Late effects in children treated with intensive multimodal therapy for high-risk neuroblastoma: high incidence of endocrine and growth problems.

Due to the poor prognosis of high-risk (HR) neuroblastoma (NBL), scant data exist on late effects after treatment. Recently, protocols utilizing intense multimodal treatment have resulted in improved long-term survival. The objective of this study was to determine the prevalence of late effects in survivors of HR NBL. A retrospective review of clinical data for serial patients completing treatment between September 1994 and October 2007 and surviving for at least 1 year was performed. Therapy included aggressive chemotherapy, surgery, radiation and single or tandem SCT. Oncology follow-up was standard; clinical criteria were utilized for referrals to endocrinology and other services. Fifty-one eligible patients were identified. Median follow-up was 6.1 years (range 1.0-15.2). Height was significantly impacted (ΔZ-score -1.91 in those treated with TBI and -0.77 in those without). Pre-diabetes or diabetes, hypothyroidism and ovarian insufficiency were observed in 50, 59 and 75% of at-risk survivors, respectively. Hearing loss and dental issues were common. Nine patients had relapse of NBL; seven died of progressive disease. As there is a high prevalence of late effects in long-term survivors of HR NBL, close monitoring and further studies after treatment are indicated, and in particular after more modern, non-TBI regimens.

Non-invasive estimation of liver fibrosis in non-alcoholic fatty liver disease using the 13 C-caffeine breath test.

BACKGROUND AND AIM: Fibrotic progression in non-alcoholic fatty liver disease (NAFLD) is associated with impaired hepatic function. The (13) C-caffeine breath test (CBT) is a non-invasive, quantitative test of liver function. We sought to determine the utility of the CBT in detecting hepatic fibrosis in NAFLD. METHODS: The CBT was applied to 48 patients with NAFLD. CBT results were compared to clinical, biochemical and histological data. Twenty-four healthy subjects served as controls. RESULTS: Patients with simple steatosis had similar CBT values (2.28 ± 0.71 Δ‰ per 100 mg caffeine) to controls (2.31 ± 0.85, P = 1.0). However, CBT was significantly reduced in patients with non-alcoholic steatohepatitis (1.59 ± 0.65, P = 0.005) and cirrhosis (1.00 ± 0.73, P < 0.001). CBT significantly correlated with Brunt's fibrosis score (r = -0.49, P < 0.001) but not with steatosis (P = 0.23) or inflammation (P = 0.08). CBT also correlated with international normalized ratio (r = -0.61, P < 0.001), albumin (r = 0.37, P = 0.009), aspartate aminotransferase/alanine aminotransferase (r = -0.34, P = 0.018) and platelets (r = 0.31, P = 0.03). On multivariate analysis, age (odds ratio 1.12, 95% confidence interval 1.042-1.203, P = 0.002) and CBT (OR 0.264, 95% CI 0.084-0.822, P = 0.02) were independent predictors of significant fibrosis (F ≥ 2). CBT yielded an area under the receiver operating characteristic curve of 0.86 for the diagnosis of cirrhosis. CONCLUSIONS: The CBT reflects the extent of hepatic fibrosis in NAFLD and represents a non-invasive predictor of fibrosis severity in this condition.

Developing mechanisms for reporting compliance violations.

Both the Federal Sentencing Guidelines and the Office of Inspector General's (OIG) Compliance Program Guidance for Hospitals can assist healthcare organizations in establishing a reporting system that encourages employees to report wrongdoing. One mechanism that is commonly used is the telephone hot line. Other mechanisms that can be used in conjunction with a hot line include a drop box or post office box, written or oral reports to supervisors, an open-door policy on the part of compliance personnel, and employee exit interviews. However the reporting system is set up, it should ensure confidentiality and a policy of nonretaliation to encourage the participation of all employees. Having a sound reporting system in place will enable healthcare organizations to investigate any alleged instances of noncompliance and take corrective action before the Federal government becomes involved.

A multicenter trial of FK506 (tacrolimus) therapy in refractory acute renal allograft rejection. A report of the Tacrolimus Kidney Transplantation Rescue Study Group.

