Does labelling a rare cancer diagnosis 'good' affect the patient's experience of treatment and recovery?

Doctors sometimes tell patients with rare but highly treatable cancers that they have 'good' cancer which some patients have found unhelpful, but this has been little explored. The aim of this study was to explore how patients reacted to being told they had a 'good' cancer. Qualitative interviews were carried out with 25 people with rare but prognostically favourable cancers who had received treatment at two hospitals within a cancer network. Results showed that despite good treatment outcomes, patients are still very shocked to hear the word cancer and react in similar ways to those with other forms of cancer. The potential effects of treatment should be recognised as having a detrimental effect on patient well-being whatever the prognosis. We should therefore avoid using 'good' and 'cancer' in the same sentence. In addition, the impact on all family members should not be underestimated. The data can be used to improve clinical practice and improve support for people affected by cancer.

The early-onset torsion dystonia gene (DYT1) encodes an ATP-binding protein.

Early-onset torsion dystonia is a movement disorder, characterized by twisting muscle contractures, that begins in childhood. Symptoms are believed to result from altered neuronal communication in the basal ganglia. This study identifies the DYT1 gene on human chromosome 9q34 as being responsible for this dominant disease. Almost all cases of early-onset dystonia have a unique 3-bp deletion that appears to have arisen idependently in different ethnic populations. This deletion results in loss of one of a pair of glutamic-acid residues in a conserved region of a novel ATP-binding protein, termed torsinA. This protein has homologues in nematode, rat, mouse and humans, with some resemblance to the family of heat-shock proteins and Clp proteases.

TorsinB expression in the developing human brain.

Familial, early onset, generalized torsion dystonia is the most common and severe primary dystonia. The majority of cases are caused by a 3-bp deletion (GAG) in the coding region of the DYT1 (TOR1A) gene. The cellular and regional distribution of torsinA protein, which is restricted to neuronal cells and present in all brain regions by the age of 2 months has been described recently in human developing brain. TorsinB is a member of the same family of proteins and is highly homologous with its gene adjacent to that for torsinA on chromosome 9q34. TorsinA and torsinB share several remarkable features suggesting that they may interact in vivo. This study examined the expression of torsinB in the human brain of fetuses, infants and children up to 7 years of age. Our results indicate that torsinB protein expression is temporarily and spatially regulated in a similar fashion as torsinA. Expression of torsinB protein was detectable beginning at four to 8 weeks of age in the cerebellum (Purkinje cells), substantia nigra (dopaminergic neurons), hippocampus and basal ganglia and was predominantly restricted to neuronal cells. In contrast to torsinA, torsinB immunoreactivity was found more readily in the nuclear envelope. High levels of torsinB protein were maintained throughout infancy, childhood and adulthood suggesting that torsinB is also needed for developmental events occurring in the early postnatal phase and is necessary for functional activity throughout life.

Phase I and pharmacokinetic study of the novel MDR1 and MRP1 inhibitor biricodar administered alone and in combination with doxorubicin.

PURPOSE: To evaluate the safety, tolerability, and pharmacokinetics of biricodar (VX-710), an inhibitor of P-glycoprotein (P-gp) and multidrug resistance-associated protein (MRP1), alone and with doxorubicin in patients with advanced malignancies. The effect of VX-710 on the tissue distribution of (99m)Tc-sestamibi, a P-gp and MRP1 substrate, was also evaluated. PATIENTS AND METHODS: Patients with solid malignancies refractory to standard therapy first received a 96-hour infusion of VX-710 alone at 20 to 160 mg/m(2)/h. After a 3-day washout, a second infusion of VX-710 was begun, on the second day of which doxorubicin 45 mg/m(2) was administered. Cycles were repeated every 21 to 28 days. (99m)Tc-sestamibi scans were performed before and during administration of VX-710 alone. RESULTS: Of the 28 patients who enrolled, 25 patients were eligible for analysis. No dose-limiting toxicity (DLT) was observed in the nine assessable patients who received 120 mg/m(2)/h or less. Among seven patients receiving VX-710 160 mg/m(2)/h, two DLTs were seen: reversible CNS toxicity and febrile neutropenia. All other adverse events were mild to moderate and reversible. Plasma concentrations of VX-710 in patients who received at 120 and 160 mg/m(2)/h were two- to fourfold higher than concentrations required to fully reverse drug resistance in vitro. VX-710 exhibited linear pharmacokinetics with a harmonic mean half-life of 1.1 hours. VX-710 enhanced hepatic uptake and retention of (99m)Tc-sestamibi in all patients. CONCLUSION: A 96-hour infusion of VX-710 at 120 mg/m(2)/h plus doxorubicin 45 mg/m(2) has acceptable toxicity in patients with refractory malignancies. The safety and pharmacokinetics of VX-710 plus doxorubicin warrant efficacy trials in malignancies expressing P-gp and/or MRP1.

