ABSTRACT
BACKGROUND: It is likely that additional genes for hereditary breast cancer can be identified using a discordant sib pair design. Using this design we identified individuals harboring a rare PMS1 c.605G>A variant previously predicted to result in loss of function. OBJECTIVES: A family-based design and predictive algorithms were used to prioritize candidate variants possibly associated with an increased risk of hereditary breast cancer. Functional analyses were performed for one of the candidate variants, PMS1 c.605G>A. METHODS: 1) 14 discordant sister-pairs from hereditary breast cancer families were identified. 2) Whole exome sequencing was performed and candidate risk variants identified. 3) A rare PMS variant was identified in 2 unrelated affected sisters but no unaffected siblings. 4) Functional analysis of this variant was carried out using targeted mRNA sequencing. RESULTS: Genotype-phenotype correlation did not demonstrate tracking of the variant with cancer in the family. Functional analysis revealed no difference in exon 6 incorporation, which was validated by analyzing PMS1 allele specific expression. CONCLUSIONS: The PMS1 c.605G>A variant did not segregate with disease, and there was no variant-dependent impact on PMS1 exon 6 splicing, supporting this variant is likely benign. Functional analyses are imperative to understanding the clinical significance of predictive algorithms.
Subject(s)
Breast Neoplasms/genetics , Exome Sequencing/methods , Gene Expression Profiling/methods , MutL Proteins/genetics , Neoplasm Proteins/genetics , Polymorphism, Single Nucleotide , Adult , Algorithms , Breast Neoplasms/pathology , Cell Line, Tumor , Female , Genetic Association Studies , Genetic Predisposition to Disease , Humans , Loss of Function Mutation , Middle Aged , Pedigree , Sequence Analysis, RNA , SiblingsABSTRACT
Ischemia-reperfusion injury is unavoidably caused by loss and subsequent restoration of blood flow during organ procurement, and prolonged ischemia-reperfusion injury IRI results in increased rates of delayed graft function and early graft loss. The endogenously produced gasotransmitter, hydrogen sulfide (H2 S), is a novel molecule that mitigates hypoxic tissue injury. The current study investigates the protective mitochondrial effects of H2 S during in vivo cold storage and subsequent renal transplantation (RTx) and in vitro cold hypoxic renal injury. Donor allografts from Brown Norway rats treated with University of Wisconsin (UW) solution + H2 S (150 µM NaSH) during prolonged (24-h) cold (4°C) storage exhibited significantly (p < 0.05) decreased acute necrotic/apoptotic injury and significantly (p < 0.05) improved function and recipient Lewis rat survival compared to UW solution alone. Treatment of rat kidney epithelial cells (NRK-52E) with the mitochondrial-targeted H2 S donor, AP39, during in vitro cold hypoxic injury improved the protective capacity of H2 S >1000-fold compared to similar levels of the nonspecific H2 S donor, GYY4137 and also improved syngraft function and survival following prolonged cold storage compared to UW solution. H2 S treatment mitigates cold IRI-associated renal injury via mitochondrial actions and could represent a novel therapeutic strategy to minimize the detrimental clinical outcomes of prolonged cold IRI during RTx.
