Triterpenoid Hydroxamates as HIF Prolyl Hydrolase Inhibitors.

Pentacyclic triterpenoid acids (PCTTAs) are pleiotropic agents that target many macromolecular end-points with low to moderate affinity. To explore the biological space associated with PCTTAs, we have investigated the carboxylate-to-hydroxamate transformation, discovering that it de-emphasizes affinity for the transcription factors targeted by the natural compounds (NF-κB, STAT3, Nrf2, TGR5) and selectively induces inhibitory activity on HIF prolyl hydrolases (PHDs). Activity was reversible, isoform-selective, dependent on the hydroxamate location, and negligible when this group was replaced by other chelating elements or O-alkylated. The hydroxamate of betulinic acid (5b) was selected for further studies, and evaluation of its effect on HIF-1α expression under normal and hypoxic conditions qualified it as a promising lead structure for the discovery of new candidates in the realm of neuroprotection.

Allergological characterisation of the storage mite Acarus gracilis (Acari: Acaridae).

BACKGROUND: Storage mites of the genus Acarus can be responsible for allergic sensitisation in domestic environments. Acarus gracilis is a frequent species in some geographical regions of the Iberian Peninsula. Since the allergenicity of this mite has not been described before, the objectives of this study were to characterise it immunologically, and to compare it with the closely related and more extensively studied species Acarus siro. METHODS: Extracts from A. gracilis and A. siro cultures were characterised by Lowry, 1D and 2D-SDS and IEF. Zymogram, and determination of different enzymatic activities were performed. Skin prick solution of A. gracilis was tested in consecutive patients attending the Hospital of Mérida (Extremadura, Spain). Serum samples from eight individuals with positive skin prick test were collected. IgE determination, immunoblot and immunoblot-inhibition studies were performed. RESULTS: Extracts of both species showed a very similar protein and allergenic profile. Allergens at 14 and 17 kDa were clearly recognised in both extracts by serum samples. Immunoblot-inhibition studies demonstrated that both extracts were totally inhibited by the opposite one. Enzymatic activity was similar in both cases with the most important differences being in kallikrein, serine protease and collagenase activities. CONCLUSION: The storage mite A. gracilis has a similar protein and allergen profile to A. siro and can induce allergic sensitisation. Due to the higher prevalence of this species respect to A. siro in some regions, more studies are needed to determine the clinical significance of sensitisation to this storage mite species.

Impact of systemic corticosteroids on length of hospitalization among patients with COVID-19. / [Artículo traducido] Impacto de los corticoides sistémicos en el tiempo de hospitalización en pacientes con COVID-19.

OBJECTIVE: The COVID-19 pandemic has posed a threat to hospital capacity due to the high number of admissions, which has led to the development of various strategies to release and create new hospital beds. Due to the importance of systemic corticosteroids in this disease, we assessed their efficacy in reducing the length of stay (LOS) in hospitals and compared the effect of 3 different corticosteroids on this outcome. MéTHOD: We conducted a real-world, controlled, retrospective cohort study that analysed data from a hospital database that included 3934 hospitalised patients diagnosed with COVID-19 in a tertiary hospital from April to May 2020. Hospitalised patients who received systemic corticosteroids (CG) were compared with a propensity score control group matched by age, sex and severity of disease who did not receive systemic corticosteroids (NCG). The decision to prescribe CG was at the discretion of the primary medical team. RESULTS: A total of 199 hospitalized patients in the CG were compared with 199 in the NCG. The LOS was shorter for the CG than for the NCG (median=3 [interquartile range=0-10] vs. 5 [2-8.5]; p=0.005, respectively), showing a 43% greater probability of being hospitalised ≤4 days than >4 days when corticosteroids were used. Moreover, this difference was only noticed in those treated with dexamethasone (76.3% hospitalised ≤4 days vs. 23.7% hospitalised >4 days [p<0.001]). Serum ferritin levels, white blood cells and platelet counts were higher in the CG. No differences in mortality or intensive care unit admission were observed. CONCLUSIONS: Treatment with systemic corticosteroids is associated with reduced LOS in hospitalised patients diagnosed with COVID-19. This association is significant in those treated with dexamethasone, but no for methylprednisolone and prednisone.

