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Diffuse large B cell lymphoma (DLBCL) is an aggressive but potentially curable malignancy; however, cure is highly dependent on the ability to deliver intensive, anthracycline-based chemoimmunotherapy. Nearly one third of cases of DLBCL occur in patients over age 75 years, and advanced age is an important adverse feature in prognostic models. Despite this incidence in older patients, there is no clear accepted standard of care due to under-representation of this group in large randomized clinical trials. Furthermore, insufficient assessments of baseline frailty and prediction of toxicity hamper clinical decision-making. Here, we present an ongoing randomized study of R-miniCHOP chemoimmunotherapy with or without oral azacitidine (CC-486, Onureg) for patients age 75 and older with newly diagnosed DLBCL and associated aggressive lymphomas. The incorporation of an oral hypomethylating agent is based on increased tumor methylation as a biologic feature of older patients with DLBCL and a desire to minimize the injection burden for this population. This is the first randomized study in this population conducted in North America by the National Clinical Trials Network (NCTN) and will enroll up to 422 patients including 40 patients in a safety run-in phase. This study incorporates an objective assessment of baseline frailty (the FIL Tool) and a serial comprehensive geriatric assessment (CGA). Key correlative tests will include circulating tumor DNA (ctDNA) assays at pre-specified timepoints to explore if ctDNA quantity and methylation patterns correlate with response. S1918 has the potential to impact future trial design and to change the standard of care for patients 75 years and older with aggressive lymphoma given its randomized design, prospective incorporation of geriatric assessments, and exploration of ctDNA correlatives. Trial registration: The trial is registered with ClinicalTrial.gov Identifier NCT04799275 [ABSTRACT FROM AUTHOR]

Abstract: N-tosyl-l-phenylalanyl-chloromethyl ketone (TPCK) suppresses apoptosis and protects neurons from damage in animal models. TPCK is thought to act by inhibiting ceramide production by sphingomyelinase. Ceramide is a proapoptotic intracellular signal that is involved in the cerebral ischemia. We wished to see whether ceramide contributes to TPCK''s neuroprotective effects in vivo. Seven-day-old rat pups had the right carotid arteries permanently ligated followed by 2.5 h of hypoxia (8% oxygen). TPCK (10 mg/kg, n =62) or vehicle (n =63) was administered by i.p. 5 min prior to hypoxia. The level of ceramide in brain cortex both in lesioned and unlesioned hemispheres was measured at 8 h, 18 h, 24 h, 2 and 5 days after hypoxia–ischemia using reversed phase high performance liquid chromatography. The level of ceramide significantly increased due to hypoxic–ischemia at 18, 24 h and 2 days after hypoxia (P <0.05 or P <0.01) but not at 8 h or 5 days after hypoxia as compared to the contralateral hemisphere or a sham group. Pretreatment with TPCK reduced this increase. We also examined the level of sphingomyelin and the activities of the ceramide synthesizing sphingomyelinase enzymes by thin layer chromatography. The activities of acidic and neutral sphingomyelinase significantly increased due to hypoxic ischemia at 24 h after hypoxia. TPCK significantly reduced this increase (P <0.05 vs. vehicle) but did not affect the level of sphingomyelin. The results are consistent with the hypothesis that ceramide is involved in TPCK''s neuroprotective effects in hypoxic–ischemic brain injury in the newborn rat. [Copyright &y& Elsevier]

Abstract: Glutamate has been implicated in the initiation and spread of seizure activity. Agmatine, an endogenous neuromodulator, is an antagonist of NMDA receptors and has anticonvulsive effects. Whether agmatine regulate glutamate release, as measured by in vivo microdialysis, is not known. In this study, we used pentylenetetrazole (PTZ)-induced seizure model to determine the effect of agmatine on extracellular glutamate in rat brain. We also determined the time course and the amount of agmatine that reached brain after peripheral injection. After i.p. injection of agmatine (50mg/kg), increase of agmatine in rat cortex and hippocampus was observed in 15min with levels returning to baseline in one hour. Rats, naïve and implanted with microdialysis cannula into the cortex, were administered PTZ (60mg/kg, i.p.) with prior injection of agmatine (100mg/kg, i.p.) or saline. Seizure grades were recorded and microdialysis samples were collected every 15min for 75min. Agmatine pre-treatment significantly reduced the seizure grade and increased the onset time. The levels of extracellular glutamate in frontal cortex rose two- to three-fold after PTZ injection and agmatine significantly inhibited this increase. In conclusion, the present data suggest that the anticonvulsant activity of agmatine, in part, could be related to the inhibition glutamate release. [Copyright &y& Elsevier]

