Graph diffusion distance: Properties and efficient computation.

We define a new family of similarity and distance measures on graphs, and explore their theoretical properties in comparison to conventional distance metrics. These measures are defined by the solution(s) to an optimization problem which attempts find a map minimizing the discrepancy between two graph Laplacian exponential matrices, under norm-preserving and sparsity constraints. Variants of the distance metric are introduced to consider such optimized maps under sparsity constraints as well as fixed time-scaling between the two Laplacians. The objective function of this optimization is multimodal and has discontinuous slope, and is hence difficult for univariate optimizers to solve. We demonstrate a novel procedure for efficiently calculating these optima for two of our distance measure variants. We present numerical experiments demonstrating that (a) upper bounds of our distance metrics can be used to distinguish between lineages of related graphs; (b) our procedure is faster at finding the required optima, by as much as a factor of 103; and (c) the upper bounds satisfy the triangle inequality exactly under some assumptions and approximately under others. We also derive an upper bound for the distance between two graph products, in terms of the distance between the two pairs of factors. Additionally, we present several possible applications, including the construction of infinite "graph limits" by means of Cauchy sequences of graphs related to one another by our distance measure.

Effect of using redberry juniper (Juniperus pinchotii) to reduce Haemonchus contortus in vitro motility and increase ivermectin efficacy.

A modified larval migration inhibition assay was used to determine if redberry juniper (Juniperus pinchotii Sudw.) can reduce Haemonchus contortus in vitro motility and increase ivermectin (IVM) efficacy. Ruminal fluid was mixed with buffer solution and either no material (CNTL) or Tifton 85 Bermudagrass hay (T85), dried juniper (DRY), fresh juniper (FRE), or distilled juniper terpenoid oil (OIL) to make treatment solutions and anaerobically incubated for 16 h. For Trial 1, larvae were incubated in CNTL, T85, DRY, or IVM. During Trial 2, larvae were incubated in CNTL, DRY, FRE, or OIL for 4h. Trials 3 (CNTL or OIL) and 4 (CNTL, DRY or FRE) evaluated larvae after incubation in treatment solution for 2h, then incubated an additional 2h in various IVM doses (0, 0.1, 1, 3, and 6 µg/mL IVM) and placed onto a screen. Larvae that passed through the 20-µm screen within a 96-well plate were considered motile. Larvae incubated in CNTL or T85 had similar (P=0.12) motility, but larvae incubated in DRY were less (P<0.02) motile than larvae incubated in CNTL or T85 (Trial 1). During Trial 2, adding DRY, FRE, or OIL reduced (P<0.001) larval motility as compared to CNTL. A treatment×IVM dose interaction (P=0.02) was observed during Trial 3, due to OIL unexpectedly decreasing IMV efficacy at IVM concentrations of 1 (P=0.07), 3, and 6 (P<0.002)µg/mL. No treatment×IVM dose interaction (P=0.57) was observed during Trial 4, but larvae incubated in DRY had less (P<0.004) total motility than larvae incubated in CNTL or FRE. Juniper forage material reduced in vitro H. contortus larval motility, but IVM efficacy was increased only by initially incubating larvae in DRY.

A modified in vitro larvae migration inhibition assay using rumen fluid to evaluate Haemonchus contortus viability.

Anthelmintic effects of plant secondary compounds may be occurring in the rumen, but in vitro larvae migration inhibition (LMI) methods using rumen fluid and forage material have not been widely used. Forage material added to an in vitro system can affect rumen pH, ammonia N, and volatile fatty acids, which may affect larvae viability (LV). Validating a LMI assay using rumen fluid and a known anthelmintic drug (Ivermectin) and a known anthelmintic plant extract (Quebracho tannins; QT) is important. Rumen fluid was collected and pooled from 3 goats, mixed with buffer solution and a treatment (1 jar/treatment), and placed into an anaerobic incubator for 16h. Ensheathed larvae (<3 months old) were then anaerobically incubated with treatment rumen fluid for 2, 4, or 16h depending on the trial. Larvae (n=15-45) were then transferred onto a screen (n=4-6 wells/treatment) within a multi-screen 96-well plate that contained treatment rumen fluid. Larvae were incubated overnight and those that passed through the 20-µm screen were considered viable. Adding dry or fresh juniper material reduced (P<0.05) pH, ammonia N, and isobutyric, butyric, isovaleric, and valeric acids, and increased (P<0.001) acetic, propionic, and total VFA. Including 4.5% (w/v) polyethylene glycol (PEG) in rumen fluid mixture with or without forage material reduced (P<0.01) LV. However, LV was similar at all PEG concentrations tested (0-2%, w/v; 89.4, 78.9, 76.5, 75.5, and 77.5% viable). Q. tannin concentrations from 0 to 1.2% (w/v) quadratically reduced (P<0.001) LV; 89.4, 65.5, 22.8, and 9.2%. Ivermectin concentrations from 0 to 15µg/mL quadratically reduced (P<0.001) LV; 90.2, 82.6, 73.6, 66.3, 51.9, 56.5, 43.5, 41.9, 29.3, and 19.9% viable, respectively. Effects of altering in vitro rumen fluid pH, ammonia N, and VFA and using PEG when evaluating LV need to be further investigated. In vitro rumen fluid assays using QT and Ivermectin resulted in decreased LV, validating the efficacy of this technique for measuring Haemonchus contortus larval viability.