Influenza-like illness in pregnant women during summertime: clinical, epidemiological and microbiological features.

It is not known whether influenza-like illnesses (ILI) in pregnant women caused by influenza virus, specifically, those caused by the 2009 Influenza A H1N1 virus (nH1N1), can be clinically distinguished from those caused by other agents. From 1st July 2009 until 20th September 2009, an observational study including all pregnant women presenting at Hospital Universitario La Paz with an ILI was carried out. A specific reverse-transcriptase polymerase chain reaction (RT-PCR) for nH1N1 in nasopharyngeal swabs was prospectively carried out in all patients. Retrospectively, samples were analysed for multiple respiratory virus panel (RT-PCR microarray). Clinical, demographical and other microbiological variables were evaluated as well. A total of 45 pregnant women with ILI were admitted. Of these, 14 (31.1%) women had nH1N1 infection and 11 with a non-influenza ILI (35.48%) were positive for other viruses (five rhinovirus, four parainfluenza virus, one bocavirus and one adenovirus). In 20 patients, no aetiologic agent was identified. The clinical course of nH1N1 was mild, without deaths or severe complications. No significant differences were found when comparing the clinical presentation and course of patients with and without nH1N1 infection. Six women with nH1N1 infection received oseltamivir. Influenza and non-influenza ILI were clinically indistinguishable among pregnant women. Many ILI in pregnant women remain undiagnosed, despite undergoing an RT-PCR microarray for several respiratory viruses.

NSAID-sensitive antihistamine-induced urticaria/angioedema.

We present a case of urticaria caused by antihistamines in a patient with nonsteroidal anti-inflammatory drug (NSAID) sensitivity. A 35-year-old man experienced, on 2 separate occasions, immediate generalized urticaria during treatment with ibuprofen and naproxen, respectively. A single-blind, placebo-controlled oral challenge (SBPCOC) with piroxicam was carried out, and resulted in urticaria and angioedema 3 hours later. Two hours after initial clinical resolution, the patient developed multiple wheals on the trunk and upper limbs. He described similar delayed reactions after oral antihistamine administration on previous occasions. SBPCOCs with acetaminophen and etoricoxib were performed, with good tolerance. Skin prick and patch tests with loratadine and cetirizine were negative. After an SBPCOC with loratadine, the patient developed generalized urticaria 90 minutes after intake. Tolerance to fexofenadine 180 mg was confirmed. We describe the first case of a possible new subset of antihistamine urticaria, and suggest calling this NSAID-sensitive antihistamine-induced urticaria/angioedema.

Pilot Study of Hyperpolarized 13C Metabolic Imaging in Pediatric Patients with Diffuse Intrinsic Pontine Glioma and Other CNS Cancers.

BACKGROUND AND PURPOSE: Pediatric CNS tumors commonly present challenges for radiographic interpretation on conventional MR imaging. This study sought to investigate the safety and tolerability of hyperpolarized carbon-13 (HP-13C) metabolic imaging in pediatric patients with brain tumors. MATERIALS AND METHODS: Pediatric patients 3 to 18 years of age who were previously diagnosed with a brain tumor and could undergo MR imaging without sedation were eligible to enroll in this safety study of HP [1-13C]pyruvate. Participants received a one-time injection of HP [1-13C]pyruvate and were imaged using dynamic HP-13C MR imaging. We assessed 2 dose levels: 0.34 mL/kg and the highest tolerated adult dose of 0.43 mL/kg. Participants were monitored throughout imaging and for 60 minutes postinjection, including pre- and postinjection electrocardiograms and vital sign measurements. RESULTS: Between February 2017 and July 2019, ten participants (9 males; median age, 14 years; range, 10-17 years) were enrolled, of whom 6 completed injection of HP [1-13C]pyruvate and dynamic HP-13C MR imaging. Four participants failed to undergo HP-13C MR imaging due to technical failures related to generating HP [1-13C]pyruvate or MR imaging operability. HP [1-13C]pyruvate was well-tolerated in all participants who completed the study, with no dose-limiting toxicities or adverse events observed at either 0.34 (n = 3) or 0.43 (n = 3) mL/kg. HP [1-13C]pyruvate demonstrated characteristic conversion to [1-13C]lactate and [13C]bicarbonate in the brain. Due to poor accrual, the study was closed after only 3 participants were enrolled at the highest dose level. CONCLUSIONS: Dynamic HP-13C MR imaging was safely performed in 6 pediatric patients with CNS tumors and demonstrated HP [1-13C]pyruvate brain metabolism.

