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PubMed2006

Hyperfractionated or accelerated radiotherapy in head and neck cancer: a meta-analysis.

BACKGROUND: Several trials have studied the role of unconventional fractionated radiotherapy in head and neck squamous cell carcinoma, but the effect of such treatment on survival is not clear. The aim of this meta-analysis was to assess whether this type of radiotherapy could improve survival. METHODS: Randomised trials comparing conventional radiotherapy with hyperfractionated or accelerated radiotherapy, or both, in patients with non-metastatic HNSCC were identified and updated individual patient data were obtained. Overall survival was the main endpoint. Trials were grouped in three pre-specified categories: hyperfractionated, accelerated, and accelerated with total dose reduction. FINDINGS: 15 trials with 6515 patients were included. The median follow-up was 6 years. Tumours sites were mostly oropharynx and larynx; 5221 (74%) patients had stage III-IV disease (International Union Against Cancer, 1987). There was a significant survival benefit with altered fractionated radiotherapy, corresponding to an absolute benefit of 3.4% at 5 years (hazard ratio 0.92, 95% CI 0.86-0.97; p=0.003). The benefit was significantly higher with hyperfractionated radiotherapy (8% at 5 years) than with accelerated radiotherapy (2% with accelerated fractionation without total dose reduction and 1.7% with total dose reduction at 5 years, p=0.02). There was a benefit on locoregional control in favour of altered fractionation versus conventional radiotherapy (6.4% at 5 years; p<0.0001), which was particularly efficient in reducing local failure, whereas the benefit on nodal control was less pronounced. The benefit was significantly higher in the youngest patients (hazard ratio 0.78 [0.65-0.94] for under 50 year olds, 0.95 [0.83-1.09] for 51-60 year olds, 0.92 [0.81-1.06] for 61-70 year olds, and 1.08 [0.89-1.30] for over 70 year olds; test for trends p=0.007). INTERPRETATION: Altered fractionated radiotherapy improves survival in patients with head and neck squamous cell carcinoma. Comparison of the different types of altered radiotherapy suggests that hyperfractionation has the greatest benefit.

Aged↗
PubMedDate not supplied

Relationship of carbamazepine reduction rate to seizure frequency during inpatient telemetry.

To establish guidelines for medication reduction during inpatient telemetry, the records of 18 children and young adults with refractory partial seizures undergoing carbamazepine (CBZ) reductions during continuous video/EEG telemetry were reviewed. Six patients were receiving CBZ monotherapy, and 12 patients were treated with an additional antiepileptic drug (AED) maintained at baseline dosage during CBZ taper. Despite relatively rapid mean reductions in dosage of 44% by day 2 of taper, no patients experienced frequent repetitive seizures or status epilepticus (SE). Seizure rate during the entire CBZ reduction period correlated significantly with rate of drug reduction. Linear regression analysis showed drug reduction rate to be a good predictor of seizure rate. Fourteen patients experienced at least three seizures during CBZ taper. On the average, the third seizure occurred on day 5 of taper at a percentage of dose reduction of 79%. In 8 patients, CBZ concentrations were measured both before taper and < or = 24 h after the third seizure. For these patients, seizure rate also correlated significantly with reduction in CBZ level. We conclude that manipulation of CBZ dose reduction rate is important in maximizing seizure frequency during telemetry and, in our patients, a relatively rapid rate of dose reduction was safe and effective in promoting seizure recordings.

Adolescent↗
PubMed1996

Radiation dose perturbation at tissue-titanium dental interfaces in head and neck cancer patients.

