Fate of selected pharmaceutically active compounds in the integrated fixed film activated sludge process.

The potential for integrated fixed film activated sludge (IFAS) processes to achieve enhanced transformation of pharmaceuticals relative to conventional activated sludge (CAS) processes was assessed. Previous studies have focused on direct comparisons of parallel reactors with and without fixed film carriers and little information is available on the impacts of how varying operating parameters impact the differences in observed pharmaceutical compound (PC) transformation capabilities between CAS reactors and those equipped with both an activated sludge (AS) and fixed film carriers. The testing was carried out using bench scale sequencing batch reactors fed with authentic municipal wastewater and operated at selected combinations of temperature and solids retention time (SRT). PC transformation efficiencies were assessed in a 22 factorial design that employed the IFAS and CAS processes, operated in parallel under identical process conditions. Nitrification rate testing that was conducted to obtain insight into the biomass activity demonstrated that IFAS consistently had improved nitrification kinetics despite lower mixed liquor volatile suspended solids levels thereby demonstrating the contribution of the biofilm to nitrification. Increased transformation of atenolol (ATEN; ranging from 10-60%) and trimethoprim (TRIM; ranging from 30-50%) in the IFAS equipped reactors relative to their respective activated sludge (AS) controls was observed under all experimental conditions. Negligible transformation of carbamazepine was observed in both reactors under all conditions investigated. More than 99% of acetaminophen was transformed in both configurations under all conditions. There was no correspondence between nitrification activity and TRIM removal in the control AS while conditions that stimulated nitrification in the control AS also resulted in enhanced removal of ATEN. The results of this study indicate that the integration of biofilms in AS processes enhances transformation of some PCs.

Recent trends in television tip over-related injuries among children aged 0-9 years.

OBJECTIVE: To describe recent trends in television tip over-related injuries among children aged 0-9 years, and to compare injury rates with sales of newer digital televisions. METHODS: Digital television sales data were obtained from marketing data provided by the Television Bureau of Advertising. Data regarding television tip over-related injuries among children aged 0-9 years were obtained from the 1998-2007 National Electronic Injury Surveillance System. A Wald chi(2) test, estimated from logistic analysis, was used to determine whether the distribution of injury types differed by age group. Pearson's correlation was used to estimate the association between digital television sales and television tip over-related injuries. RESULTS: An estimated 42 122 (95% CI 35 199 to 49 122) injuries from television tip-overs were treated in US emergency departments from 1998 to 2007. The injury rate was highest for children aged 1-4 years (18.6/100 000). A majority of injuries (63.9%) involved the head and neck for children under 1 year of age, while a higher proportion of injuries among children aged 1-4 involved the hip and lower extremity (42.9% and 31.0%, respectively), and shoulder and upper extremity (16.8%) for children aged 5-9. A strong, positive correlation was observed between television sales and annual injury rates (r = 0.89, p<0.001). CONCLUSION: Estimates of injury rates were similar to previously reported estimates, particularly for the increased proportion of head and neck injuries among very young children. While digital television sales were strongly correlated with increased injury rates, the lack of information regarding the type of television involved prevents inference regarding causation.

Methotrexate improves the health-related quality of life of children with juvenile idiopathic arthritis.

OBJECTIVES: To examine the change in health-related quality of life (HRQOL) and its determinants in children with juvenile idiopathic arthritis (JIA) treated with methotrexate (MTX). METHODS: Patients were extracted from the PRINTO clinical trial which aimed to evaluate the efficacy and safety profile of MTX administered in standard, intermediate or higher doses (10, 15 and 30 mg/m(2)/week respectively). Children with polyarticular-course JIA, who were less than 18 years and had a complete HRQOL assessment were included. RESULTS: A total of 521 children were included. At baseline, patients with JIA showed poorer HRQOL (p<0.01) than healthy children. In 207/412 (50%) and 63 (15%) children, HRQOL values were 2 standard deviations below the mean of healthy controls in the physical and psychosocial summary scale, respectively. After 6 months of treatment with standard dose MTX, there was a statistically significant improvement in all HRQOL health concepts, particularly the physical ones. Similar improvements were observed in those who did not respond to a standard dose of MTX and were subsequently randomised to a higher dose. The presence of marked disability at baseline was associated with a fivefold increased risk of retaining poor physical health after 6 months of active treatment with standard dose MTX. Other less important determinants of retaining poor physical well-being were the baseline level of systemic inflammation, pain intensity and an antinuclear-antibody-negative status. CONCLUSIONS: MTX treatment produces a significant improvement across a wide range of HRQOL components, particularly in the physical domains, in patients with JIA.