Tetrahydrocannabinolic acid A (THCA-A) reduces adiposity and prevents metabolic disease caused by diet-induced obesity.

Medicinal cannabis has remarkable therapeutic potential, but its clinical use is limited by the psychotropic activity of Δ9-tetrahydrocannabinol (Δ9-THC). However, the biological profile of the carboxylated, non-narcotic native precursor of Δ9-THC, the Δ9-THC acid A (Δ9-THCA-A), remains largely unexplored. Here we present evidence that Δ9-THCA-A is a partial and selective PPARγ modulator, endowed with lower adipogenic activity than the full PPARγ agonist rosiglitazone (RGZ) and enhanced osteoblastogenic effects in hMSC. Docking and in vitro functional assays indicated that Δ9-THCA-A binds to and activates PPARγ by acting at both the canonical and the alternative sites of the ligand-binding domain. Transcriptomic signatures in iWAT from mice treated with Δ9-THCA-A confirmed its mode of action through PPARγ. Administration of Δ9-THCA-A in a mouse model of HFD-induced obesity significantly reduced fat mass and body weight gain, markedly ameliorating glucose intolerance and insulin resistance, and largely preventing liver steatosis, adipogenesis and macrophage infiltration in fat tissues. Additionally, immunohistochemistry, transcriptomic, and plasma biomarker analyses showed that treatment with Δ9-THCA-A caused browning of iWAT and displayed potent anti-inflammatory actions in HFD mice. Our data validate the potential of Δ9-THCA-A as a low adipogenic PPARγ agonist, capable of substantially improving the symptoms of obesity-associated metabolic syndrome and inflammation.

Successful kidney transplantation reduces hyperplastic parathyroid gland.

INTRODUCTION: In dialysis patients, the parathyroid glands (PTGs) may increase progressively, producing abnormal bone metabolism. Changes in PTG volume among patients with hyperplastic PTGs are not well known after kidney transplantation. This study investigated PTG volume by ultrasound (US). METHODS: US of PTG was performed immediately (US-0) and 12 months after (US-12) transplantation to identify glands in all recipients. We calculated the percentage reduction in PTG volume (R%PTG). We declared it significant when it was > or =35%. Bone biochemical markers and renal function were recorded sequentially. RESULTS: Among engrafted patients, parathyroid US-0 was performed in 47 and US-0 and US-12 in 36. Some visible gland was observed upon US-0 in 13 recipients, a group that showed higher pretransplantation parathyroid hormone (PTH) levels than the remaining 34 patients with no visible glands (627 +/- 360.0 vs 280 +/- 240.9 pg/mL; P < .05). Of 36 recipients with US-0 and US-12, the baseline study identified PTGs in 12 patients (p+ group), while the remaining 24 had no identified glands (p- group). In the p+ group, no PTG, at US-12 were visible in four patients, and a significant R%PTG was observed in three at this time, representing a reduction in gland volume after transplantation among 58.3% of p+ patients. There was a progressive reduction in PTH among both groups. Patients with glandular volume reduction displayed better renal function: serum creatinine 1.7 +/- .79 versus 2.9 +/- .74 mg/dL (P < .05). CONCLUSIONS: Transplantation reversed hyperparathyroidism and PTG volume among recipients who achieved nearly normal renal function.