Subject(s)
Cold Ischemia , Graft Survival , Hydrogen Sulfide/administration & dosage , Kidney Transplantation , Mitochondria/metabolism , Organ Preservation/methods , Reperfusion Injury/prevention & control , Animals , Gasotransmitters/administration & dosage , Kidney/blood supply , Male , Rats , Rats, Inbred BN , Rats, Inbred Lew , Reperfusion Injury/pathology , Transplantation, HomologousABSTRACT
Hydrogen sulfide (H2S) has been highlighted as an endogenous signaling molecule and we have previously found that it can inhibit histamine-mediated itching. Pruritus is the most common symptom of cutaneous diseases and anti-histamines are the usual treatment; however, anti-histamine-resistant pruritus is common in some clinical settings. In this way, the involvement of mediators other than histamine in the context of pruritus requires new therapeutic targets. Considering that the activation of proteinase-activated receptor 2 (PAR-2) is involved in pruritus both in rodents and humans, in this study we investigated the effect of H2S donors on the acute scratching behavior mediated by PAR-2 activation in mice, as well as some of the possible pharmacological mechanisms involved. The intradermal injection of the PAR-2 peptide agonist SLIGRL-NH2 (8-80nmol) caused a dose-dependent scratching that was unaffected by intraperitoneal pre-treatment with the histamine H1 antagonist pyrilamine (30mg/kg). Co-injection of SLIGRL-NH2 (40nmol) with either the slow-release H2S donor GYY4137 (1 and 3nmol) or the spontaneous donor NaHS (1 and 0.3nmol) significantly reduced pruritus. Co-treatment with the KATP channel blocker glibenclamide (200nmol) or the nitric oxide (NO) donor sodium nitroprusside (10nmol) abolished the antipruritic effects of NaHS; however, the specific soluble guanylyl cyclase inhibitor ODQ (30µg) had no significant effects. The transient receptor potential ankyrin type 1 (TRPA1) antagonist HC-030031 (20µg) significantly reduced SLIGRL-NH2-induced pruritus; however pruritus induced by the TRPA1 agonist AITC (1000nmol) was unaffected by NaHS. Based on these data, we conclude that pruritus secondary to PAR-2 activation can be reduced by H2S, which acts through KATP channel opening and involves NO in a cyclic guanosine monophosphate (cGMP)-independent manner. Furthermore, TRPA1 receptors mediate the pruritus induced by activation of PAR-2, but H2S does not interfere with this pathway. These results provide additional support for the development of new therapeutical alternatives, mainly intended for treatment of pruritus in patients unresponsive to anti-histamines.
Subject(s)
Hydrogen Sulfide/pharmacology , Oligopeptides/pharmacology , Pruritus/drug therapy , Receptor, PAR-2/metabolism , Animals , Disease Models, Animal , Glyburide/pharmacokinetics , Histamine/metabolism , Histamine Antagonists/pharmacology , Isothiocyanates/pharmacology , Male , Mice , Mice, Inbred C57BL , Morpholines/pharmacology , Nitroprusside/pharmacology , Organothiophosphorus Compounds/pharmacology , Pruritus/metabolism , Transient Receptor Potential Channels/metabolismABSTRACT
Hydrogen sulfide (H2S) is an important gasotransmitter in both animals and plants. Many physiological events, including responses to stress, have been suggested to involve H2S, at least in part. On the other hand, numerous responses have been reported following treatment with H2S, including changes in the levels of antioxidants and the activities of transcription factors. Therefore, it is important to understand and unravel the events that are taking place downstream of H2S in signaling pathways. H2S is known to interact with other reactive signaling molecules such as reactive oxygen species (ROS) and nitric oxide (NO). One of the mechanisms by which ROS and NO have effects in a cell is the modification of thiol groups on proteins, by oxidation or S-nitrosylation, respectively. Recently, it has been reported that H2S can also modify thiols. Here we report a method for the determination of thiol modifications on proteins following the treatment with biological samples with H2S donors. Here, the nematode Caenorhabditis elegans is used as a model system but this method can be used for samples from other animals or plants.
Subject(s)
Caenorhabditis elegans/drug effects , Helminth Proteins/isolation & purification , Hydrogen Sulfide/pharmacology , Protein Processing, Post-Translational , Sulfhydryl Compounds/metabolism , Animals , Behavior, Animal/drug effects , Caenorhabditis elegans/metabolism , Disulfides/chemistry , Disulfides/metabolism , Electrophoresis, Polyacrylamide Gel , Fluoresceins/chemistry , Helminth Proteins/chemistry , Helminth Proteins/metabolism , Hydrogen Peroxide/pharmacology , Hydrogen Sulfide/metabolism , Movement/drug effects , Nitric Oxide/metabolism , Oxidation-Reduction , Reactive Oxygen Species/metabolism , Signal Transduction , Staining and Labeling/methods , Sulfhydryl Compounds/chemistry , Sulfides/chemistry , Sulfides/pharmacologyABSTRACT
AIM: To investigate an interaction between the calcium and sulphide signalling pathways, particularly effects of the slow H2 S release donor morpholin-4-ium-4-methoxyphenyl-(morpholino)-phosphinodithioate (GYY4137) on the expression of inositol 1,4,5-trisphosphate receptors (IP3 R) with the possible impact on the apoptosis induction in HeLa cells. METHODS: Gene expression, Western blot analysis, apoptosis determination by Annexin-V-FLUOS and drop in mitochondrial membrane potential by 5,5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimidazolyl-carbocyanine iodide (JC1) and immunofluorescence were used to determine differences in control and GYY4137-treated HeLa cells. RESULTS: In HeLa cell line, GYY4137 (10 µm) up-regulated expression of the IP3 R1 and IP3 R2, but not IP3 R3 on both mRNA and protein levels. Concurrently, cytosolic calcium increased and reticular calcium was depleted in concentration-dependent manner, partially by the involvement of IP3 R. Depletion of calcium from reticulum was accompanied by increase in endoplasmic reticulum (ER) stress markers, such as X-box, CHOP and ATF4, thus pointing to the development of ER stress due to GYY4137 treatment. Also, GYY4137 treatment of HeLa cells increased the number of apoptotic cells. CONCLUSION: These results suggest an involvement of H2 S in both IP3 -induced calcium signalling and induction of apoptosis, possibly through the activation of ER stress.