Electrophysiologic testing in patients with unexplained syncope: clinical and noninvasive predictors of outcome.

To assess whether the level of risk of having significant electrophysiologic abnormalities can be determined, 29 clinical variables were analyzed in 104 patients with unexplained syncope who underwent electrophysiologic testing. A positive electrophysiologic study was defined as: a sinus node recovery time greater than or equal to 3 seconds; HV interval greater than or equal to 100 ms; infranodal block during atrial pacing; unimorphic ventricular tachycardia; and supraventricular tachycardia associated with hypotension. Thirty-one patients had a positive study, with inducible ventricular tachycardia being the most common finding (71% of positive studies). A left ventricular ejection fraction less than or equal to 0.40 was the most powerful predictor of a positive electrophysiologic study (p less than 0.00001), followed by the presence of bundle branch block (p less than 0.00003), coronary artery disease (p less than 0.0003), remote myocardial infarction (p less than 0.00006), use of type 1 antiarrhythmic drugs (p less than 0.00003), injury related to loss of consciousness (p less than 0.01) and male sex (p less than 0.01). A negative electrophysiologic study was associated with an ejection fraction greater than 0.40 (p less than 0.00001), the absence of structural heart disease (p less than 0.00001), a normal electrocardiogram (ECG) (p less than 0.0001) and normal ambulatory ECG monitoring (p less than 0.0001). The probability of a negative study increased as the number and duration of syncopal episodes increased.(ABSTRACT TRUNCATED AT 250 WORDS)

TorsinA expression is detectable in human infants as young as 4 weeks old.

Familial, early onset, generalized torsion dystonia is the most common and severe primary dystonia. The majority of cases are caused by a 3-bp deletion (GAG) in the coding region of the DYT1 (TOR1A) gene. The cellular and regional distribution of torsinA protein and its message has been described previously in several regions of normal adult human and rodent brain. This study examines the expression of torsinA in the developing human brain of fetuses, infants and children up to 7 years of age in four selected brain regions. Expression of torsinA protein was detectable beginning at 4 to 8 weeks of age postnatally in the cerebellum (Purkinje cells), substantia nigra (dopaminergic neurons), hippocampus and basal ganglia. Prominent torsinA immunoreactivity was not seen before 6 weeks of age postnatally, a period associated with synaptic remodeling, process elimination and the beginning of myelination. Our results indicate that torsinA protein expression is temporally and spatially regulated and is present in all brain regions studied by the age of 2 months on into adulthood.

Effect of nebulized albuterol on blood glucose in patients with diabetes mellitus with and without cystic fibrosis.

Over 90% of cystic fibrosis (CF) patients are treated with bronchodilators, and 6% have diabetes. Some with asthma also have diabetes, and most are treated with bronchodilators. Systemic administration of adrenergic agents can cause increases in blood glucose, but the effect of inhaled agents is unclear. A double-blind study was performed on 10 patients with type 1 diabetes mellitus (DM) without CF (3 male, 7 female, mean age 25.5 years) and 9 patients with insulin-dependent CF-related diabetes (CFRD) (8 male, 1 female, mean age 21.9 years). On 2 separate days before 9 AM fasting and the morning dose of insulin, 2.5 mg of albuterol or nebulized placebo were given. Blood glucose was measured by finger stick with a glucose reflectance meter before and 15, 30, 45, and 60 min after treatment. No significant changes from baseline or differences between placebo and albuterol occurred in either group. The mean maximum increase from baseline in DM was 20 mg/dl on placebo, and 38 mg/dl on albuterol; in the CFRD, the respective changes were 7 and 7 mg/dl. Two DM patients had a > 50 mg/dl increase on albuterol vs. placebo; no CFRD patients had differences of such magnitude. DM patients had greater increases from baseline than CFRD patients on placebo and albuterol. Differences reached statistical significance at 30 and 45 min on placebo, and 45 min on albuterol. Albuterol 2.5 mg by nebulizer causes no clinically significant increases in blood glucose in DM or CFRD patients. Diabetes patients without CF have a significantly greater increase of glucose with time (placebo or albuterol) than CFRD patients.

Growth and maturation of children with insulin-dependent diabetes mellitus.

