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- Joint modeling of longitudinal health-related quality of life data and survival. [JOURNAL ARTICLE]
- Qual Life Res 2014 Oct 14.
In cancer research, outcome measures may co-vary. Treatment and treatment related impairment of health-related quality of life (HRQoL) may affect survival. When these effects are analyzed separately, bias may arise. Therefore, we investigated the combined effect of treatment and longitudinally measured HRQoL on survival.Patients with anaplastic oligodendrogliomas (n = 288) who were randomized (EORTC 26951) to radiotherapy (RT) alone or RT plus procarbazine, lomustine, and vincristine (PCV) chemotherapy were analyzed. HRQoL [appetite loss (AP)] was assessed with the EORTC QLQ-C30. We compared survival results from different analysis strategies: Cox model with treatment only [model 1 (M1)] or with treatment and time-dependent AP score [model 2 (M2)] and the joint model combining longitudinal AP score and survival [model 3 (M3)].The estimated hazard ratio (HR) for RT plus PCV was 0.76 (95 % CI 0.58-1.00) for M1, 0.72 (0.55-0.96) for M2, and 0.69 (0.52-0.92) for M3. This corresponds to a lower risk of death of 24 % in M1, 28 % in M2, and 31 % in M3, for patients treated with RT plus PCV chemotherapy. AP resulted in an increased risk of death, with estimated HR of 1.06 (1.01-1.12) for M2 and 1.13 (1.03-1.23) for M3: Every 10-point increase of AP resulted in a 13 % increased risk of death in M3 as compared to 6 % in M2.Part of the survival benefit of treatment with RT plus PCV chemotherapy can be masked by the negative effect that this treatment has on patients' HRQoL. In our study, up to 7 % of the theoretical treatment efficacy was lost when AP was not adjusted through joint modeling.
- [Management of gliomas.] [JOURNAL ARTICLE]
- Cancer Radiother 2014 Sep 4.
Gliomas are the most frequent primary brain tumors. Their care is difficult because of the proximity of organs at risk. The treatment of glioblastoma includes surgery followed by chemoradiation with the protocol of Stupp et al. The addition of bevacizumab allows an increase in progression-free survival by 4 months but it does not improve overall survival. This treatment is reserved for clinical trials. Intensity modulation radiotherapy may be useful to reduce the neurocognitive late effects in different types of gliomas. In elderly patients an accelerated radiotherapy 40Gy in 15 fractions allows a similar survival to standard radiotherapy. O(6)-methylguanine-DNA methyltransferase (MGMT) status may help to choose between chemotherapy and radiotherapy. There is no standard for the treatment of recurrent gliomas. Re-irradiation in stereotactic conditions allows a median survival of 8 to 12.4 months. Anaplastic gliomas with 1p19q mutation have a greater sensibility to chemotherapy by procarbazine, lomustine and vincristine. Chemoradiotherapy in these patients has become the standard treatment. Many studies are underway testing targeted therapies, their place in the therapeutic management and new radiotherapy techniques.
- The Effect of Common Antineoplastic Agents on Induction of Apoptosis in Canine Lymphoma and Leukemia Cell Lines. [JOURNAL ARTICLE]
- In Vivo 2014 09-10; 28(5):843-850.
Background/Aim: Lymphoma, the most common hematopoietic cancer in dogs is sensitive to chemotherapy which is the dominant treatment method. The aim of the present study was to evaluate the concentration-dependent cytotoxicity and ability to induce apoptosis of the anti-neoplastic agents cyclophosphamide (CYC), chlorambucil (CBL), cytosine arabinoside (ARA), dexamethasone (DEX), doxorubicin (DOX), etoposide (ETO), lomustine (LOM), prednisone (PRED) and vincristine (VINK) against GL-1, CL-1, CLBL-1 and Jurkat cell lines. Materials and Methods: To determine cell viability and level of apoptosis, three different tests were performed: Thiazolyl Blue Tetrazolium Bromide (MTT), annexin V/propidium iodide (An/PI) staining and flow cytometric DNA fragmentation. Results: All tested substances exhibited concentration-dependent inhibitory effects on the proliferation of the examined cell lines with a different level of apoptosis induction. VINK and DOX strongly decreased the viability of canine cell lines, whereas CYC induced the highest level of apoptosis. Conclusion: Canine lymphoma (CL-1, CLBL-1) and leukemia (GL-1) cell lines are a useful tool for developing new and more effective treatment regimes for canine neoplasia.