The results of the Prostate Cancer Prevention Trial spurred debate because finasteride was found to reduce the period prevalence of prostate cancer by about 25% while also increasing the rate of high-grade prostate cancers. Assessing how finasteride would impact mortality at the population level is key to evaluating the public health implications of these results. Any model for evaluating the impact of chemoprevention at the population level will involve methods for assigning weights to competing outcomes of the chemoprevention. The person-years saved model, which uses survival to weigh outcomes, assesses the impact on population mortality and has particular strengths. The person-years saved model shows that more than 300,000 person-years would be saved during a period of 10 years with the widespread use of finasteride, assuming no change in the rate of high-grade prostate cancers. The rate of high-grade prostate cancers in the population, about 20% in any given year, would have to nearly triple to 60% for the net positive impact of finasteride to be zero. The person-years saved model shows that the administration of finasteride is likely to result in a net positive impact of finasteride on population mortality, even with an increase in the rate of high-grade prostate cancers. Future models may use other outcomes to assess population impact, including economic, quality-of-life, or various combinations of outcomes. [Copyright &y& Elsevier]

Abstract: Nicotinamide reduces ischemic brain injury in adult rats. Can similar brain protection be seen in newborn animals? Seven-day-old rat pups had the right carotid artery permanently ligated followed by 2.5h of 8% oxygen. Nicotinamide 250 or 500mg/kg was administered i.p. 5min after reoxygenation, with a second dose given at 6h after the first. Brain damage was evaluated by weight deficit of the right hemisphere at 22 days following hypoxia. Nicotinamide 500mg/kg reduced brain weight loss from 24.6±3.6% in vehicle pups (n =28) to 11.9±2.6% in the treated pups (n =29, P <0.01), but treatment with 250mg/kg did not affect brain weight. Nicotinamide 500mg/kg also improved behavior in rotarod performance. Levels of 8-isoprostaglandin F2α measured in the cortex by enzyme immune assay 16h after reoxygenation was 115±7pg/g in the shams (n =6), 175±17pg/g in the 500mg/kg nicotinamide treated (n =7), and 320±79pg/g in the vehicle treated pups (n =7, P <0.05 versus sham, P <0.05 versus nicotinamide). Nicotinamide reduced the increase in caspase-3 activity caused by hypoxic ischemia (P <0.01). Nicotinamide reduces brain injury in the neonatal rat, possibly by reducing oxidative stress and caspase-3 activity. [Copyright &y& Elsevier]

Abstract: Previous work has established that 1-benzyl-1,2,3,4-tetrahydroisoquinoline (1-BnTIQ) causes a parkinsonian syndrome in rats. The present study reports the blood–brain barrier (BBB) permeability of 1-BnTIQ in freely moving rats with the aid of in vivo microdialysis-based measurements. The microdialysis probe was implanted in the frontal cortex of rat brain. Brain dialysate samples were analyzed using an HPLC-MS/MS assay. 1-BnTIQ, when administered i.p., dose-dependently appeared in brain extracellular fluid (ECF), reaching a maximum concentration after about 40min. Two other tetrahydroisoquinoline derivatives, 1,2,3,4-tetrahydroisoquinoline (TIQ) and 6,7-dihydroxy-1-methyl-1,2,3,4-tetrahydroisoquinoline [salsolinol (SAL)], served as positive and negative controls, respectively. The results confirmed an earlier report that SAL does not reach the brain after i.p. administration. In contrast, TIQ readily passed through the BBB. The brain dialysate concentration of 1-BnTIQ was about 24% that of TIQ when administered i.p. at the same dose. Both of them decreased quickly with a half-life of about 50min. [Copyright &y& Elsevier]