PURPOSE: To determine the dose perturbation effects at the tissue-metal implant interfaces in head and neck cancer patients treated with 6 MV and 10 MV photon beams. METHODS AND MATERIALS: Phantom measurements were performed to investigate the magnitude of dose perturbation to the tissue adjacent to the titanium alloy implants with (100 mu and 500 mu thick) and without hydroxylapatite (HA) coating. Radiographic and radiochromic films were placed at the upper (and lower) surface of circular metal discs (diameter x thickness: 15 x 3.2, 48 x 3.2, 48 x 3.8 mm2) in a solid water phantom and were exposed perpendicular to radiation beams. The dosimeters were scanned with automatic film scanners. Using a thin-window parallel-plate ion chamber, dose perturbation were measured for a 48 x 3.2 mm2 disc. RESULTS: At the upper surface of the tissue-dental implant interface, the radiographic data indicate that for 15 x 3.2 mm2 uncoated, as well as 100 mu coated discs, dose perturbation is about +22.5% and +20.0% using 6 MV and 10 MV photon beams, respectively. For 48 x 3.2 mm2 discs, these values basically remain the same. However, for 48 x 3.8 mm2 discs, these values increase slightly to about +23.0% and +20.5% for 6 MV and 10 MV beams, respectively. For 48 x 3.2 mm2 discs with 500 mu coating, dose enhancement is slightly lower than that obtained for uncoated and 100 mu coated discs for each beam energy studied. At the lower interface for 15 x 3.2 mm2 and 48 x 3.2 mm2 uncoated and 100 mu coated discs, dose reduction is similar and is about -13.5% and -9.5% for 6 MV and 10 MV beams, respectively. For 48 x 3.8 mm2 discs, dose reduction is about -14.5% and -10.0% for 6 MV and 10 MV beams, respectively. For 48 x 3.2 mm2 discs with 500 mu coating, the dose reduction were slightly higher than those for uncoated and 100 mu coated discs. CONCLUSIONS: For the beam energies studied, dose enhancement is slightly larger for the lower energy beam. The results of dose perturbation were similar for 100 mu coated and uncoated discs. These results were slightly lower for the 500 mu coated discs but are not clinically significant. The dosimetry results obtained from radiochromic films were similar to the ones obtained from radiographic film. The dose enhancement results obtained from ion chamber dosimetry are higher than those obtained from film dosimetry. The ion chamber data represent the data at "true" tissue-titanium interface, whereas the ones obtained from film dosimetry represent the data at film-titanium interface.

Biocompatible Materials↗
PubMed2006

Weekly fluorouracil at 425 mg/m(2) plus low-dose folinic acid for 24 weeks as adjuvant treatment for colorectal cancer: assessment of toxicity and delivery.

AIMS: To assess the toxicity and dose delivery of weekly bolus 5-fluorouracil (5-FU) at 425 mg/m(2) plus low-dose folinic acid (FA) for 24 weeks as adjuvant treatment for colorectal cancer. MATERIALS AND METHODS: Data were collected on toxicity and dose reductions, stoppages, delays and intensity from 100 consecutive patients receiving this adjuvant regimen after curative surgery. RESULTS: There were 53 men and 47 women (median age: 64 and 65 years, respectively); 77 patients with colon cancer and 23 with cancer of the rectum; 34 patients with Dukes' stage B and 66 with Dukes' stage C. Thirty-seven patients experienced at least one grade 3 or 4 toxicity, mainly diarrhoea (20 patients) or fatigue (14 patients). Only one grade 4 toxicity was noted (diarrhoea). In multivariate analysis, increased grade 3 and 4 toxicity was significantly associated with female gender (P = 0.001) and age >65 years (P = 0.046). Forty patients completed the 24 cycles without dose reduction or delay. Forty-one patients required at least one dose reduction. The median 'conventional' dose intensity (DI), calculated from the first cycle to the last, was 408 mg/m(2)/week (96%). The median DI over 24 weeks was 387 mg/m(2)/week (91%). A higher median 24-week DI was delivered to men (407 mg/m(2)/week, 96%) than women (361 mg/m(2)/ week, 85%; P = 0.009). Women older than 65 years showed a significantly reduced median DI over 24 weeks (347 mg/ m(2)/week, 82%) compared with men aged 65 years or younger (407 mg/m(2)/week, 96%; P = 0.049) and men older than 65 years (425 mg/m(2)/week, 100%; P = 0.001), although the difference against women aged 65 years or younger (377 mg/ m(2)/week, 89%) was not statistically significant (P = 0.09). CONCLUSION: This regimen has shown what might be considered high rates of grade 3 and 4 toxicity for an adjuvant treatment, although the delivered DI was acceptable. Caution is urged in the treatment of elderly female patients who have statistically higher rates of grade 3 and 4 toxicity and lower DI.

Adult↗
PubMed1990

Two years experience of daily self-administered subcutaneous erythropoietin.