Safety and Efficacy of Prasugrel and Ticagrelor in Acute Coronary Syndrome. Results of a "Real World" Multicenter Registry.

INTRODUCTION AND OBJECTIVES: The incorporation of the new antiplatelet agents (NAA) prasugrel and ticagrelor into routine clinical practice is irregular and data from the "real world" remain scarce. We aimed to assess the time trend of NAA use and the clinical safety and efficacy of these drugs compared with those of clopidogrel in a contemporary cohort of patients with acute coronary syndromes (ACS). METHODS: A multicenter retrospective observational study was conducted in patients with ACS admitted to coronary care units and prospectively included in the ARIAM-Andalusia registry between 2013 and 2015. In-hospital rates of major cardiovascular events and bleeding with NAA vs clopidogrel were analyzed using propensity score matching and multivariate regression models. RESULTS: The study included 2906 patients: 55% received clopidogrel and 45% NAA. A total of 60% had ST-segment elevation ACS. Use of NAA significantly increased throughout the study. Patients receiving clopidogrel were older and were more likely to have comorbidities. Total mortality, ischemic stroke, and stent thrombosis were lower with NAA (2% vs 9%, P < .0001; 0.1% vs 0.5%, P = .025; 0.07% vs 0.5%, P = .025, respectively). There were no differences in the rate of total bleeding (3% vs 4%; P = NS). After propensity score matching, the mortality reduction with NAA persisted (OR, 0.37; 95%CI, 0.13 to 0.60; P < .0001) with no increase in total bleeding (OR, 1.07; 95%CI, 0.18 to 2.37; P = .094). CONCLUSIONS: In a "real world" setting, NAA are selectively used in younger patients with less comorbidity and are associated with a reduction in major cardiac events, including mortality, without increasing bleeding compared with clopidogrel.

Treatment of recurrent gliomas with eflornithine.

BACKGROUND: Oral eflornithine in combination with intravenous mitoguazone (methylbisguanylhydrazone) has shown activity against recurrent anaplastic gliomas. Eflornithine alone, however, has not been evaluated against recurrent gliomas. PURPOSE: This study compared the antitumor activity of oral eflornithine with that of oral eflornithine combined with intravenous mitoguazone in the treatment of patients with recurrent or progressive glioblastoma multiforme as well as nonglioblastoma anaplastic gliomas. METHODS: During the 1st year of therapy with eflornithine alone, the drug was given at a dose of 3.6 g/m2 on days 1-14, 22-35, and 43-56 every 8 hours; cycles were repeated every 63 days until progression. For the 2nd year, the drug was given on days 1-14, 29-42, and 57-70, with 84 days between cycles. For the 1st and 2nd years of eflornithine-mitoguazone therapy, eflornithine was given at 1.8 g/m2 on the same schedule. Mitoguazone was given intravenously at 200 mg/m2 on the final day of each 2-week sequence of eflornithine therapy. Response was determined by evaluating changes in the size of contrast-enhanced neuroimages. RESULTS: Because of two cases of lethal hepatic necrosis, the initial random allocation of patients to the eflornithine-mitoguazone arm was stopped after 23 patients had been accrued. Ninety-eight patients were entered in the eflornithine arm; 80 patients (36 glioblastoma multiforme patients and 44 anaplastic glioma patients) were assessable for response. Antitumor activity (partial response, minor response, and stable disease) was seen in 45% of the patients with anaplastic gliomas, for a median of 49 weeks, but in only 17% of patients with glioblastoma multiforme (median not attained). Twenty-one (20%) of the patients with anaplastic glioma and 33% of the patients with glioblastoma multiforme were removed from the study before completing the first 8-week course of therapy because of neurological deterioration and tumor progression by the 5th week of treatment. CONCLUSION: This study suggests that eflornithine alone is an effective palliative therapy for recurrent anaplastic gliomas. Additional studies are needed to confirm our finding.