Subject(s)
Apoptosis/physiology , Calcium Signaling/physiology , Hydrogen Sulfide/metabolism , Inositol 1,4,5-Trisphosphate Receptors/metabolism , Up-Regulation , HeLa Cells , Humans , Inositol 1,4,5-Trisphosphate Receptors/genetics , Morpholines , Organothiophosphorus CompoundsABSTRACT
BACKGROUND: Risk stratification based on family history is a feature of screening guidelines for a number of cancers and referral guidelines for genetic counseling/testing for cancer risk. AIMS: Our aim was to describe primary care physician perceptions of their role in managing cancer risk based on family history. METHODS: Structured interviews were conducted by a medical anthropologist with primary care physicians in 3 settings in 2 north-eastern states. Transcripts were systematically analyzed by a research team to identify major themes expressed by participants. RESULTS: Forty interviews were conducted from May 2003 through May 2006. Physicians provided a diversity of views on roles in management of cancer risk based on family history, management practices and patient responses to risk information. They also provided a wide range of perspectives on criteria used for referral to specialists, types of specialists referred to and expected management roles for referred patients. CONCLUSION: Some primary care physicians appeared to make effective use of family history information for cancer risk management, but many in this sample did not. Increased focus on efficient assessment tools based on recognized guidelines, accessible guides to management options, and patient education and decision aids may be useful directions to facilitate broader use of family history information for cancer risk management.
Subject(s)
Genetic Predisposition to Disease , Medical History Taking , Neoplasms/epidemiology , Practice Management, Medical/organization & administration , Primary Health Care/organization & administration , Referral and Consultation , Female , Humans , Male , Medicine , Neoplasms/genetics , Practice Patterns, Physicians' , Risk FactorsABSTRACT
We hypothesized that exemestane (EXE) would reduce mammographic breast density and have unique effects on biomarkers of bone and lipid metabolism. Healthy postmenopausal women were randomized to EXE (25 mg daily) or placebo (PLAC) for 12 months and followed for a total of 24 months. The primary endpoint was change in percent breast density (PD) between the baseline and 12-month mammograms and secondary endpoints were changes in serum lipid levels, bone biomarkers, and bone mineral density (BMD). Ninety-eight women were randomized (49 to EXE; 49 to PLAC) and 65 had PD data at baseline and 12 months. Among women treated with EXE, PD was not significantly changed from baseline at 6, 12, or 24 months and was not different from PLAC. EXE was associated with significant percentage increase from baseline in N-telopeptide at 12 months compared with PLAC. No differences in percent change from baseline in BMD (lumbar spine and femoral neck) were observed between EXE and PLAC at either 12 or 24 months. Patients on EXE had a significantly larger percent decrease in total cholesterol than in the PLAC arm at 6 months and in HDL cholesterol at 3, 6, and 12 months. No significant differences in percent change in LDL or triglycerides were noted at any time point between the two treatment arms. EXE administered for 1 year to healthy postmenopausal women did not result in significant changes in mammographic density. A reversible increase in the bone resorption marker N-telopeptide without significant change in bone specific alkaline phosphatase or BMD during the 12 months treatment period and 1 year later was noted. Changes in lipid parameters on this trial were modest and reversible.