Abstract: Focal cerebral hypoxia–ischemia due to isolated vascular insufficiency is well known to cause ipsilateral, but not contralateral, cerebral apoptosis. Hypoxic–ischemic damage to the cerebellum and brainstem in such a model has not been established. This experimental rodent study demonstrates, through deoxyribonucleic acid fragmentation and terminal deoxynucleotidyl transferase-mediated deoxyuridine 5′-triphosphate-digoxigenin nick end labeling analysis, that neuronal cells in these infratentorial regions also suffer mild apoptosis and necrosis after focal cerebral hypoxic–ischemic injury in the newborn rat. These data provide additional insight into the mechanisms of neurological injury in the cerebellum and brainstem areas resulting from a focal cerebral hypoxic–ischemic insult and demonstrate that future therapeutic interventions for hypoxic–ischemic encephalopathy system should deal with the entire central nervous system. [Copyright &y& Elsevier]

Abstract: Estrogen is neuroprotective in adult animals. We wished to determine if estrogen protects against brain injury in the newborn. Four-day-old rat pups were treated with subcutaneously implanted pellets containing 0.05 mg (2.4 μg/day) of 17β-estradiol or vehicle, designed to release the estrogen over 21 days. At 7 days old the pups had the right carotid artery ligated followed by 2.5 h of 8% oxygen. Brain damage was evaluated by weight deficit of the right hemisphere at 22 days following hypoxia. Estradiol treatments reduced brain weight loss from −17.4±2.8% S.E.M. in the vehicle group (n=32) to −9.3±2.7% in the treated group (n=32, P&#60;0.05). Brain cortex thiobarbituric acid reacting substances and caspase activities were assessed 24 h after reoxygenation. Estradiol significantly reduced a hypoxia-induced increase in brain thiobarbituric acid reactive substances (P&#60;0.05). Levels of caspase-3, -8 and -9 activity increased due to hypoxia–ischemia. Estradiol had no effect on caspase activity. Estradiol reduced brain injury in the neonatal rat. [Copyright &y& Elsevier]

Tamoxifen, an estrogen receptor modulator, is neuroprotective in adult rats. Does tamoxifen reduce brain injury in the rat pup? Seven-day-old rat pups had the right carotid artery permanently ligated followed by 2.5 h of hypoxia (8% oxygen). Tamoxifen (10 mg/kg) or vehicle was given i.p. 5 min prior to hypoxia, or 5 min after reoxygenation, with a second dose given 6 h after the first. Brain damage was evaluated by weight deficit of the right hemisphere 22 days following hypoxia and gross and microscopic morphology. Tamoxifen pre-treatment reduced brain weight loss from 21.5±4.0% in vehicle pups (n=27) to 2.6±2.5% in the treated pups (n=22, P<0.05). Treatment 5 min after reoxygenation reduced brain weight loss from 27.5±4.0% in vehicle pups (n=42) to 12.0±3.9% in the treated pups (n=30, P<0.05). Tamoxifen reduces brain injury in the neonatal rat. [Copyright &y& Elsevier]

A broad spectrum caspase inhibitor reduces brain injury. Will a caspase-8 inhibitor provide protection? Seven-day-old rat pups had the right carotid artery ligated, then were subjected to 2.5 h of 8% oxygen. Caspase-8 activity in the right cortex was measured enzymatically. Caspase-8 activity was increased at 12 and 24 h after injury and IETD-CHO, (Ac-Ala-Ala-Val-Ala-Leu-Leu-Pro-Ala-Val-Leu-Leu-Ala-Pro-Ile-Glu-Thr-Asp-CHO, CHO is aldehyde) a cell permeable caspase-8 inhibitor, given by i.c.v. injection after the hypoxic period eliminated this increase with significant effect at 15 and 50 μg/pup (1.7 μmol/kg). Thirty pups were randomly assigned to receive 50 μg/pup of IETD-CHO or vehicle i.c.v. immediately after the hypoxic period. The loss of brain weight in the right hemisphere 22 days after injury was 29±5% in the vehicle-treated animals and 12±5% in the IETD-CHO-treated animals (P<0.05). Inhibiting caspase-8 activity after hypoxic–ischemic brain injury reduces brain injury. [Copyright &y& Elsevier]

