Circulating Tumor Cells (CTC) Are Associated with Defects in Adaptive Immunity in Patients with Inflammatory Breast Cancer.

BACKGROUND: Circulating tumor cells (CTCs) play a crucial role in tumor dissemination and are prognostic in primary and metastatic breast cancer. Peripheral blood (PB) immune cells contribute to an unfavorable microenvironment for CTC survival. This study aimed to correlate CTCs with the PB T-cell immunophenotypes and functions of patients with inflammatory breast cancer (IBC). METHODS: This study included 65 IBC patients treated at the MD Anderson Cancer Center. PB was obtained from patients prior to starting a new line of chemotherapy for CTCs enumeration by CellSearch(®), and T cell phenotype and function by flow cytometry; the results were correlated with CTCs and clinical outcome. RESULTS: At least 1 CTC (≥1) or ≥5 CTCs was detected in 61.5% or 32.3% of patients, respectively. CTC count did not correlate with total lymphocytes; however, patients with ≥1 CTC or ≥5 CTCs had lower percentages (%) of CD3+ and CD4+ T cells compared with patients with no CTCs or <5 CTCs, respectively. Patients with ≥1 CTC had a lower percentage of T-cell receptor (TCR)-activated CD8+ T cells synthesizing TNF-α and IFN-γ and a higher percentage of T-regulatory lymphocytes compared to patients without CTCs. In multivariate analysis, tumor grade and % CD3+ T-cells were associated with ≥1 CTC, whereas ≥5 CTC was associated with tumor grade, stage, % CD3+ and % CD4+ T cells, and % TCR-activated CD8 T-cells synthesizing IL-17. CONCLUSIONS: IBC patients with CTCs in PB had abnormalities in adaptive immunity that could potentially impact tumor cell dissemination and initiation of the metastatic cascade.

Clinical relevance of cancer stem cells in bone marrow of early breast cancer patients.

BACKGROUND: Cancer stem cells (CSCs) are epithelial tumor cells that express CD44(+)CD24(-/lo). CSCs can be further divided into those that have aldehyde dehydrogenase (ALDH) activity (Aldefluor(+)) and those that do not. We hypothesized that if CSCs are responsible for tumor dissemination, their presence in bone marrow (BM) would be prognostic in early stages of breast cancer (EBC) patients. PATIENTS AND METHODS: BM aspirates were collected at the time of surgery from 108 patients with EBC. BM was analyzed for CSCs and ALDH activity by flow cytometry. Overall survival and disease-free survival (DFS) were calculated from the date of diagnosis and analyzed with Kaplan-Meier survival plots. Cox multivariate proportional hazards model was also carried out. RESULTS: Patients with CSCs in BM had a hazard ratio (HR) of 8.8 for DFS (P = 0.002); patients with Aldefluor(+) CSCs had a HR of 5.9 (P = 0.052) for DFS. All deceased patients (n = 7) had CSCs in BM. In multivariate analysis, the presence of CSCs in BM was a prognostic factor of DFS (HR = 15.8, P = 0.017). CONCLUSIONS: The presence of BM metastasis is correlated with CSCs and these CSCs irrespective of ALDH activity are an independent adverse prognostic factor in EBC patients.

Peptide T improves psoriasis when infused into lesions in nanogram amounts.

In each of 14 patients, two small but comparable psoriatic lesions were infused for 2 weeks with either saline or a saline solution of peptide T (as its analog D-ala1-peptide T amide) at 10(-7) mol/L with Alzet osmotic pumps worn extracorporeally. During infusion, lesions were photographed and scored for clinical features of psoriasis on a 9-point scale. After another 7 days, biopsy specimens were taken from the infused sites, and sections were scored for features of psoriasis on a 19-point scale. The differences between means for data from saline- and peptide T-infused lesions were evaluated statistically. Peptide T-infused lesions improved clinically; scores decreased from a mean of 4.35 initially to 1.57 at biopsy, whereas control lesions changed from 4.43 to 3.57 (p less than 0.01 for 1.57 vs 3.57). Histologic scores were also significantly different (5.28 for peptide T vs 10.00 for controls, 0.05 greater than p greater than 0.02). This study provides evidence that intralesionally infused peptide T demonstrates some clearing effect in psoriasis.