Subject(s)
Androstadienes/therapeutic use , Aromatase Inhibitors/therapeutic use , Bone Density/drug effects , Bone and Bones/metabolism , Breast/drug effects , Lipid Metabolism/drug effects , Lipids/blood , Postmenopause/metabolism , Alkaline Phosphatase/blood , Breast Neoplasms/prevention & control , Collagen Type I/urine , Double-Blind Method , Female , Humans , Mammography , Middle Aged , Peptides/urineABSTRACT
Effects of hydrogen sulfide (H(2)S) on plant physiology have been previously studied, but such studies have relied on the use of NaSH as a method for supplying H(2)S to tissues. Now new compounds which give a less severe H(2)S shock and a more prolonged exposure to H(2)S have been developed. Here the effects of one such compound, GYY4137, has been investigated to determine its effects on stomatal closure in Arabidopsis thaliana. It was found that both NaSH and GYY4137 caused stomatal opening in the light and prevented stomatal closure in the dark. Nitric oxide (NO) has been well established as a mediator of stomatal movements and here it was found that both NaSH and GYY4137 reduced the accumulation of NO in guard cells, perhaps suggesting a mode of action for H(2)S in this system. GYY4137, and future related compounds, will be important tools to unravel the effects of plant exposure to H(2)S and to determine how H(2)S may fit into plant cell signalling pathways.
Subject(s)
Arabidopsis/drug effects , Hydrogen Sulfide/pharmacology , Morpholines/pharmacology , Nitric Oxide/metabolism , Organothiophosphorus Compounds/pharmacology , Plant Stomata/drug effects , Sulfhydryl Compounds/pharmacology , Arabidopsis/physiology , Darkness , Light , Plant Stomata/physiologyABSTRACT
Assessing the risk of breast and ovarian cancer starts with obtaining a complete and accurate family history. This can reveal evidence of inherited cancer risk. The highest risk of cancer is associated with germ-line abnormalities in several genes, including BRCA1, BRCA2, and TP53. Moderate-risk genes associated with syndromes that are inherited in an autosomal dominant pattern (such as Cowden's disease, hereditary non-polyposis colorectal cancer, Muir-Torre syndrome, and Peutz-Jeghers syndrome) exhibit lower penetrance and thus less risk of breast and/or ovarian cancer. Low-risk genes likely require significant environmental exposure, and although they are associated with the lowest risk of cancer, they account for more cancer than high- and moderate-risk genes. Lifetime risks for breast or ovarian cancer can be estimated. The Gail and Claus models, the more widely utilized models for calculation of lifetime breast cancer risk, are discussed. Models are also available for determining the likelihood of finding a BRCA1/2 mutation (the BRCAPRO and Myriad models). Appropriate candidates for testing include affected individuals who are most likely to have a hereditary form of cancer. Testing should proceed only after a thorough discussion of the risks, benefits, and limitations of testing. Risk-reducing options are available to women with a strong family history of breast and ovarian cancer. These options include high-risk screening, chemoprevention, and prophylactic surgery.
Subject(s)
Breast Neoplasms/genetics , Ovarian Neoplasms/genetics , Age Distribution , Age of Onset , Breast Neoplasms/epidemiology , Breast Neoplasms/prevention & control , Female , Genes, BRCA1 , Genes, BRCA2 , Genes, p53 , Genetic Testing , Humans , Mutation , Ovarian Neoplasms/epidemiology , Ovarian Neoplasms/prevention & control , Penetrance , RiskABSTRACT
A range of fluorescent in situ hybridization techniques have been used to reveal hidden variant Philadelphia translocations in two cases of Ph-positive chronic-phase chronic myeloid leukaemia. In one patient, a highly complex variant Ph translocation affecting four chromosomes had resulted in the formation of structures with the appearance of i(17q) and +8. Misinterpretation of these karyotypes has direct clinical relevance. Our findings illustrate that even established cytogenetic abnormalities may contain cryptic abnormalities beyond the resolution of conventional cytogenetic methods.