A broad spectrum caspase inhibitor reduces hypoxic ischemic brain injury. We hypothesized that a specific caspase-9 inhibitor would provide similar protection. Seven-day-old rat pups had the right carotid artery ligated, then were subjected to 2.5 h of 8% oxygen. Caspase-9 activity in the right cortex was measured enzymatically. Caspase-9 activity was increased at 6, 12, and 24 h after injury. LEHD-CHO is a specific cell permeable caspase-9 inhibitor. LEHD-CHO given intracerebroventricularly (i.c.v.) into the brain after the hypoxic period eliminated the increase in caspase-9 activity. The greatest effect was at a dose of 50 μg/pup (1.6 μmol/kg). Fifty-two pups were randomly assigned to receive 50 μg/pup of i.c.v. LEHD-CHO or vehicle immediately after the hypoxic period. The loss of cortical neurons in the right hemisphere 22 days after injury was 52.0±8% in the vehicle treated animals, and 25±9% in the LEHD-CHO treated animals (P<0.05). Inhibiting caspase-9 activity reduces loss of neurons after brain injury. [Copyright &y& Elsevier]

Background: The Lung Cancer Master Protocol (Lung-MAP; S1400) is a completed biomarker-driven master protocol designed to address an unmet need for better therapies for squamous non-small-cell lung cancer. Lung-MAP (S1400) was created to establish an infrastructure for biomarker screening and rapid regulatory intent evaluation of targeted therapies and was the first biomarker-driven master protocol initiated with the US National Cancer Institute (NCI).Methods: Lung-MAP (S1400) was done within the National Clinical Trials Network of the NCI using a public-private partnership. Eligible patients were aged 18 years or older, had stage IV or recurrent squamous non-small-cell lung cancer, had previously been treated with platinum-based chemotherapy, and had an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2. The study included a screening component using the FoundationOne assay (Foundation Medicine, Cambridge, MA, USA) for next-generation sequencing, and a clinical trial component with biomarker-driven substudies and non-match substudies for patients who were ineligible for biomarker-driven substudies. Patients were pre-screened and received their substudy assignment upon progression, or they were screened at progression and received their substudy assignment upon completion of testing. Patients could enrol onto additional substudies after progression on a substudy. The study is registered with ClinicalTrials.gov, NCT02154490, and all research related to Lung-MAP (S1400) is completed.Findings: Between June 16, 2014, and Jan 28, 2019, 1864 patients enrolled and 1841 (98·9%) submitted tissue. 1674 (90·9%) of 1841 patients had biomarker results, and 1404 (83·9%) of 1674 patients received a substudy assignment. Of the assigned patients, 655 (46·7%) registered to a substudy. The biomarker-driven substudies evaluated taselisib (targeting PIK3CA alterations), palbociclib (cell cycle gene alterations), AZD4547 (FGFR alteration), rilotumumab plus erlotinib (MET), talazoparib (homologous recombination repair deficiency), and telisotuzumab vedotin (MET). The non-match substudies evaluated durvalumab, and nivolumab plus ipilimumab for anti-PD-1 or anti-PD-L1-naive disease, and durvalumab plus tremelimumab for anti-PD-1 or anti-PD-L1 relapsed disease. Combining data from the substudies, ten (7·0%) of 143 patients responded to targeted therapy, 53 (16·8%) of 315 patients responded to anti-PD-1 or anti-PD-L1 therapy for immunotherapy-naive disease, and three (5·4%) of 56 responded to docetaxel in the second line of therapy. Median overall survival was 5·9 months (95% CI 4·8-7·8) for the targeted therapy groups, 7·7 months (6·7-9·2) for the docetaxel groups, and 10·8 months (9·4-12·3) for the anti-PD-1 or anti-PD-L1-containing groups. Median progression-free survival was 2·5 months (95% CI 1·7-2·8) for the targeted therapy groups, 2·7 months (1·9-2·9) for the docetaxel groups, and 3·0 months (2·7-3·9) for the anti-PD-1 or anti-PD-L1-containing groups.Interpretation: Lung-MAP (S1400) met its goal to quickly address biomarker-driven therapy questions in squamous non-small-cell lung cancer. In early 2019, a new screening protocol was implemented expanding to all histological types of non-small-cell lung cancer and to add focus on immunotherapy combinations for anti-PD-1 and anti-PD-L1 therapy-relapsed disease. With these changes, Lung-MAP continues to meet its goal to focus on unmet needs in the treatment of advanced lung cancers.Funding: US National Institutes of Health, and AbbVie, Amgen, AstraZeneca, Bristol Myers Squibb, Genentech, and Pfizer through the Foundation for the National Institutes of Health. [ABSTRACT FROM AUTHOR]