Recombinant human erythropoietin (EPO) has been used for 4 years in end-stage renal disease patients, administered intravenously 3 times a week. A study was undertaken to determine the optimal way of administration comparing 3 times weekly intravenous EPO to self-administered daily subcutaneous EPO (SADSCEPO). In a first group of 4 patients, we demonstrated that the change from 3 times weekly intravenous EPO to SADSCEPO permitted a dose reduction of 70%. In a second group of 20 patients who started the EPO therapy with the daily subcutaneous route at a median dose of 12 U/kg/day, the hematocrit increased from 20 to 30% in 4 months and remained over 30% in spite of a median dose reduction to 9 U/kg/day. The patients' acceptance of SADSCEPO was good. The mechanism allowing such a dose reduction is unknown. However, the significant reduction in median dosage requirement with the subcutaneous route should allow a greater number of patients to be treated more cost-effectively.

Adult↗
PubMed2005

Erythropoietic growth factors for treatment-induced anemia in hepatitis C: a cost-effectiveness analysis.

BACKGROUND & AIMS: Treatment-induced anemia undermines the efficacy of antiviral therapy in hepatitis C by mandating ribavirin dose reduction and diminishing adherence to therapy. Erythropoietic growth factors (EGFs) may correct treatment-induced anemia, facilitate maintenance of full-dose therapy, and improve rates of sustained virologic response (SVR). We sought to determine the cost effectiveness of adjunctive treatment with an EGF vs standard care in the treatment of hepatitis C. METHODS: We used a decision analysis to calculate the cost effectiveness of 2 treatment strategies for a patient cohort with chronic hepatitis C, increased transaminase levels, and no cirrhosis who were receiving pegylated-interferon and ribavirin (RBV): (1) RBV dose-reduction for anemia, followed by discontinuation of therapy if anemia persisted (standard care strategy), (2) adjunctive treatment with EGF therapy for anemia, with RBV dose reduction reserved for persistent anemia despite EGF therapy (EGF strategy). We conducted cost-effectiveness and cost-utility analyses to compare short- and long-term outcomes between the strategies. RESULTS: The percentage achieving SVR was 52.3% in the standard care strategy and 59.5% in the EGF strategy. Compared with standard care, the EGF strategy cost an incremental $36,568 per unadjusted life-year gained and $16,443 per quality-adjusted life-year gained. In a sensitivity analysis, if a third-party payer was willing to pay $50,000 per quality-adjusted life-year gained for the use of an EGF, then 86.1% of patients would be within the budget. CONCLUSIONS: Compared with standard care, adjunctive therapy with an EGF for the management of treatment-induced anemia may increase the probability of achieving SVR, increase unadjusted lifespan, and increase quality-adjusted lifespan at an acceptable cost.

Anemia↗
PubMed2004

Role of epoetin alfa in maintaining ribavirin dose.

Current therapy for the treatment of hepatitis C virus (HCV) infection is standard interferon (IFN) or pegylated interferon (PEG-IFN) in combination with ribavirin (RBV). Hematologic side effects (neutropenia, thrombocytopenia, anemia) are a major reason for dose reduction of anti-HCV therapy. Because treatment adherence and maintenance of IFN or PEG-IFN and RBV doses have been shown to be important in achieving a sustained virologic response, appropriate management of hematologic side effects might play a substantial role in optimizing treatment outcomes. Neutropenia and thrombocytopenia are usually managed by IFN or PEG-IFN dose reduction; the role of hematopoietic growth factors to ameliorate these side effects needs further evaluation, but some studies suggest granulocyte colony-stimulating factor (G-CSF) may be useful in the management of IFN/PEG-IFN-associated neutropenia. Anemia is primarily due to RBV-induced hemolytic anemia, but IFN/PEG-IFN also suppresses bone marrow erythroid precursors. Treatment-induced anemia has usually been managed by RBV dose reduction or discontinuation. However, recent studies suggest that epoetin alfa can increase hemoglobin levels and facilitate maintenance of RBV dosage in patients with chronic hepatitis C who became anemic during standard combination therapy. Results of a randomized, randomized, double-blind, placebo-controlled trial suggest that epoetin alfa therapy can maintain RBV dosage, increase hemoglobin levels, and improve quality of life in this population. In patients who have chronic hepatitis C who experience hematologic toxicities during standard therapy, the use of hematopoietic growth factors such as epoetin alfa might have the potential to improve treatment adherence rates and allow optimal doses of IFN or PEG-IFN and RBV to be maintained, thereby leading to improved treatment outcomes.

Anemia↗
PubMed2001

Conformal photon-beam therapy with transverse magnetic fields: a Monte Carlo study.