Effectiveness of infliximab in the treatment of refractory juvenile dermatomyositis with calcinosis.

OBJECTIVES: Some juvenile dermatomyositis (JDM) patients have a disease course which is refractory to multiple drug treatments. Prolonged disease activity is associated with increased mortality and morbidity. TNF-alpha has been identified in high levels in JDM patients who have a long disease course and calcinosis. We assessed the response of five refractory JDM patients to the anti-TNF-alpha monoclonal antibody, infliximab. METHODS: For all five patients intravenous infliximab was initially given at a dose of 3 mg/kg. Further doses were then given at weeks 2, 6 and every 8 weeks thereafter. The dose and frequency were tailored in accordance with clinical response. Clinical and laboratory data were collected prospectively. RESULTS: We report results between 8 and 30 months after starting infliximab. Improvements were seen in all five patients as shown by positive changes in physician visual analogue scale (VAS), Childhood Myositis Assessment Score (CMAS), Childhood Health Assessment Questionnaire (CHAQ), joint range of movement and, in some, regression of calcinosis and skin signs. There were no major side effects observed with addition of infliximab to the therapeutic regime. CONCLUSIONS: Major clinical benefit was demonstrated after the initiation of infliximab in all five cases of refractory JDM.

Alternative donor bone marrow transplant for children with Philadelphia chromosome ALL.

Children with Philadelphia chromosome positive (Ph+) acute lymphocytic leukemia (ALL) have only a 20% event-free survival when treated with chemotherapy alone. Bone marrow transplant (BMT) for patients with matched siblings has been associated with significantly better long-term survival. We asked whether children who lack a matched sibling donor would do as well if an alternative donor was utilized. Between 1987 and 2002, we transplanted 29 children and adolescents using either an unrelated donor (23) or a mismatched family member (six). The conditioning regimen included cytosine-arabinoside, cyclophosphamide and total body irradiation. Graft-versus-host disease (GVHD) prophylaxis consisted of T-cell depletion (antibody T10B9 or OKT3 and complement) with post transplant cyclosporine (CSA). All patients engrafted. Four developed grades III-IV acute GVHD. Three of 24 evaluable patients developed extensive chronic GVHD. Two patients died of relapse (7%). Two long-term survivors (>6 years) died of malignant glioblastoma multiforme. Event-free survival at 3, 5, and 10 years is 56, 51, and 46%, respectively. Five of six patients in >CR2 or relapse at the time of transplant died. Our data should encourage the use of alternative donor transplants early in the course of disease for children with Ph+ ALL.

Central lymphatic irradiation for stage III nodular malignant lymphoma: long-term results.

PURPOSE: To report the long-term results of central lymphatic irradiation for stage III nodular malignant lymphoma. PATIENTS AND METHODS: Between 1969 and 1985, 34 patients (26 with nodular poorly differentiated lymphoma, four with nodular mixed lymphocytic/histiocytic lymphoma, and four with nodular histiocytic lymphoma) were treated with central lymphatic irradiation. Median age of the group was 51 years (range, 30 to 73). There were 15 men and 19 women. Staging work-up included a physical examination and bone marrow biopsy in all patients. Seventy-four percent had a lymphangiogram (LAG) and 44% a laparotomy (LAP). Eighty-two percent had either a LAP or a LAG. Thirty-two patients were Ann Arbor stage IIIA and two were stage IIIB. All patients received lymphatic irradiation that encompassed cervical, supraclavicular, axillary, mediastinal, paraaortic, mesenteric, pelvic, and femoral lymphatics to total doses ranging from 20 to 30 Gy in 1.0- to 1.8-Gy fractions. Waldeyer's ring was initially treated in 17 patients. Follow-up information is available on all 34 patients. Median follow-up is 9 years, 8 months (range, 15 to 244 months). RESULTS: Life-table actuarial overall, disease-free, and cause-specific survival rates at 15 years are 28%, 40%, and 46%, respectively. Only one relapse was observed after 9 years. Disease-free survival was significantly improved in patients with five or fewer sites of involvement (P = .02). Age, sex, B symptoms, histology, and technique of irradiation were not prognostically significant. Salvage therapy, including further irradiation and/or chemotherapy, was delivered to 20 patients. Ten percent of these patients remain alive without evidence of disease. Toxicity data were available for the patients treated at the Medical College of Wisconsin (MCW). Radiation Therapy Oncology Group (RTOG) acute hematologic, gastrointestinal, and salivary toxicity scores were < or = 2 in 83% of patients. Late toxicity scores were < or = 2 in 96%. Persistent xerostomia was noted in 23% of patients who received initial treatment to Waldeyer's ring. CONCLUSION: These results suggest that initial comprehensive central lymphatic irradiation may be the preferred approach to achieve a durable relapse-free interval for this group of patients.