High-speed, multicolor fluorescent two-dimensional gene scanning.

Two-dimensional gene scanning (TDGS) is a method for analyzing multiple DNA fragments in parallel for all possible sequence variations, using extensive multiplex PCR and two-dimensional electrophoretic separation on the basis of size and melting temperature. High throughput application of TDGS is limited by the prolonged time periods necessary to complete the second-dimension electrophoretic separation step--denaturing gradient gel electrophoresis--and the current need for gel staining. To address these problems, we constructed a high-voltage, automatic, two-dimensional electrophoresis system and used this in combination with thinner gels to reduce two-dimensional electrophoresis time about 80%. Instead of gel staining, we used three different fluorophores to simultaneously analyze three samples in the same gel. These improvements greatly increase TDGS speed and throughput and make the method highly suitable for large-scale single-nucleotide polymorphism discovery and genetic testing.

Pilot evaluation of 1p and 19q deletions in anaplastic oligodendrogliomas collected by a national cooperative cancer treatment group.

Radiation Therapy Oncology Group (RTOG) trial 94-02 is designed to compare the effectiveness of radiation therapy alone with radiation therapy plus procarbazine, lomustine, and vincristine (PCV) chemotherapy in patients with anaplastic oligodendrogliomas and mixed oligoastrocytomas. This prospectively collected, randomly treated, prospectively followed cohort is the ideal set of patients to validate the observation that anaplastic oligodendrogliomas with 1p and 19q deletions have a prolonged survival and a better response to chemotherapy. For patients entered on RTOG 94-02, fresh blood specimens, as well as slides and paraffin blocks, have been obtained (with informed consent) on enrollment. Peripheral blood leukocytes (buffy coats) have been frozen and stored and Epstein-Barr-virus-immortalized lymphoblastoid lines have been prepared from the blood specimens. In this report, the authors describe a pilot 1p/19q deletion analysis of 26 tumors from RTOG trial 94-02. In this analysis, it is shown that 1p/19q deletion analysis by fluorescence in situ hybridization is feasible on blocks collected from this trial. Also demonstrated is that the incidence of 1p and 19q deletions in this pilot series of anaplastic oligodendrogliomas and mixed oligoastrocytomas is similar to that reported in previous studies. When the clinical follow-up on this prospective trial is mature and the deletion studies have been completed, the authors should be able to determine whether 1p and 19q deletions predict a prolonged survival and/or responsiveness to PCV chemotherapy plus radiation in patients with anaplastic oligodendrogliomas and mixed oligoastrocytomas.

Collagen characteristics and organization during the progression of cholesterol-induced atherosclerosis in Japanese quail.

This study reports the concentration of collagen and its hydroxypyridinoline crosslinks, collagen fibril organization in the dorsal aortas, and systolic blood pressure during the progression of atherosclerosis in Japanese quail selected for cholesterol-induced atherosclerosis. The quail were placed on either a control or 0.5% cholesterol-added diet at approximately 16 weeks of age. The concentration of total collagen did not change in the control arteries during the course of the study, whereas at 5 and 10 weeks of cholesterol feeding, collagen levels decreased in the cholesterol-fed birds. Hydroxypyridinoline concentration increased during the duration of the study in the cholesterol-fed birds and by 15 and 20 weeks of cholesterol feeding, levels were significantly increased over those observed in the control arteries. Transmission electron microscopy showed changes in the organization of collagen fibrils. Increased systolic blood pressure was noted beginning at 10 weeks of cholesterol feeding, which is suggestive of other systemic changes induced by hypercholesterolemia. These results demonstrated remodeling of the collagen component of the dorsal aorta extracellular matrix during the progression of atherosclerosis and are suggestive of other systemic cardiovascular system changes.