- Translesion polymerase eta is upregulated by cancer therapeutics and confers anticancer drug resistance. [JOURNAL ARTICLE]
- Cancer Res 2014 Aug 14.
DNA repair processes are a key determinant of the sensitivity of cancer cells to DNA damaging chemotherapeutics, which may induce certain repair genes as a mechanism to promote resistance. Here we report the results of a screen for repair genes induced in cancer cells treated with DNA crosslinking agents, which identified the translesion polymerase eta (PolH) as a p53-regulated target acting as one defense against interstrand crosslink (ICL)-inducing agents. PolH was induced by fotemustine, mafosfamide and lomustine in breast cancer, glioma and melanoma cells in vitro and in vivo, with similar inductions observed in normal cells such as lymphocytes and diploid fibroblasts. PolH contributions to the protection against ICL-inducing agents were evaluated by its siRNA-mediated attenuation in cells, which elevated sensitivity to these drugs in all tumor cell models. Conversely, PolH overexpression protected cancer cells against these drugs. PolH attenuation reduced repair of ICL lesions as measured by host cell reactivation assays and enhanced persistence of γH2AX foci. Moreover, we observed a strong accumulation of PolH in the nucleus of drug-treated cells along with direct binding to damaged DNA. Taken together, our findings implicated PolH in ICL repair as a mechanism of cancer drug resistance and normal tissue protection.
- Evaluation of O6-methylguanine-DNA methyltransferase enzyme expression effect on survival of patients with Grade 4 brain astrocytoma. [Journal Article]
- J Res Med Sci 2014 May; 19(5):426-32.
High-grade astrocytoma (Grade 4) or glioblastoma multiforme (GBM) are deadly brain tumors. New therapies attempt to increase lifetime and quality of life in patients with malignant astrocytoma. O6-methylguanine-DNA methyltransferase (MGMT) enzyme expression may be effective in prognosis and response to treatment of these patients. The aim of this study was assessment of MGMT enzyme expression in patients with astrocytoma Grade 4.In this study, 48 patients with GBM that were treated with surgery, chemotherapy and radiotherapy were investigated and followed-up for 47 months for the survival rate. Pathology blocks of patients were examined for MGMT enzyme expression using immunohistochemistry method.The patients were 34 males and 14 females. The ages ranged from 24 to 77 years, with a mean age of 53.52 ± 13.39 years. There was no significant difference between two groups (positive and negative MGMT enzyme expression) in overall survival (median [range] 11.5 [4-30] vs. 13 [5-22], P = 0.9). The results of our study showed that patients although who were undergone near total surgery had higher overall survival than the group of patients who had biopsy only however, it was not significant. Patients who were treated with temozolomide (TMZ) (Temodal, Merck Canada) had significant overall median survival (14.5) more than the patients who were treated with Procarbazine (Roche, Swiss)-Lomustine (Lilly, USA)-Vincristine (Lilly, USA) regimen (8.75) (P < 0.05).O6-methylguanine-DNA methyltransferase enzyme expression had no effect on survival of patients with Grade 4 brain astrocytoma TMZ may increase survival rate.
- Emerging biomarkers in anaplastic oligodendroglioma: implications for clinical investigation and patient management. [Journal Article]
- CNS Oncol 2013 Jul; 2(4):351-8.
SUMMARY Oligodendrogliomas are heterogeneous tumors with a variable response to treatment. This clinical variability underlines the urgent need for markers that can reliably aid diagnosis and guide clinical decision-making. Long-term follow-up data from the EORTC 26951 and RTOG 9402 clinical trials in newly diagnosed anaplastic oligodendroglioma have established chromosome 1p19q codeletion as a predictive marker of response to procarbazine, lomustine and vincristine chemotherapy in anaplastic oligodendrogliomas. In addition, MGMT promoter hypermethylation has been strongly associated with glioma CpG island hypermethylation phenotype (G-CIMP(+)) status, this has been suggested as an epiphenomenon of genome-wide methylation, conferring a more favorable prognosis. Molecular profiling of these tumors has identified several other markers with potential clinical significance: mutations of IDH, CIC, FUBP1 and CDKN2A require further validation before they can be implemented as clinical decision-making tools. Additionally, recent data on the clinical significance of intrinsic glioma subtyping appears promising. Indeed, existing evidence suggests that comprehensive analyses such as intrinsic glioma subtyping or G-CIMP status are superior to single molecular markers. Clearly, with evolving treatment strategies and in the era of individualized therapy, broader omics-based molecular evaluations are required to improve outcome prediction and to identify patients who will benefit from specific treatment strategies.
