Contraception in India: exploring met and unmet demand.

Our study examines factors influencing demand for contraception for spacing as well as for limiting births in India. Data on socio-economic, demographic and program factors affecting demand for contraception in India are from the National Family Health Survey, 1998--99. The recent document from the National Rural Health Mission has completely ignored the use of contraception in controlling fertility in India. Empirical results of our study suggest giving priority to and focusing attention on supply-side factors such as a regular and sustained supply of quality contraceptive methods to improve accessibility and affordability. Further, strengthening the information, education and communication (IEC) component of the reproductive and child health (RCH) package would allay misapprehensions about the side effects and health risks of contraception. Focusing attention on demand-side factors such as women's empowerment through education, gainful employment and exposure to mass-media would help reduce the unmet demand for family planning. The resulting reduction in fertility would hasten the process of demographic transition and population stabilization in India.

p53 gene mutation in the bone-marrow of a patient with diffuse mixed cell type lymphoma at diagnosis predicting eventual progression to large cell lymphoma.

Mutations of the p53 tumor suppressor gene have been used as molecular genetic markers of disease and serve as a prognostic indicator in various malignancies including non-Hodgkin's lymphoma (NHL). Alterations in the p53 gene were investigated in a bone marrow sample from a NHL patient admitted for autologous bone marrow transplantation. Diffuse mixed small and large cell NHL, was initially diagnosed which eventually progressed to large cell lymphoma at relapse following poly-chemotherapy. A sequential technique of polymerase chain reaction-mediated single-strand conformational polymorphism (PCR-SSCP) of the p53 gene revealed a shift in one band of exon 6 in the bone marrow, collected at the time of initial diagnosis. No mutations were detected in exons 5, 7, 8 and 9. Direct sequencing of exon 6 detected a single base change from G to C resulting in an amino acid substitution from glycine to histidine. Results of this study and data reviewed from other publications suggest that the missense p53 mutation seen in this patient at the time of diagnosis may perhaps have been used to predict the eventual outcome of the disease. This could, therefore, serve as an important genetic disease marker particularly in bone marrow or peripheral blood samples initially collected and cryopreserved for future possible autologous transplantation.

Long-term cryopreservation: successful trilineage engraftment after autologous bone marrow transplantation with bone marrow cryopreserved for seven years.

Successful autologous bone marrow transplantation (ABMT) and peripheral blood stem cell transplantation depend on safe hematopoietic stem cell (HSC) cryopreservation and storage. Several successful methods for cryopreservation and storage have been established and are commonly used all over the world. However, little is known about the effects of long-term cryopreservation on the capacity to sustain a complete immunohematopoietic engraftment. Several authors have investigated stem cell viability after cryopreservation and storage for more than 5 years and reported preclinical good viabilities in terms of dye-exclusion or colony-forming capability in vitro. Only two studies using BM cryopreserved for more than 5 years for transplantation are reported, but they did not provide proof of trilineage engraftment. In February 1997 at our institution, a patient with relapsed non-Hodgkin's lymphoma underwent ABMT with BM harvested in February 1990. He achieved a granulocyte count > 500 x 10(6)/L on day 21 and a self-supporting platelet count > 20 x 10(9)/L on day 30. After day 29, his hemoglobin level was satisfactory without need of transfusion support. This successful trilineage engraftment with cryopreserved BM that had been stored for 7 years suggests that HSC are able to maintain their capability to reconstitute hematopoiesis for a long time.

High-dose induction chemoradiotherapy followed by autologous bone marrow transplantation as consolidation therapy in rhabdomyosarcoma, extraosseous Ewing's sarcoma, and undifferentiated sarcoma.

PURPOSE: To improve response and survival rates in patients with high-risk rhabdomyosarcoma (RMS), extraosseous Ewing's sarcoma, and undifferentiated sarcoma, we used a short course of induction with multi-agent chemotherapy, hyperfractionated radiotherapy, and surgery when possible. Consolidation was with intensive chemotherapy and autologous bone marrow transplantation (ABMT). PATIENTS AND METHODS: Twenty-six patients (21 with RMS, three with undifferentiated sarcoma, and two with extraosseous Ewing's sarcoma) were entered onto the protocol between June 1990 and March 1994. Induction consisted of ifosfamide, etoposide, doxorubicin, dactinomycin, cyclophosphomide, and vincristine, and a split course of hyperfractionated radiotherapy. Patients who attained a complete response (CR) or good partial response (GPR) received consolidation with high-dose melphalan and etoposide followed by ABMT. RESULTS: Of 26 previously untreated patients 19 (73%) achieved a CR (n=13) or GPR (n=6) at the completion of induction and underwent ABMT. Two-year overall survival (OS) was 56% (95% confidence interval [CI], 36% to 76%) and progression-free survival (PFS) was 53% for the whole group (95% CI, 33% to 73%). CONCLUSION: Consolidation of response by myeloablative chemotherapy was well tolerated. Split-course hyperfractionated radiotherapy did not increase the rate of local control. The results of this short-course therapy were comparable to previous therapies of 1 to 2 years' duration. Induction and consolidation chemotherapy, as well as radiation dose, could be further intensified, since no death due to toxicity occurred among these patients.