Phase III trial of neoadjuvant chemotherapy in patients with invasive bladder cancer treated with selective bladder preservation by combined radiation therapy and chemotherapy: initial results of Radiation Therapy Oncology Group 89-03.

PURPOSE: To assess the efficacy of neoadjuvant methotrexate, cisplatin, and vinblastine (MCV) chemotherapy in patients with muscle-invading bladder cancer treated with selective bladder preservation. PATIENTS AND METHODS: One hundred twenty-three eligible patients with tumor, node, metastasis system clinical stage T2 to T4aNXMO bladder cancer were randomized to receive (arm 1, n=61 ) two cycles of MCV before 39.6-Gy pelvic irradiation with concurrent cisplatin 100 mg/m2 for two courses 3 weeks apart. Patients assigned to arm 2 (n=62) did not receive MCV before concurrent cisplatin and radiation therapy. Tumor response was scored as a clinical complete response (CR) when the cystoscopic tumor-site biopsy and urine cytology results were negative. The CR patients were treated with an additional 25.2 Gy to a total of 64.8 Gy and one additional dose of cisplatin. Those with less than a CR underwent cystectomy. The median follow-up of all patients who survived is 60 months. RESULTS: Seventy-four percent of the patients completed the protocol with, at most, minor deviations; 67% on arm 1 and 81% on arm 2. The actuarial 5-year overall survival rate was 49%; 48% in arm 1 and 49% in arm 2. Thirty-five percent of the patients had evidence of distant metastases at 5 years; 33% in arm 1 and 39% in arm 2. The 5-year survival rate with a functioning bladder was 38%, 36% in arm 1 and 40% in arm 2. None of these differences are statistically significant. CONCLUSION: Two cycles of MCV neoadjuvant chemotherapy were not shown to increase the rate of CR over that achieved with our standard induction therapy or to increase freedom from metastatic disease. There was no impact on 5-year overall survival.

Cyclic AMP and mechanisms of vasodilation.

Cyclic AMP and the mechanism of vasodilation have been reviewed by first discussing the enzymes involved (adenyl cyclase, cyclic nucleotide phosphodiesterases, cyclic AMP-dependent protein kinase) and then agents that increase cAMP in smooth muscle. Two mechanisms of vasodilation are described: (i) effects on contractile proteins; (ii) effects on Ca2+ levels. Evidence for compartments of cAMP is also presented.

Selective small molecule inhibitors of glycogen synthase kinase-3 modulate glycogen metabolism and gene transcription.

BACKGROUND: Glycogen synthase kinase-3 (GSK-3) is a serine/threonine protein kinase, the activity of which is inhibited by a variety of extracellular stimuli including insulin, growth factors, cell specification factors and cell adhesion. Consequently, inhibition of GSK-3 activity has been proposed to play a role in the regulation of numerous signalling pathways that elicit pleiotropic cellular responses. This report describes the identification and characterisation of potent and selective small molecule inhibitors of GSK-3. RESULTS: SB-216763 and SB-415286 are structurally distinct maleimides that inhibit GSK-3alpha in vitro, with K(i)s of 9 nM and 31 nM respectively, in an ATP competitive manner. These compounds inhibited GSK-3beta with similar potency. However, neither compound significantly inhibited any member of a panel of 24 other protein kinases. Furthermore, treatment of cells with either compound stimulated responses characteristic of extracellular stimuli that are known to inhibit GSK-3 activity. Thus, SB-216763 and SB-415286 stimulated glycogen synthesis in human liver cells and induced expression of a beta-catenin-LEF/TCF regulated reporter gene in HEK293 cells. In both cases, compound treatment was demonstrated to inhibit cellular GSK-3 activity as assessed by activation of glycogen synthase, which is a direct target of this kinase. CONCLUSIONS: SB-216763 and SB-415286 are novel, potent and selective cell permeable inhibitors of GSK-3. Therefore, these compounds represent valuable pharmacological tools with which the role of GSK-3 in cellular signalling can be further elucidated. Furthermore, development of similar compounds may be of use therapeutically in disease states associated with elevated GSK-3 activity such as non-insulin dependent diabetes mellitus and neurodegenerative disease.

