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Biomedical subjects

F Richards

Publications and source records attributed to F Richards.

At least 37 records · Page 2Linked to original sources
PubMed1996

Leucovorin and high-dose fluorouracil in metastatic prostate cancer. A phase II trial of the piedmont Oncology Association.

We performed a Phase II trial of oral leucovorin and high-dose fluorouracil (5FU) in hormone refractory patients with metastatic prostate cancer who had not had prior chemotherapy. 5FU was given as a 24-hour infusion at a dosage of 4 g/m2 and oral leucovorin at a dosage of 50 mg every 6 hours for four doses, starting with the infusion of 5FU. Fifteen patients were treated and three were not evaluable for response. There were no complete (CR) or partial responses (PR) in 12 evaluable patients (95% confidence interval for CR+PR of 0 to 26%). Three patients had stable disease and the remainder progressed. Toxicities were generally mild to moderate, but one patient died of sepsis while neutropenic. This dose and schedule of leucovorin and 5FU is not better than single-agent 5FU in patients with metastatic prostate cancer.

Aged↗
PubMed1996

Phase I study of N-(phosphonacetyl)-L-aspartate with fluorouracil and with or without dipyridamole in patients with advanced cancer.

We conducted a combined biochemical modulation trial of N-(phosphonacetyl)-L-aspartate (PALA), dipyridamole (DP), and fluorouracil (5-FU) in patients with cancer. Eighty-eight patients with advanced cancer were entered into this Phase I trial. During the first part of the study, four doses of PALA (125, 250, 500, and 1000 mg/m2, administered on day 1) were evaluated to determine the PALA dose with maximal suppression of aspartate transcarbamylase (ATCase) activity that was clinically tolerable. Patients were randomized to receive DP (or no DP), 50 mg/m2, p.o. every 6 h on days 1-6, and all patients received 5-FU, 400 mg/m2, by bolus administration on days 2-5. Prior to and during therapy, WBCs were collected and assayed for ATCase activity. After the maximally tolerated PALA dose with 400 mg/m2 5-FU +/- 50 mg/m2 DP was defined, the 5-FU dose was escalated using the same administration schedule of 5-FU, PALA, and DP. The dose of 5-FU was escalated by 25% in each of the DP cohorts until dose-limiting toxicity was reached. ATCase activity was inhibited in a dose-dependent manner with PALA doses of 125, 250, 500, and 1000 mg/m2, resulting in 0, 13, 17, and 49% inhibition of ATCase activity. Only at the higher PALA doses (i.e., 500 and 1000 mg/m2) was ATCase activity suppressed during days 2-5, but the activity returned to pretreatment levels by day 15. Based on the clinical tolerance and significant suppression of ATCase activity, a PALA dose of 500 mg/m2 was selected for the 5-FU dose escalation phase. At a 5-FU dose of 625 mg/m2, dose-limiting toxicity (leukopenia, stomatitis, and diarrhea) occurred in both DP cohorts. We recommend that for this monthly treatment schedule, 500 mg/m2 PALA and 500 mg/m2 5-FU, with or without 50 mg/m2 DP, be used in subsequent Phase II trials.

Adult↗
PubMed1995

Increased instability of intermediate alleles in families with sporadic Huntington disease compared to similar sized intermediate alleles in the general population.

We have directly compared intergenerational stability of intermediate alleles (IAs) derived from new mutation families (IANM) for Huntington disease (HD) with IAs in the general population (IAGP) which occur in approximately 1 in 50 persons. Analysis of meiotic events in blood and sperm reveals that IANM are significantly more unstable than IAGP despite similar size. However, for both IANM and IAGP CAG changes were small and risks for inheriting an expansion into the HD affected range were low. Sequence analysis reveals that the CAG tract is generally interrupted by a penultimate CAA in IAGP, IANM and alleles in the affected range. In one new mutation family, however, two A-->G mutations result in a pure CAG tract which is associated with very marked instability. These mutations alter the predicted DNA hairpin structure with a predicted increase in the likelihood of large expansion, supporting the model that hairpin loop formation plays an important role in trinucleotide instability.

Alleles↗
PubMed1995

Schedule dependency of 21-day oral versus 3-day intravenous etoposide in combination with intravenous cisplatin in extensive-stage small-cell lung cancer: a randomized phase III study of the Cancer and Leukemia Group B.