A multicenter trial was conducted to evaluate the efficacy and safety of tacrolimus in the treatment of refractory renal allograft rejection. Renal transplant recipients experiencing biopsy-proven recurrent acute allograft rejection were eligible if the current rejection episode was refractory to corticosteroids. A total of 73 patients were enrolled, of whom 59 (81%) had previously received at least one course of antilymphocyte antibody as rejection therapy. One-year follow-up was available in 93% of patients. Median time to tacrolimus rescue therapy was 75 days after transplantation (range, 18-1448 days). Therapeutic responses to tacrolimus included improvement in 78% of patients, stabilization in 11%, and progressive deterioration in 11%. The risk of experiencing progressive deterioration was related to the pretacrolimus serum creatinine level: serum creatinine < or = mg/dl, 3%; 3.1-5 mg/dl, 16% (P < 0.04); > 5 mg/dl, 23% (P < 0.02). Twelve-month (from the time of initiation of tacrolimus therapy) actuarial patient and graft survival rates were 93% and 75%. Graft loss occurred in 19 patients (25%) at a median time of 108 days. Fourteen episodes of recurrent rejection were diagnosed in 10 patients (14%), at a median time of 101 days. Eleven episodes of recurrent rejection were treated (three patients underwent transplant nephrectomy), with resolution achieved in nine patients. Antilymphocyte antibody therapy was not used to treat recurrent rejection. Serum creatinine values improved during tacrolimus therapy: median serum creatinine level before tacrolimus, 3.2 mg/dl; median at 1 year after tacrolimus, 1.8 mg/dl. Twelve infections were documented in 11 patients (15%), including cytomegalovirus infection in three patients (4%). Posttransplant lymphoproliferative disorder was diagnosed in a single patient. Tacrolimus whole blood levels averaged 15.0 +/- 9.9 ng/ml at day 7 of tacrolimus therapy and 9.4 +/- 5.1 ng/ml at 1 year, and were consistent among individual centers. Treatment outcome did not correlate with tacrolimus blood levels. The most commonly observed adverse events were neurological and gastrointestinal. Seventy-four percent of patients received tacrolimus for at least 1 year. Tacrolimus therapy was discontinued in 18% of patients for rejection (11% for progressive, unrelenting rejection, and 7% for recurrent rejection). Tacrolimus therapy was discontinued in 8% of patients due to adverse events. In conclusion, tacrolimus rescue therapy provides (1) prompt, effective reversal of refractory renal allograft rejection, (2) good long-term renal allograft function, (3) a low incidence of recurrent rejection, and (4) an acceptable safety profile in renal allograft recipients experiencing refractory rejection.

The advanced clinical skills program in medical interviewing: a block curriculum for residents in medicine.

OBJECTIVE: This study sought to demonstrate whether an intensive block curriculum would lead to learning of basic medical interviewing skills by first year residents in medicine. METHOD: Pairs of brief clinical interviews done before and after a four week block program in medical interviewing were rated using the Rhode Island Hospital Interview Checklist (RIC). The data were analyzed using the McNemar Test to look for possible improvement following the course. RESULTS: Of the nineteen categories measured, fourteen showed statistically significant improvement (p < .05) in Year 1 and twelve in Year 2. Combining the data for the two years gave statistically significant results in sixteen of the nineteen categories. CONCLUSIONS: An intensive block curriculum in medical interviewing led to a significant degree of learning of basic skills by first year medical residents as judged by interviews done at the end of the block. The intensive approach also allowed for a degree of personal growth and solidification of identity as a physician. These factors can be expected to influence interviewing proficiency as well.

Prevention and reversal of dopamine receptor supersensitivity by cyclo(leucyl-glycyl) (CLG): biphasic dose-response curves.