This work studies the idea of using strong transverse magnetic (B) fields with high-energy photon beams to enhance dose distributions for conformal radiotherapy. EGS4 Monte Carlo code is modified to incorporate charged particle transport in B fields and is used to calculate effects of B fields on dose distributions for a variety of high-energy photon beams. Two types of hypothetical B fields, curl-free linear fields and dipole fields, are used to demonstrate the idea. The major results from the calculation for the linear B fields are: (1) strong transverse B fields (> 1 T) with high longitudinal gradients (G) (> 0.5 T/cm) can produce dramatic dose enhancement as well as dose reduction in localized regions for high-energy photon beams; (2) the magnitude of the enhancement (reduction) and the geometric extension and the location of this enhancement (reduction) depend on the strength and gradient of the B field, and photon-beam energy; (3) for a given B field, the dose enhancement generally increases with photon-beam energy; (4) for a 5 T B field with infinite longitudinal gradient (solenoidal field), up to 200% of dose enhancement and 40% of dose reduction were obtained along the central axis of a 15 MV photon beam; and (5) a 60% of dose enhancement was observed over a 2 cm depth region for the 15 MV beam when B = 5 T and G = 2.5 T/cm. These results are also observed, qualitatively, in the calculation with the dipole B fields. Calculations for a variety of B fields and beam configurations show that, by employing a well-designed B field in photon-beam radiotherapy, it is possible to achieve a significant dose enhancement within the target, while obtaining a substantial dose reduction over critical structures.

Biophysical Phenomena↗
PubMed2006

Cost-effectiveness of hematologic growth factors for anemia occurring during hepatitis C combination therapy.

In hepatitis C virus (HCV)-infected patients who develop anemia during combination therapy, erythropoietic growth factors maintain higher drug treatment levels compared to ribavirin dose reduction, which may lead to an increase in treatment response rates. This study estimated the cost-effectiveness of growth factor therapy in maintaining anemic HCV-infected patients on target drug levels during combination therapy. A decision analysis using a Markov model was developed with 7 health states: Sustained viral response, chronic HCV, compensated cirrhosis, decompensated cirrhosis, hepatocellular carcinoma, liver transplantation, and death. Data sources included population-based studies of growth factor therapy, previously published estimates of costs and natural history of hepatitis C, and recent prospective studies. Our reference case was a 45-year-old Caucasian man with HCV infection (genotype 1, 2, or 3) who developed anemia while undergoing combination therapy with ribavirin and pegylated interferon. We compared growth factor injections (darbepoetin alpha or epoetin alpha) during combination therapy with standard ribavirin dose reduction. Compared to a ribavirin dose reduction strategy, the cost of darbepoetin per additional quality-adjusted life-year was 34,793 dollars for genotype 1 and 33,832 dollars for genotypes 2 or 3 versus 60,600 dollars and 64,311 dollars for epoetin. For all genotypes, the results were sensitive to changes in the cure rates of HCV therapy, the utility of chronic HCV, the costs of growth factors, and the age at which therapy is begun. In conclusion, use of erythropoietic growth factors, specifically darbepoetin, for patients with anemia occurring during HCV combination therapy appears to be cost-effective for genotypes 1, 2, or 3.

Anemia↗
PubMed1992

Dose intensity of chemotherapy with cyclophosphamide, methotrexate and 5-fluorouracil in the elderly with advanced breast cancer.

Toxicity and results of two different dose levels of chemotherapy with cyclophosphamide, methotrexate and 5-fluorouracil (CMF) in older (greater than 70 years) patients with advanced breast cancer were evaluated in a prospective (non-randomised) study. During the first three courses of chemotherapy dose reduction for haematological toxicity was necessary in all of 10 and 8 of 13 patients treated with an intended dose of 100% and 75% of standard dose CMF, respectively. The median percentages of CMF, administered during the first three courses were about 75% in both groups of patients corresponding with a median dose intensity of 72% (range 49-87%) and 64% (range 36-78%) for patients of the 100% and 75% dose group, respectively. In 34 younger postmenopausal women (mean age 57 years) treated in our institution for advanced breast cancer the median percentages of CMF in the second and third course were 86% and 84%, respectively with a median dose intensity during the three courses of 82%. Dose reductions of CMF and bone marrow toxicity, though interdependent, were statistically significantly correlated with the endogenous creatinine clearance, but not with age. 1 patient died during severe leukopenia and thrombocytopenia. Non-haematological side effects were most pronounced in the 100% group. Results of therapy in both groups of patients were about equal and compared well with those of CMF therapy in general. It is advised that the dose of CMF in patients above 70 years should not exceed 75% of standard dose. Further dose reduction of methotrexate in case of severe renal failure is required.