Artificial feeding and patients' rights: recent developments and recommendations.

The rejection of technologically supplied nutrition and hydration (artificial feeding) has emerged in the last five years as one of the most controversial aspects of the right to refuse treatment. This article summarizes the trends in the legal and medical literature recognizing that individuals have the right to reject artificial feeding as to refuse any other medical treatment. It also addresses non-legal concerns and offers recommendations for effective implementation of patient preferences.

Adverse effects of nitrous oxide.

Although once considered completely devoid of complications, it is now recognised that the misuse or inappropriate use of nitrous oxide (N2O) often results in adverse side effects. Hypoxia, particularly the entity 'diffusion hypoxia', can occur with the administration of inadequate amounts of oxygen during or immediately after a N2O anaesthetic. N2O will diffuse into air-containing cavities within the body faster than nitrogen diffuses out. This results in a temporary increase in either the pressure and/or volume of the cavity depending upon the distensibility of its walls. The magnitude of the effect is proportional to the blood supply of the cavity, the concentration of N2O inhaled and the length of time the patient is exposed to N2O. Significant morbidity or even death can result from this phenomenon. A property unique to N2O is its ability to oxidise and inactivate the vitamin B12 components of certain enzymes in both animals and man. One such enzyme, methionine synthetase is essential for normal DNA production. Animal and human studies have demonstrated that the haematological, immune, neurological and reproductive systems are each affected. These adverse effects of N2O can occur after both acute (surgical) or long term (occupational) exposure to the gas. Because of its effects on the pressure and volume characteristics of air-containing spaces, N2O should not be used for patients with bowel obstruction, pneumothorax, middle ear and sinus disease, and following cerebral air-contrast studies. Many anaesthesiologists feel that use of N2O should be restricted during the first two trimesters of pregnancy because of its effects on DNA production and the experimental and epidemiological evidence that N2O causes undesirable reproductive outcomes. Since N2O affects white blood cell production and function, it has been recommended that N2O not be administered to immunosuppressed patients or to patients requiring multiple general anaesthetics. Many anaesthesiologists believe that the potential dangers of N2O are so great that it should no longer be used at all for routine clinical anaesthesia. However, the continued use of N2O remains a controversial topic since, at present, a suitable substitute gas is not available.

Occupational exposure to mercury in dentistry and pregnancy outcome.

A questionnaire was mailed to dentists and dental assistants requesting information about work, health, and reproductive history. Statistical analysis of the data indicated that there were no increased rates of spontaneous abortions or congenital abnormalities in the children of men and women who were exposed to low versus high levels of mercury in a dental environment.

Sperm studies in anesthesiologists.

Semen samples were collected from 46 anesthesiologists each of whom had worked a minimum of one year in hospital operating rooms ventilated with modern gas-scavenging devices. Samples collected from 26 beginning residents in anesthesiology served as controls. Concentrations of sperm and percentages of sperm having abnormal head shapes were determined for each sample. No significant differences were found between anesthesiologists and beginning residents. Limiting the analyses to men having no confounding factors (varicocele, recent illness, medications, heavy smoking, frequent sauna use) did not change the results. The sperm concentration and morphology in 13 men did not change significantly after one year of exposure to anesthetic gases. However, the group of mean who had one or more confounding factors (excluding exposure to anesthetic gases) showed significantly higher percentages of sperm abnormalities than did the group of men without such factors. These results suggest that limited exposure to anesthetic gases does not significantly affect sperm production as judged by changes in sperm concentration and morphology. These data are reassuring, but since the hospitals surveyed used modern gas-scavenging devices, men who are occupationally exposed to anesthetic gases without this protection should be studied for fuller assessment of the possible human spermatotoxic effects.

Exposure to nitrous oxide and neurologic disease among dental professionals.

Questionnaires, mailed to approximately 30,000 dentists and an equal number of dental assistants requesting information regarding professional exposure to anesthetics and health problems, showed an increased incidence of neurologic complaints in dental professionals who worked with nitrous oxide. The most striking differences were noted in individuals reporting symptoms of numbness, tingling, and/or muscle weakness. For dentists heavily exposed to nitrous oxide, the rate of these complaints was 4-fold greater than for nonanesthetic-exposed dentists. For dental assistants heavily exposed to nitrous oxide, a 3-fold increase in these same complaints was noted. In view of recent evidence that nitrous oxide abuse may lead to polyneuropathy, the results suggest that occupational exposure to nitrous oxide by both dentists and dental assistants may be associated with similar neuropathy.