The purpose of this paper is to define criteria used for classifying patients into varying degrees of diabetic control and to verify that children with diabetes maintained in higher degrees of metabolic control do not have delayed growth and maturation. Growth records of 252 children with insulin-dependent diabetes who have been under continuous observation in our clinic at three- to five-month intervals for at least three years and up to 16 years have been individually reviewed and analyzed. All children received two daily injections of a mixture of two parts of an intermediate to one part of regular insulin and were instructed to eat structured meals of high-quality selected foods. An over-all rating for diabetic control based primarily on the frequency and degree of glycosuria was made for the time period between clinic visits. The over-all diabetic control rating and the size of the subgroups were "good"--20 per cent, "fair to good"--64 per cent, and "fair"--16 per cent. All children maintained in "good" and "fair to good" control (84 per cent), grew and matured at a normal rate regardless of the age at onset or duration of diabetes. All children in lower degrees of control coming under care for greater than 24 months after diagnosis had accelerated growth during the early months after attaining a higher degree of control.

Hemoglobin A1c levels in children and adolescents with diabetes mellitus.

Hemoglobin A1c (HbA1c) was measured as an indicator of glucose control in 180 children and adolescents with diabetes mellitus who received two daily injections of insulin as part of a highly structured treatment program. A total of 426 HbA1c determinations was made in the group of 180 patients. HbA1c values were elevated in most patients despite the aggressive treatment. The HbA1c level was very elevated at diagnosis, fell to near normal after 60-90 days of insulin therapy, increased gradually, and reached a plateau after approximately 4 yr duration (at about twice the level in normal subjects) (mean +/- SEM, 10.0 +/- 0.2% and 5.34 +/- 0.07%, respectively). Mean insulin dose (U/kg/24 h) paralleled both HbA1c and duration of diabetes. The relationship between endogenous insulin secretion and glucose control was examined in those patients with diabetes for longer than 5 yr. Patients were separated into three groups based on HbA1c levels: those with HbA1c less than 9% (N = 22), between 9 and 11% (N = 26), and greater than 11% (N = 28). Serum C-peptide and glucose concentrations were measured 2 h after a standard breakfast in those patients in the "low" and "high" HbA1c groups (mean HbA1c values 8.2% and 12.7%, respectively). C-peptide was detectable in all patients and the mean C-peptide levels did not differ significantly in the two groups, although postprandial glucose concentrations were significantly lower in the "low" HbA1c group (means +/- SEM, 96 +/- 11 and 211 +/- 21 mg/dl, respectively; P less than 0.001).

Jugular Venous Flow Abnormalities in Multiple Sclerosis Patients Compared to Normal Controls.

BACKGROUND: To determine if extracranial venous structural and flow abnormalities exist in patients with multiple sclerosis (MS). METHODS: Magnetic resonance imaging was used to assess the anatomy and function of major veins in the neck in 138 MS patients and 67 healthy controls (HC). Time-of-flight MR angiography (MRA) was used to assess stenosis while 2-dimensional phase-contrast flow quantification was used to assess flow at the C2/C3 and C5/C6 levels. Venous flow was normalized to the total arterial flow. The MS patients were divided into stenotic (ST) and nonstenotic (NST) groups based on MRA assessment, and each group was compared to the HC group in anatomy and flow. RESULTS: The MS group showed lower normalized internal jugular vein (IJV) blood flow (tIJV/tA) than the HC group (P < .001). In the MS group, 72 (52%) were classified as ST while 66 (48%) were NST. In the HC group, 11 (23%) were ST while 37 (77%) were NST. The ST-MS group had lower IJV flow than both HC and NST-MS groups. CONCLUSION: After categorizing the MS population into two groups based upon anatomical stenosis, as determined from an absolute quantification of IJV cross section, clear differences in IJV flow between the ST-MS and HC samples became evident. Despite the unknown etiology of MS, abnormal venous flow was noted in a distinct group of MS patients compared to HC.

Functional coexpression of HSV-1 thymidine kinase and green fluorescent protein: implications for noninvasive imaging of transgene expression.