Age Factors↗
PubMed2004

Feasibility study of concurrent weekly cisplatin and whole abdominopelvic irradiation followed by doxorubicin/cisplatin chemotherapy for advanced stage endometrial carcinoma: a Gynecologic Oncology Group trial.

PURPOSE: A prospective Phase I study to determine toxicity of concurrent weekly intravenous cisplatin/whole abdominopelvic radiation therapy followed by four cycles of intravenous doxorubicin/cisplatin chemotherapy. MATERIALS AND METHODS: Ten patients with advanced endometrial cancer confined to the abdominal cavity and/or paraaortic lymph nodes with small residual disease were treated postoperatively with 3000 cGy whole abdominopelvic irradiation combined with 1500 cGy boost to the pelvis or pelvic and aortic fields. Cisplatin 15 mg/m(2) was given every week during irradiation. After completing radiotherapy, patients were to receive doxorubicin 50 mg/m(2) and cisplatin 50 mg/m(2) every 3 weeks for four cycles. Graduated dose reduction and acceleration of the doxorubicin dose were specified depending upon hematologic toxicity. Toxicities were monitored with weekly laboratory studies during treatment and frequent examinations. RESULTS: Five patients with Stage IIIC (paraaortic node involvement) and five with Stage IVB disease were treated on this study. Acute toxicity during chemoirradiation included one patient with grade 4 neutropenia and one patient with persistent grade 1 thrombocytopenia. Seven patients received chemotherapy after completing radiation therapy, two progressed before chemotherapy, and one had thrombocytopenia. Toxicity during chemotherapy included grade 4 neutropenia in all patients with four having five episodes of febrile neutropenia. Despite doxorubicin dose reductions for hematologic toxicity, three patients exhibited grade 4 neutropenia after both the second and third cycles. One patient developed a small bowel obstruction from radiation therapy that required surgery. There were no treatment-related deaths. Overall median survival was 14 months, with only one long-term survivor free of disease at 58 months. CONCLUSIONS: Without cytokine support, whole abdominopelvic irradiation and concurrent weekly cisplatin followed by doxorubicin/cisplatin chemotherapy without cytokine support has prohibitive hematologic toxicity.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2003

Buprenorphine: how to use it right.

The unique pharmacology of buprenorphine at the mu-opioid receptor (i.e. high affinity, low intrinsic activity and slow dissociation) results in buprenorphine having: (1) a good safety profile, (2) low physical dependence, and (3) flexibility in dose scheduling. Early studies assessed the effectiveness of buprenorphine for the treatment of opioid dependence using a sublingual solution formulation. More recently, a combination tablet (buprenorphine/naloxone in a 4:1 ratio) has been assessed with the goal of decreasing diversion and abuse. Controlled studies with buprenorphine solution, buprenorphine mono-tablet, and buprenorphine/naloxone combination tablet have uniformly demonstrated the effectiveness of buprenorphine for opioid dependence treatment and the combination tablet appears to decrease (but not eliminate) abuse potential. There is general agreement across studies regarding buprenorphine induction and maintenance dose schedules. The clinical effects of buprenorphine and buprenorphine/naloxone are similar and most patients can be treated initially with and maintained on a daily buprenorphine/naloxone dose of 4:1-24:6 mg. Dosing is possible on a less-than-daily schedule; however, multiples of the daily-dose should be administered to cover the increased interval between doses. If buprenorphine withdrawal is indicated, gradual dose reduction is recommended over a rapid dose reduction or abrupt cessation. Both tablet formulations are approved by the US FDA for opioid dependence treatment as Schedule III narcotics and are, therefore, available for use in office-based practice. The buprenorphine plus naloxone combination product should provide additional safeguards for use in office-based practice by decreasing risk of diversion, and office-based treatment should expand the availability of services to opioid dependent patients.

Buprenorphine↗
PubMed2001

"Burst" ketamine for refractory cancer pain: an open-label audit of 39 patients.