A cyclic nucleotide PDE5 inhibitor corrects defective mucin secretion in submandibular cells containing antibody directed against the cystic fibrosis transmembrane conductance regulator protein.

A selective cyclic nucleotide PDE5 inhibitor corrected the defective mucin secretion response to the beta-agonist isoproterenol in submandibular acinar cells inhibited by antibody directed against the cystic fibrosis transmembrane conductance regulator. The PDE5 inhibitor was as effective as cpt-cyclic AMP or a selective PDE4 inhibitor. However, the PDE5 inhibitor had no effect on basal or isoproterenol-stimulated cyclic AMP levels and did not stimulate mucin secretion. The results showing, for the first time, correction of the CFTR mucin secretion defect by a PDE5 inhibitor, which may involve cyclic GMP, will have a major impact in development of a rational drug treatment for cystic fibrosis.

Event-free survival of children with biologically favourable neuroblastoma based on the degree of initial tumour resection: results from the Pediatric Oncology Group.

We analysed the 2-year event-free survival (EFS) of 49 patients 1 year of age and older, with stage 2B or 3 neuroblastoma, treated on Pediatric Oncology Group protocols 8742 and 9244, with respect to the degree of tumour resection at diagnosis. The 2-year EFS rate for 21 children whose tumours were completely resected at diagnosis was 85% (SE = 10%) compared with an EFS rate of 70% (SE = 9%) for the 28 children whose tumours were incompletely resected at diagnosis. Despite the observed trend in favour of complete resection, these EFS curves were not statistically significantly different (P = 0.259). Patients with favourable Shimada histology tumours had an EFS rate of 92% (SE = 7%) compared with a rate of 58% (SE = 15%) for patients with unfavourable histology tumours. EFS curves for the two histologic groups were significantly different (P = 0.009). The impact of aggressive surgery and adjuvant chemotherapy on the outcome of patients with biologically favourable regional neuroblastoma is still unclear.

Echographic monitoring of response of extraocular muscles to irradiation in Graves' ophthalmopathy.

PURPOSE: Confirmation of the efficacy of orbital irradiation in Graves' ophthalmopathy is needed due to the unpredictable natural history of the disease, the variation in individual clinical presentations, the contribution of other simultaneous treatments, and the lack of controlled studies using objective criteria to classify and assess response over time. Orbital echography before and at select intervals following orbital irradiation is proposed as an objective parameter of tissue response to orbital irradiation over time. METHODS AND MATERIALS: From January, 1983 to September, 1993, 55 patients with progressive Graves' ophthalmopathy underwent 20 Gy retrobulbar irradiation. On retrospective review, standardized orbital echography was performed randomly prior to irradiation in 37 of the 55 patients to assess the acoustic characteristics of the extraocular muscles and to quantitate their individual and summed diameters. Twenty-one patients had at least one follow-up echographic evaluation at random intervals of 0 to 27.5 months following completion of irradiation. Twelve patients received steroids before or during irradiation, which were tapered in proximity to completion of radiation. Follow-up ranged from 2 to 65 months with the majority followed at least 6 months (18 patients). RESULTS: Of the 21 patients with serial studies, 18 showed an interval decrease in individual and summed muscle size over time and return of symmetry. Interval improvement was documented as early as the 1 month follow-up study, with continued improvement seen during the 3-9-month studies, with stability typically achieved within 12 months. One patient had further changes between the 21 and 27.5 month follow-up studies. Exacerbation of disease was, however, echographically demonstrated in three patients at 6.5, 8.5, and 13 months. Follow-up studies in two of these patients again revealed improvement, one following tapered steroids. The third patient required orbital decompression. CONCLUSION: Objective parameters of response are needed to document both the immediate and long-term outcome of orbital irradiation on the course of Graves' ophthalmopathy and confirm its efficacy. Serial echography is proposed as a new technique for providing parameters to judge response.

Improved dose localization with dual energy photon irradiation in treatment of lateralized intracranial malignancies.

