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Biomedical subjects

L S Rosen

Publications and source records attributed to L S Rosen.

At least 19 recordsLinked to original sources
PubMed2002

Low-dose trimetrexate glucuronate and protracted 5-fluorouracil infusion in previously untreated patients with advanced pancreatic cancer.

BACKGROUND: 5-Fluorouracil (5-FU)-based regimens have not been shown to prolong survival or provide clinical benefit in patients with advanced pancreatic cancer. The purpose of this study was to determine the tolerability of protracted venous infusion (PVI) of 5-FU, modulated by a low dose of the synthetic antifolate trimetrexate, in patients with advanced pancreatic cancer. PATIENTS AND METHODS: Twenty-three chemotherapy-naïve patients were evaluated. Patients were enrolled in four consecutive cohorts in which the weekly dose of trimetrexate was escalated in 10 mg/m2 increments, from 20 to 50 mg/m2. PVI 5-FU was administered at a fixed dose of 225 mg/m2/day. Treatment was administered for 6 successive weeks, every 8 weeks. RESULTS: Twenty-two patients were assessable. The maximum tolerated dose of trimetrexate was 40 mg/m2. The most common grade 3 and 4 toxicity was diarrhea. There were no treatment-related deaths. Preliminary analysis of activity revealed a response rate of 9%, with 41% of the patients having stable disease for a median duration of 3.8 months. The median survival for the entire group was 6.9 months (range 1-29 months). A clinical benefit response was experienced by 27.2% of patients. CONCLUSIONS: Low-dose trimetrexate can be safely administered in combination with PVI 5-FU. This treatment is well tolerated and is associated with palliative activity in advanced pancreatic cancer.

Adult↗
PubMed2001

Zoledronic acid reduces skeletal-related events in patients with osteolytic metastases.

BACKGROUND: This study evaluated the dose-response relation for zoledronic acid, a new generation high potency bisphosphonate, given as a 5-minute infusion in patients with malignant osteolytic disease. METHODS: Two-hundred eighty patients with osteolytic lesions due to metastatic breast carcinoma or multiple myeloma were randomized to double-blind treatment with either 0.4, 2.0, or 4.0 mg of zoledronic acid or 90 mg pamidronate. The primary efficacy endpoint was the proportion of patients receiving radiation to bone. Other skeletal-related events, bone mineral density (BMD), bone markers, Eastern Cooperative Oncology Group performance status, pain and analgesic scores, and safety also were evaluated. RESULTS: Zoledronic acid at doses of 2.0 and 4.0 mg and pamidronate at a dose of 90 mg each significantly reduced the need for radiation therapy to bone (P < 0.05) in contrast with 0.4 mg zoledronic acid, which did not. Skeletal-related events of any kind, pathologic fractures, and hypercalcemia also occurred less frequently in patients treated with 2.0 or 4.0 mg zoledronic acid or pamidronate than with 0.4 mg zoledronic acid. Increases in lumbar spine BMD (6.2-9.6%) and decreases in the bone resorption marker N-telopeptide (range, -37.1 to -60.8%) were observed for all treatment groups. Skeletal pain, fatigue, nausea, vomiting, and headache were the most commonly reported adverse events. Adverse events were similar in nature and frequency with zoledronic acid and pamidronate. CONCLUSIONS: A 5-minute infusion of 2.0-4.0 mg zoledronic acid was at least as effective as a 2-hour 90-mg pamidronate infusion in treatment of osteolytic metastases. A 0.4-mg dose of zoledronic acid was significantly less effective. Both zoledronic acid and pamidronate were well tolerated.

Antineoplastic Agents↗
PubMed2001

A phase I dose-ranging trial of monthly infusions of zoledronic acid for the treatment of osteolytic bone metastases.

Bisphosphonates are potent inhibitors of bone resorption and provide a therapeutic benefit for patients with bone metastases. Zoledronic acid is a highly potent, nitrogen-containing bisphosphonate. In the present trial, we assessed the safety and tolerability of increasing doses of zoledronic acid and its effects on urinary markers of bone resorption in cancer patients with bone metastases. Fifty-nine cancer patients with bone metastases were enrolled sequentially into one of 8 treatment groups in the core protocol. Each patient received a 5-min i.v. infusion of 0.1, 0.2, 0.4, 0.8, 1.5, 2, 4, or 8 mg zoledronic acid monthly for 3 months. Patients were monitored for clinical findings, adverse events, electrocardiograms, markers of bone resorption, as well as routine hematology, blood chemistries, and urinalysis. Thirty patients who demonstrated a radiographic response to treatment or stable disease in the core protocol were enrolled in a humanitarian extension protocol and continued to receive monthly infusions. Zoledronic acid was well tolerated at all dose levels. Adverse events reported by >10% of patients included skeletal pain, nausea, fatigue, upper respiratory tract infection, constipation, headache, diarrhea, and fever. Three patients in the core protocol and one patient in the extension protocol experienced grade 3 skeletal pain, "flu-like" symptoms, or hypophosphatemia, which were possibly related to treatment; all recovered completely. Adverse events were reported with similar frequency across all of the dosage groups. Zoledronic acid resulted in sustained, dose-dependent decreases in urinary markers of bone resorption. Zoledronic acid was safe and well tolerated and demonstrated potent inhibition of bone resorption.