Subject(s)
Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics , Philadelphia Chromosome , Translocation, Genetic , Aged , Chromosome Banding , Chromosomes, Human, Pair 1 , Chromosomes, Human, Pair 22 , Chromosomes, Human, Pair 9 , Diagnosis, Differential , Female , Humans , In Situ Hybridization, Fluorescence , MetaphaseABSTRACT
OBJECTIVE: Chronic hyperglycemia is known to increase tissue glycation and diabetic complications, but controversy exists regarding the independent role of increased postprandial glucose excursions. To address this question, we have studied the effect of postprandial glycemic excursions (PPGEs) on levels of methylglyoxal (MG) and 3-deoxyglucosone (3-DG), two highly reactive precursors of advanced glycation end products (AGEs). RESEARCH DESIGN AND METHODS: We performed 4-month crossover studies on 21 subjects with type 1 diabetes and compared the effect of premeal insulin lispro or regular insulin on PPGEs and MG/3-DG excursions. PPGE was determined after standard test meal (STMs) and by frequent postprandial glucose monitoring. HbA1c and postprandial MG and D-lactate were measured by HPLC, whereas 3-DG was determined by gas chromatography/mass spectroscopy. RESULTS: Treatment with insulin lispro resulted in a highly significant reduction in PPGEs relative to the regular insulin-treated group (P = 0.0005). However, HbA1c levels were similar in the two groups, and no relationship was observed between HbA1c and PPGE (P = 0.93). Significant postprandial increases in MG, 3-DG, and D-lactate occurred after the STM. Excursions of MG and 3-DG were highly correlated with levels of PPGE (R = 0.55, P = 0.0002 and R = 0.61, P = 0.0004; respectively), whereas a significant inverse relationship was seen between PPGE and D-lactate excursions (R = 0.40, P = 0.01). Conversely, no correlation was observed between HbAlc and postprandial MG, 3-DG, or D-lactate levels. CONCLUSIONS: Increased production of MG and 3-DG occur with greater PPGE, whereas HbA1c does not reflect these differences. Reduced PPGE also leads to increased production of D-lactate, indicating a role for increased detoxification in reducing MG levels. The higher postprandial levels of MG and 3-DG observed with greater PPGE may provide a partial explanation for the adverse effects of glycemic lability and support the value of agents that reduce glucose excursions.
Subject(s)
Blood Glucose/metabolism , Deoxyglucose/blood , Diabetes Mellitus, Type 1/blood , Diabetes Mellitus, Type 1/drug therapy , Hyperglycemia/epidemiology , Hypoglycemic Agents/therapeutic use , Insulin/therapeutic use , Pyruvaldehyde/blood , Adolescent , Adult , Aged , Biomarkers/blood , Blood Glucose/drug effects , Cross-Over Studies , Deoxyglucose/analogs & derivatives , Double-Blind Method , Drug Administration Schedule , Glycation End Products, Advanced/blood , Humans , Hyperglycemia/blood , Hypoglycemic Agents/administration & dosage , Insulin/administration & dosage , Insulin/analogs & derivatives , Insulin Lispro , Middle Aged , Postprandial Period , Regression AnalysisABSTRACT
We report here a case of recurrent venous and arterial thromboembolism, Trousseau's syndrome, in a cancer patient who developed heparin-induced thrombocytopenia. She was treated with lepirudin and after establishing the patient-specific half-life for subcutaneous lepirudin, she was successfully maintained on this therapy for more than eight months. To our knowledge this case represents the longest reported use of subcutaneous lepirudin.
Subject(s)
Hirudins/administration & dosage , Paraneoplastic Syndromes/drug therapy , Recombinant Proteins/administration & dosage , Anticoagulants/administration & dosage , Arterial Occlusive Diseases/drug therapy , Arterial Occlusive Diseases/etiology , Female , Heparin/adverse effects , Hirudins/analogs & derivatives , Humans , Injections, Subcutaneous , Kinetics , Middle Aged , Partial Thromboplastin Time , Recurrence , Thrombocytopenia/chemically induced , Thromboembolism/drug therapy , Thromboembolism/etiology , Venous Thrombosis/drug therapy , Venous Thrombosis/etiologyABSTRACT
The role of both primary and secondary cigarette smoke exposure in the causation of lung cancer appears certain. An estimated 90% of lung cancer is attributed to cigarette smoke. Remarkably, however, less then 20% of cigarette smokers develop lung cancer. Investigators have suggested that a genetic predisposition to lung cancer may contribute to familial aggregation of this cancer. To understand the contribution of familial aggregation to this type of cancer and potentially identify individuals and families, which may be important in identifying gene(s) responsible for lung cancer, we developed criteria for identification of high-risk families. We have tested the feasibility and utility of these criteria at three Denver, CO hospitals with very different patient populations. Four hundred eighteen individuals were diagnosed with lung cancer at these three hospitals between 1/1/95 and 8/31/95. Twenty-nine percent of individuals expired prior to the time of initial contact. Family history data were obtained on 182 individuals. To be considered positive (suggesting possible autosomal dominant inheritance of lung cancer), families must have at least two first-degree relatives with lung cancer, one of which must be diagnosed before the age of 55. Seventeen of 182 (9.3%) families in the study population met these criteria. We reviewed the remaining family histories that did not meet the established criteria and identified another 2.3% (5/182) of families had evidence for autosomal dominant transmission of lung cancer. An additional 15% (23/182) of families had histories which could not be classified without further information. This study suggests that at least 11.6% of individuals diagnosed with lung cancer will have a positive family history of lung cancer. Use of the criteria developed for this study may lead to an underestimation of the inherited etiology of lung cancer.