PURPOSE: This was a randomized phase III study to test the schedule dependency of etoposide given as a conventional 3-day intravenous (IV) regimen versus a prolonged 21-day oral regimen for extensive-stage small-cell lung cancer (SCLC). Both regimens contained IV cisplatin. The objectives were to compare survival (primary end point) and to establish response rates, failure-free survival, and toxicity (secondary end points). PATIENTS AND METHODS: Patients with untreated measurable or assessable disease and normal organ function were eligible. Randomization was stratified according to performance status 0 versus 1 or 2. Treatment consisted of etoposide 130 mg/m2/d IV for 3 days and cisplatin 25 mg/m2/d IV for 3 days every 21 days for eight courses (schedule 1) versus etoposide 50 mg/m2/d orally for 21 days and cisplatin 33 mg/m2/d IV for 3 days every 28 days for six courses (schedule 2). In 1990, bioavailability of oral etoposide was assumed to be 50%, and the study was designed to deliver the same total doses of etoposide and cisplatin on both regimens over 24 weeks without the use of growth factors. RESULTS: Between December 1990 and October 1993, 306 eligible patients were entered. Of these, 69% were male and 66% were > or = 60 years of age; 21% had a performance status of 0, 47% a performance status of 1, and 32% a performance status of 2; 156 were randomized to receive schedule 1 and 150 to receive schedule 2. Overall median survival estimates were 9.5 and 9.9 months (difference not significant) for schedule 1 and schedule 2, respectively. The 95% confidence interval (CI) for overall survival, 8 to 11 months, was the same for both schedules, with 126 and 117 deaths on schedule 1 and 2, respectively. Both schedules also resulted in the same median failure-free survival estimate of 7 months (95% CI, 6 to 8 months on either schedule). Complete and partial responses were observed in 15% and 42% of patients on schedule 1 and 14% and 47% on schedule 2, respectively. The overall maximal hematologic toxicities grade 3 and 4 for leukocytes, neutrophils, platelets, and hemoglobin were, respectively, as follows: schedule 1, 62%, 85%, 32%, and 32%; schedule 2, 83%, 83%, 52%, and 53%. Lethal toxicity due to neutropenia and infection occurred in 4% of patients on schedule 1 and 10% on schedule 2 (difference not statistically significant). CONCLUSION: The two schedules of etoposide in combination with cisplatin did not result in differences in treatment outcome with respect to tumor response and survival. However, a significantly greater rate of severe or life-threatening hematologic toxicity was noted on the 21-day oral etoposide treatment schedule.

Administration, Oral↗
PubMed1995

Oculocutaneous albinism and bruising in two sisters--probable Hermansky-Pudlak syndrome.

Cases of Hermansky-Pudlak syndrome may present to the dermatologist, ophthalmologist or haematologist. Classically the diagnosis rests on the triad of oculocutaneous albinism, a bruising tendency and the presence of characteristic pigmented-containing cells in the bone marrow. Specific tests of platelet function can, however, suggest the diagnosis without recourse to invasive techniques. We describe the disease in two young sisters.

Adenosine Diphosphate↗
PubMed1994

Local intramural drug delivery using an infusion balloon following angioplasty in normal and atherosclerotic vessels.

Local intramural delivery of various pharmacologic agents following angioplasty has been proposed as a means of reducing restenosis. This study tested whether local intramural delivery of aqueous solutions using an infusion balloon could be accomplished safely in normal vessels and whether such infusion was safe following standard angioplasty in diseased vessels. Infusion of aqueous agents into normal canine arteries had no adverse effect. Infusion of several aqueous agents (< or = 4 cc at 4 atm) into diseased swine iliac arteries following balloon angioplasty did not worsen existing or create new dissections. Histologically, infusion treated vessels did not differ in either model from vessels treated with angioplasty alone. We conclude that local intramural drug infusion does not create new, or worsen existing, dissections produced during standard balloon angioplasty in diseased vessels.

Angioplasty, Balloon, Coronary↗
PubMed1994

Occurrence, etiology, and clinical significance of extreme thrombocytosis: a study of 280 cases.