- Single-agent bevacizumab or lomustine versus a combination of bevacizumab plus lomustine in patients with recurrent glioblastoma (BELOB trial): a randomised controlled phase 2 trial. [Journal Article]
- Lancet Oncol 2014 Aug; 15(9):943-53.
Treatment options for recurrent glioblastoma are scarce, with second-line chemotherapy showing only modest activity against the tumour. Despite the absence of well controlled trials, bevacizumab is widely used in the treatment of recurrent glioblastoma. Nonetheless, whether the high response rates reported after treatment with this drug translate into an overall survival benefit remains unclear. We report the results of the first randomised controlled phase 2 trial of bevacizumab in recurrent glioblastoma.The BELOB trial was an open-label, three-group, multicentre phase 2 study undertaken in 14 hospitals in the Netherlands. Adult patients (≥18 years of age) with a first recurrence of a glioblastoma after temozolomide chemoradiotherapy were randomly allocated by a web-based program to treatment with oral lomustine 110 mg/m(2) once every 6 weeks, intravenous bevacizumab 10 mg/kg once every 2 weeks, or combination treatment with lomustine 110 mg/m(2) every 6 weeks and bevacizumab 10 mg/kg every 2 weeks. Randomisation of patients was stratified with a minimisation procedure, in which the stratification factors were centre, Eastern Cooperative Oncology Group performance status, and age. The primary outcome was overall survival at 9 months, analysed by intention to treat. A safety analysis was planned after the first ten patients completed two cycles of 6 weeks in the combination treatment group. This trial is registered with the Nederlands Trial Register (www.trialregister.nl, number NTR1929).Between Dec 11, 2009, and Nov 10, 2011, 153 patients were enrolled. The preplanned safety analysis was done after eight patients had been treated, because of haematological adverse events (three patients had grade 3 thrombocytopenia and two had grade 4 thrombocytopenia) which reduced bevacizumab dose intensity; the lomustine dose in the combination treatment group was thereafter reduced to 90 mg/m(2). Thus, in addition to the eight patients who were randomly assigned to receive bevacizumab plus lomustine 110 mg/m(2), 51 patients were assigned to receive bevacizumab alone, 47 to receive lomustine alone, and 47 to receive bevacizumab plus lomustine 90 mg/m(2). Of these patients, 50 in the bevacizumab alone group, 46 in the lomustine alone group, and 44 in the bevacizumab and lomustine 90 mg/m(2) group were eligible for analyses. 9-month overall survival was 43% (95% CI 29-57) in the lomustine group, 38% (25-51) in the bevacizumab group, 59% (43-72) in the bevacizumab and lomustine 90 mg/m(2) group, 87% (39-98) in the bevacizumab and lomustine 110 mg/m(2) group, and 63% (49-75) for the combined bevacizumab and lomustine groups. After the reduction in lomustine dose in the combination group, the combined treatment was well tolerated. The most frequent grade 3 or worse toxicities were hypertension (13 [26%] of 50 patients in the bevacizumab group, three [7%] of 46 in the lomustine group, and 11 [25%] of 44 in the bevacizumab and lomustine 90 mg/m(2) group), fatigue (two [4%], four [9%], and eight [18%]), and infections (three [6%], two [4%], and five [11%]). At the time of this analysis, 144/148 (97%) of patients had died and three (2%) were still on treatment.The combination of bevacizumab and lomustine met prespecified criteria for assessment of this treatment in further phase 3 studies. However, the results in the bevacizumab alone group do not justify further studies of this treatment.Roche Nederland and KWF Kankerbestrijding.
- Cutaneous T-cell lymphoma in two captive Tasmanian devils (Sarcophilus harrisii). [Journal Article]
- J Zoo Wildl Med 2014 Jun; 45(2):367-71.