Energy expenditure of heavy to severe exercise and recovery.

A method of indirect calorimetry is proposed that attempts to better quantify the energy expenditure associated with heavy/severe exercise and the recovery from that exertion. To accomplish this objective, the energy expenditure associated with rapid anaerobic glycolysis is separated from that of mitochondrial respiration both during and after heavy/severe exercise. This model contrasts with those hypotheses that employ oxygen uptake as the sole measure of energy expenditure (e.g. the oxygen debt) or that utilizing a measure of anaerobic energy expenditure while ignoring the recovery energy expenditure. Anaerobic metabolism and its energy promoting effect on oxidative recovery must be independently acknowledged regardless of the eventual fate of lactate.

Cancer pain management by radiotherapists: a survey of radiation therapy oncology group physicians.

PURPOSE: Radiation Therapy Oncology Group (RTOG) physicians were surveyed to determine their approach to and attitudes toward cancer pain management. METHODS AND MATERIALS: Physicians completed a questionnaire assessing their estimates of the magnitude of pain as a specific problem for cancer patients, their perceptions of the adequacy of pain management, and their report of how they manage pain in their own practice setting. RESULTS: Eighty-three percent believed the majority of cancer patients with pain were undermedicated. Forty percent reported that pain relief in their own practice setting was poor or fair. Assessing a case scenario, 23% would wait until the patient's prognosis was 6 months or less before starting maximal analgesia. Adjuvants and prophylactic side effect management were underutilized in the treatment plan. Barriers to pain management included poor pain assessment (77%), patient reluctance to report pain (60%), patient reluctance to take analgesics (72%), and staff reluctance to prescribe opioids (41%). CONCLUSIONS: Physicians' perceptions of barriers to cancer pain management remain quite stable over time, and physicians continue to report inadequate pain treatment education. Future educational efforts should target radiation oncologists as an important resource for the treatment of cancer pain.

Psychoeducational group increases vaginal dilation for younger women and reduces sexual fears for women of all ages with gynecological carcinoma treated with radiotherapy.

PURPOSE: The association between radiotherapy for gynecological carcinoma and sexual dysfunction is well established. Regular vaginal dilation is widely recommended to these women as a way for them to maintain vaginal health and good sexual functioning. However, the compliance rate with this recommendation is low. The purpose of this study was to test the effectiveness of a group psychoeducational program based on the "information-motivation-behavioral skills" model of behavior change in increasing the rate of compliance. METHODS AND MATERIALS: Thirty-two women with Stage I or II cervical or endometrial carcinoma who were being treated with radiotherapy were randomized and received either the experimental group program or the control intervention that consisted of written information and brief counseling. Outcome measures included global sexual health, knowledge about sexuality and cancer, fears about sexuality after cancer, and vaginal dilation compliance. RESULTS: Younger women attending the experimental program (44.4%) were significantly more likely to follow recommendations for vaginal dilation than those who received the control intervention (5.6%). Women, regardless of age, who received the experimental intervention reported less fear about sex after cancer treatment. The older women who received the experimental intervention gained more sexual knowledge. There was no evidence that the experimental intervention improved global sexual health. CONCLUSIONS: This is the first controlled study to provide evidence of an intervention's effectiveness 1. in increasing women's vaginal dilation following radiotherapy for gynecological carcinoma and 2. in reducing their fears about sex after cancer. Most women, particularly younger women, are unlikely to follow the recommendation to dilate unless they are given assistance in overcoming their fears and taught behavioral skills.

Addition of chemotherapy to radiation therapy alters failure patterns by cell type within non-small cell carcinoma of lung (NSCCL): analysis of radiation therapy oncology group (RTOG) trials.

