ABCB1 haplotype is associated with major molecular response in chronic myeloid leukemia patients treated with standard-dose of imatinib

Background: Imatinib mesylate (IM) is a selective tyrosine kinase inhibitor used for treating chronic myeloid leukemia (CML). IM has high efficacy, however some individuals develop a resistance due to impaired bio-availability. Polymorphisms in genes encoding membrane transporters such as ABCB1 have been associated with differences in protein expression and function that influence the response to several drugs. Aim: To investigate the relationship of ABCB1 polymorphisms with markers of response to IM in patients with CML Methods: One hundred eighteen CML patients initially treated with a standard dose of IM (400 mg/day) for 18 months were selected at two health centers in Sao Paulo City, Brazil. The response criteria were based on the European LeukemiaNet recommendations. ABCB1 polymorphisms c.1236C>T (rs1128503), c.3435C>T (rs1045642) and c.2677G>T/A (rs2032582) were evaluated by PCR-RFLP. Results: ABCB1 polymorphisms were not related with a risk for CML in this sample population (p<0.05). In the CML group, frequencies of ABCB1 SNPs were similar between responder and non-responder patients (p>0.05). In the responder group, the frequency of ABCB11236CT/2677GT/3435CT haplotype was higher in patients with major molecular response (MMR) (51.7%) than in patients without MMR (8.3%, p = 0.010). Furthermore, carriers of this haplotype had increased the probability of reaching the MMR compared with the non-carriers (OR: 11.8; 95% CI: 1.43-97.3, p = 0.022). Conclusions: The ABCB1 1236CT/2677GT/3435CT haplotype is positively associated with the major molecular response to IM in CML patients. (C) 2011 Elsevier Inc. All rights reserved.

Electromyographic Study in Patients With Surgically Treated Facial Fractures

This study, using surface electromyography, analyzed the activity of the masseter muscles of 30 patients with facial bone fractures that were surgically treated. Evaluations were made before surgery and in the 7th, 30th, and 60th days after surgery. The value of each measure and the average of 3 maximum voluntary isometric contractions lasting 5 seconds each were registered, and statistical analyses were performed. Patients had a mean age of 31 years and an average of 1.33 fractures. They were grouped according to the type of fracture as follows: mandibular (50%), zygomatic complex (33%), maxilla (10%), and associated fractures (6.7%). There was a lower masseter activity in the preoperative period, when compared with normal values in all groups of fractures. There was a sharp drop in the masseter activity in the postoperative period of 7 days, and all groups showed recovery of activity in 60 days but still below the normal value referenced in the literature. The mean values of the masseter activity, in descending order, were from the zygomatic complex, mandibular, maxillary, and associated fractures. The unilateral mandibular fractures showed higher values than the bilateral fractures in most of the evaluations. There was a highly significant difference in the comparison of the evolution of the masseter activity on both sides, for mandibular and zygomatic complex fractures, and the pairwise comparison showed significant difference between most groups. It was concluded that facial fractures and surgical procedures had negative effects in the muscle activity as observed using electromyography.

Cognitive function in patients with chronic pain treated with opioids: characteristics and associated factors

Background The paucity of studies regarding cognitive function in patients with chronic pain, and growing evidence regarding the cognitive effects of pain and opioids on cognitive function prompted us to assess cognition via neuropsychological measurement in patients with chronic non-cancer pain treated with opioids. Methods In this cross-sectional study, 49 patients were assessed by Continuous Reaction Time, Finger Tapping, Digit Span, Trail Making Test-B and Mini-mental State Examination tests. Linear regressions were applied. Results Patients scored poorly in the Trail Making Test-B (mean?=?107.6?s, SD?=?61.0, cut-off?=?91?s); and adequately on all other tests. Several associations among independent variables and cognitive tests were observed. In the multiple regression analyses, the variables associated with statistically significant poor cognitive performance were female sex, higher age, lower annual income, lower schooling, anxiety, depression, tiredness, lower opioid dose, and more than 5?h of sleep the night before assessment (P?<?0.05). Conclusions Patients with chronic pain may have cognitive dysfunction related to some reversible factors, which can be optimized by therapeutic interventions.

Overall Survival Improvement in Patients with Lung Cancer and Bone Metastases Treated with Denosumab Versus Zoledronic Acid Subgroup Analysis from a Randomized Phase 3 Study

Introduction: Denosumab, a fully human anti-RANKL monoclonal antibody, reduces the incidence of skeletal-related events in patients with bone metastases from solid tumors. We present survival data for the subset of patients with lung cancer, participating in the phase 3 trial of denosumab versus zoledronic acid (ZA) in the treatment of bone metastases from solid tumors (except breast or prostate) or multiple myeloma. Methods: Patients were randomized 1:1 to receive monthly subcutaneous denosumab 120 mg or intravenous ZA 4 mg. An exploratory analysis, using Kaplan-Meier estimates and proportional hazards models, was performed for overall survival among patients with non-small-cell lung cancer (NSCLC) and SCLC. Results: Denosumab was associated with improved median overall survival versus ZA in 811 patients with any lung cancer (8.9 versus 7.7 months; hazard ratio [HR] 0.80) and in 702 patients with NSCLC (9.5 versus 8.0 months; HR 0.78) (p = 0.01, each comparison). Further analysis of NSCLC by histological type showed a median survival of 8.6 months for denosumab versus 6.4 months for ZA in patients with squamous cell carcinoma (HR 0.68; p = 0.035). Incidence of overall adverse events was balanced between treatment groups; serious adverse events occurred in 66.0% of denosumab-treated patients and 72.9% of ZA-treated patients. Cumulative incidence of osteonecrosis of the jaw was similar between groups (0.7% denosumab versus 0.8% ZA). Hypocalcemia rates were 8.6% with denosumab and 3.8% with ZA. Conclusion: In this exploratory analysis, denosumab was associated with improved overall survival compared with ZA, in patients with metastatic lung cancer.