PURPOSE: To determine the etiology and to evaluate the clinical consequences of an extremely elevated platelet count. PATIENTS AND METHODS: A review of the medical records was performed on all patients encountered during a 5 1/2-year period who had at least one platelet count of 1,000 x 10(9)/L or greater. RESULTS: Of the total of 280 patients with extreme thrombocytosis (EXT), 231 (82%) had reactive thrombocytosis (RT), 38 (14%) had a myeloproliferative disorder (MPD), and 11 (4%) had cases of uncertain etiology. RT was more common than MPD in all age groups except those in the eighth decade and older. Symptoms of bleeding and/or vaso-occlusive phenomena were noted in association with EXT in 21 (56%) of the MPD patients but in only 10 (4%) of the RT patients. Treatment to lower the platelet count and/or inhibit platelet function was employed in 36 MPD patients and 23 RT patients. Eight patients with MPD and 34 with RT are known to have died, but no patient in either group is known to have died of a thrombotic or bleeding event when the platelet count was greater than or equal to 1,000 x 10(9)/L. CONCLUSIONS: Platelet counts greater than or equal to 1,000 x 10(9)/L should not be considered rare events in the general, acute-care hospital population, and usually represent a reactive phenomenon.

Adolescent↗
PubMed1993

A phase I trial of ifosfamide, mesna, and cisplatin in advanced non-small cell lung cancer. A cancer and leukemia group B study.

BACKGROUND: This Phase I study was designed to determine the maximum tolerated dose of ifosfamide-mesna with a fixed dose of cisplatin without growth factor or hematopoietic precursor support. METHODS: Twenty-five patients with previously untreated advanced non-small cell lung cancer were treated at four dose levels. Initially, the cisplatin dose was 100 mg/m2 given on day 1. Seven patients were treated with ifosfamide 2.0 g/m2 days 1 to 3, and six patients received ifosfamide 2.5 g/m2 days 1 to 3. Mesna was given at 20% of the ifosfamide dose at 0, 4, and 6 hours after ifosfamide. Cycles were repeated every 4 weeks. RESULTS: Dose-limiting toxicities (myelosuppression and renal toxicity) were seen at dose level 2 (ifosfamide 2.5 g/m2). Because 5 of the first 13 patients experienced Grade 3 renal toxicity, the study was amended to give cisplatin in divided doses. An additional six patients each were treated at dose level 3 (ifosfamide 2.0 g/m2 days 1-3) and dose level 4 (ifosfamide 2.5 g/m2 days 1-3) with cisplatin 33 mg/m2 days 1 to 3. Dose-limiting toxicity (myelosuppression) was reached at ifosfamide 2.5 g/m2. No further Grade 3 renal toxicity was seen. Grade 3 or worse toxicities were seen as follows: neutropenia 80%, thrombocytopenia 48%, nausea/vomiting 36%, anemia 32%, renal 20%, central nervous system 16%, and infection 16%. Two toxic deaths occurred, both with infection, renal failure, and neutropenia. Partial responses were seen in 8 of 25 eligible patients (32%). CONCLUSIONS: The maximum tolerated dose in this group of patients was defined as ifosfamide 2.0 g/m2 days 1 to 3 when given with cisplatin 33 mg/m2 days 1 to 3. When combining high-dose cisplatin with ifosfamide, it is advisable to give cisplatin in divided doses.

Adult↗
PubMed1993

von Hippel-Lindau disease: identification of deletion mutations by pulsed-field gel electrophoresis.

Von Hippel-Lindau disease (VHL) is an inherited multisystem neoplastic disorder. We prepared a 2.5-megabase (Mb) restriction map of the region surrounding the VHL gene and identified and characterized overlapping deletions in three unrelated patients affected with VHL. The smallest nested deletion (100 kb) was located within a 510-kb NruI fragment detected by 19-63'. The rearrangements detected will be useful in isolating and evaluating candidate cDNAs for the VHL gene. The detailed physical map will be useful in studying the organization and structure of genes in the VHL region.

Adult↗
PubMed1993

Neovaginal reconstruction with a rectus abdominis myocutaneous flap.

BACKGROUND: Neovaginal reconstruction after pelvic exenteration has several advantages. Besides the obvious psychosocial benefit to the patient and her partner, the incorporation of viable tissue into the pelvic cavity decreases the incidence of infection and small-bowel complications. Several surgical techniques are available to the gynecologic oncologist for construction of a functional vagina. Recently, myocutaneous flaps incorporating the rectus abdominis and gracilis muscles have been used. Disadvantages of the gracilis myocutaneous flap are the 10-20% incidence of flap loss due to vascular compromise and the potential for prolapse. The rectus abdominis myocutaneous flap is a large flap with a reliable blood supply that allows mobilization without tension on the vascular pedicle, resulting in a much lower incidence of vascular compromise. CASE: We present two case reports, a review of the gynecologic and surgical literature, and the techniques for vaginal reconstruction using the rectus muscle as a myocutaneous flap. CONCLUSIONS: The outcome for both patients was a satisfactory functional vagina that was technically easy to construct. The rectus abdominis myocutaneous flap can provide an adequate neovagina with minimal morbidity.