Genetic subgroups of anaplastic astrocytomas correlate with patient age and survival.

Astrocytomas are brain tumors with variable responses to radiation and chemotherapy. Tumor grade and patient age are important prognostic factors but do not account for the variability in clinical outcome. We hypothesized that genetic subgroups play a role in the outcome of grade III astrocytomas and studied 80 grade III astrocytomas by comparative genomic hybridization. Some chromosomal aberrations (+7p/q, -9p, -10q, -13q, +19q) were related to aberrations that are frequent in grade IV astrocytoma, whereas others (+10p, -11q, +11p, -Xq) were more frequent in grade III astrocytoma. +7p, +19 and -4q were more frequent in tumors from older patients while -11p was more frequent in tumors from younger patients. Finally, gains of 7p and 7q were associated with shorter patient survival, independent of age. Our results indicate that genetic events underlie the well-known effects of age on survival in grade III astrocytoma and demonstrate the importance of molecular classification in astrocytic tumors.

Retrospective study of the correlation between the DNA repair protein alkyltransferase and survival of brain tumor patients treated with carmustine.

We tested the hypothesis that the level of the DNA repair protein O6-alkylguanine-DNA alkyltransferase in brain tumors was correlated with resistance to carmustine (BCNU) chemotherapy. Alkyltransferase levels in individual cells in sections from 167 primary brain tumors treated with BCNU were quantitated with an immunofluorescence assay using monoclonal antibodies against human alkyltransferase. Patients with high levels of alkyltransferase had shorter time to treatment failure (P = 0.05) and death (P = 0.004) and a death rate 1.7 times greater than patients with low alkyltransferase levels. Furthermore, the size of the subpopulation of cells with high levels of alkyltransferase was correlated directly with drug resistance. For all tumors the variables most closely correlated with survival, in order of importance, were age, tumor grade, and alkyltransferase levels. For glioblastoma multiforme, survival was more strongly correlated with alkyltransferase levels than with age. These results should encourage prospective studies to evaluate alkyltransferase levels as a method, for identifying brain tumor patients with the best likelihood of response to BCNU chemotherapy.

Analysis of complex relationships between age, p53, epidermal growth factor receptor, and survival in glioblastoma patients.

Glioblastoma multiforme (GBM) carries a dismal prognosis. However, a range of survival times exists, and parameters that define prognostic groups may help to optimize treatment. To identify such prognostic groups, we analyzed tumor tissue from 110 cases of newly diagnosed GBM from two clinical protocols. Similar to other studies, we found no association of epidermal growth factor receptor (EGFR) overexpression (as assessed by immunohistochemistry), p53 immunopositivity, or p53 mutation with survival in the entire sample. However, EGFR overexpression showed trends toward worse prognosis in patients younger than the median age, but better prognosis in patients older than the median age. This interaction of EGFR with age group was statistically significant and led us to focus our further analyses on the younger patients. In this group, a statistically significant association of EGFR overexpression with worse survival was identified in the p53-negative but not p53-positive tumors. We found a similar result after screening these cases for mutations in p53: EGFR overexpression was negatively associated with survival only in the p53 wild-type cases. To confirm this unexpected result, this finding was reproduced in a validation sample of an additional 42 tumors from younger patients on the same two clinical protocols. This complex relationship between EGFR and p53 in younger patients remained in a multivariate analysis that incorporated additional prognostic variables. The results suggest that analysis of prognostic markers in GBM is complex, and maximal information may require analysis of subgroups based on age and the status of specific markers such as p53. In addition, they suggest a specific group of patients on which to focus promising therapies targeting EGFR.

Studies on regulation of the ascorbic acid transporter in a cell line derived from rabbit non-pigmented ciliary epithelium.