Chronic administration (21 days) of haloperidol (HAL) (IP, 1.0 mg/kg/day) induced a behavioral supersensitivity (stereotypic sniffing) to dopamine (DA) agonists (apomorphine) and upregulation (increased Bmax for sulpiride-inhibitable [3H]spiroperidol binding) of striatal and limbic D2 DA receptors (DAr). Coadministration of cyclo(leucyl-glycyl) (CLG; 8mg/kg, SC; every third day, every other day, but not every day) with HAL attenuated the behavioral supersensitivity. D2-DAr binding assays showed 1) that CLG-induced changes in Bmax parallel these behavioral changes and 2) that the biphasic CLG dose-response curve may involve CLG failure at high cumulative doses to lower Bmax. CLG also reversed an already established D2 DAr supersensitivity/upregulation (i.e., when CLG was injected daily for four days after the withdrawal of HAL). CLG alone did not alter behavior or binding. CLG's ability to both prevent and reverse D2 DAr upregulation/supersensitivity in animal models suggests that CLG may be useful, within a therapeutic window, in clinical disorders that are thought to involve upregulated DAr (e.g., tardive dyskinesia, L-DOPA-induced dyskinesias, and schizophrenia).

Fluorodeoxyuridine with continuous leucovorin infusion. A phase II clinical trial in patients with metastatic colorectal cancer.

BACKGROUND: Chemotherapy of colon cancer has used the modulation of 5-fluorouracil (5-FU) by leucovorin; however, early studies indicate that leucovorin with fluorodeoxyuridine (FUDR) may be clinically superior. The authors report their experience in patients with metastatic colorectal cancer. METHODS: One hundred twelve evaluable patients with metastatic colorectal cancer were treated with leucovorin and FUDR. Leucovorin was given by continuous intravenous infusion at 500 mg/m2/day on days 1-6, and FUDR was given by intravenous push on days 2-6 at 3:00 p.m. daily, with doses ranging from 270-1350 mg/m2/day. RESULTS: This regimen was well tolerated with dose-limiting toxicity of diarrhea and stomatitis, while hematologic toxicity was minimal. At least one chemotherapy regimen had previously failed in 90 of 112 patients (80%). Twenty major responses greater than or equal to partial remission, lasting from 2-40+ months, were observed in this patient population for an overall response rate of 18%. Twelve of 22 previously untreated patients (55%) had major responses. Overall survival of previously untreated patients was 73% (14 of 19) and 50% (11 of 22) at 1 and 2 years, respectively. Of 66 patients who had received prior leucovorin-5-FU (LVFU) therapy with subsequent disease progression, 4 had major responses lasting 95, 241, 350, and 432 days, respectively. CONCLUSIONS: These data suggest that the modulation of FUDR by leucovorin may have clinical use. The recommended starting dose of FUDR is 800 mg/m2/day on days 2-6, with subsequent escalation each month in those patients who do not display stomatitis.

Staff distress among haemophilia nurses.

To investigate the severity, sources, and means used to cope with the distress experienced by haemophilia nurses as a result of the widespread infection with Human Immunodeficiency Virus among haemophiliacs, we collected anonymous questionnaire data from all nurses in the Haemophilia Nursing Network Directory, compiled by the National Haemophilia Foundation in June, 1990. Questionnaires were returned by 136 of the 181 (75%) nurses in the sample. Over 50% of the sample gave distress responses to 15 of 44 statements. Areas associated with the greatest distress were: (1) Failure of patients to take steps to prevent transmission of HIV; (2) Fear of getting infected, and (3) the repeated loss experienced as patients died from infection. Nurses working with haemophiliacs for 11-15 years were particularly vulnerable to feelings of guilt for having participated in the treatment that resulted in HIV infection. Fear of contagion and distress from patient deaths were mutually exclusive ways of reacting to HIV in haemophiliacs. Looking for a new job was related to all major sources of distress. Interaction with peers was perceived as being the most useful source of emotional support.

Chronic ethanol feeding produces a muscarinic receptor upregulation, but not a muscarinic supersensitivity in lower esophageal sphincter muscle.

