that do not bind PNA and UEA-1. Mucinous cystadenomas exhibited binding patterns identical with cervical epithelium. Malignant counterparts of the described tumors were characterized by the partial loss of lectin binding and uneven distribution of the binding reaction.

The H, HI, I and i blood group antigens in butanol extracts of rabbit tissues.

Aqueous and butanol phase extracts of rabbit erythrocytes and the tissues gastric mucosa, liver, lung and kidney were examined by inhibition of agglutination for the presence of H, HI, I and i blood group substances. Of the four specificities, only I substance was recovered from erythrocytes and only in the aqueous phase extracts. Both aqueous and butanol extracts of gastric mucosae contained H substance, but HI and I were present only in the aqueous extracts of this tissue. Extracts of rabbit lungs only had H and I activity and only in the aqueous phase. No H, HI, I or i substance was detected in any of the extracts of liver and kidney. Reduced levels of H substance were found in aqueous extracts of gastric mucosae of 'A-like' rabbits. Three H specificities were demonstrated in the butanol phase extracts of gastric mucosae of rabbits. These specificities were similar to those previously shown in extracts of gastric mucosae and erythrocytes of humans.

Retroperitoneal radical hysterectomy.

A surgical technique is presented which combines both the abdominal and vaginal approaches to radical hysterectomy with significant modifications to allow it to be named "retroperitoneal" radical hysterectomy. Small oblique skin incisions are made 1 cm superior to the inguinal ligament exposing the retroperitoneal structures. The round ligament, uterine artery, ovarian vessels, and cardinal ligament are divided without entering the peritoneal cavity. The remainder of the procedure is completed by a modified Schauta technique. Eight patients with Stage I cancer of the cervix underwent this operation. The expected surgery time should be 3 1/2-4 hr once the surgical team becomes familiar with the procedure, with a blood loss similar to that of the Meigs procedure. Patients tolerated the procedure with minimal discomfort. Total hospital days was limited to 4 days or less in all but the first patient. One patient was discharged on the evening of surgery. No significant complications were reported except some degree of bladder atony that required self-catheterization for a short period of time. We believe that this surgical procedure fulfills the principles of a radical abdominal hysterectomy with less operative time and shorter hospital stay, and employs conventional surgical skills.

Detection of localized breast cancer by prospective mammographic screening criteria.

From 1983 to 1986, 1110 gynecology office patients met our prospective mammographic screening criteria. Ninety-eight mammographically guided, needle-localized breast biopsies were performed on 89 patients (8.0%). Twenty-one nonpalpable breast cancers (22.0%) were diagnosed in 18 patients with these methods. Treatment alternatives chosen in patients with positive biopsy specimens are presented. The importance of establishing consistent criteria for mammography and breast biopsy in the early diagnosis of localized breast cancer is discussed. The unique opportunity of the gynecologist to change the morality rate of breast cancer is emphasized.

DNA ploidy, proliferation index, grade, and stage as prognostic factors for vulvar squamous cell carcinomas.

DNA analysis by flow cytometry has been reported to be a useful prognostic technique for a variety of malignant tumors. The goal of this study was to examine DNA ploidy status and proliferation index as potential predictors of recurrence and survival for patients with squamous cell vulvar carcinomas. The DNA ploidy, percentage of cells in the S-phase of the cell cycle, stage, and histologic grade were analyzed in 42 patients. Flow cytometry was performed on archival paraffin-embedded tissue. The histologic specimens were reviewed by a single pathologist. Thirty-four tumors (81%) were diploid and eight (19%) demonstrated an aneuploid peak. The percentage of cells in the S-phase (proliferation index) was calculated for all patients. The 5-year survival rate was 68% for diploid tumors and was 75% for aneuploid tumors. The difference between these rates was not statistically significant (P < or = 0.65). S-phase fraction was also not a useful predictor for recurrence or overall survival. FIGO stage and histologic grade were accurate predictors for both recurrence and 5-year survival. Multiple predictor analysis using stage, grade, ploidy status, and proliferation index did not identify any subgroup which would predict recurrence better than FIGO stage and grade. DNA ploidy and S-phase fraction analysis do not appear to be clinically useful prognostic factors for vulvar squamous cell carcinomas.