Dual energy photon irradiation (6 MV and 20 MV) was compared to conventional treatment planning with 6 MV photons in a lateralized intracranial malignancy. Dose volume analysis was performed of both the tumor plus a 2 cm margin (target volume, TV) and normal tissues (NT). Parallel opposed treatment using weightings of 1:1, 1.5:1, and 2:1 were compared for 6 MV photons alone or in combination with 20 MV photons. Uniform treatment of the TV was accomplished within the 60 Gy isodose. Significant differences were observed, however, in NT volumes receiving greater than or equal to 60 Gy and 45-59 Gy. Dual photon energy reduced treatment of NT volumes to greater than or equal to 60 Gy by 13% (177 cm3 vs 204 cm3 in 2:1 weighting) to 70% (147 cm3 vs 498 cm3 in 1:1 weighting) for comparable plans. Dose optimization was also performed for both 6 MV alone or in combination with 20 MV photons. Usual approaches to achieve dose lateralization with conventional isocentric techniques were applied including parallel opposed 6 MV photons ipsilaterally weighted 3.4:1 (POP), and a 110 degrees arc rotational field used to limit treatment to the eye (ARC). Dual energy photon optimized plans included a three beam parallel opposed plan (TOP) and a mixed photon ipsilateral (IPSI) approach. The technique using parallel opposed 20 MV photons and ipsilateral 6 MV photons (TOP) used beam weightings of 1.1 (contralateral 20 MVX): 1.6 (ipsilateral 6 MVX): 1 (ipsilateral 20 MVX) to achieve dose optimization. The ipsilateral approach with 6 MVX and 20 MVX (IPSI) used beam weightings of 1:1.4, respectively. All optimized plans demonstrated a 41% (120 cm3; POP) to 53% (95 cm3; TOP) improvement over parallel opposed 6 MV photons weighted 2:1 (204 cm3) in NT volume receiving greater than or equal to 60 Gy. Comparison of optimized treatment showed the IPSI plan to be superior, treating 12% of NT volume to greater than or equal to 60 Gy and 38% to 45-59 Gy; the 6 MV POP plan resulted in NT volumes of 15% and 51%, respectively, for those dose levels. Dual photon energy irradiation of lateralized intracranial malignancies allows reduction of dose to normal tissue volumes while achieving excellent coverage of the target volume. Treatment planning should be performed in all lateralized intracranial lesions to achieve dose optimization exploiting depth dose characteristics.

Importance of the mini-mental status examination in the treatment of patients with brain metastases: a report from the Radiation Therapy Oncology Group protocol 91-04.

PURPOSE: Little information is available on the importance of pretreatment Mini-Mental Status Exam (MMSE) on long-term survival and neurologic function following treatment for unresectable brain metastases. This study examines the importance of the MMSE in predicting outcome in a group of patients treated with an accelerated fractionation regimen of 30 Gy in 10 daily fractions in 2 weeks. MATERIALS AND METHODS: The Radiation Therapy Oncology Group (RTOG) accrued 445 patients to a Phase III comparison of accelerated hyperfractionated (AH) radiotherapy (1.6 Gy b.i.d.) to a total dose of 54.4 Gy vs. an accelerated fractionation (AF) of 30 Gy in 10 daily fractions from 1991 through 1995. All patients had histologic proof of malignancy at the primary site. Brain metastases were measurable by CT or MRI scan and all patients had a Karnofsky performance score (KPS) of at least 70 and a neurologic function classification of 1 or 2. Two hundred twenty-four patients were entered on the accelerated fractionated arm, and 182 were eligible for analysis (7 patients were judged ineligible, no MMSE information in 29, no survival data in 1, no forms submitted in 1). RESULTS: Average age was 60 years; 58% were male and 25% had a single intracranial lesion on their pretherapy evaluation. KPS was 70 in 32%, 80 in 31%, 90 in 29%, and 100 in 14%. The average MMSE was 26.5, which is the lower quartile for normal in the U.S. population. The range of the MMSE scores was 11-30 with 30 being the maximum. A score of less than 23 indicates possible dementia, which occurred in 16% of the patients prior to treatment. The median time from diagnosis to treatment was 5 days (range, 0-158 days). The median survival was 4.2 months with a 95% confidence interval of 3.7-5.1 months. Thirty-seven percent of the patients were alive at 6 months, and 17% were alive at 1 year. The following variables were examined in a Cox proportional-hazards model to determine their prognostic value for overall survival: age, gender, KPS, baseline MMSE, time until MMSE below 23, time since diagnosis, number of brain metastases, and radiosurgery eligibility. In all Cox model analyses, age, KPS, baseline MMSE, time until MMSE below 23, and time since diagnosis were treated as continuous variables. Statistically significant factors for survival were pretreatment MMSE (p = 0.0002), and KPS (p = 0.02). Age was of borderline significance (p = 0.065) as well as gender (p = 0.074). A poorer outcome is associated with an increasing age, male gender, lower MMSE, and shorter time until MMSE below 23. Improvement in MMSE over time was assessed; 62 patients died prior to obtaining follow-up MMSE, and 30 patients had a baseline MMSE of 30 (the maximum), and, therefore, no improvement could be expected. Of the remaining 88, 48 (54.5%) demonstrated an improvement in their MMSE at any follow-up visit. Lack of decline of MMSE below 23 was seen in long-term survivors, with 81% at 6 months and 66% at 1 year of patients maintaining a MMSE above 23. Analysis of time until death from brain metastases demonstrated that decreasing baseline MMSE (p = 0.003) and primary site (breast vs. lung vs. other p = 0.032) were highly associated with a terminal event. CONCLUSION: While gender and perhaps age remain significant predictors for survival, MMSE is also an important way of assessing a patient's outcome. Accelerated fractionation used in the treatment of brain metastases (30 Gy in 10 fractions) appears to also be associated with an improvement in MMSE and a lack of decline of MMSE below 23 in long-term survivors.