Muscarinic acetylcholine receptors (mAChR) are important in esophageal physiology, and mAChR alterations may be involved in ethanol-induced esophageal dysfunction. We previously demonstrated that acute ethanol decreases lower esophageal sphincter pressure (LESP), whereas withdrawal from chronic ethanol results in pressure increases which are reversible by acute ethanol. To see if this increase in LESP is due to upregulation of mAChR, we evaluated both mAChR binding and dose-response curves for bethanechol and atropine-induced changes in LESP before and after acute and chronic ethanol exposure. The number of mAChR sites (Bmax) in LES (3.4 fmol/mg tissue) was lowered by acute ethanol (1.72, -50%); withdrawal from chronic ethanol raised Bmax (5.2, +54%). Acute injection of ethanol into cats in withdrawal reversed this increase in mAChR density (3.1, -10%). These changes correlated with our earlier data on ethanol-induced changes in LESP. However, the dose-response curve for bethanechol-induced pressure increases shifted to the right [ED25 (micrograms/kg); control, 8.6; withdrawal, 21.3], paralleled by an increase in the number of low-affinity agonist binding sites. Thus, 1) the withdrawal-associated increase in Bmax (up-regulation) is more likely to be a compensatory response to deficits (functional subsensitivity) distal to the receptor recognition site than to proximal deficits; 2) the increase in Bmax does not cause LESP hyperactivity; and 3) receptor binding changes do not necessarily translate into physiological changes.

Long-lasting dopamine receptor up-regulation in amphetamine-treated rats following amphetamine neurotoxicity.

Amphetamine (A) (9.2 mg/kg, IP), in combination with iprindole (I) (10.0 mg/kg, IP), caused long-lasting dopamine (DA) depletions in striatum (-49%, 4 weeks) but not in nucleus accumbens following one A/I injection. Striatal DA had recovered by 4 months. DA receptors (DAr) were up-regulated: 1) behavioral responses to a DA receptor agonist (apomorphine) were significantly elevated. These included apomorphine-induced locomotor activity (+103% and +160%, on weeks 3 and 10) and apomorphine-induced stereotypy (day 10). 2) Bmax for [3H]spiroperidol binding to striatal D2 DAr (12 weeks) increased (+53%, week 12). Injection of the DAr neuromodulator cyclo(leucyl-glycyl) (8 mg/kg/day x 4 days, SC) reversed the Bmax increase. Thus toxicity (DA depletion) following high-dose amphetamine appears to induce compensatory changes in DAr. This DAr upregulation may explain the lack of abnormal movements despite enduring DA depletion. Additionally, the A/I paradigm as an animal model of long-lasting DAr up-regulation, could be used to screen neuromodulatory agents, like CLG, that might treat disorders (e.g., tardive dyskinesia and schizophrenia) thought to involve up-regulated DAr.

Neurochemical basis for the absence of overt "stereotyped" behaviors in rats with up-regulated striatal D2 dopamine receptors.

Because of substantial evidence for the hyperdopaminergic hypothesis of tardive dyskinesia (TD), animal models, especially rats, treated chronically with neuroleptics continue to be used to study this disorder. The rat model has been criticized because, unlike TD, in rats there is an apparent lack of spontaneous abnormal movements even when striatal D2 dopamine receptor (DAr) density is substantially increased. Our data suggest a mechanism by which rats suppress these abnormal movements normally associated with elevated DAr levels. We correlated neurochemical with behavioral changes using several animal models, including nonneuroleptic ones, which elicit varied levels of DAr upregulation. There was (as expected) a robust, significant, positive correlation between striatal DAr density and apomorphine-induced stereotypic behaviors. In contrast, there was a significant negative correlation between increased DAr density and synthesis capacity for striatal DA (Vmax for tyrosine hydroxylase). We conclude that this decrease in Vmax is a compensatory adjustment of the nigrostriatal DA tract for the increased DAr density induced in our animal models. Our data further suggest the generalization that an observed increase in receptor density doesn't necessarily predict a functional change (spontaneous behavior, neuropathology) because compensatory neural mechanisms exist. In TD these compensatory neural mechanisms may fail, leading to spontaneous behaviors.

Permanent haloperidol-induced dopamine receptor up-regulation in the ovariectomized rat.