Serration phenomena during tensile testing on certain alloys with diffusing solute atoms (i.e., Portevin–Le Chatelier effect) have been observed for a long time, but detailed mechanisms are not fully clear yet. This study is intended to find the mechanism from different approaches verified by tensile testing on a series of single-phase face-centered-cubic (FCC) pure metal and alloys: Ni, CoNi, CoFeNi, CoCrFeNi, and CoCrFeMnNi, which range from low to high configurational entropy. The results of tensile tests, at strain rates from 1 × 10−5 to 1 × 10−2/s and temperature from room temperature to 700 °C, show that serrations occur on stress-strain curves of CoFeNi, CoCrFeNi, and CoCrFeMnNi alloys in their specific temperature and strain-rate regime. A mechanism for dislocation pinning is proposed and verified with theoretical calculation for the present substitutional alloys. The proposed mechanism involves the in-situ rearrangement of substitutional solute atoms by "local dislocation-core diffusion" and might also be applied to similar substitutional alloys. Image 1 • PLC effect and its trend are identified in Ni, CoNi, CoFeNi, CoFeNiCr, and CoCrFeMnNi alloys from low to high entropy. • Actual mechanism of PLC effect relating with in-situ dislocation pinning by dislocation-core diffusion is proved. • The mechanism could be generalized to substitutional solid solution alloys. [ABSTRACT FROM AUTHOR]

Based on promising pilot data a phase II tandem autologous hematopoietic stem cell transplant (AHSCT) trial for relapsed/refractory Hodgkin lymphoma (HL) was performed in the US intergroup setting to determine if long-term progression-free survival (PFS) could be improved. Patients were enrolled after salvage therapy and stem cell collection. Sensitivity to salvage was defined by 1999 Standardized Response Criteria and did not include fluorodeoxyglucose-positron emission tomography. Cycle 1 consisted of melphalan 150 mg/m 2 with half of the stem cells. For stable disease or better, patients received cycle 2 consisting of single doses of etoposide 60 mg/kg and cyclophosphamide 100 mg/kg and either total body radiation 12 Gy in 8 fractions over 4 days or BCNU 150 mg/m 2 /day for 3 days with the remaining stem cells. Of 98 enrolled patients, 89 were eligible and treated: 82 completed both cycles of AHSCT, 47 (53%) had primary refractory HL, and 72 (81%) were resistant to salvage therapy. There were no treatment-related deaths in the first year after AHSCT. With a median follow-up of 6.2 years (range, 2 to 7.7) for eligible patients who remained alive, the 2-year and 5-year PFS were 63% (95% CI, 52% to 72%) and 55% (95% CI, 44% to 64%) respectively; the 2-year and 5-year overall survival were 91% (95% CI, 83% to 95%) and 84% (95% CI, 74% to 90%), respectively. Univariate Cox regression analysis showed Zubrod performance status and lactate dehydrogenase levels > 1 times upper limit of normal at the time of enrollment were significantly associated with PFS. The observed 5-year PFS of 55% suggests the tandem approach appears to be effective in treating HL patients demonstrated to have poor prognosis in prior single AHSCT trials. This trial was registered at www.clinicaltrials.gov as NCT00233987. [ABSTRACT FROM AUTHOR]