Quality-adjusted survival analysis of malignant glioma. Patients treated with twice-daily radiation (RT) and carmustine: a report of Radiation Therapy Oncology Group (RTOG) 83-02.

PURPOSE: To quantify the quality of life of malignant glioma patients treated on a randomized Phase I/II trial of twice-daily radiation therapy (RT) and carmustine, using a modified quality adjusted survival (QAS) model, and to compare the QAS among assigned treatment arms. MATERIALS AND METHODS: The Radiation Therapy Oncology Group (RTOG) accrued 786 malignant glioma patients to a Phase I/II randomized dose escalation trial of twice-daily RT with carmustine from 1983 to 1989. Patients were randomized to one of four arms of hyperfractionated RT in 1.2 Gy twice daily (BID) fractions (64.8 Gy, 72.0 Gy, 76.8 Gy, or 81.6 Gy) or to either of two accelerated hyperfractionated RT arms in 1.6 Gy BID fractions (48.0 or 54.4 Gy). Although preliminary toxicity and survival data have been published, little information is available regarding the quality of these patients' lives during and following such therapy. QAS is a refinement of the methodology for assessing survival quality among breast cancer patients receiving adjuvant chemotherapy. The QAS method allows for inclusion of both improvement and decline in neurologic functional status. Patients were scored by the presence or absence of 15 neurologic signs and symptoms at on-study and at every follow-up. Within each category were gradations of severity, with the quality survival time (Q-TIME) adjusted according to any changes in these neurologic findings. The summation of all changes in signs and symptoms were weighted by 1/15th and incorporated into the QAS model as QAS = Q-TIME-TOX-RRX. TOX was the time spent with treatment-related toxicities, and RRX was the time spent in recovery from subsequent therapy. RESULTS: Of 747 evaluable patients, the average QAS time was 18.5 months. The average QAS for the hyperfractionated arms of 64.8 Gy, 72.0 Gy, 76.8 Gy, and 81.6 Gy were 15.6, 20.8, 10.0, and 13.7 months, respectively. For the accelerated hyperfractionated RT arms of 48.0 and 54.4 Gy, the average QAS times were 13.1 and 13.4 months. The QAS time of the 72.0 Gy arm was significantly longer than that of all other groups, except the 64.8 Gy arm. As expected, the QAS times were strongly discriminated by both age and Karnofsky Performance Scores (KPS) (p < 0.001). Younger patients and patients with high KPS benefited most from assignment to the 72.0 Gy arm; QAS time was not significantly longer in any treatment arm among patients over age 50 or with KPS scores of 80 or less. CONCLUSIONS: This quality-adjusted survival methodology can be successfully applied to malignant glioma patients and permits a quantitative assessment of the influence of investigational therapies on patient quality of life. This analysis confirms the potential benefit of intermediate dose (72.0 Gy) hyperfractionated RT for selected malignant glioma patients.

Non-Hodgkin's lymphoma of the brain: can high dose, large volume radiation therapy improve survival? Report on a prospective trial by the Radiation Therapy Oncology Group (RTOG): RTOG 8315.