Changes in bacterial community composition and dynamics and viral mortality rates associated with enhanced flagellate grazing in a mesoeutrophic reservoir.

Bacterioplankton from a meso-eutrophic dam reservoir was size fractionated to reduce (<0.8-microm treatment) or enhance (<5-microm treatment) protistan grazing and then incubated in situ for 96 h in dialysis bags. Time course samples were taken from the bags and the reservoir to estimate bacterial abundance, mean cell volume, production, protistan grazing, viral abundance, and frequency of visibly infected cells. Shifts in bacterial community composition (BCC) were examined by denaturing gradient gel electrophoresis (DGGE), cloning and sequencing of 16S rDNA genes from the different treatments, and fluorescence in situ hybridization (FISH) with previously employed and newly designed oligonucleotide probes. Changes in bacterioplankton characteristics were clearly linked to changes in mortality rates. In the reservoir, where bacterial production about equaled protist grazing and viral mortality, community characteristics were nearly invariant. In the "grazer-free" (0.8-microm-filtered) treatment, subject only to a relatively low mortality rate (approximately 17% day(-1)) from viral lysis, bacteria increased markedly in concentration. While the mean bacterial cell volume was invariant, DGGE indicated a shift in BCC and FISH revealed an increase in the proportion of one lineage within the beta proteobacteria. In the grazing-enhanced treatment (5-microm filtrate), grazing mortality was approximately 200% and viral lysis resulted in mortality of 30% of daily production. Cell concentrations declined, and grazing-resistant flocs and filaments eventually dominated the biomass, together accounting for >80% of the total bacteria by the end of the experiment. Once again, BCC changed strongly and a significant fraction of the large filaments was detected using a FISH probe targeted to members of the Flectobacillus lineage. Shifts of BCC were also reflected in DGGE patterns and in the increases in the relative importance of both beta proteobacteria and members of the Cytophaga-Flavobacterium cluster, which consistently formed different parts of the bacterial flocs. Viral concentrations and frequencies of infected cells were highly significantly correlated with grazing rates, suggesting that protistan grazing may stimulate viral activity.

Strong, weak, and missing links in a microbial community of the N.W. Mediterranean Sea.

Planktonic microbial communities often appear stable over periods of days and thus tight links are assumed to exist between different functional groups (i.e. producers and consumers). We examined these links by characterizing short-term temporal correspondences in the concentrations and activities of microbial groups sampled from 1 m depth, at a coastal site of the N.W. Mediterranean Sea, in September 2001 every 3 h for 3 days. We estimated the abundance and activity rates of the autotrophic prokaryote Synechococcus, heterotrophic bacteria, viruses, heterotrophic nanoflagellates, as well as dissolved organic carbon concentrations. We found that Synechococcus, heterotrophic bacteria, and viruses displayed distinct patterns. Synechococcus abundance was greatest at midnight and lowest at 21:00 and showed the common pattern of an early evening maximum in dividing cells. In contrast, viral concentrations were minimal at midnight and maximal at 18:00. Viral infection of heterotrophic bacteria was rare (0.5-2.5%) and appeared to peak at 03:00. Heterotrophic bacteria, as % eubacteria-positive cells, peaked at midday, appearing loosely related to relative changes in dissolved organic carbon concentration. Bacterial production as assessed by leucine incorporation showed no consistent temporal pattern but could be related to shifts in the grazing rates of heterotrophic nanoflagellates and viral infection rates. Estimates of virus-induced mortality of heterotrophic bacteria, based on infection frequencies, were only about 10% of cell production. Overall, the dynamics of viruses appeared more closely related to Synechococcus than to heterotrophic bacteria. Thus, we found weak links between dissolved organic carbon concentration, or grazing, and bacterial activity, a possibly strong link between Synechococcus and viruses, and a missing link between light and viruses.