Stress testing or forced degradation studies of denagliptin (1) tosylate in solution and solid-state, its blends with excipients, and capsules were conducted in order to elucidate degradation pathways, aid formulation development, and generate data to support regulatory filings. In solution, denagliptin was stressed in acid, water, and base using organic cosolvents. In the solid-state, denagliptin was stressed under heat, humidity, and light. Blends of denagliptin with various excipients were stressed under heat and humidity in order to evaluate whether tablet was a viable dosage form. Capsules were stressed under heat, humidity, and light. It was found that denagliptin was stable in the solid-state, but degraded in solution, in blends with all excipients, and in capsules predominantly by cyclization to (3S,7S,8aS) amidine (2), which epimerized to (3S,7S,8aR) amidine (3). (3S,7S,8aR) amidine (3) subsequently hydrolyzed to the corresponding diketopiperazine (4). The purpose of this manuscript is to discuss the results of stress testing studies conducted during the development of denagliptin and the elucidation of its key degradation pathway. © 2010 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99:3030–3040, 2010 [ABSTRACT FROM AUTHOR]

Abstract: Oxygen radicals play a crucial role in brain injury. Grape seed extract is a potent anti-oxidant. Does grape seed extract reduce brain injury in the rat pup? Seven-day-old rat pups had the right carotid arteries permanently ligated followed by 2.5h of hypoxia (8% oxygen). Grape seed extract, 50mg/kg, or vehicle was administered by i.p. 5min prior to hypoxia and 4h after reoxygenation and twice daily for 1 day. Brain damage was evaluated by weight deficit of the right hemisphere at 22 days following hypoxia and by histopathology. Grape seed extract reduced brain weight loss from 20.0±4.4% S.E.M. in vehicle pups (n =21) to 3.1±1.6% in treated pups (n =20, P &#60;0.01). Grape seed extract improved the histopathologic brain score in cortex, hippocampus and thalamus (P &#60;0.05 versus vehicle). Concentrations of brain 8-isoprostaglandin F2α and thiobarbituric acid reacting substances significantly increased due to hypoxic ischemia. Grape seed extract reduced this increase. Treatment with grape seed extract suppresses lipid peroxidation and reduces hypoxic ischemic brain injury in neonatal rat. [Copyright &y& Elsevier]

Purpose: Image localization of head-and-neck squamous cell carcinoma lags behind current techniques to deliver a precise radiation dose with intensity-modulated radiotherapy. This pilot study prospectively examined the use of registered 18-F-fluorodeoxyglucose (FDG)-positron emission tomography (PET)/CT for preradiotherapy staging of the neck. Methods and Materials: Sixty-three patients with squamous cell carcinoma of the oral cavity, oropharynx, larynx, or hypopharynx were enrolled into an institutional FDG-PET imaging protocol between September 2000 and June 2003. Of these patients, 20 went on to immediate neck dissection surgery and were studied further. Of these 20, 17 (85%) had American Joint Committee on Cancer Stage III or IV disease. All patients underwent preoperative FDG-PET and contrast-enhanced CT of the head and neck. FDG-PET/CT images were created using a nonrigid image registration algorithm developed at the University of Washington. Alternate primary and nodal gross tumor volumes were contoured with radiotherapy treatment planning software, blinded to each other and to the pathology results. One set of volumes was designed with CT guidance alone and the other with the corresponding FDG-PET/CT images. Neck dissection specimens were subdivided into surgical nodal levels intraoperatively, and the histopathologic findings were correlated with the CT and FDG-PET/CT nodal level findings. Results: FDG-PET/CT detected 17 of 17 heminecks and 26 of 27 nodal zones histologically positive by dissection (100% and 96% sensitivity, respectively). The nodal level staging sensitivity and specificity for FDG-PET/CT was 96% (26 of 27) and 98.5% (68 of 69), respectively. FDG-PET/CT correctly detected nodal disease in 2 patients considered to have node-negative disease by CT alone. Agreement between the imaging results and pathology findings was stronger for FDG-PET/CT (kappa 0.95, 95% confidence interval 0.82-0.99) than for CT alone (kappa 0.81, 95% confidence interval 0.63-0.91; p = 0.06 by two-sided McNemar's testing). Conclusion: These early findings suggest that FDG-PET/CT is superior to CT alone for geographic localization of diseased neck node levels. Confirmatory trials to substantiate the accuracy of FDG-PET/CT neck staging should be prioritized. [ABSTRACT FROM AUTHOR]