The results of a novel approach to the use of ketamine in refractory cancer pain are reported. In this prospective, multicenter, unblinded, open-label audit, 39 patients (with a total of 43 pains) received a short duration (3 to 5 days) ketamine infusion. The initial dose of 100 mg/24 hr was escalated if required to 300 mg/24 hr and then to a maximum dose of 500 mg/24hr. The overall response rate was 29/43 (67%). Analysis of results according to pain mechanisms showed that 15/17 somatic and 14/23 neuropathic pains responded. In 5 patients who appeared to respond, it is possible that another concurrent intervention may have contributed in whole or part for the pain relief observed. After cessation of ketamine, 24/29 maintained good pain control, with a maximum documented duration of eight weeks. However, 5 of the initial 29 responders experienced a recurrence of pain within 24 hours, and ketamine was recommenced. Of these, 2 underwent another intervention for pain control while 3 continued on ketamine until their deaths between two and four weeks later. Twelve patients reported adverse psychomimetic effects, with the incidence rising with increasing dose. Four of these were non-responders and the ketamine was stopped. Eight were responders, and in 3 the adverse effects were rendered acceptable with dose reduction; the other 5 rejected a dose reduction. The results reported suggest the need for further investigation of the place of ketamine in cancer pain management.

Adult↗
PubMed1998

Phase II trial of paclitaxel and carboplatin in the treatment of advanced urothelial carcinoma.

PURPOSE: Both paclitaxel and carboplatin have single-agent activity against carcinoma of the urothelium. We evaluated the combination of paclitaxel and carboplatin in the treatment of advanced cancers of the urothelium. PATIENTS AND METHODS: Patients with cancers of the urothelium who had no prior chemotherapy (prior adjuvant chemotherapy > 6 months allowed) were eligible for treatment. Eligibility requirements were performance status of 2 or less, creatinine level less than 2.0 mg/dL, granulocyte count (AGC) 1,500/microL or greater, platelet count 100,000/microL or greater, and total bilirubin level less than 1.5 mg/dL. Paclitaxel 200 mg/m2 followed by carboplatin (area under the curve [AUC] 5, Calvert formula) were administered every 21 days. Patients were evaluated for toxicity weekly and assessed for response every 6 weeks. RESULTS: Thirty-six patients were entered onto the study and 35 patients were assessable for response. A total of 184 cycles were administered (median, six cycles per patient). Nine patients required one dose reduction, and seven patients required two dose reductions for a nadir AGC less than 500/microL, with only one episode of febrile neutropenia and sepsis. Myalgias and arthralgias of grades 1 to 2 occurred in 16 patients and usually lasted 2 to 3 days after treatment. There were no treatment delays because of toxicity. There were 18 responses; seven complete responses (CRs) and 11 partial responses (PRs) (response rate 51.5%; 95% confidence interval, 35 to 68). Median response durations for CR and PR were 6 and 4 months, respectively. Overall median survival was 9.5 months. CONCLUSION: The combination of paclitaxel and carboplatin is an active and well-tolerated regimen for the treatment of advanced urothelial carcinoma. Because of the modest toxicity of this combination, paclitaxel and carboplatin should be considered for addition to other agents with activity in urothelial carcinomas.

Adult↗
PubMed1994

Dose-dependent reduction of tissue loss and functional impairment after spinal cord trauma with the AMPA/kainate antagonist NBQX.

Initial studies on the role of glutamate receptors in traumatic spinal cord injury (SCI) implicated the NMDA subclass of ionotropic glutamate receptors in contributing to functional deficits. Recently we obtained evidence suggesting that non-NMDA ionotropic receptors may participate in producing a portion of the behavioral impairment after SCI. To test this hypothesis we have conducted a dose-response experiment, focally injecting 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(f)quinoxaline (NBQX; 1.5, 5, or 15 nmol), a highly selective antagonist of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)/kainate receptors, or vehicle alone, into the injury site beginning at 15 min after a standardized contusive SCI. Behavioral tests of hindlimb reflex and coordinated sensorimotor function were performed 1 d after injury and weekly thereafter. At 4 weeks, spinal cord tissue was examined using quantitative histopathological and immunocytochemical techniques. We found a dose-dependent reduction in tissue loss at the thoracic injury site, with greater residual amounts of both gray matter and myelinated white matter. The maximum dose (15 nmol) significantly reduced the average length of the lesions and doubled the area of residual white matter at the epicenter. Serotonin immunoreactivity caudal to the lesion, used as a marker for descending motor control axons, was also increased in a dose-related manner and nearly tripled with the highest dose of NBQX as compared to controls. Most importantly, the reduced tissue loss in NBQX-treated groups was correlated with reduced functional deficits. There was a dose-dependent enhancement of speed and degree of recovery of both reflex and coordinated hindlimb motor activity, and reduction in the time required for establishing a reflex bladder. The long-term functional deficits at 4 weeks after SCI were reduced in a dose-related manner. Further, regression analyses demonstrated a significant correlation between the increase in amount of residual tissue and improvement in hindlimb function. Our results suggest that in this type of incomplete contusive SCI, a large and functionally important proportion of the tissue loss appears to be due to secondary injury mediated by local AMPA/kainate receptors.