Pregnancy after bone marrow transplantation.

PURPOSE: To evaluate the occurrence of pregnancy after bone marrow transplantation (BMT). DESIGN: Medline literature review of reported pregnancies in the BMT population published in the English language. RESULTS: Multiple case reports and a few series studies showed more than 250 offspring from BMT recipients. CONCLUSION: BMT patients receive high-dose chemotherapy and often radiation, as well. These agents are associated with gonadal dysfunction and the fertility of patients after BMT is of concern because BMT patients are often young people who wish to resume a normal quality of life, which for many patients involves the desire to have children. Our experience with the successful pregnancy of one of our BMT patients led to the investigation of reported cases that showed numerous other births. The issue of counseling BMT patients about fertility, pregnancy complications, and potential birth defects is becoming increasingly complex and warrants further investigation.

Role of cytokines in healing chronic skin wounds.

In the chronic wound, the normal cascade of inflammation, granulation and reconstruction phases of healing is interrupted. Cytokines are now known to orchestrate different biochemical mediators resulting in the restoration of the healing phases. Growth factors may play a significant role in stimulating wound repair by stimulating growth and proliferation. Since growth factors stimulate a variety of functions depending on cell type and wound stage and since wound-healing defects may occur at any phase of healing, a mixed combination of growth factors would be predicted to be more effective than a single factor. Factors that may modulate the action of growth factors include electrical stimulation, weight bearing, debriding and ischemia.

GM-CSF accelerates neutrophil recovery after autologous hematopoietic stem cell transplantation.

Patients with non-myeloid hematologic malignancies (including Hodgkin's and non-Hodgkin's lymphomas, myeloma and acute lymphoid leukemia) or solid tumors underwent cytoreductive conditioning regimens followed by either autologous bone marrow transplantation (ABMT) (n = 343) or transplantation of peripheral blood stem cells (PBSC) with (n = 44) or without bone marrow (BM) (n = 16). In a randomized double-blind phase III multi-center trial, patients received either granulocyte-macrophage colony-stimulating factor (GM-CSF, 10 micrograms/kg/day) or placebo by daily i.v. infusion beginning 24 h after bone marrow infusion and continuing until the absolute neutrophil count (ANC) had recovered to > or = 1000/mm3, or for a maximum of 30 days. Median time to neutrophil recovery was significantly shorter in the GM-CSF group (18 vs 27 days, P < 0.001), and more GM-CSF patients had neutrophil recovery by day 30 (70 vs 48%). Median duration of hospitalization was significantly shorter in the GM-CSF group (29 vs 32 days, P = 0.02). GM-CSF significantly reduced the median time to neutrophil recovery in patients receiving bone marrow only (19 vs 27 days, P < 0.001) or PBSC with or without bone marrow (14 vs 21 days, P < 0.001). The overall incidence of adverse events was comparable in the two groups, although more patients in the GM-CSF group discontinued treatment due to adverse events (17 vs 9%, P < 0.001). No difference was noted in infection incidence or time to platelet independence. GM-CSF had no negative impact on time to relapse or long-term survival. These data indicate the positive influence of GM-CSF on neutrophil recovery and hospital stay in patients receiving ABMT for a variety of clinical indications.

Autologous bone marrow harvesting in outpatients.