Several single-institution pilot studies have suggested that augmented preparative regimens, including those containing total body irradiation combined with an autologous bone marrow transplantation, are superior to standard regimens for the treatment of relapsed or refractory Hodgkin disease. On the basis of these data, we undertook, in the cooperative group setting, a phase II trial of augmented preparative regimens for patients experiencing treatment failure with conventional chemotherapy. Eighty-one patients with either sensitive or refractory (induction failures or chemoresistant) relapse received etoposide (60 mg/kg), cyclophosphamide (100 mg/kg), and either total body irradiation (12 Gy) or, if previously irradiated, carmustine (15 mg/kg), followed by an autologous bone marrow transplantation. Progression-free (PFS) and overall (OS) survival were estimated, and a Cox regression model was used to assess potential prognostic variables. The 5-year PFS and OS for the 74 eligible patients treated at 20 Southwest Oncology Group centers were 41% (95% confidence interval [CI], 29%–53%) and 54% (95% CI, 43%–65%), respectively, despite a median remission after initial chemotherapy of only 6 months. The 3-year OS for those whose induction therapy failed was 72% (95% CI, 52%–93%). There was 1 (1.4%) early treatment-related death, 2 late deaths due to lung toxicity, and only 1 death due to myelodysplasia. There were no differences in PFS or OS on the basis of regimen or chemosensitivity. A Cox prognostic factor analysis determined that >2 prior regimens, relapse in a radiated field, and extranodal disease were adverse prognostic factors. Among the 46 patients who received prior radiotherapy, the 5-year OS was 38% (95% CI, 14%–61%) for patients with 2 or 3 adverse factors, versus 60% (95% CI, 42%–78%) for those with 0 factors or 1 adverse factor. Augmented preparative regimens seem promising for the treatment of relapsed or refractory Hodgkin disease, without an increase in regimen-related mortality. A poor-prognosis group was identified that should be treated with novel therapies. [Copyright &y& Elsevier]

The purpose of the present study was to determine whether oxypurinol, a xanthine oxidase inhibitor, reduces free radicals and brain injury in the rat pup hypoxic–ischemia (HI) model. Seven-day-old rat pups had right carotid arteries ligated followed by 2.5 h of hypoxia (8% oxygen). Oxypurinol or vehicle was administered by i.p. injection at 5 min after reoxygenation and once daily for 3 days. Brain damage was evaluated by weight deficit of the right hemisphere at 22 days following hypoxia. Oxypurinol treatments did not reduce weight loss in the right hemisphere. Brain weight loss in the right hemisphere were −26.2±3.6, −15.2±6.9, −21.7±4.4, −15.8±5.1, and −16.7±3.4% in vehicle (n=33), 10 (n=17), 20 (n=16), 40 (n=15), and 135 mg/kg (n=13) oxypurinol-treated groups (p>0.05), respectively. Brain thiobarbituric acid-reacting substances (TBARS) were assessed 3 and 6 h after reoxygenation. Concentrations of TBARS rose 1.5-fold due to HI. Oxypurinol did not significantly reduce an HI-induced increase in brain TBARS. Thus, xanthine oxidase may not be the primary source of oxy-radicals in pup brain and as such oxypurinol does not prevent free radical-mediated lipid peroxidation or protect against brain injury in the neonatal rat HI model. [Copyright &y& Elsevier]