Current gene therapy technology is limited by the paucity of methodology for determining the location and magnitude of therapeutic transgene expression in vivo. We describe and validate a paradigm for monitoring therapeutic transgene expression by noninvasive imaging of the herpes simplex virus type 1 thymidine kinase (HSV-1-tk) marker gene expression. To test proportional coexpression of therapeutic and marker genes, a model fusion gene comprising green fluorescent protein (gfp) and HSV-1-tk genes was generated (tkgfp gene) and assessed for the functional coexpression of the gene product, TKGFP fusion protein, in rat 9L gliosarcoma, RG2 glioma, and W256 carcinoma cells. Analysis of the TKGFP protein demonstrated that it can serve as a therapeutic gene by rendering tkgfp transduced cells sensitive to ganciclovir or as a screening marker useful for identifying transduced cells by fluorescence microscopy or fluorescence-activated cell sorting (FACS). TK and GFP activities in the TKGFP fusion protein were similar to corresponding wild-type proteins and accumulation of the HSV-1-tk-specific radiolabeled substrate, 2'-fluoro-2'-deoxy-1beta-D-arabinofuranosyl-5-iodo-uracil (FIAU), in stability transduced clones correlated with gfp-fluorescence intensity over a wide range of expression levels. The tkgfp fusion gene itself may be useful in developing novel cancer gene therapy approaches. Valuable information about the efficiency of gene transfer and expression could be obtained by non-invasive imaging of tkgfp expression with FIAU and clinical imaging devices (gamma camera, positron-emission tomography [PET], single photon emission computed tomography [SPECT]), and/or direct visualization of gfp expression in situ by fluorescence microscopy or endoscopy.

Pharmacogenetic characteristics of the eosinophilia-myalgia syndrome.

This study tested the hypothesis that patterns of xenobiotic metabolism in patients with eosinophilia-myalgia syndrome (EMS) differed from healthy control subjects. We determined the genotypes of 27 EMS patients with EMS and 114 control subjects for the cytochrome P450 CYP2D6 polymorphism. The metabolic phenotypes of patients with EMS for S-mephenytoin hydroxylation (n = 17) and dapsone acetylation (n = 19) were determined and compared with 29 healthy control subjects. The incidence of the CYP2D6 poor metabolizer genotype (mutant/mutant) was 0.185 in patients with EMS and 0.061 in control subjects (Mantel-Haenszel, chi 2 = 7.213, p = 0.007). The mephenytoin S/R ratios were 0.39 +/- 0.23 in patients with EMS versus 0.18 +/- 0.13 in control subjects (p < or = 0.005). There was no difference in dapsone acetylation between the two groups. A pattern of xenobiotic metabolism may play a role in the pathogenesis of EMS, but the precise role that it plays remains unclear.

The hydroxylation of omeprazole correlates with S-mephenytoin metabolism: a population study.

We compared omeprazole and mephenytoin as probes for the CYP2C19 metabolic polymorphism. Single oral doses of omeprazole (20 mg) or mephenytoin (100 mg) were administered at least 1 week apart to 167 healthy volunteers. Mephenytoin metabolism was measured using the amount of 4'-hydroxymephenytoin and the S/R ratio of mephenytoin in an 8-hour urine collection. Omeprazole hydroxylation was measured using the ratio of omeprazole to 5'-hydroxyomeprazole in serum 2 hours after dosing. All three methods separated poor- or extensive-metabolizer phenotypes with complete concordance. Omeprazole hydroxylation correlated with the S/R ratio of mephenytoin in extensive metabolizers (r2 = 0.681; p < 0.001). Genotyping tests showed that six poor metabolizers of omeprazole were homozygous for a single base pair mutation in exon 5 of CYP2C19. These results support the hypothesis that omeprazole 5'-hydroxylation cosegregates with the CYP2C19 metabolic polymorphism.

Vitamin A status of preterm infants: correlation between plasma retinol concentration and retinol dose response.

Retinol dose response tests were performed on 83 preterm infants shortly before discharge by giving orally 5000 IU of an aqueous dispersion of retinol. Predose plasma retinol concentrations were 2.5-20.5 micrograms/dL (0.087-0.72 mumol/L) and the retinol dose responses were 0-59.8%. The regression of retinol dose response on predose retinol was -0.58. There was a parallel increase in both retinol and retinol-binding protein and an increase in the molar ratio of retinol-binding protein to prealbumin. Prealbumin did not increase. These findings suggest that preterm infants have reduced liver stores of vitamin A.

Vitamin A status of preterm infants: the influence of feeding and vitamin supplements.

Consecutive weekly determinations of plasma retinol, alpha-tocopherol, retinol-binding protein, prealbumin, and zinc were performed on a group of 58 infants weighing less than 2000 g at birth in an intensive-care nursery. Data were classified by the feeding regimen of the preceding week: parenteral, premature formula, or own mother's milk. Mean plasma-retinol values were less than 20 mcg/dl, the lower limit of normal for adults, with the highest values in the formula-fed group. Retinol-binding protein and prealbumin values were lowest in the parenterally-fed group. Alpha-tocopherol concentrations were consistently maintained at levels higher than 500 mcg/dl only in infants fed their own mother's milk. Mean zinc concentrations above 70 mcg/dl, the lower limit of normal for adults, occurred only in parenterally fed infants. Doubling the recommended vitamin supplement in formula-fed infants did not produce a significant increase in plasma retinol or tocopherol.