A cell line was derived from rabbit non-pigmented ciliary epithelium. The non-pigmented ciliary epithelium is one of the two cell layers which secrete aqueous humor into the eye and concentrate ascorbic acid in the newly-formed fluid. The cultured non-pigmented epithelial cells accumulated ascorbic acid at a rate of 3-5 pmol/micrograms protein per h. As in freshly-isolated native tissue, the ascorbate uptake mechanism was sodium-dependent and could be inhibited by phloretin (apparent Ki = 2-10(-5) M). Phorbol 12,13-dibutyrate (PDBu), a protein kinase C activator, reduced the ascorbate uptake rate. The PDBu effect was concentration-dependent; at a concentration of 10(-6) M, PDBu reduced the ascorbate uptake rate to 65% of the control value. PDBu reduced the maximal rate of ascorbate uptake (determined at 200-500 microM external ascorbate) but caused no detectable change in the Km for ascorbic acid (approx. 80 microM). The PDBu-induced inhibition of ascorbate uptake persisted in the presence of ouabain and in low sodium (25 mM Na) medium, suggesting that the effect is not secondary to a change in the sodium gradient. Furthermore, no detectable elevation of cell sodium content was seen in cells equilibrated with 22Na prior to PDBu treatment. The PDBu-induced inhibition of ascorbate uptake was apparently mediated by protein kinase C because the effect was not observed in the presence of staurosporine (10(-6) M), a protein kinase C inhibitor, or in cells in which protein kinase C was downregulated. These observations suggest that activation of protein kinase C causes inhibition of the ascorbate transporter in this cultured cell line.

Nucleotide sequence of a cDNA for the beta 2 subunit isoform of Na+,K(+)-ATPase from human retina.

Using as probe the entire human liver cDNA clone coding for the beta 2 subunit isoform of the Na+,K(+)-ATPase, which lacks the initiation codon ATG, and the entire 5'-untranslated region (Martin-Vasallo, P., Dackowski, W., Emanuel, J.R. and Levenson, R. (1989) J. Biol. Chem. 264, 4613-4618), we isolated a larger clone from a directional human adult retina cDNA library (Swaroop, A. and Xu, J. (1993) Cytogenet. Cell Genet. 64, 292-294). This clone, pNH beta 2, shows 100% homology with the nucleotide sequence of the human liver cDNA clone and also contains additional 407 nucleotides in the 5'-untranslated region, the initiation codon and a poly(A) tail. Northern blot hybridization analysis reveals that the human mRNA (3.6 kb) is approx. 300 nucleotides larger than the major transcript size expressed in rat (3.3 kb). The larger human size mRNA for the human beta 2 Na+,K(+)-ATPase indicates species differences in gene processing.

Treatment of recurrent gliomas and metastatic brain tumors with a polydrug protocol designed to combat nitrosourea resistance.

PURPOSE: The study was undertaken to evaluate a chemotherapy protocol against recurrent malignant gliomas that was designed to combat presumed chloroethyl-nitrosourea (NU) resistance. PATIENTS AND METHODS: All patients had malignant gliomas and had failed prior therapy. Patients were stratified as having either glioblastoma multiforme (GM) or anaplastic gliomas (AG) and as having failed radiotherapy (RT) only or both RT and chemotherapy. Chemotherapy consisted of six drugs: before lomustine (CCNU), thioguanine (TG), dibromodulcitol (mitolactol; DBD), and procarbazine (PCB) were given to enhance CCNU-induced tumor-cell kill and to reduce alkyltransferase repair of ethylated DNA. A fluorouracil-hydroxyurea (FUHU) combination was given 2 weeks later to kill cells that began to cycle after the challenge of the first four drugs (TPDC-FUHU chemotherapy). RESULTS: Of the 88 assessable patients, 37 had GM, 38 had AG, and 13 had other primary and metastatic brain tumors. For GM patients, 61% had a partial response (PR) or stable disease (SD) for a median of 9.3 months if RT only failed, and 58% had a PR or SD for a median of 5.1 months if they had previously been treated with an NU. For AG patients, 92% had a PR or SD for a median of 15 months if RT only had failed, but only 38% had a PR or SD for a median of 10.6 months if they had been previously treated with a NU. Activity was also seen against other recurrent or progressive primary and metastatic brain tumors. CONCLUSIONS: TDPC-FUHU chemotherapy is a highly effective form of chemotherapy for both recurrent GM and AG patients. This study suggests but does not prove that this combination may be superior to other NU-based treatments for recurrent malignant glioma patients who fail RT. Because of the activity of this chemotherapy, we intend to evaluate more fully this approach in a randomized study.