Subject(s)
Genetic Predisposition to Disease , Lung Neoplasms/genetics , Adult , Aged , Aged, 80 and over , Female , Genetic Testing , Humans , Male , Middle Aged , Pedigree , Pilot ProjectsABSTRACT
We sought to understand better the impact of genetic testing and counseling in a group of women who had early breast cancer (age <50) or ovarian cancer and a family history of cancer. Thirty-five women underwent genetic counseling and genetic testing for BRCA1/2 at the University of Colorado Cancer Center, Hereditary Cancer Clinic. Psychological assessment (IES and Hopkins Symptom Checklist) was made before counseling, and 1 month after genetic test results were reported to women. A statistically significant decrease in anxiety was evidenced 1 month after results were given (p = 0.024). Decreased intrusive thoughts related to genetic testing were seen only for those testing negative (p = 0.0003). Women diagnosed with cancer less than 1 year prior to genetic testing experienced the greatest cancer-specific distress (p = 0.01) and distress related to genetic testing (p = not significant). Satisfaction with the counseling and testing process was high. In conclusion, genetic testing and counseling can occur with little anxiety and stress. However, women less than 1 year from a cancer diagnosis will experience the greatest distress associated with genetic testing and counseling. Women who are considering genetic testing and counseling close to a diagnosis of cancer may require greater psychological support.
Subject(s)
Breast Neoplasms/diagnosis , Genes, BRCA1 , Genetic Counseling , Genetic Testing , Ovarian Neoplasms/diagnosis , Adult , Aged , Breast Neoplasms/genetics , Breast Neoplasms/psychology , DNA Mutational Analysis , Female , Humans , Middle Aged , Ovarian Neoplasms/genetics , Ovarian Neoplasms/psychology , Pilot Projects , Prospective StudiesABSTRACT
The discourse of the new sciences of homosexuality interacts with, reproduces, and sometimes challenges other discourses that inform and intersect it--popular discussions of scientific discoveries, legal discourse, debates about gay and lesbian identity, and religious discourse. Despite their different intentions and vocabularies, what links the discourse of the Christian right to that of contemporary sexology research and its popularized versions is its reproduction of a binary gender system, in which women are figured as both within and outside of "nature." Researchers in gay, lesbian, and bisexual sexuality can make a significant contribution by exposing the ways their research contends with discursive practices that have a context and a history (in connections between Aquinas's theology and Aristotle's science, for example). The narrative, rooted in traditional Christian theology and early Western science, that produces gender as binary and heterosexuality as normative can be rewritten to reveal the constructedness of both gender and sexuality.