Abdominal Muscles↗
PubMed1992

Smoking and pulmonary function in five Solomon Island populations.

The relationship between smoking and lung function was examined in a large sample of healthy Solomon Island Melanesians and Polynesians as part of a multidisciplinary study carried out in 1985 and 1986. Comparisons are made between samples of smokers and non-smokers to determine if smoking is associated with a reduction in pulmonary function among males and females between 25 and 75 years of age. The results of this study indicate that cigarette smoking causes significant reductions in the pulmonary function of these populations. In addition, a clear difference in pulmonary function between males and females, as well as a general reduction in female FEV1 values, suggests that cooking smoke inhalation may be operating as a possible risk factor to the pulmonary health of women. Further research is needed to quantify exposure to smoke of both males and females and relate this measure to declines in pulmonary function.

Adult↗
PubMed1992

Menogaril in the treatment of relapsed multiple myeloma. A phase II trial of the Cancer Center of Wake Forest University.

Fifteen patients with relapsed multiple myeloma (MM) were treated with menogaril 160 mg/m2 intravenously (IV) every 28 days. No responses were seen: 8 patients had stable disease, 4 progressed after one course of therapy, and 3 patients were removed from study after 1 course for other reasons. Four of the 8 patients with stable disease had an improved performance status, and 3 had a decrease in analgesic use. The major toxicity was myelosuppression. The median progression-free interval was 3.0 months with a range of 0.7 to 22 months and median survival was 11.3 months with a range of 0.7 to 39+ months. Menogaril displays little activity in patients with previously treated MM.

Antineoplastic Agents↗
PubMed1992

Correlation between the conformational phenotype of p53 and its subcellular location.

In order to obtain insight into the parameters determining the subcellular localization of mutant and wild-type forms of p53, we analysed the subcellular distribution of p53 in four Balb/c mouse-derived cell lines ranging in their cellular phenotypes from normal (3T3), via minimal transformant (T3T3), to maximally transformed (3T3tx, Meth A). Epitope mapping showed the p53 proteins in 3T3 and in T3T3 cells to be in a wild-type conformation, as they reacted with PAb246, whereas p53 in 3T3tx and in Meth A cells were PAb246 negative and thus displayed a mutant conformation. Despite its reactivity with PAb246, p53 in T3T3 cells had an extended half-life and accumulated to abnormally high levels. We show that the conformationally wild-type p53 in 3T3 and T3T3 cells predominantly localized to the cell nucleus, with about half of it being tightly associated with nuclear structures. In contrast, approximately 60% of mutant p53 in 3T3tx and Meth A cells localized to the cytoplasm, the rest residing in the cell nucleus; all the nuclear p53 in these cells appeared to be structurally bound. The cytoplasmic location of mutant p53 in 3T3tx and Meth A cells was not seen by immunofluorescence microscopic analysis, and required cell fractionation for its detection. Both cytoplasmic and nuclear p53 of the mutant phenotype bound to hsc proteins with a similar stoichiometry, suggesting that hsc binding is not directly related to the subcellular distribution of these proteins. We suggest that the conformational phenotype of p53 is a major determinant of its subcellular location.

Animals↗
PubMed1991

Interrupted versus continuous chemotherapy in patients with metastatic breast cancer. The Piedmont Oncology Association.

BACKGROUND: Chemotherapy for metastatic breast cancer is palliative, and the optimal duration of therapy is unknown. We designed a trial to determine whether continuous treatment is superior to stopping treatment after a brief induction period and resuming treatment when the disease progresses. METHODS: We treated 250 women with metastatic breast cancer with six courses of cyclophosphamide, doxorubicin, and fluorouracil given every three weeks. At the completion of this induction period, women whose disease either regressed or remained stable were randomly assigned to receive either continued treatment with cyclophosphamide, methotrexate, and fluorouracil (maintenance therapy) or no further treatment (observation) followed by treatment with cyclophosphamide, methotrexate, and fluorouracil when disease progression became evident (reinduction). RESULTS: The combined rate of complete and partial responses after initial therapy was 30 percent (71 of 233 patients who could be evaluated; 95 percent confidence interval, 25 percent to 37 percent). In another 42 percent (98 patients), the disease remained stable. A total of 145 patients were randomized. Seventy-one were randomly assigned to the maintenance-therapy group, and 74 to the observation group. The median time to progression was 9.4 months for patients in the maintenance-therapy group and 3.2 months for patients in the observation group (P less than 0.001). After reinduction therapy, the median time to progression was 3.5 months. The median length of survival from the time of initial therapy was 14.8 months for all 250 patients; it was 21.1 months for the 71 patients in the maintenance-therapy group and 19.6 months for the 74 patients in the observation group (P = 0.67). Maintenance therapy was the most important determinant of the time before progression (P less than 0.001), but it was not associated with prolonged survival. The changes in performance status were similar in the patients in both groups, but nausea, vomiting, and mucositis were significantly more frequent in the maintenance-therapy group. CONCLUSIONS: In patients with breast cancer who received induction chemotherapy for 18 weeks, subsequent continuous chemotherapy was associated with a significant prolongation of the time before progression as compared with those receiving no further therapy; overall survival, however, was not significantly different in the two groups.