Recombinant interferon beta: a phase I-II trial in children with recurrent brain tumors.

A multicenter phase I-II trial of intravenous (IV) human recombinant interferon beta (rIFN-beta; Betaseron; Triton Bioscience Inc, Almeda, CA) was conducted in children with recurrent or progressive primary brain and spinal cord tumors. A total of 29 patients were enrolled: high-grade astrocytoma (12), brainstem glioma (nine), and primitive neuroectadermal tumor (three), ependymoma (two), germ cell (two), and spinal cord astrocytoma (one). Betaseron was given by IV infusion over 30 minutes 3 times per week (Monday-Wednesday-Friday [MWF]). Four dose levels were studied, and at least three patients were entered at each dose level. The treatment plan began with a three-step dose escalation for each patient over 6 weeks (initiation phase). The dose-escalation schema for the four dose levels was: 50-100-200, 100-200-400, 200-300-500, and 300-400-600 x 10(6) (M) IU/m2. Patients experiencing an objective response or stable disease after 6 weeks entered the maintenance phase at the final escalated dose, ie, 200, 400, 500, or 600 mlU/m2 (MWF). Common transient effects included chills, fever, and fatigue. Dose-limiting toxicities were hematologic, hepatic, and CNS. The maintenance maximum-tolerable dose (MTD) was 500 mlU/m2, ie, dose level 3. Response was assessed at completion of the initiation phase and at 2-month intervals during the maintenance phase. Objective partial responses were seen in patients with high-grade astrocytoma (two) and brain-stem glioma (two). Thus, four of 21 (19%) assessable patients had partial responses for a median of 4 months. Eight patients had stable disease for a median of 5+ (2 to 14+) months. Antineoplastic activity has been identified in children with high-grade astrocytomas and brainstem gliomas in a dose-intensive regimen.

Health-related quality of life in patients treated with temozolomide versus procarbazine for recurrent glioblastoma multiforme.

PURPOSE: To determine whether chemotherapy with temozolomide (TMZ) versus procarbazine (PCB) for recurrent glioblastoma multiforme (GBM) was associated with improvement in health-related quality of life (HRQOL). PATIENTS AND METHODS: HRQOL was assessed at baseline and during treatment using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30 and a Brain Cancer Module (BCM20) in two clinical trials that enrolled a total of 366 patients. Two hundred eighty-eight patients provided HRQOL data that could be used for analysis; 109 patients received TMZ in a phase II study, whereas 89 patients received TMZ and 90 received PCB in a randomized phase III study. Changes from baseline in the scores of seven preselected HRQOL domains (role and social functioning, global quality of life [QOL], visual disorders, motor dysfunction, communication deficit, and drowsiness) were calculated for all groups. Statistical significance, effect sizes, and proportions of patients with improved HRQOL scores (changes of > or = 10 points) were calculated. RESULTS: Before disease progression, patients treated with TMZ were found to have an improvement in most of the preselected HRQOL domain scores compared with their baseline (pretreatment) scores. Those who were progression-free on TMZ at 6 months had improvement in all the preselected HRQOL domains. Conversely, patients treated with PCB reported deterioration in HRQOL that was independent of whether or not the disease had progressed by 6 months. Patients with disease progression, regardless of treatment, experienced a sharp decline in all domains at the time of progression. CONCLUSION: Treatment with TMZ was associated with improvement in HRQOL scores compared with treatment with PCB. The deterioration reported by PCB-treated patients was likely because of toxicity. Delaying disease progression by treatment with TMZ is beneficial to the HRQOL status of patients with recurrent GBM.