Adult↗
PubMed2000

Consensus statement on the live organ donor.

OBJECTIVE: To recommend practice guidelines for transplant physicians, primary care providers, health care planners, and all those who are concerned about the well-being of the live organ donor. PARTICIPANTS: An executive group representing the National Kidney Foundation, and the American Societies of Transplantation, Transplant Surgeons, and Nephrology formed a steering committee of 12 members to evaluate current practices of living donor transplantation of the kidney, pancreas, liver, intestine, and lung. The steering committee subsequently assembled more than 100 representatives of the transplant community (physicians, nurses, ethicists, psychologists, lawyers, scientists, social workers, transplant recipients, and living donors) at a national conference held June 1-2, 2000, in Kansas City, Mo. CONSENSUS PROCESS: Attendees participated in 7 assigned work groups. Three were organ specific (lung, liver, and kidney) and 4 were focused on social and ethical concerns (informed consent, donor source, psychosocial issues, and live organ donor registry). Work groups' deliberations were structured by a series of questions developed by the steering committee. Each work group presented its deliberations to an open plenary session of all attendees. This information was stored and shaped into a statement circulated electronically to all attendees for their comments, and finally approved by the steering committee for publication. The term consensus is not meant to convey universal agreement of the participants. The statement identifies issues of controversy; however, the wording of the entire statement is a consensus by approval of all attendees. CONCLUSION: The person who gives consent to be a live organ donor should be competent, willing to donate, free from coercion, medically and psychosocially suitable, fully informed of the risks and benefits as a donor, and fully informed of the risks, benefits, and alternative treatment available to the recipient. The benefits to both donor and recipient must outweigh the risks associated with the donation and transplantation of the living donor organ.

Health Status↗
PubMed2000

Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. Irinotecan Study Group.

BACKGROUND: The combination of fluorouracil and leucovorin has until recently been standard therapy for metastatic colorectal cancer. Irinotecan prolongs survival in patients with colorectal cancer that is refractory to treatment with fluorouracil and leucovorin. In a multicenter trial, we compared a combination of irinotecan, fluorouracil and leucovorin with bolus doses of fluorouracil and leucovorin as first-line therapy for metastatic colorectal cancer. A third group of patients received irinotecan alone. METHODS: Patients were randomly assigned to receive irinotecan (125 mg per square meter of body-surface area intravenously), fluorouracil (500 mg per square meter as an intravenous bolus), and leucovorin (20 mg per square meter as an intravenous bolus) weekly for four weeks every six weeks; fluorouracil (425 mg per square meter as an intravenous bolus) and leucovorin (20 mg per square meter as an intravenous bolus) daily for five consecutive days every four weeks; or irinotecan alone (125 mg per square meter intravenously) weekly for four weeks every six weeks. End points included progression-free survival and overall survival. RESULTS: Of 683 patients, 231 were assigned to receive irinotecan, fluorouracil, and leucovorin; 226 to receive fluorouracil and leucovorin; and 226 to receive irinotecan alone. In an intention-to-treat analysis, as compared with treatment with fluorouracil and leucovorin, treatment with irinotecan, fluorouracil, and leucovorin resulted in significantly longer progression-free survival (median, 7.0 vs. 4.3 months; P=0.004), a higher rate of confirmed response (39 percent vs. 21 percent, P<0.001), and longer overall survival (median, 14.8 vs. 12.6 months; P=0.04). Results for irinotecan alone were similar to those for fluorouracil and leucovorin. Grade 3 (severe) diarrhea was more common during treatment with irinotecan, fluorouracil, and leucovorin than during treatment with fluorouracil and leucovorin, but the incidence of grade 4 (life-threatening) diarrhea was similar in the two groups (<8 percent). Grade 3 or 4 mucositis, grade 4 neutropenia, and neutropenic fever were less frequent during treatment with irinotecan, fluorouracil, and leucovorin. Adding irinotecan to the regimen of fluorouracil and leucovorin did not compromise the quality of life. CONCLUSIONS: Weekly treatment with irinotecan plus fluorouracil and leucovorin is superior to a widely used regimen of fluorouracil and leucovorin for metastatic colorectal cancer in terms of progression-free survival and overall survival.