Adult↗
PubMed1991

Chemotherapy with 5-fluorouracil (5-FU) and cisplatin or 5-FU, cisplatin, and vinblastine for advanced non-small cell lung cancer. A randomized phase II study of the cancer and leukemia group B.

Two hundred forty-seven patients with previously untreated nonresectable non-small cell lung cancer (NSCLC) were entered in a prospective, randomized Phase II trial. Response assessment was possible in 232 patients, and 237 patients were evaluable for survival. Thirteen partial responses (11%) and 5 regressions (4%) of evaluable disease were obtained for the 116 patients treated with 5-fluorouracil (5-FU) and cisplatin (C) (95% confidence interval [CI], 8.5% to 21.5%). The median time to progression was 2.2 months and the median survival time was 4.6 months for 5-FU plus C. Twenty-three partial responses (20%) and 4 regressions (3%) of evaluable disease were obtained for the 116 patients treated with 5-FU, C, and vinblastine (V) (95% CI, 15.3% to 30.7%). The median time to progression was 2.8 months and the median survival time was 5.6 months for 5-FU, C, and V. The 5-FU and C doses were equivalent in the two treatment regimens. Sixteen of 85 patients (19%) with a performance status of 0 and 18 of 103 patients (17%) with a performance status of 1 responded, whereas only 2 of 44 patients (5%) with a performance status of 2 or greater responded (P = 0.009). Patients who had received locoregional radiation therapy had a lower overall response rate then those in the no prior radiation therapy group (P = 0.028). The median survival time for patients with a performance status of 0 or 1 was 6.3 months compared with 1.9 months for patients with a performance status of 2 or greater (P less than 0.001). Performance status also appeared to be a significant factor for time to progression. More frequent and severe leukopenia, fever, genitourinary (GU) toxicity, and pulmonary toxicity was reported with 5-FU, C, and V. There were three treatment-related deaths with 5-FU, C, and V and one treatment-related death with 5-FU plus C. Grade III/VI myelotoxicity was not influenced by prior radiation therapy or performance status. Neither regimen is active enough to be considered as standard therapy for advanced NSCLC.

Adenocarcinoma↗
PubMed1991

A randomized trial of chemotherapy (L-PAM vs CMF) and irradiation for node positive breast cancer. Eleven year follow-up of a Piedmont Oncology Association trial.

158 evaluable patients with stage II, lymph node positive, carcinoma of the breast were randomized to adjuvant therapy with either melphalan (L-PAM) or cyclophosphamide, methotrexate, and fluorouracil (CMF) after mastectomy. In addition, patients were randomized to be treated with or without post-operative irradiation therapy (RT) in addition to their chemotherapy. At a median follow-up time of 11 years, there is no difference in time to relapse (P = 0.69) or survival (P = 0.55) among the four treatment groups. Multivariate analysis including treatment arm, age, race, tumor size, histologic type, performance status, time to onset of treatment, menopausal status, and number of positive nodes, revealed that only the number of positive nodes (less than 4 vs greater than or equal to 4) was related to disease-free and overall survival. Ten year relapse-free survival for patients with less than 4 positive nodes compared to those with greater than or equal to 4 positive nodes was 63% versus 30%, and overall survival 63% versus 41%, respectively. Patients who received post-operative radiation therapy had significantly less local recurrence than those treated with chemotherapy alone (P = 0.03) but without improvement in relapse-free or overall survival. In this trial, post-operative radiation therapy when added to chemotherapy decreased the risk of local recurrence without adverse effects on survival. Treatment outcome was not influenced by chemotherapy regimen, but differences may have been obscured by the small sample size.

Adult↗