PURPOSE: To evaluate the influence of cell type within non-small cell carcinoma of lung (NSCCL) on failure patterns when chemotherapy (CT) is combined with radiation therapy (RT). METHODS AND MATERIALS: Data from 4 RTOG studies including 1415 patients treated with RT alone, and 5 RTOG studies including 350 patients also treated with chemotherapy (RT + CT) were analyzed. Patterns of progression were evaluated for squamous cell carcinoma (SQ) (n = 946), adenocarcinoma (AD) (n = 532) and large cell carcinoma (LC) (n = 287). RESULTS: When treated with RT alone, SQ was more likely to progress at the primary site than LC (26% vs. 20%, p = 0.05). AD and LC were more likely to progress in the brain than SQ (20% and 18% vs. 11%, p = 0.0001 and 0.011, respectively). No differences were found in intrathoracic and distant metastasis by cell type. When treated with RT + CT, AD was less likely to progress at the primary than either SQ or LC (23% vs. 34% and 40%, respectively; p = 0.057 and 0.035). AD was more likely than SQ to metastasize to the brain (16% vs. 8%, p = 0.03), and other distant sites (26% vs. 14%,p = 0.019). No differences were found in intrathoracic metastasis. LC progressed at the primary site more often with RT + CT than with RT alone (40% vs. 20%, p = 0.036). Death with no clinical progression was more likely with SQ than AD or LC for RT alone and RT + CT (p < 0.01). Brain metastasis was altered little by the addition of CT, but other distant metastases were significantly decreased (p < 0.001) in all cell types by the addition of CT. CONCLUSION: CT, although effective in reducing distant metastasis in all types of NSCCL, has different effects on the primary tumor by cell type, and has no effect on brain metastasis or death with no progression. Different treatment strategies should be considered for the different cell types to advance progress with RT + CT in NSCCL.

Oxygen deficit and slow oxygen component relationships between intermittent and continuous exercise.

Above the lactate/ventilatory threshold, prolonged steady-state exercise produces a secondary rise in oxygen uptake, the slow oxygen component. The slow oxygen component 'represents an additional energetic requirement' above steady state; however, a lack of consensus on how to measure anaerobic energy expenditure makes it difficult to ascertain how or if anaerobic metabolism also contributes to energy expenditure. The aim of this study was to establish if the slow oxygen component is the sole source of 'additional energetic requirements' during steady-state exercise above the lactate/ventilatory threshold. Ten participants completed an 8 min continuous treadmill run and four 2 min intermittent runs at a speed of 2.67 m x s(-1) and a grade located halfway between the ventilatory threshold and maximum oxygen uptake. Each participant performed five submaximal runs below the ventilatory threshold to estimate energy expenditure at this exercise intensity. Both the oxygen deficit and the slow oxygen component were derived from this estimated energy expenditure. Oxygen equivalent units (ml O2) were used for comparison. The slow oxygen component for the 8 min continuous run began 2-4 min into exercise (73 ml O2), rose quickly at 4 6 min (178 ml O2) and declined at 6-8 min (96 ml O2). For the intermittent 2 min runs, a decrease in the oxygen deficit was seen between the first and second trial (-273 ml O2), indicating a larger aerobic energy expenditure contribution. The oxygen deficit began to increase when the third and fourth trials (+62 ml O2) were compared, suggesting a larger contribution to anaerobic energy expenditure. At the end of exercise, the intermittent oxygen deficit and continuous slow oxygen component revealed inverse associations; that is, in participants with large slow oxygen component contributions, the oxygen deficit was minimal; participants who had an increased oxygen deficit had smaller slow oxygen component contributions. The results suggest larger aerobic contributions to 'additional energetic requirements' when the slow oxygen component itself is large; however, smaller slow oxygen components do not necessarily indicate a lower energy expenditure. Individuals with smaller slow oxygen components during continuous exercise have larger oxygen deficits during intermittent exercise; thus an anaerobic contribution to the 'additional energetic requirement' may exist.

Issues in quality of life assessment during cancer therapy.

Current treatments for cancer do not differentiate between malignant and normal cells; this limitation results in the adverse effects associated with radiotherapy and chemotherapy. Adverse effects of treatment severely impact the cancer patient's quality of life. Quality of life assessment can help the clinician gauge the efficacy of interventions that reduce the adverse effects of radiotherapy and chemotherapy. Quality of life is an increasingly important outcome measure in the evaluation of cancer treatments, and a variety of tools have been developed for evaluating changes in quality of life. This report reviews several of these measurement tools, focusing primarily on those used in lung cancer trials.

Failure patterns by prognostic group determined by recursive partitioning analysis (RPA) of 1547 patients on four radiation therapy oncology group (RTOG) studies in inoperable nonsmall-cell lung cancer (NSCLC).