Adult↗
PubMed1998

Irinotecan in lymphoma, leukemia, and breast, pancreatic, ovarian, and small-cell lung cancers.

Irincotecan (CPT-11 [Camptosar] has a board range of antitumor activity. Extensive preclinical and early clinical work has demonstrated its activity against many tumor types--head and neck, esophagus, stomach, pancreas, liver, colon/rectum, kidney, lymph nodes, ovary, uterine, cervix, sarcoma, melanoma, acute and chronic leukemia, mesothelioma, and cancers of unknown primary site. Most of the phase II and III trials have focused on colorectal and other gastrointestinal, non-small-cell lung, and cervical cancers (discussed elsewhere in this monograph). This article presents preliminary results of studies exploring the use of irinotecan in lymphoma, leukemia, and breast, pancreatic, ovarian, and small-cell lung cancers. In all of these studies, the number of patients enrolled is small, drug doses and schedules differ (often within the same case series), and little information is available on response duration and overall survival. Nevertheless, irinotecan has shown reproducible if at times modest activity in almost all of the diseases in which it has been studied. Future research should be directed at conducting well-designed clinical trials of irinotecan alone and in combination with other agents.

Animals↗
PubMed1996

Adapting a statewide patient database for comparative analysis and quality improvement.

BACKGROUND: In 1991 the Michigan Health and Hospital Association established the Michigan Patient Outcome Measures Program to support quality improvement activities among member hospitals. Data submitted by each hospital are based on the Uniform Hospital Discharge Data Set (UHDDS). REPORTING THE MEASURES: Each participating hospital is provided with tabulations for each of the 18 indicators, along with comparative data for each of five hospital peer groups. CASE STUDY 1: FACILITATING DEVELOPMENT OF A CLINICAL PATHWAY: Review of data on stroke patients indicated that patients discharged to home represented the single largest group of patients and that their length of stay was lower than for other groups of stroke patients. Hospital A used a clinical pathway to achieve reduction in length of stay of almost a day for this group. CASE STUDY 2: IMPROVING OBSTETRICS AND GYNECOLOGIC SERVICES THROUGH EDUCATION: The Department of Obstetrics and Gynecological Surgery at Hospital B achieved improvement in birth trauma, hysterectomy, cesarean section (C-section) births, and vaginal births after C-section. Program participants are considering adopting a birth trauma indicator. CASE STUDY 3: ESTABLISHING A HOSPITALWIDE QI PROGRAM: The Newborn Team at Hospital C initiated several QI initiatives aimed at reducing the newborn mortality rate, including guidelines for earlier identification of high-risk obstetric cases and for earlier intervention by the perinatalogist. CONCLUSIONS: Data that are not risk or severity adjusted have value in assessing hospital procedures and systems and can be used to educate and effect change in practice patterns.

Adult↗
PubMed1988

X-ray diffraction studies of 14-filament models of deoxygenated sickle cell hemoglobin fibers. II. Models based on the deoxygenated sickle hemoglobin crystal structure.

The calculated transforms of a number of crystal-based models of the deoxygenated sickle cell hemoglobin fiber have been compared with X-ray diffraction data of 15 A (1 A = 0.1 nm) resolution. The fiber models consist of 14 single strands of sickle cell hemoglobin (HbS) molecules, which associate into seven protofilaments arranged similarly to those present in the crystal structure. Six of the protofilaments are arranged in three crystallographic until cells extending in the c-axis direction with the seventh protofilament positioned so as to provide an elliptical cross-section when the assemblage is viewed down the fiber axis. Models were generated by systematically and independently translating each of the model's three subcells in steps of 3.5 A along the fiber axis. The seventh protofilament was kept fixed as a point of reference. Each translation of a subcell corresponded to a different fiber model whose transform was then compared with observed data. In all, over 46,000 transforms were computed; of these, three models with minimal residuals were identified. The free energy of packing for all crystal-based models was evaluated to find configurations of protofilaments possessing minimal free energies. The results of the calculations support the subcell configurations of two of the three models with minimal residuals.

Hemoglobin, Sickle↗
PubMed1985

Erabutoxin b. Initial protein refinement and sequence analysis at 0.140-nm resolution.

