Autologous SCT with a dose-reduced BU and CY regimen in older patients with non-Hodgkin's lymphoma.

Autologous SCT is a potentially curative procedure for patients with relapsed lymphoma (NHL). We analyzed the outcomes of 34 patients > or =60 years old, including eight patients > or =70 years old, who received BU and CY and SCT for NHL. Patients received BU 0.8 mg/kg i.v. (n=25) or 1 mg/kg p.o. (n=9) q 6 h x 14 doses and CY 60 mg/kg i.v. q day x 2 days. The median age was 66 (range, 60-78) years. Twenty-two patients had large cell, 10 follicular and two-mantle cell lymphoma. Fifteen patients were in a second or greater CR and 19 patients were in a PR. The median days to ANC >500/microl and platelet count >50,000/microl were 10 and 13 days respectively. The 100-day transplant-related mortality was 0%. Toxicities included interstitial lung disease (n=2), seizures in a patient with CNS lymphoma (n=1), mild veno-occlusive disease (n=2), and transient atrial fibrillation (n=4). With a median follow-up of 40 months, the 2-year overall survival and PFS were 67 and 54% respectively. BU/CY is a well-tolerated conditioning regimen for older patients with NHL. Age alone should not be used as an exclusion criterion for autologous SCT.

Paclitaxel resistance: molecular mechanisms and pharmacologic manipulation.

It has been approximately ten years since the Food and Drug Administration (FDA) approved paclitaxel for the treatment of platinum resistant epithelial ovarian carcinoma. Since the approval, the drug has found therapeutic applications in a variety of schedules and in a wide variety of epithelial malignancies. Its novel mechanism of action provided the hope that it would demonstrate anti-neoplastic activity in multidrug resistant tumor cells. Unfortunately, as with other chemotherapeutic drugs, resistance is commonly seen. Laboratory investigation has defined a wide variety of resistance mechanisms including overexpression of multidrug resistance (MDR-1) gene, molecular changes in the target molecule (betatubulin), changes in apoptotic regulatory and mitosis checkpoint proteins, and more recently changes in lipid composition and potentially the overexpression of interleukin 6 (IL-6). This review describes the in vitro molecular data that define and support the various mechanisms of resistance and critically evaluates the evidence for the participation of these mechanisms in clinically relevant paclitaxel resistance. This review also explores pharmacologic attempts to modulate paclitaxel resistance, principally through inhibition of the MDR-1 drug efflux pump. Future avenues for drug resistance research and its pharmacologic manipulation in the clinic are discussed.

Overexpression of human phosphoglycerate kinase 1 (PGK1) induces a multidrug resistance phenotype.

BACKGROUND: Multidrug resistance is a significant barrier to the development of successful cancer treatment. To identify genetic alterations that are directly involved in paclitaxel resistance, a functional cloning strategy was developed. MATERIALS AND METHODS: Using mRNA from paclitaxel resistant human ovarian cancer cell line SW626TR, a cDNA library was established in a pCMV-Script vector that permits expression of cDNA inserts in mammalian cells. Transfection of the pCMV-Script/SW626TR cDNA library into the paclitaxel-sensitive human osteogenic sarcoma cell line, U-20S, resulted in several paclitaxel-resistant clones. RESULTS: DNA sequencing of clone C16 demonstrates complete homology to human phosphoglycerate kinase 1 (PGK1). Retransfection of the PGK1 insert into U-20S confers a multidrug resistant phenotype, characterized by a 30-fold increase in paclitaxel resistance, and cross-resistance to vincristine; adriamycin and mitoxantrone, but not methotrexate or cisplatin. Enzymatic analysis of the PGK1 transfectants demonstrates an increase in PGK1 activity as compared to the parental cell line, U-20S. Northern and Western analysis of PGK1 transfectants reveals no change in MDR-1 expression compared with the parental cell line. In addition, co-culture of PGK1 transfectants with verapamil only partially reverses the multidrug resistant phenotype. Rhodamine 123 studies are also consistent with an MDR-1 independent mechanism of increased drug efflux. CONCLUSION: Together this data suggests that PGK1 can induce a multidrug resistant phenotype through an MDR-1 independent mechanism.