PURPOSE: To identify groups of patients who might benefit from more aggressive systemic or local treatment, based on failure patterns when unresectable NSCLC was treated by radiation therapy (RT) alone. METHODS: From 4 RTOG trials, 1547 patients treated by RT alone were analyzed for patterns of first failure by RPA class defined by prognostic factors, including KPS, weight loss, nodal stage, pleural effusion, age and radiation therapy dose. All patients had NSCLC AJCC Stage II, IIIA, or IIIB, KPS > 50, with no previous RT or chemotherapy. Progressions in the primary (within irradiated fields), thorax (outside irradiated area, but within thorax), brain and distant metastasis other than brain were compared (2-sided) for each failure category by RPA. RESULTS: The RPA classes were 4 distinct subgroups that had significantly different median survivals of 12.6, 8.3, 6.3 and 3.3 months for Classes I, II, III and IV, respectively, (all groups, p = 0.0002). There were 583, 667, 249 and 48 patients in Classes I, II, III and IV, respectively. Primary failure was seen in 27%, 25%, 21% and 10% for Classes I, II, III, and IV, respectively (I vs. IV, p = 0.014; II vs. IV, p = 0.022). Distant metastasis, including brain metastasis, occurred at significantly higher rates among Classes I and II (58% and 54%) than in Classes III and IV (42% and 27%). A higher rate (58%) of death without an identifiable site of failure was found in Class IV than in Classes I, II and III (27%, 28% and 36%, respectively). CONCLUSIONS: The data suggest that physiologic compromise from the intrathoracic disease in Class IV patients is sufficient to cause death before specific sites of failure became evident. Clinical investigations using treatments directed at specific sites of failure could lead to improved outcome for Class I, II and, possibly, Class III patients. Inclusion of Class IV patients in clinical trials may obscure outcomes.

Aerobic and anaerobic energy expenditure during exhaustive ramp exercise.

Ramp tests are often manipulated so that oxygen uptake is able to interpret energy expenditure in its entirety. We hypothesized that oxygen deficits during ramp exercise to exhaustion would be significant, providing a more complete description of the types of energy expenditure available for this mode of testing. Oxygen deficits were obtained during a slow ramp (681 +/- 71 s) and a fast ramp (275 +/- 33 s) to exhaustion. Twelve healthy men (age 35 +/- 3 yrs; VO2max 51 +/- 10 ml x kg(-1) x min(-1)) performed several 10 min submaximal bike rides (at or below ventilatory threshold) to determine work rate -O2 uptake demands. Estimated O2 demands were compared to measured O2 uptake during each ramp test, the difference representing an oxygen deficit. Work levels were controlled and measurements collected with a commercially available electrically braked bike ergometer and metabolic testing system (MedGraphics, Minn., MN). Data were collected and averaged in 30 s time periods, power in watts (W), energy expenditure in cumulative O2 (L). Using a paired t-test, cumulative O2 uptakes were significantly lower (p = 0.0001) when measured O2 uptakes (26.0 L +/- 4.5 for slow ramp; 10.8 L +/- 2.8 for fast ramp) were compared to estimated O2 demands (29.0 L +/- 3.7 for slow ramp; 14.1 L +/- 3.5 for fast ramp). Anaerobic energy expenditures (oxygen deficits) represented 10.8% and 23.4% of total energy expenditure for slow ramps and fast ramps, respectively. Comparisons of the slopes for each test condition revealed significant differences (steady state > slow ramp > fast ramp; p = 0.0001,ANOVA). We conclude that the oxygen deficit during ramp testing represents a significant part of total energy expenditure.

Re-interpreting anaerobic metabolism: an argument for the application of both anaerobic glycolysis and excess post-exercise oxygen comsumption (EPOC) as independent sources of energy expenditure.

Due to current technical difficulties and changing cellular conditions, the measurement of anaerobic and recovery energy expenditure remains elusive. During rest and low-intensity steady-state exercise, indirect calorimetric measurements successfully represent energy expenditure. The same steady-state O2 uptake methods are often used to describe the O2 deficit and excess post-oxygen consumption (EPOC): 1 l O2 = 5 kcal = 20.9 kJ. However, an O2 deficit plus exercise O2 uptake measurement ignores energy expenditure during recovery, and an exercise O2 uptake plus EPOC measurement misrepresents anaerobic energy expenditure. An alternative solution has not yet been proposed. Anaerobic glycolysis and mitochondrial respiration are construed here as a symbiotic union of metabolic pathways, each contributing independently to energy expenditure and heat production. Care must be taken when using O2 uptake alone to quantify energy expenditure because various high-intensity exercise models reveal that O2 uptake can lag behind estimated energy demands or exceed them. The independent bioenergetics behind anaerobic glycolysis and mitochondrial respiration can acknowledge these discrepancies. Anaerobic glycolysis is an additive component to an exercise O2 uptake measurement. Moreover, it is the assumptions behind steady-state O2 uptake that do not permit proper interpretation of energy expenditure during EPOC; 1 l O2 not = 20.9 kJ. Using both the O2 deficit and a modified EPOC for interpretation, rather than one or the other, leads to a better method of quantifying energy expenditure for higher intensity exercise and recovery.