One of the confounding problems associated with the study of tardive dyskinesia in rodent models has been the inability to produce a permanent supersensitivity to dopamine (DA) following neuroleptic drugs. We recently observed that ovariectomy (OVX) results in a permanent dopamine receptor (DA-R) up-regulation in the striatum of the rat. This permanent up-regulation of striatal D2 DA-R required three months to fully develop and lasted for at least 12 months post-OVX. In the present study we further characterized this model by examining the development of both apomorphine-induced stereotypy and D2 DA-R density in the striatum of OVX and Sham-operated rats following haloperidol (16 days at 1.0 mg/kg/day, IP). Following the chronic haloperidol treatment, both the OVX and the Sham-operated animals increased both their behavioral responses (stereotypic sniffing) to apomorphine, and the density of striatal D2 DA-R. However, by 30 days posthaloperidol, the Sham animals had reverted to normal behavioral responses to apomorphine and normal levels of striatal DA-R, while both the behavioral responses and the density of D2 DA-R in the OVX animals treated with haloperidol remained up-regulated. These data indicate that 1) the time required to develop this unique animal model of a permanent DA-R up-regulation in the ovariectomized (OVX) rat can be considerably shortened; 2) there is probably a unique neurochemical change induced by haloperidol in the OVX but not in Sham rats that leads to the DA-R up-regulation becoming permanent.

Phase I clinical trial with floxuridine and high-dose continuous infusion of leucovorin calcium.

Sixty-two patients with metastatic disease were treated with continuous infusion folinic acid (leucovorin calcium; Lv) and 2-deoxy-5-fluorouridine (floxuridine; FUDR). Lv was given by constant intravenous (IV) infusion at 500 mg/m2/d, days 1 to 6, while FUDR was given by IV push, days 2 to 6, at 3:00 PM daily with doses ranging from 294 to 1,214 mg/m2/d. This program was well tolerated with dose-limiting toxicities of diarrhea and stomatitis, while hematologic toxicity was minimal. Eighty-two percent of the assessable patients (46 of 56) had failed at least one chemotherapy regimen. One complete remission lasting 9 months and 10 partial remissions ranging from 5 to 10 months were observed in this heavily pretreated patient population for an overall response rate of 20%. These data suggest that the combination therapy with Lv and FUDR may have clinical use. Because of differing patient sensitivity to this drug combination, the recommended dose of FUDR for the initial therapy cycle is 500 mg/m2/d, days 2 to 6, with subsequent escalation to 900 mg/m2/d in those patients without extreme sensitivity. Phase II studies are now in progress with these doses.

The effects of cyclo(leucyl-glycyl) on nigrostriatal dopaminergic supersensitivity--inhibition of apomorphine-induced climbing.

In a previous study we showed that cyclo(leu-gly) (CLG) prevents the behavioural supersensitivity induced in the mesolimbic dopamine (DA) tract (in mice) by chronic haloperidol (HAL). In the current study, we evaluated the effects of CLG on supersensitivity to DA agonists in the nigrostriatal DA tract induced by chronic HAL (1.0 mg/kg, i.p. x 21 days--Experiment 1) or by acute injection of a high dose of apomorphine (APO) (Experiment 2). In Experiment 1 CLG was given at doses of either (a) 0 mg/kg/day (b) 1 mg/kg every third day (30 minutes prior to HAL), (c) 1 mg/kg every day, or (d) 8 mg/kg every third day. In Experiment 2 the dose of CLG was 8 mg/kg, s.c., given 24h after APO. Co-administration of CLG with HAL attenuated the development of HAL-induced supersensitivity in both paradigms (b) and (c) above, although the attenuation was significantly greater in (c) compared to (b). This biphasic dose response (D-R) curve for CLG in Experiment 1 indicates that a therapeutic window exists for CLG (bell-shaped D-R curve) and is similar to previous curves for CLG effects on the mesolimbic DA tract. In Experiment 2, CLG attenuated the DA receptor supersensitivity caused by acute high dose APO. The capacity of CLG to down-regulate DA receptors and attenuate dopaminergic supersensitivity in these experiments suggests a potential therapeutic use in the prevention of tardive and/or L-dopa-induced dyskinesias.

Role of reactive oxygen metabolites in experimental colitis.

