Who shall live? Who shall die? "No treatment" orders and guidelines

For more than ten years the medical profession, the legal profession, and perhaps thousands of patients and their relatives have wrestled with the issues of therapy withdrawal, removal of life-sustaining machinery when recovery is hopeless. This major article presents a wide range of insights useful for the individual physician, the hospital governing board, the nurse as well as for policy and lawmakers who confront this issue.     

Randomized phase II trial of gemcitabine-cisplatin with or without trastuzumab in HER2-positive non-small-cell lung cancer.

BACKGROUND: Trastuzumab provides significant clinical benefits in HER2-positive metastatic breast cancer patients when administered in combination with chemotherapy. Chemotherapy has also been shown to be beneficial in some patients with advanced non-small-cell lung cancer (NSCLC). The present randomized phase II trial examined the effect of adding trastuzumab to a standard chemotherapeutic combination (gemcitabine-cisplatin) in patients with HER2-positive NSCLC. PATIENTS AND METHODS: Patients with untreated stage IIIB/IV HER2-positive NSCLC received up to six 21-day cycles of gemcitabine 1250 mg/m(2) (days 1 and 8) and cisplatin 75 mg/m(2) (day 1). Patients in the trastuzumab arm received trastuzumab 4 mg/kg intravenously (i.v.) followed by 2 mg/kg/week i.v. until progression. RESULTS: Of 619 patients screened, 103 were eligible. Fifty-one patients were treated with trastuzumab plus gemcitabine-cisplatin and 50 with gemcitabine-cisplatin alone. Efficacy was similar in the trastuzumab and control arms: response rate 36% versus 41%; median time to progression 6.3 versus 7.2 months; and median progression-free survival (PFS) 6.1 versus 7 months. Response rate (83%) and median PFS (8.5 months) appeared relatively good in the six trastuzumab-treated patients with HER2 3+ or fluorescence in situ hybridization (FISH)-positive NSCLC. Addition of trastuzumab to gemcitabine-cisplatin was well tolerated, side-effects were as expected, and trastuzumab did not exacerbate the known toxicity of gemcitabine and cisplatin. Symptomatic cardiotoxicity was observed in one trastuzumab-treated patient. Serum trastuzumab concentrations in the presence of gemcitabine-cisplatin were comparable to those of trastuzumab alone. CONCLUSIONS: Trastuzumab plus gemcitabine-cisplatin is well tolerated. Clinical benefit was not observed. Although HER2 3+/FISH-positive patients may benefit from trastuzumab, the subgroup is too small to provide definitive information. No significant effect of gemcitabine-cisplatin on trastuzumab pharmacokinetics was observed.     

Infants born to narcotic dependent mothers: Physical growth patterns in the first 12 months of life

Objectives: To describe the physical growth patterns of infants born to narcotic dependent mothers (INDM) over a 12 months period and, if possible, to relate the growth to drug taking patterns during pregnancy.
Methodology: The growth of a cohort of 43 INDM was measured during the first 12 months of life. Weight and length measurements were compared with percentile charts and converted to Z scores. Questionnaire data about drug taking practices, demographic variables and the neonatal period (including withdrawal scores) were obtained.
Results: Twenty-four (55.8%) of INDM had evidence of neonatal drug withdrawal requiring treatment with phenobarbitone. At birth, Z scores for weight and length indicated relative intrauterine growth retardation. By 12 months, there had been some catch up growth, but Z scores for weight and length were still below zero. Persistent weight retardation at 12 months was correlated with methadone dosage during pregnancy, but not the need for phenobarbitone therapy.
Conclusions: The growth patterns of INDM in the first 12 months of life indicated that at birth there was evidence of intrauterine growth retardation, but by 12 months the growth was little different from the rest of the community. There appears to be some influence of narcotic agents taken while pregnant on subsequent growth of INDM.     

Identification of differentially expressed genes in aflatoxin B1- treated cultured primary rat hepatocytes and Fischer 344 rats

Aflatoxin B1 (AFB1), a mutagen and hepatocarcinogen in rats and humans, is a contaminant of the human food supply, particularly in parts of Africa and Asia. AFB1-induced changes in gene expression may play a part in the development of the toxic, immunosuppressive and carcinogenic properties of this fungal metabolite. An understanding of the-role of AFB1 in modulating gene regulation should provide insight regarding mechanisms of AFB1-induced carcinogenesis. We used three PCR- based subtractive techniques to identify AFB1-responsive genes in cultured primary rat hepatocyte RNA: differential display PCR (DD-PCR), representational difference analysis (RDA) and suppression subtractive hybridization (SSH). Each of the three techniques identified AFB1- responsive genes, although no individual cDNA was isolated by more than one technique. Nine cDNAs isolated using DD-PCR, RDA or SSH were found to represent eight genes that are differentially expressed as a result of AFB1 exposure. Genes whose mRNA levels were increased in cultured primary rat hepatocytes after AFB1 treatment were corticosteroid binding globulin (CBG), cytochrome P450 4F1 (CYP4F1), alpha-2 microglobulin, C4b-binding protein (C4BP), serum amyloid A-2 and glutathione S-transferase Yb2 (GST). Transferrin and a small CYP3A-like cDNA had reduced mRNA levels after AFB1 exposure. Full-length CYP3A mRNA levels were increased. When liver RNA from AFB1-treated male F344 rats was evaluated for transferrin, CBG, GST, CYP3A and CYP4F1 expression, a decrease in transferrin mRNA and an increase in CBG, GST, CYP3A and CYP4F1 mRNA levels was also seen. Analysis of the potential function of these genes in maintaining cellular homeostasis suggests that their differential expression could contribute to the toxicity associated with AFB1 exposure.      

The Impact of Nonalcoholic Fatty Liver Disease in Primary Care: A Population Health Perspective

Nonalcoholic fatty liver disease (NAFLD) is the leading cause of liver disease worldwide, with rising rates in parallel to those of obesity, type 2 diabetes, and metabolic syndrome. NAFLD encompasses a wide spectrum of pathology from simple steatosis to nonalcoholic steatohepatitis (NASH) and cirrhosis, which are linked to poor outcomes. Studies confirm a significant amount of undiagnosed NAFLD and related fibrosis within the community, increasing the overall burden of the disease. NAFLD appears to be more prevalent in certain populations, such as those with type 2 diabetes and metabolic syndrome. Early detection and lifestyle modifications, including weight loss and regular exercise, have been shown to improve outcomes. Adverse cardiovascular events are a key contributor to NAFLD-associated morbidity and mortality, and efforts to minimize their occurrence are essential. A targeted and algorithmic approach using noninvasive diagnostic techniques is promptly required to identify and risk-stratify patients with NAFLD. Patients at low risk of progression to NASH and advanced fibrosis can be managed in the primary care setting, while those at high risk of disease progression should be referred to hepatology specialists for surveillance and treatment. This review summarizes the key data of NAFLD's impact within primary care populations and proposes a potential algorithmic approach to identifying and managing such patients.