Animals↗
PubMed2000

Mycophenolic acid trough levels after kidney transplantation in a cyclosporine-free protocol.

Twenty-seven stable kidney transplant recipients treated with cyclosporine and prednisone were converted to mycophenolate mofetil (MMF) and prednisone 1 year after transplantation. After conversion the patients were treated with a standard daily dose of 1 g MMF b.i.d. and 10 mg prednisone for 4 months. Thereafter, two MMF dose reductions were performed with a 4-month interval. Mycophenolic acid (MPA) trough levels were measured at regular intervals. A relation was found between MPA trough levels and MMF dose. The median MPA trough level for patients treated with 1 g MMF b.i.d. was 4.3 microg/ml (0.95-15.5) and 3.0 microg/ml (0.73-7.8) for patients treated with 750 mg b.i.d. (P = 0.0002). The MPA trough levels further decreased from 3.0 to 2.3 microg/ml (0.6-6.63) in patients treated with 500 mg MMF b.i.d. (P = 0.01). Dose reduction of MMF from 1 g to 750 mg b.i.d. could be performed without acute rejections. A further dose reduction to 500 mg b.i.d. elicited 3 rejections. Patients experiencing an acute rejection had a median MPA trough level of 2.3 microg/ml (1.26-3.38) compared to 3.8 microg/ml (1.48-6.52) in patients without an acute rejection (P = 0.25). We conclude that there is a significant relation between MPA trough levels and MMF dose. MPA trough levels were not predictive of rejection in the present study.

Area Under Curve↗
PubMed1993

Chemotherapy dose and survival in advanced Hodgkin's disease.

We analysed the effect of chemotherapy dose reductions on survival in 35 patients with Hodgkin's disease stage IIIB or IV treated at our institution by three double courses of C-MOPP/ABVD chemotherapy followed by either one further course or by involved-field radiotherapy. Patients receiving reduced doses of alkylating agents had markedly slower responses and worse survival than those not requiring dose reductions. This experience with a very limited number of cases suggests that dose intensity may be an important prognostic factor in advanced Hodgkin's lymphoma, although dose reductions might have been necessary in patients with an intrinsically poor prognosis. Prospective randomized trials comparing standard chemotherapy with intensified protocols supported by hematopoietic growth factors are needed and are being conducted to determine the role of total chemotherapy dose and delivery time in the cure of Hodgkin's disease.

Adult↗
PubMed1996

Use of G-CSF to Sustain Dose Intensity in Breast Cancer Patients Receiving Adjuvant Chemotherapy: A Pilot Study.

BACKGROUND: Adjuvant chemotherapy for breast cancer is frequently accompanied by neutropenia requiring dose reduction or treatment delay that can potentially compromise therapeutic effectiveness. Recombinant granulocyte-colony stimulating factor (G-CSF) reduces the duration and severity of neutropenia. METHODS: Nineteen patients with newly diagnosed breast cancer receiving adjuvant systemic chemotherapy met criteria for dose reduction or treatment delay due to neutropenia. All were treated with G-CSF. The mean duration of G-CSF therapy was five days. RESULTS: An increase in mean absolute neutrophil count was seen in cycles with G-CSF. Chemotherapy treatment was delayed less often following the use of G-CSF. CONCLUSIONS: Breast cancer patients receiving adjuvant chemotherapy who face treatment delays or dose reductions can continue on full-dose intensity therapy using supportive G-CSF. Prospective trials are needed to accurately measure the impact of G-CSF on dose intensity and long-term disease control.

Journal Article↗