Two captive adult female Tasmanian devils (Sarcophilus harrisii) were investigated for pruritis and dermatitis. In both cases skin lesions consisted of multifocal, superficial patches of crusting, hyperkeratosis, and ulceration. Lesions started on the ventral surfaces of the animal but then appeared on the dorsum as the disease progressed. In both animals, a diagnosis of cutaneous T-cell lymphoma was made based on histologic appearance of skin biopsies using immunohistochemistry. Attempt at treatment with lomustine 20 mg p.o. once every 3 wk in one individual did not slow progression of the condition. As a result of their propensity for developing neoplastic conditions, the use of chemotherapeutic agents in Tasmanian devils warrants further investigation.
- Treatment of Children With Central Nervous System Primitive Neuroectodermal Tumors/Pinealoblastomas in the Prospective Multicentric Trial HIT 2000 Using Hyperfractionated Radiation Therapy Followed by Maintenance Chemotherapy. [Journal Article]
- Int J Radiat Oncol Biol Phys 2014 Jul 15; 89(4):863-71.
The prognosis for children with central nervous system primitive neuroectodermal tumor (CNS-PNET) or pinealoblastoma is still unsatisfactory. Here we report the results of patients between 4 and 21 years of age with nonmetastatic CNS-PNET or pinealoblastoma diagnosed from January 2001 to December 2005 and treated in the prospective GPOH-trial P-HIT 2000-AB4.After surgery, children received hyperfractionated radiation therapy (36 Gy to the craniospinal axis, 68 Gy to the tumor region, and 72 Gy to any residual tumor, fractionated at 2 × 1 Gy per day 5 days per week) accompanied by weekly intravenous administration of vincristine and followed by 8 cycles of maintenance chemotherapy (lomustine, cisplatin, and vincristine).Twenty-six patients (15 with CNS-PNET; 11 with pinealoblastoma) were included. Median age at diagnosis was 11.5 years old (range, 4.0-20.7 years). Gross total tumor resection was achieved in 6 and partial resection in 16 patients (indistinct, 4 patients). Median follow-up of the 15 surviving patients was 7.0 years (range, 5.2-10.0 years). The combined response rate to postoperative therapy was 17 of 20 (85%). Eleven of 26 patients (42%; 7 of 15 with CNS-PNET; 4 of 11 with pinealoblastoma) showed tumor progression or relapse at a median time of 1.3 years (range, 0.5-1.9 years). Five-year progression-free and overall survival rates (±standard error [SE]) were each 58% (±10%) for the entire cohort: CNS-PNET was 53% (±13); pinealoblastoma was 64% (±15%; P=.524 and P=.627, respectively).Postoperative hyperfractionated radiation therapy with local dose escalation followed by maintenance chemotherapy was feasible without major acute toxicity. Survival rates are comparable to those of a few other recent studies but superior to those of most other series, including the previous trial, HIT 1991.
- Multiple cutaneous histiocytomas treated with lomustine in a dog. [JOURNAL ARTICLE]
- Vet Dermatol 2014 Jun 25.
Histiocytoma is a common benign neoplasm of young dogs. Multiple histiocytomas are rare. Surgical or medical treatment of solitary tumours is not required in the majority of cases because the tumour usually undergoes spontaneous regression. Therapy is required when lesions are persistent, recurrent, ulcerated or in uncomfortable locations.To describe a case of canine multiple cutaneous histiocytomas treated with lomustine.A 5-year-old miniature Pinscher dog was presented with multiple, disseminated, alopecic cutaneous nodules, with no associated systemic signs on initial presentation.Histopathological examination of skin biopsies and immunocytochemistry of biopsy imprints were performed. Inguinal lymph node, liver, spleen and bone marrow cytological examination and abdominal ultrasound examination were also performed.The clinical, histopathological and immunocytochemical findings supported a diagnosis of canine multiple cutaneous histiocytomas. Owing to the increasing number and size of the nodules, medical treatment was initiated. Prednisone and ciclosporin resulted in worsening of lesions. Lomustine orally once monthly led to complete resolution followed by relapse. Metabolic disorders such as increased serum alanine transaminase and alkaline phosphatase activities were recorded, and therapy was stopped. Increase in size of the tumours, severe dullness and anorexia led the owner to elect euthanasia.To the best of the authors' knowledge, this is the first case report of canine multiple cutaneous histiocytomas treated with lomustine. Lomustine is effective in histiocytic diseases, but adverse effects must be considered because they can be severe and life threatening.