Low-level binding of halothane metabolites to rat liver histones in vivo.

Binding of halothane metabolites to rat liver histones was investigated after in vivo administration of 14C-halothane. Animals were injected with either a mixture of triiodothyronine, glucagon and heparin (TGH) to stimulate liver growth or with saline as a control. Twenty-four hours later, animals were administered 14C-halothane and maintained at 8--10 per cent O2 for 6 hours. Detergent washed nuclei from liver homogenates were subfractionated to allow quantitative measurements of 14C-halothane binding to histones. Although our studies suggest that much of the previously reported binding of halothane metabolites to major cell fractions was a result of redistribution of endoplasmic reticulum components during isolation procedures, carefully controlled experiments demonstrated that the radioactivity associated with histones could not be due to residual microsomal lipid. Of the initial 132 mumol of 14C-halothane administered, 1.1 mumol remained as nonvolatile metabolites in the liver homogenate and 25 pmol were associated with purified histones. This corresponds to approximately one halothane moiety per 15,000 histone molecules. No significant binding to liver cell RNA or DNA was observed. With this low level of histone modification and lack of convincing evidence of halothane metabolite binding to hepatic DNA or RNA, it is unlikely that significant alteration of the genome occurs after exposure to halothane.

Surgery during pregnancy and fetal outcome.

As many as 2% of all pregnant women undergo surgery during gestation, but there are few reports of the effects of anesthesia and surgery on fetal outcome. The present paper presents information on 287 women who had surgery during pregnancy. Surgery during early pregnancy was associated with a significant increase in the rate of spontaneous abortion compared to the rate in a control group that did not have surgery. There were no differences in the incidence of congenital abnormalities in this offspring of women who had surgery during early pregnancy. The data suggest that elective surgery be deferred during early pregnancy to minimize potential fetal loss.

Occupational disease in dentistry and chronic exposure to trace anesthetic gases.

A mail survey of 30,650 dentists and 30,547 chairside assistants grouped according to occupational exposure to inhalation anesthetic and sedatives in the dental operatory indicated increased general health problems and reproductive difficulties among respondents exposed to anesthetics. For male dentists who were heavily exposed to anesthetics, the increase in liver disease was 1.7-fold, kidney disease was 1.2-fold, and neurological disease was 1.9-fold. For wives of male dentists who were heavily exposed to anesthetics, the increase in spontaneous abortion rate was 1.5-fold. Among female chairside assistants who were heavily exposed to anesthetics, the increase in liver disease was 1.6-fold, kidney disease was 1.7-fold, and neurological disease was 2.8-fold. The increase in spontaneous abortion rate among assistants who were heavily exposed was 2.3-fold. Cancer rates in women heavily exposed to inhalation anesthetics were increased 1.5-fold but this finding was not statistically significant (P = .06). Separate analysis of the data for disease rates and birth difficulties by type of inhalation anesthetic indicates that in both dentists and chairside assistants chronic exposure to nitrous oxide alone is associated with an increase rate of adverse response.

Metabolism of nitrous oxide by human and rat intestinal contents.

Nitrous oxide labeled with a stable heavy nitrogen isotope was used for in-vitro studies of nitrous oxide metabolism in man and rat. At 5 per cent oxygen tension, which is comparable to normal oxygen tension in the intestine in vivo, each gram of intestinal contents during a 16-hr in-vitro incubation produced 47 +/- 13 nmol of molecular nitrogen for the rat and 103 +/- 17 nmol for man. Active reductive metabolism of nitrous oxide by intestinal contents was significantly inhibited by antibiotics and by 20 per cent oxygen tension. It is suggested that the reduction of nitrous oxide to nitrogen may proceed through a single-electron transfer process with formation of free radicals. Under these circumstances, metabolism of nitrous oxide could produce toxic intermediates, even thought the end-metabolite is inert.