The crystal structure of the protein postsynaptic neurotoxin, erabutoxin b, has been refined at 0.140-nm resolution (R = 0.22) by restrained least-squares and interactive computer graphics. The study has established complete structural identity of the two sea-snake venom toxins, erabutoxin b and neurotoxin b, isolated from Laticauda semifasciata snakes taken in different Pacific Ocean waters. Two chemical-sequence inversion errors in erabutoxin b have been discovered during refinement, corrected and subsequently confirmed in both erabutoxin b and erabutoxin a by chemical analysis. The correct sequences are His6-Gln7, hitherto unsuspected, and Ser18-Pro19. The sequence correction His6-Gln7 explains the anomalous results of 1H NMR solution studies and those of early chemical modification experiments, which were in conflict with the previously published three-dimensional structure of erabutoxin b. On refinement, the five-stranded beta sheet described earlier is now shown to be discontinuous, split into a two-stranded beta loop and a three-stranded beta sheet. Unique features of the Pro44-Gly49 peripheral segment have now been identified. 51 water molecule positions have been located.

Amino Acid Sequence↗
PubMed1985

X-ray diffraction studies of 14-filament models of deoxygenated sickle cell hemoglobin fibers. Models based on electron micrograph reconstructions.

The transforms of a large number of models of deoxygenated sickle hemoglobin fibers, related to that derived from image reconstruction of electron micrographs, have been calculated and compared with X-ray diffraction data of 15 A resolution. The model of the fiber, determined from the reconstructed image, is a helix consisting of 14 filaments that associate in a specific mode to form seven pairs, or protofilaments. Pairs were identified through the pattern of filament loss in partially disassembled fibers and by the separation between molecules, in adjacent filaments, of half a molecular diameter, along the fiber axis. An alternative mode of filament association can be derived also from the surface lattice of the reconstruction, which meets these criteria for the pairing of molecular filaments. Both pairing modes have been used in the search for structures whose transforms show the best agreement with the diffraction data. Models were generated by the systematic translation of six protofilaments, taken in symmetry related pairs, in steps of 3.5 A along the fiber axis relative to a fixed central protofilament. Each translation of a protofilament corresponds to a different fiber model, whose transform was compared with observed data. In all, over 11,000 transforms were calculated. Of all the models considered, three have been found whose residuals are minimal. At 30 A resolution, similar to that of electron micrographs, the model derived from image reconstruction and the three found through our search procedure are indistinguishable. At 15 A, however, the transforms of these models show better agreement with the observed data than the transform of the reconstructed image. Comparison of residuals shows that the model derived from the reconstructed image can be rejected with 99.5% probability relative to the model, with the same pairing scheme, found by our search procedures. The two other models, derived from the alternative pairing scheme, are also more credible than the reconstructed image, but at a lower confidence level. Each of our three models is equally acceptable. Their existence may reflect structural polymorphism of the fiber.

Hemoglobin, Sickle↗
PubMed1982

Triclinic crystals associated with fibers of deoxygenated sickle hemoglobin.

Triclinic crystals have been found in capillaries that initially contained deoxygenated sickled erythrocytes, and in solutions of sickle hemoglobin that were stirred during deoxygenation. In both cases these crystals occur as a phase transition from fibers. They have been observed only as twins; the a-axis of one member is related to that of its twin by 180 degrees rotation about the b* direction. The volume of the triclinic crystal unit cell is half that of the monoclinic crystals that have also transformed from fibers. Analysis of X-ray diffraction data indicates that the two molecules in the triclinic unit cell that repeat at an interval of 64 A form double filaments similar to those found in the monoclinic crystals and in the fiber. The existence of the triclinic crystals which contain only one double filament per unit cell removes a postulated requirement that antipolar double filament pairs be the sole unit of the fiber architecture.

Crystallization↗
PubMed1976

Three dimensional structure of erabutoxin b neurotoxic protein: inhibitor of acetylcholine receptor.

The three-dimensional structure of erabutoxin b, a neurotoxin in the venom of the sea snake Laticauda semifasciata, has been determined from a 2.75 A resolution electron density map. Erabutoxin b is one of a family of snake venom neurotoxins, all low-molecular-weight proteins, which block neuromuscular transmission at the postsynaptic membrane. They specifically inhibit the acetylcholine receptor. The molecular shape is that of a shallow elongated saucer with a footed stand formed by the six-membered ring at the COOH-terminal end. The central core of the molecule is an assembly of four disulfide bridges. Three long chain loops emerge as broad fronds from the core region. Approximately 40% of the main chain is organized into a twisted antiparallel beta-pleated sheet of five short strands. In 28 snake venom neurotoxins of established sequence which inhibit the acetylcholine receptor, the four disulfide bridges and seven other residues remain invariant. Three substitution positions conserve residue type. In one wing of the molecule, there is a broad shallow depression which may characterize the reactive site. It is populated by the sevent invariant residues and two of the three type conserved residues. This region is "anchored" on the undersurface of the molecule by the hydroxyl group of Ser-9, the remaining conservatively substituted residue.

Erabutoxins↗