Inducible nitric oxide synthase expression in cultures enriched for mature oligodendrocytes is due to microglia

Hewett JA, Hewett SJ, Winkler S, Pfeiffer SE. 1999. Inducible nitric oxide synthase expression in cultures enriched for mature oligodendrocytes is due to microglia. J Neurosci Res 56:189-198. In the article referenced above, the LPS concentration employed in all studies was 1 &mgr;g/ml, not 1 mg/ml as published. This correction appears: in the Materials and Methods section on page 190, column 1, line 47; in the Results section on page 191, column 2, legend to Figure 1, line 3; on page 192, column 2, legend to Figure 2, line 3; on page 194, column 2, legend to Figure 5, line 4; on page 195, column 1, legend to Figure 6, line 3; and in the Discussion section on page 196, column 1, line 9. The publisher regrets this error.

Clinical and clinicopathologic effects of samarium-153-EDTMP administered intravenously to normal beagle dogs.

A study was undertaken to determine the degree of acute bone marrow and vital organs injury sustained when dogs were administered doses of 153Sm-EDTMP calculated to irradiate an acute bone lesion arising from cancer metastasis to a dose considered palliative or even therapeutic (20-160 Gy). The study revealed significant (p less than 0.05) temporary depression of the bone marrow in all doses in the therapeutic (greater than 40 Gy) range. Palliative (20 Gy) doses caused significant leukocyte depression but insignificant (p greater than 0.05) depression of platelet and packed cell volumes when compared to control animals. A mild transient rise in the levels of serum alkaline phosphatase occurred immediately following radioisotope administration. All hematologic parameters had returned to normal by six weeks after the last injection of radioisotope. The study indicates potential for this compound as a safe, therapeutic radiopharmaceutical for treatment of cancer bone metastasis.

Physical fitness and work capacity in women with rheumatoid arthritis.

OBJECTIVE: To investigate physical fitness and work capacity in women with rheumatoid arthritis (RA). METHODS: The 42 subjects were a subset of a prospective trial of conditioning exercise in rheumatic disease. Assignment to an exercise or nonexercise group was determined by proximity to the intervention, a 3-month supervised group exercise program. Physical fitness and work capacity were assessed at baseline, 3 months, and 12 months. RESULTS: At baseline, subjects were deconditioned and limited in hand function, lifting ability, and lower extremity mobility. Only the exercise group improved their aerobic capacity and exercise tolerance. There were no significant changes in measured work capacity in either group. Moderate to strong correlations were found between aerobic capacity, mobility, hand function, and work capacity. Grip strength was a strong and consistent correlate of work capacity. CONCLUSION: Our findings suggest that physical capacity, particularly hand function, may be important in the complex phenomenon of work disability in RA.

Multivariate outcome research in arthritis. Implications for sample sizes.

Planning appropriate sample sizes prior to data collection is critical to the overall success of a research project. However, the investigator often encounters practical limitations regarding the number of subjects available. While the literature discusses the various options of analysis of clinical trial data, there is little discussion as to the sample size implications of the statistical method chosen. Since the analysis technique employed affects the required sample size, the investigator should select the analysis that is most appropriate for the data and has the most efficient sample size requirement. This paper addresses the sample size implications of three commonly used methods for comparing two populations when there are two or more outcome measures (multivariate outcome). The concepts and methods are illustrated using a Pain Management Study that was conducted using people with rheumatoid arthritis as subjects.

Self-efficacy, pain, and physical activity among fibromyalgia subjects.

PURPOSE: The purpose of this study was to examine the effects of self-efficacy on self-report pain and physical activities among subjects with fibromyalgia (FM). In addition, descriptive statistics of the Arthritis Impact Measurement Scale (AIMS), a measure developed for use with arthritis patients, were reported. METHODS: Seventy-nine subjects with FM, as classified by the American College of Rheumatology (ACR) criteria, completed the Visual Analogue Scale for Pain, the AIMS, and the Arthritis Self-Efficacy Scale. A myalgic score was obtained during a tender point evaluation. Hierarchical multiple regression analyses were used to assess the effect of self-efficacy on self-report pain and physical activities measures after controlling for demographic variables (age, education, and symptom duration), disease severity (myalgic scores), and psychological distress (negative affect from the AIMS). RESULTS: Higher self-efficacy was associated with less pain and less impairment on the physical activities measure after controlling for demographic and disease severity measures. CONCLUSIONS: This study underscores the unique importance of self-efficacy in understanding pain and physical activities impairment.