Between 1983 and 1987 the Radiation Therapy Oncology Group conducted a prospective phase II study to evaluate survival in primary non-Hodgkin's lymphoma of the brain treated with whole brain irradiation to 40 Gy and a 20 Gy boost to tumor plus a 2 cm margin. Forty-one patients are reported. Full follow-up is available on 35/41 who have died. Six are alive at 8.8-67.2 months from start of radiation therapy with a median followup of 53.9 months. Overall median survival was 11.6 months from start of radiation therapy and 12.2 months from diagnosis, with 48% surviving 1 year and 28% surviving 2 years. Karnofsky Performance Status and age were significant prognostic factors. Patients with a Karnofsky Performance Status of 70-100 had a median survival of 21.1 months compared to 5.6 months for patients with a status of 40-60 (p less than .001). Fourteen patients less than 60 years of age had a median survival of 23.1 months, while 27 patients greater than or equal to 60 years of age had a median survival of 7.6 months (log-rank p = .001). Disease recurred in the brain in 25/41 (61%) of the patients, (21/41 in the brain only and 4/41 in the brain plus distant metastases). Despite high dose and large volume irradiation, primary Central Nervous System lymphoma still exhibits excessive mortality, especially in older patients. This paradox of the relative radioresistance of primary Central Nervous System lymphoma remains unresolved.

Influence of renal shielding on the incidence of late renal dysfunction associated with T-lymphocyte deplete bone marrow transplantation in adult patients.

Late renal dysfunction following allogeneic bone marrow transplantation has been described by a number of centers including our own. Total body irradiation appears to play a major causative role in the development of this syndrome. In an effort to decrease the incidence of this renal toxicity we have added customized partial transmission renal blocking to our total body irradiation regimen. This partial renal shielding decreases the total dose to the kidneys from 14 Gy to 12 Gy. This report compares 71 adult patients who have received total body irradiation associated with bone marrow transplantation using renal shielding with 72 adult patients who were treated without the shielding; all of the patients have survived a minimum of 100 days post-BMT. Eighteen months following BMT, 26% of patients who did not have renal shielding have developed late renal dysfunction compared to only 6% of patients with renal shielding (p less than .05). Median follow-up in the nonblocked patients is 536 days post-transplant versus 341 days for the blocked patients. This added renal blocking has not adversely affected engraftment rates or relapse rates to date. Customized renal shielding as part of 14 gray total body irradiation in preparation for bone marrow transplantation appears to have decreased the incidence of late renal dysfunction in this group of adult patients and should be considered for all patients undergoing total body irradiation in conjunction with bone marrow transplantation.

Technical modifications in hyperfractionated total body irradiation for T-lymphocyte deplete bone marrow transplant.

The Medical College of Wisconsin implemented a major bone marrow transplant (BMT) program in July 1985. The type of transplants to be focused on were allogeneic T-lymphocyte deplete. Total body irradiation (TBI) was initially patterned after the Memorial method. Patients received total body irradiation in a sitting position at a dose rate of 20-25 cGy/minute with 50% attenuation lung blocks used both anterior/posterior and posterior/anterior. Electron boosting was utilized for the ribs beneath the lung blocks. Occasionally, lower extremity boosting was required because of the sitting position. A dose of 14 Gy was chosen since T-lymphocyte deplete bone marrow transplant data suggest the need for higher total doses to consistently obtain engraftment. This dose was given in 3 equal daily fractions over 3 days following conditioning chemotherapy. Six of 11 patients treated in this manner developed lethal pulmonary events. In response to the pulmonary toxicity, partial lung shielding was increased to 60% attenuation. In the next 107 patients receiving this program of total body irradiation there was a reduced incidence of fatal pulmonary events (10 cases of fatal idiopathic interstitial pneumonitis and 12 cases of fatal pulmonary infections) after a median follow-up of 9 months. This was an obvious improvement over the initial group. A significant level of hepato-renal toxicity was also observed with 14 Gy total body irradiation when no liver or kidney blocking was used. Of the first 20 patients treated, three cases of fatal veno-occlusive disease resulted. Subsequently, a 10% attenuation right sided liver block was added. Five of 98 patients treated with this block have developed fatal hepatic dysfunction, (median follow-up of 7.2 months). This incidence is not statistically different from the initial group but favors the use of the liver block. Some renal toxicity was also detected with the earlier regimen, especially in pediatric patients. Partial kidney blocking has been implemented to minimize this toxicity. Our current dose rate has been reduced to 8 cGy/minute in a further attempt to reduce organ toxicity. To date, this selective blocking has not adversely affected the excellent rate (96%) of first time engraftments.