Influence of bromodeoxyuridine radiosensitization on malignant glioma patient survival: a retrospective comparison of survival data from the Northern California Oncology Group (NCOG) and Radiation Therapy Oncology Group trials (RTOG) for glioblastoma multiforme and anaplastic astrocytoma.

PURPOSE: To examine the effect of treatment using Bromodeoxyuridine (BrdU) during radiation therapy on malignant glioma patient survival by comparing historical survival data from several large clinical trials. METHODS: A retrospective analysis of patient data from Radiation Therapy Oncology Group (RTOG) trials 74-01, 79-18, and 83-02 and the Northern California Oncology Group (NCOG) study 6G-82-1 was conducted. Patient data was supplied by both groups, and analyzed by the RTOG. Pretreatment characteristics including age, extent of surgery, Karnofsky Performance Status (KPS), and histopathology were collected; the only treatment variable evaluated was the use of BrdU during radiation therapy. Radiation dose, dose-fractionation schedule, use of chemotherapy, and/or type of chemotherapy was not controlled for in the analyses. Univariate and multivariate analyses were conducted to examine the potential treatment effect of BrdU on patient survival. RESULTS: Data from 334 patients treated with BrdU on NCOG 6G-82-1 and 1743 patients treated without BrdU on 3 RTOG studies was received. Patients were excluded from the review if confirmation of eligibility could not be obtained, if the patient was ineligible for the study they entered, if central pathology review was not done, or if radiotherapy data was not available. Patients treated according to the RTOG studies had to start radiotherapy within 4 weeks of surgery; no such restriction existed for the NCOG studies. To ensure comparability between the studies, patients from the NCOG studies who began treatment longer than 40 days from surgery were also excluded. The final data set included 296 cases from the NCOG studies (89%) and 1478 cases from the RTOG studies (85%). For patients with glioblastoma multiforme (GBM) the median survival was 9.8 months in the RTOG studies and 13.0 months in the NCOG trial (p < 0.0001). For patients with AA the median survival was 35.1 months for the RTOG studies and 42.8 months in the NCOG trial (p = 0.126). Univariate results showed consistent results favoring BrdU among patients over 30 years of age, across the extent of surgery, and for GBM patients. A proportional hazards regression model that included treatment, histopathology, KPS, age, and extent of surgery demonstrated that treatment with BrdU was included in the best model only for the GBM group of patients (risk ratio 0.83). CONCLUSIONS: Because of the heterogeneity of the treatment groups, including potentially important differences in pathology reviewers assessment of nonglioblastoma cases, differences in radiation dose and schedules, and chemotherapy during or after radiation, these analyses cannot provide the definitive answer as to whether BrdU given during radiation therapy improves survival in patients with malignant glioma. There does appear to be a favorable treatment effect seen in patients with GBM, with a lesser effect in patients with AA.

Validation and predictive power of Radiation Therapy Oncology Group (RTOG) recursive partitioning analysis classes for malignant glioma patients: a report using RTOG 90-06.