STUDY OBJECTIVE: To assess the experience with autologous bone marrow harvesting in outpatients. DESIGN: Retrospective analysis of outpatients who underwent autologous bone marrow harvesting from 1990 to 1992. SETTING: University-affiliated surgical day hospital. SUBJECTS: 235 outpatients who underwent 264 autologous bone marrow harvests. Patients are candidates for autologous bone marrow harvesting on an outpatient basis if they are Karnofsky performance status of 80-100 and ASA status I, II or III. MEASUREMENTS AND MAIN RESULTS: The incidence of perioperative complications and hospital admission from the Surgical Day Hospital, the duration of the harvesting procedure and postanesthesia care unit (PACU) stay, details of the postoperative pain management, and costs and charges of the outpatient procedure compared with the same procedure performed on inpatients were assessed. Mean age was 37.7 years +/- 10.5 SD; + 7.7% patients were male and 52.3% were female. The disease process included non-Hodgkin's lymph/ma (30.3%), leukemia (24.3%), metastatic breast cancer (18.4%), Hodgkin's disease (17.3%), testicular carcinoma (6.5%) and other (1.6%). The patients were ASA status II (54.5%) or ASA III (45.5%) and received general endotracheal anesthesia. Each patient had 10.7 ml/kg +/- 2.8 SD of marrow harvested over a period of 110.7 minutes + 30.4 SD and total recovery room time of 233.7 minutes +/- 85.5 SD. Of 251 harvest, only three (1.1%) required hospital admission. PACU complaints included transient hypotension and dizziness (5.3%), nausea (3.8%), vomiting (3.4%), and (1.9%) temperature elevation. 83.7% of patients were reached at home the following day and 4.1% complained of nausea and/or vomiting at home. 6.8% of patients experienced temperature elevation at home. Only 27.1% of patients took the acetaminophen with codeine that was prescribed. The reminder required no opioid at home. Outpatient charge/ inpatient charge was 51.1%, and outpatient cost/inpatient was 74.4%. CONCLUSION: Autologous bone marrow harvesting is an acceptable ambulatory surgical procedure that results in a very law postanesthesia complication rate. Postoperative pain is easily controlled. The outpatient setting offers cost and time advantages to the patient.

Granulocyte-macrophage colony-stimulating factor as adjunct therapy in relapsed lymphoid malignancy: implications for economic analyses of phase III clinical trials.

With the increasing concern over the high cost of health care, policy makers have incorporated economic analyses into phase III clinical trials as the randomized clinical trials can provide important information on the efficacy and potential cost-effectiveness of new pharmaceutical agents. Economic analyses of single-hospital experience during phase III trials of granulocyte-macrophage colony-stimulating factor (GM-CSF) as adjunct therapy for high dose chemotherapy with autologous stem cell support found significant shortening of neutropenia with GM-CSF at each hospital, but shortened hospitalization (and lower costs) at only two of three hospitals. In this study, we added data from three additional hospitals and found that the 103 patients who received GM-CSF had, on average, 5.7 days shorter durations of severe neutropenia than the 95 patients who received placebo (p < 0.0001) and 3.4 days shorter in hospitalization (p = 0.06). However, the duration of hospitalization, the primary determinant of health care costs, was shorter for GM-CSF patients in only four of the six centers and the duration of hospitalization of placebo patients was shorter at the other two centers. Careful analyses must be carried out when phase III clinical trial results are used to derive estimates of cost-effectiveness of new pharmaceutical agents. The interpretation of economic analyses of phase III clinical trials raises issues related to the perspective of the investigators, study design, collection of data on resource utilization, learning curve effects and generalizability of the results to other settings.

Is bone marrow purging proving to be of value?

Although the role of hematopoietic stem-cell transplantation (HSCT) in cancer treatment is rapidly expanding, decreasing the side effects of stem-cell infusion is a major challenge. Cancer cells present in the stem-cell collection can cause relapse after autologous transplantation. In allogeneic transplantation. T lymphocytes contribute to graft-versus-host disease. Various methods of purging have been used to remove these unwanted cells, and there is some evidence that such manipulations are clinically useful. Nevertheless, the inability to detect minimal disease makes it difficult to determine whether relapse is caused by incomplete disease eradication in the patient or by the infused cells. This makes it hard to justify the clinical benefit of ex vivo purging. Researchers can focus on this issue by designing studies with minimal variation in other factors that affect the success of stem-cell transplantation.

Economic analyses of clinical trials in cancer: are they helpful to policy makers?

Although clinical trials are being used to evaluate economic outcomes of new agents, there are methodological problems. Decisions based on these analyses may lead to inefficient use of medical resources. Randomized clinical trials provide important information on the efficacy of new pharmaceutical agents for cancer patients. Policy makers are likely to require both economic and clinical data in order to approve pharmaceuticals for widespread use. Clinical trials provide an opportunity to evaluate economic outcomes for new agents. However, the interpretation of economic analyses of clinical trials raises issues related to perspective of the investigators, study design, collection of data on resource utilization, and generalizability of data to other settings. In this paper, we review these issues and illustrate problems associated with analyses of economic data from a recent phase III trial of hematopoietic growth factors. Clinical results were similar in both Paris and New York in this phase III trial. However, economic results differed markedly between the hospital in Paris and the hospital in New York. While significant savings in terms of fewer days in the hospital and fewer laboratory tests and radiographs for the granulocyte-macrophage colony-stimulating factor (GM-CSF) patients were noted at the New York hospital, resource savings were not identified at the hospital in France. Caution must be used when reimbursement policies are based on economic analyses of clinical trials. Policy decisions must be based on studies that are carefully conducted, analyzed, and interpreted from both a clinical and an economic perspective.