A randomized phase III study of accelerated hyperfractionation versus standard in patients with unresected brain metastases: a report of the Radiation Therapy Oncology Group (RTOG) 9104.

PURPOSE: To compare 1-year survival and acute toxicity rates between an accelerated hyperfractionated (AH) radiotherapy (1.6 Gy b.i.d.) to a total dose of 54.4 Gy vs. an accelerated fractionation (AF) of 30 Gy in 10 daily fractions in patients with unresected brain metastasis. METHODS AND MATERIALS: The Radiation Therapy Oncology Group (RTOG) accrued 445 patients to a Phase III comparison of accelerated hyperfractionation vs. standard fractionation from 1991 through 1995. All patients had histologic proof of malignancy at the primary site. Brain metastasis were measurable by CT or MRI scan and all patients had a Karnofsky performance score (KPS) of at least 70 and a neurologic function classification of 1 or 2. For AH, 32 Gy in 20 fractions over 10 treatment days (1.6 Gy twice daily) was delivered to the whole brain. A boost of 22.4 Gy in 14 fractions was delivered to each lesion with a 2-cm margin. RESULTS: The average age in both groups was 60 years; nearly two-thirds of all patients had lung primaries. Of the 429 eligible and analyzable patients, the median survival time was 4.5 months in both arms. The 1-year survival rate was 19% in the AF arm vs. 16% in the AH arm. No difference in median or 1-year survival was observed among patients with solitary metastasis between treatment arms. Recursive partitioning analysis (RPA) classes have previously been identified and patients with a KPS of 70 or more, a controlled primary tumor, less than 65 years of age, and brain metastases only (RPA class I), had a 1-year survival of 35% in the AF arm vs. 25% in the AH arm (p = 0.95). In a multivariate model, only age, KPS, extent of metastatic disease (intracranial metastases only vs. intra- and extracranial metastases), and status of primary (controlled vs. uncontrolled) were statistically significant (at p < 0.05). Treatment assignment was not statistically significant. Overall Grade III or IV toxicity was equivalent in both arms, and one fatal toxicity at 44 days secondary to cerebral edema was seen in the AH arm. CONCLUSION: Although a previous RTOG Phase I/II report had suggested a potential benefit in patients with limited metastatic disease, a good Karnofsky performance status, or neurologic function when treated with an AH regimen, this randomized comparison could not demonstrate any improvement in survival when compared to a conventional regimen of 30 Gy in 10 fractions. Therefore, this accelerated hyperfractionated regimen to 54.4 Gy cannot be recommended for patients with intracranial metastatic disease.

Influence of an oligodendroglial component on the survival of patients with anaplastic astrocytomas: a report of Radiation Therapy Oncology Group 83-02.

PURPOSE: Seven percent of patients with high grade gliomas enrolled in RTOG 83-02 had mixed astrocytoma/oligodenroglial elements on central pathology review. It has often been assumed that the most aggressive histologic component of a tumor determines biologic behavior; however in this trial, the survival of patients who had mixed glioblastomas/oligodenrogliomas was significantly longer than that of patients with pure glioblastomas (GBM). We therefore evaluated the effect of an oligodendroglial component on the survival of patients who had anaplastic astrocytomas (AAF) treated in the same trial. METHODS AND MATERIALS: One hundred nine patients who had AAF and 24 patients with mixed AAF/oligodendrogliomas (AAF/OL) were enrolled in a Phase I/II trial of randomized dose-escalation hyperfractioned radiotherapy plus BCNU. AAF/OL patients were older and more likely to have had more aggressive surgery than AAF patients. Other pretreatment characteristics were balanced between groups, as was assigned treatment. RESULTS: The median survival time for AAF was 3.0 years versus 7.3 years for AAF/OL (p = 0.019). In a multivariate analysis, adjusting for extent of surgical resection and age, an oligodendroglial component was an independent prognostic factor for survival. CONCLUSION: The results support the concept that AAFs with an oligodendroglial component have a better prognosis than pure AAF tumors, similar to the effect seen among patients with glioblastoma multiforme tumors. This better survival outcome should be taken into consideration in the design and stratification of future trials. Additionally, in contrast to patients with GBMs, patients who have AAF/OL have the potential for prolonged survival; therefore, late sequelae of treatment (both radiation and chemotherapy) must be weighed more heavily in the benefits to risks analysis.