PURPOSE: The recursive partitioning analysis (RPA) classes for malignant glioma patients were previously established using data on over 1500 patients entered on Radiation Therapy Oncology Group (RTOG) clinical trials. The purpose of the current analysis was to validate the RPA classes with a new dataset (RTOG 90-06), determine the predictive power of the RPA classes, and establish the usefulness of the database norms for the RPA classes. PATIENTS AND METHODS: There are six RPA classes for malignant glioma patients that comprise distinct groups of patients with significantly different survival outcome. RTOG 90-06 is a randomized Phase III study of 712 patients accrued from 1990 to 1994. The minimum potential follow-up is 18 months. The treatment arms were combined for the purpose of this analysis. There were 84, 13, 105, 240, 150, and 23 patients in the RPA Classes I-VI from RTOG 90-06, respectively. RESULTS: The median survival times (MST) and 2-year survival rates for the six RPA classes in RTOG 90-06 are compared to those previously published. The MST and 2-year survival rates for the RTOG RPA classes were within 95% confidence intervals of the 90-06 estimates for Classes I, III, IV, and V. The RPA classes explained 43% of the variation (squared error loss). By comparison, a Cox model explains 30% of the variation. The RPA classes within RTOG 90-06 are statistically distinct with all comparisons exceeding 0.0001, except those involving Class II. A survival analysis from a prior RTOG study indicated that 72.0 Gy had superior outcome to literature controls; analysis of this data by RPA classes indicates the survival results were not superior to the RTOG database norms. CONCLUSION: The validity of the model is verified by the reliability of the RPA classes to define distinct groups with respect to survival. Further evidence is given by prediction of MST and 2-year survival for all classes except Class II. The RPA classes explained a good portion of the variation in survival outcome in the data. Lack of correlation in RPA Class II between datasets may be an artifact of the small sample size or an indication that this class is not distinct. The validation of the RPA classes attests to their usefulness as historical controls for the comparison of future Phase II results.

A simple system for automated two-dimensional electrophoresis: applications to genetic testing.

Two-dimensional gene scanning (TDGS) is a method for mutation detection based on two-dimensional electrophoretic separation of PCR-amplified DNA fragments according to size and base pair sequence. To facilitate two-dimensional electrophoresis without manual interference, a simple three-chamber unit was designed on top of an existing vertical electrophoresis instrument. Application of this system to genetic testing is demonstrated by the performance of a complete two-dimensional mutational scanning assay of one of the hereditary nonpolyposis colon cancer syndrome susceptibility genes, hMLH1.

Induction cisplatin/vinblastine and irradiation vs. irradiation in unresectable squamous cell lung cancer: failure patterns by cell type in RTOG 88-08/ECOG 4588. Radiation Therapy Oncology Group. Eastern Cooperative Oncology Group.

PURPOSE: To analyze disease failure patterns by pretreatment characteristics and treatment groups in a prospective randomized trial. METHODS AND MATERIALS: Patients with medically inoperable Stage II, unresectable IIIA and IIIB nonsmall cell lung cancer with KPS > or =70 and weight loss < or =5% were randomized to one of three treatment groups: standard radiation therapy with 60 Gy at 2.0 Gy per day (STD RT), induction chemotherapy with cisplatin 100 mg/m2 days 1 and 29 with vinblastine 5 mg/m2 weekly for 5 weeks followed by 60 Gy at 2.0 Gy per day (CT + RT), or hyperfractionated radiation therapy with 69.6 Gy at 1.2 Gy b.i.d. (HFX RT). Of 490 patients enrolled, 458 were evaluable. Minimum and median periods of observation for this analysis were 4 years and 6 years, respectively. RESULTS: Pretreatment characteristics were equally distributed. Toxicities were previously reported. Median survival rates were 11.4, 13.6, and 12.3 months for STD RT, CT + RT, and HFX RT, respectively (log rank p = 0.05, Wilcoxon p = 0.04). Survivals were 20, 31, and 24% at 2 years, and 4, 11, and 9% at 4 years in the STD RT, CT + RT, and HFX RT groups, respectively. There were no differences in local tumor control rates among the treatments. Patterns of first failure showed less distant metastasis (DM) (other than brain) for CT + RT compared to the RT alone arms (p = 0.04). Within squamous cell carcinoma (SCC), DM (other than brain) rates were 43%, 16%, and 38% in SCC for STD RT, CT + RT, and HFX RT, respectively (p = 0.0015). Patients with peripheral/chest wall lesions were significantly more likely to fail first in the thorax when treated on STD RT compared to CT + RT and HFX RT (p = 0.009). Survival rates were similar among the treatment arms for patients with squamous cell carcinoma. Among patients with nonsquamous cell carcinoma, failure patterns did not differ by treatment group, but survival was significantly better in those who were treated by induction chemotherapy (p = 0.04). CONCLUSION: Patients with squamous cell carcinoma treated on the CT + RT arm had a significant reduction of first DM other than brain, but there was difference in survival. Survival favored CT + RT in nonsquamous carcinoma despite similar failure patterns. Reasons for improved survival with CT + RT in NSCLC are not yet available.