ABSTRACT
The impact of the follicular lymphoma (FL) histologic grade on outcomes after high-dose therapy (HDT) and autologous stem cell transplantation (ASCT) is unknown. We evaluated 219 consecutive patients with grades 1-3 FL who underwent HDT and ASCT at our center. Overall survival (OS), progression-free survival (PFS), relapse and non-relapse mortality (NRM) was estimated for each grade after controlling for other predictive factors. The number of patients with grades 1, 2 and 3 FL was 106 (48%), 75 (34%) and 38 (17%), respectively. Five-year outcome estimates for the entire cohort included 60% OS, 39% PFS and 46% relapse (median follow-up=7.8 years). PFS and relapse were nearly identical among patients with grade 3 FL versus grades 1-2 FL after adjusting for other contributing factors (hazard ratio (HR)=0.90, P=0.68; HR=1.07, P=0.80, respectively). The hazard for mortality (HR=0.70, P=0.23) and NRM (HR=0.33, P=0.07) was non-significantly lower among patients with grade 3 FL compared to patients with grades 1-2 disease. Factors associated with inferior PFS included elevated lactate dehydrogenase (HR=1.52, P=0.03), chemoresistance (HR=1.82, P=0.02), > or =2 prior therapies (HR=1.8, P=0.03) and prior radiation (HR=1.99, P=0.003). These data suggest that the histologic grade of FL does not impact PFS or relapse following HDT and ASCT.
Subject(s)
Antineoplastic Agents/therapeutic use , Hematopoietic Stem Cell Transplantation , Lymphoma, Follicular/drug therapy , Lymphoma, Follicular/pathology , Adult , Aged , Cohort Studies , Combined Modality Therapy , Disease Progression , Dose-Response Relationship, Drug , Female , Humans , Kaplan-Meier Estimate , Male , Middle Aged , Prognosis , Radiotherapy, Adjuvant , Retrospective Studies , Transplantation Conditioning , Transplantation, AutologousABSTRACT
BACKGROUND: Lung cancer is the most common cause of cancer death in women in the USA. Lung cancer arising during pregnancy is rare and has been reported only 15 times since the 1950s. However, the use of chemotherapy for lung cancer during pregnancy has not previously been reported. METHODS: The history, treatment and outcome of a patient with stage IV non-small-cell lung carcinoma (NSCLC) diagnosed during pregnancy is presented. Previous published reports on lung cancer were retrieved by a literature search of Medline and Cancerlit. RESULTS: A 31-year-old woman was diagnosed as having stage IV NSCLC with bilateral pulmonary involvement when 26 weeks pregnant. Her shortness of breath progressed to dyspnea at rest on 100% inspired oxygen. Therefore, she was treated with systemic chemotherapy using cisplatin and vinorelbine. Despite this treatment, her oxygenation declined further over the next 4 days and thus the baby was delivered via cesarean section after 27 weeks of gestation. Four cycles of vinorelbine and cisplatin have now been administered. Following this treatment, the patient has experienced a significant clinical improvement and no longer requires supplemental oxygen. No chemotherapy-related adverse effects have been noted in the baby. In the 15 previously reported patients with concurrent lung cancer and pregnancy, chemotherapy administration during pregnancy has not been described. CONCLUSIONS: Treatment of lung cancer with chemotherapy during pregnancy should be considered on an individual basis with regard to the stage of the cancer and the maturity of the fetus. To our knowledge, the case presented here is the first report of a woman receiving chemotherapy for lung cancer while pregnant.
Subject(s)
Adenocarcinoma/drug therapy , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma, Non-Small-Cell Lung/drug therapy , Lung Neoplasms/drug therapy , Pregnancy Complications, Neoplastic/drug therapy , Vinblastine/analogs & derivatives , Adenocarcinoma/diagnosis , Adenocarcinoma/pathology , Adult , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Carcinoma, Non-Small-Cell Lung/diagnosis , Carcinoma, Non-Small-Cell Lung/pathology , Cesarean Section , Cisplatin/administration & dosage , Cisplatin/adverse effects , Diagnostic Errors , Dyspnea/etiology , Female , Fetus/drug effects , Gestational Age , Humans , Infant, Newborn , Lung Neoplasms/diagnosis , Lung Neoplasms/pathology , Male , Oxygen/therapeutic use , Pneumonia/diagnosis , Pregnancy , Pregnancy Complications, Neoplastic/diagnosis , Pregnancy Complications, Neoplastic/pathology , Pregnancy Outcome , Smoking , Vinblastine/administration & dosage , Vinblastine/adverse effects , VinorelbineABSTRACT
Cys2His2 zinc finger proteins are composed of modular DNA-binding domains and provide an excellent framework for the design and selection of proteins with novel site specificity. Crystal structures of zinc finger-DNA complexes have shown that many Cys2His2 zinc fingers use a conserved docking arrangement that juxtaposes residues at key positions in the "recognition helix" with corresponding base positions in the three to four base-pair subsite. Several groups have proposed that specificity can be explained with a zinc finger-DNA recognition code that correlates specific amino acids at these key positions in the alpha-helix with specific bases in each position of the corresponding subsite. Here, we explore the utility of such a code through detailed studies of zinc finger variants selected via phage display. These proteins provide interesting systems for detailed analysis since they have affinities and specificities for their sites similar to those of naturally occurring DNA-binding proteins. Comparisons are facilitated by the fact that only key DNA-binding residues are varied in each finger while leaving all other regions of the structure unchanged. We study these proteins in detail by (1) selecting their optimal binding sites and comparing these binding sites with sites that might have been predicted from a code; (2) by examining the "evolutionary history" of these proteins during the phage display protocol to look for evidence of context-dependent effects; and (3) by reselecting finger 1 in the presence of the optimized finger 2/finger 3 domains to obtain further data on finger modularity. Our data for optimized fingers and binding sites demonstrate a clear correlation with contacts that would be predicted from a code. However, there are enough examples of context-dependent effects (not explained by any existing code) that selection is the most reliable method for maximizing the affinity and specificity of new zinc finger proteins.
Subject(s)
DNA-Binding Proteins/genetics , DNA-Binding Proteins/metabolism , Molecular Biology/methods , Zinc Fingers/genetics , Amino Acid Sequence , Bacteriophages , Base Sequence , Binding Sites , DNA-Binding Proteins/chemistry , Evolution, Molecular , Molecular Sequence Data , Receptors, Steroid/metabolism , Sequence Analysis , Substrate Specificity , TATA Box/genetics , TATA-Box Binding Protein , Transcription Factors/metabolism , Tumor Suppressor Protein p53/metabolismABSTRACT
A method is described for selecting DNA-binding proteins that recognize desired sequences. The protocol involves gradually extending a new zinc finger protein across the desired 9- or 10-base pair target site, adding and optimizing one finger at a time. This procedure was tested with a TATA box, a p53 binding site, and a nuclear receptor element, and proteins were obtained that bind with nanomolar dissociation constants and discriminate effectively (greater than 20,000-fold) against nonspecific DNA. This strategy may provide important information about protein-DNA recognition as well as powerful tools for biomedical research.