Subject(s)
Christianity , Homosexuality , Humans , Politics , Religion and Psychology , Religion and SexABSTRACT
This Phase I study was designed to determine the maximally tolerated dose (MTD) of paclitaxel with standard doses of cisplatin and etoposide for patients with untreated extensive stage small cell lung cancer (SCLC). Secondary objectives were to determine the toxicities, response rate, response duration, and overall survival in this cohort. Twenty-eight SCLC patients were enrolled into four dose levels. All patients received a fixed dose of cisplatin at 80 mg/m2, i.v., day 1. The first group received etoposide 50 mg/m2, i.v. day 1 and 100 mg/m2 p.o., days 2-3, whereas all subsequent groups received etoposide 80 mg/m2, i.v., day 1 and 160 mg/m2, p.o., days 2-3. The paclitaxel starting dose was 135 mg/m2, i.v., over a 3-h period and was escalated to 175 and 200 mg/m2. Cycles were repeated every 21 days for a maximum of six cycles. Granulocyte-colony stimulating factor was not given prophylactically but was allowed in subsequent cycles according to the American Society of Clinical Oncologists guidelines. All 28 SCLC patients were evaluable for toxicity, and 23 patients were evaluable for response. Myelosuppression was the major toxicity, with grade 4 neutropenia occurring in 23 of 28 patients (82%), but febrile neutropenia was uncommon and developed in 4 patients (14%). Grade 4 thrombocytopenia and anemia were rare, occurring as isolated events in one patient each. Dose-limiting peripheral neuropathy was observed at a paclitaxel dose of 200 mg/m2. Grade 4 nausea/vomiting and diarrhea were also noted at this dose level. Five patients had complete responses (22%), and 14 patients had partial responses (61%). The overall response rate was 83% with a median time to progression of 7.5 months, a median survival of 10 months, and a 1-year survival rate of 39%. This three-drug combination of paclitaxel with cisplatin and etoposide is active with acceptable toxicity. Neurotoxicity was dose limiting at 200 mg/m2 of paclitaxel. Neutropenia was frequent but not associated with significant morbidity. The recommended doses for future clinical trials are 175 mg/m2 paclitaxel, i.v., over a 3-h period on day 1 with 80 mg/m2 cisplatin, i.v., on day 1 and 80 mg/m2 etoposide, i.v., on day 1 and 160 mg/m2 p.o. on days 2 and 3 with growth factor support. The Southwestern Oncology Group has instituted a Phase II study with this dose schedule.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/adverse effects , Carcinoma, Small Cell/drug therapy , Lung Neoplasms/drug therapy , Adult , Aged , Carcinoma, Small Cell/mortality , Carcinoma, Small Cell/pathology , Cisplatin/administration & dosage , Dose-Response Relationship, Drug , Drug Administration Schedule , Etoposide/administration & dosage , Female , Granulocyte Colony-Stimulating Factor/therapeutic use , Humans , Lung Neoplasms/mortality , Lung Neoplasms/pathology , Male , Middle Aged , Neoplasm Staging , Neutropenia/chemically induced , Neutropenia/prevention & control , Paclitaxel/administration & dosage , Survival Rate , Time FactorsABSTRACT
The diagnosis and classification of diabetes mellitus have been reviewed and revised for the first time since 1979. A precedent-setting recommendation by the American Diabetes Association for routine screening of adults is an effort to identify the estimated 8 million people in the United States with undiagnosed diabetes. Stricter diagnostic criteria will identify more accurately those who are at risk for diabetic complications. Classification and nomenclature have been revised to describe the cause rather than the treatment of diabetes.
Subject(s)
Diabetes Mellitus, Type 1/classification , Diabetes Mellitus, Type 1/diagnosis , Diabetes Mellitus, Type 2/classification , Diabetes Mellitus, Type 2/diagnosis , Mass Screening/methods , Adult , Diabetes Mellitus, Type 1/etiology , Diabetes Mellitus, Type 1/prevention & control , Diabetes Mellitus, Type 2/etiology , Diabetes Mellitus, Type 2/prevention & control , Humans , Practice Guidelines as Topic , Risk FactorsABSTRACT
PURPOSE: Previous studies of mutations in BRCA1 or BRCA2 have used detection methods that may underestimate the actual frequency of mutations and have analyzed women using heterogeneous criteria for risk of hereditary cancer. PATIENTS AND METHODS: A total of 238 women with breast cancer before age 50 or ovarian cancer at any age and at least one first- or second-degree relative with either diagnosis underwent sequence analysis of BRCA1 followed by analysis of BRCA2 (except for 27 women who declined analysis of BRCA2 after a deleterious mutation was discovered in BRCA1). Results were correlated with personal and family history of malignancy. RESULTS: Deleterious mutations were identified in 94 (39%) women, including 59 of 117 (50%) from families with ovarian cancer and 35 of 121 (29%) from families without ovarian cancer. Mutations were identified in 14 of 70 (20%) women with just one other relative who developed breast cancer before age 50. In women with breast cancer, mutations in BRCA1 and BRCA2 were associated with a 10-fold increased risk of subsequent ovarian carcinoma (P = .005). CONCLUSION: Because mutations in BRCA1 and BRCA2 in women with breast cancer are associated with an increased risk of ovarian cancer, analysis of these genes should be considered for women diagnosed with breast cancer who have a high probability of carrying a mutation according to the statistical model developed with these data.