Reactive oxygen metabolites are potent inflammatory mediators that may be involved in tissue injury in inflammatory bowel disease. To evaluate their role in inflammatory bowel disease, we investigated the effects of lowering the activities of reactive oxygen metabolites in experimental colitis induced by intracolonic administration of acetic acid in rats. Intracolonic administration of 5% acetic acid caused severe inflammation (mean (SEM) inflammatory score was 24.3 (0.7) of a maximum score of 32). Acetic acid at 2.5% produced moderate inflammation (score = 17 (1.4) v 4.0 (0.5) in control rats). This lower dose was used for subsequent experiments. Specific superoxide anion scavenger methoxypolyethylene glycol:superoxide dismutase, and reactive oxygen metabolites scavenger, sulfasalazine, significantly decreased the severity of inflammation (scores: 8 (4.4) and 9.8 (2.2) respectively). The xanthine oxidase inhibitors, tungsten and pterin aldehyde, failed to improve inflammation but another xanthine oxidase inhibitor, allopurinol, a compound with known superoxide anion scavenging effect, did limit the inflammation (10(2)). Inhibition of hydroxyl radical production by deferoxamine or lowering hydroxyl radical values by a scavenger, dimethyl sulfoxide, did not affect the severity of inflammation. These data suggest: (1) that reactive oxygen metabolites play an important role in experimental colitis, (2) that the xanthine oxidase pathway is not a major source of reactive oxygen metabolites in colitis, and (3) that tissue injury in experimental colitis is not caused by generation of hydroxyl radicals.

Canine gastric muscarinic receptors up-regulate after vagotomy.

Postvagotomy (PV) gastroparesis is an infrequent but troublesome problem. To test the hypothesis that the rarity of the PV syndrome is due to compensatory up-regulation of muscarinic cholinergic receptors (mAChR), we measured changes in stomach mAChR and gastric acid secretion in dogs before and three weeks after truncal vagotomy. Maximum acid output dropped significantly one week PV and then partially recovered by three weeks PV. mAChR density changed in parallel and was significantly increased in body mucosa, body muscle, and antrum mucosa. In the body, changes in mAChR in mucosa correlated positively with changes in muscle, suggesting that mAChR binding in pinch biopsies of gastric mucosa might become useful in evaluating patients for postvagotomy syndrome. PV up-regulation of mAChR in the mucosa of the canine gastric body might explain PV recovery of gastric acid secretion.

MPTP-induced duodenal ulcers in rat. Prevention by reuptake blockers for serotonin and norepinephrine, but not dopamine.

Abnormal activity of dopamine, serotonin, and norepinephrine may contribute to the pathophysiology of duodenal ulcers. We therefore studied the effects of neuropharmacological manipulations on 1-methly-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP)-induced duodenal ulcers. Duodenal ulcers were produced in rats by 12 subcutaneous injections of a neurotoxin, MPTP, over 4 days. At an MPTP dose of 20 mg.kg. injection, duodenal ulcers developed in 91% (43 of 47) of animals with low mortality. When neuropharmacological agents were preadministered before MPTP, the following effects on duodenal ulcers incidence were obtained. MAO-B inhibitors (pargyline [55%], deprenyl [43%]) but not MAO-A inhibitors (clorgyline [91%]) significantly decreased the frequency of duodenal ulcers suggesting that, like MPTP-induced parkinsonism, formation of a toxic metabolite, probably 1-methyl-4-phenyl-pyridinium is involved. Reuptake blockers for serotonin (fluoxetine [18%], indalpine [25%]) also decreased the frequency of duodenal ulcers. Reuptake blockers for norepinephrine (desmethylimipramine [17%], tomoxepine [31%], but not amfonelic acid [82%]) decreased the frequency of duodenal ulcers. Reuptake blockers for dopamine (benztropine [73%], amfonelic acid [82%], GBR-12909 [80%]) did not protect against duodenal ulcers. However, GBR-12909 significantly decreased the severity of those duodenal ulcers that were produced. These data suggest that abnormally low levels of synaptic transmission in serotonergic and possibly noradrenergic neurons play an important role in the pathogenesis of duodenal ulcer while the role of dopamine may be limited to modulation of ulcer severity.