Cytogenetic studies of spontaneous miscarriages: a seven year study to compare significance of primary vs. secondary culture methods for assessment of fetal karyotype yield and maternal cell contamination.

Primary in-situ culture (PIC) and secondary trypsinized culture (STC) are the two currently used methods for culturing chorionic villi in order to cytogenetically evaluate products of conception (POC) from spontaneous miscarriages. We compare these culture techniques in our laboratory over a period of seven years to evaluate fetal karyotype yield and maternal cell contamination. Data from a total of 2077 cases from 1992-1999 was entered into a data entry program created in Epi Info version 6. Analysis, using the chi square test of significance, was performed in the same program. Our data demonstrated a statistically significant excess of normal female karyotype detected by the STC method and a statistically significant excess of abnormal karyotypes detected by the PIC method. We attribute these findings to the greater risk of maternal cell contamination with the STC method. We conclude that the PIC method is more accurate in detecting the fetal karyotype and the STC method has a higher risk of maternal cell contamination. We suggest that the PIC method should be adopted as the method of choice when evaluating POC by culturing chorionic villi.

Losing God.

Shortly before his death in 1995, Kenneth B. Schwartz, a cancer patient at Massachusetts General Hospital (MGH), founded the Kenneth B. Schwartz Center. The Schwartz Center is a non-profit organization dedicated to supporting and advancing compassionate health care delivery, which provides hope to the patient, support to caregivers, and sustenance to the healing process. The center sponsors the Schwartz Center Rounds, a monthly multidisciplinary forum where caregivers reflect on important psychosocial issues faced by patients, their families, and their caregivers, and gain insight and support from fellow staff members. Nebulous language, distrust, and dogma confound spiritual aspects of cancer care. However, existential well being is an important determinant of quality of life: finding meaning and purpose make suffering more tolerable. The case presented is of a patient who experienced "losing God" as a Hodgkin's disease survivor with metastatic prostate cancer and severe coronary artery disease. His caregivers were able to provide the sense of community in which he could re-establish his faith. Health care providers do not have to be religious in order to help patients to deal with a spiritual crisis. The clinical skills of compassion need to be deployed to diagnose and respond to spiritual suffering. Acknowledging and addressing anger or guilt, common sources of suffering, are essential to adjustment. Simply being there for the patient and being open to their hurt can help resolve their spiritual crisis, a responsibility that is shared by the whole health care team.

Flow cytometric analysis of childhood leukemias.

OBJECTIVE: To collect demographic data for childhood (less than 15 years) leukemias in Karachi, describe the accuracy of the cell surface markers routinely used in the flow cytometric analysis of leukemic cells and arrive at an ideal panel of antibodies for analyzing leukemic samples. MATERIALS AND METHODS: Data from 62 consecutive cases of childhood leukemias referred to the Department of Pathology, Aga Khan University Hospital, (AKUH) between January 1995 and December 1998 was analyzed using Epi Info Version 6. Flow cytometry on all samples was performed using standard protocols. RESULTS: The mean age of patients was 8.2 years and 49 (79%) were males. Fifty (81%) had acute lymphoblastic leukemias of which 50% were CD10 positive and 24% CD10 negative Pre-B cell leukemias. Among all Pre B cell All 98% were positive for CD19, 96% for CD22, 89% for HLA-DR and 67% for CD10. Of the 10 AML cases, 100% were positive for CD33, 90% for CD13, 80% for CD19 and 70% for HLA-DR. CONCLUSION: The mean age in this study population was significantly higher and percentage of CD10 positive Pre-B All is lower than that in the West. Both these factors might be responsible for the poorer prognosis of these patients. It is not possible to specify a minimum or maximum panel of antibodies that should be used for phenotyping all cases of childhood leukemias. A certain degree or redundancy is essential in any panel of antibodies used for flow cytometry of leukemias.