Audiometric evaluation of patients treated for pulmonary tuberculosis

Objective: To evaluate the hearing status of patients being treated for pulmonary tuberculosis at referral hospitals in Brazil. Methods: This was a descriptive study involving 97 male and female inpatients/outpatients between 18 and 60 years of age who were undergoing treatment for active pulmonary tuberculosis at one of two referral hospitals in the state of Rio de Janeiro. After being interviewed, all of the patients underwent pure tone audiometry. Results: OF the 97 patients studied, 65 (67%) were male, 52 (54%) were receiving first-line treatment, and 45 (46%) were receiving second-line treatment, which included aminoglycosides. Smoking, alcohol consumption, exposure to noise, and ototoxic medication use were identified in 65 (67%), 51 (53%), 53 (55%), and 45 (46.4%) of the patients, respectively. The most common auditory and vestibular complaints were dizziness, in 28 patients (28.8%); tinnitus, in 27 (27.8%); and hypoacusis, in 23 (23.7%). Conclusions: Due to the great number of patients with hearing loss in the present study, we recommend that all patients under tuberculosis treatment be submitted to auditory monitoring.

Applying the National Institute for Clinical Excellence criteria to patients treated with the Genous (TM) Bio-engineered R stent (TM): a sub-study of the e-HEALING (Healthy Endothelial Accelerated Lining Inhibits Neointimal Growth) worldwide registry

The National Institute for Clinical Excellence (NICE) guidelines recommend the use of bare-metal stents (BMS) in non-complex lesions with a low risk of restenosis (diameter a parts per thousand yen3 mm and lesion length a parts per thousand currency sign15 mm) and the use of drug-eluting stents (DES) in more complex lesions with a high risk of restenosis (diameter < 3.0 mm or lesion length > 15 mm). However, the guidelines were created based on studies evaluating BMS and DES only. We performed an analysis of patients undergoing non-urgent percutaneous coronary intervention with the novel endothelial cell capturing stent (ECS). The ECS is coated with CD34(+) antibodies that attract circulating endothelial progenitor cells to the stent surface, thereby accelerating the endothelialization of the stented area. We analyzed all patients enrolled in the worldwide e-HEALING registry that met the NICE criteria for either low-risk or high-risk lesions and were treated with a parts per thousand yen1 ECS. The main study outcome was target vessel failure (TVF) at 12-month follow-up, defined as the composite of cardiac death or MI and target vessel revascularization (TVR). A total of 4,241 patients were assessed in the current analysis. At 12-month follow-up, TVF occurred in 7.0% of the patients with low-risk lesions and in 8.8% of the patients with high-risk lesions (p = 0.045). When evaluating the diabetic patients versus the non-diabetic patients per risk group, no significant differences were found in TVF, MI or TVR in either risk group. The ECS shows good clinical outcomes in lesions carrying either a high or a low risk of restenosis according to the NICE guidelines with comparable rates of cardiac death, myocardial infarction, and stent thrombosis. The TVF rate with ECS was slightly higher in patients with high-risk lesions, driven by higher clinically driven TLR. The risk of restenosis with ECS in patients carrying high-risk lesions needs to be carefully considered relative to other risks associated with DES. Furthermore, the presence of diabetes mellitus did not influence the incidence of TVF in either risk group.

Functional independence in patients with chronic kidney disease being treated with haemodialysis

Purpose: This study has described and analysed the functional independence of the patients served in the haemodialysis services of a countryside town in the State of Sao Paulo, Brazil, using the Functional Independence Measure (FIM). Method: The population considered was that of 214 patients being treated with haemodialysis, assessed in 2011, by means of a social, demographic and clinical report, a Mini-Mental State Examination (MMSE) and also the FIM. Results: The mean age of the population under study was 58.01 years, while the mean FIM point score was 118.38 points, showing a level of complete or modified independence within this population. Even though the level of dependence found has been low, this can be highlighted, within the locomotion domain, in the activity of going up and down stairs (10.28%). Age, complications arising from haemodialysis, and comorbidities show a negative correlation with FIM. Conclusion: Awareness of the level of functional independence of the patients being subjected to treatment with haemodialysis is essential in order to back up intervention for the improvement of nursing assistance provided to this population.

Are we able to correctly identify prostate cancer patients who could be adequately treated by focal therapy?

Introduction and Objective: Because of the improvements on detection of early stage prostate cancer over the last decade, focal therapy for localized prostate cancer (PC) has been proposed for patients with low-risk disease. Such treatment would allow the control of cancer, thereby diminishing side effects, such as urinary incontinence and sexual dysfunction, which have an enormous impact on quality of life. The critical issue is whether it is possible to preoperatively predict clinically significant unifocal or unilateral prostate cancer with sufficient accuracy. Our aim is to determine whether there is any preoperative feature that can help select the ideal patient for focal therapy. Material and methods: A total of 599 patients who underwent transrectal ultrasound, (TRUS)-guided prostate biopsy followed by radical prostatectomy to treat PC were examined in our laboratory between 2001 and 2009. We established very restricted criteria to select patients with very-low-risk disease for whom focal therapy would be suitable (only I biopsy core positive, tumor no larger than 80% of a single core, no perineural invasion, PSA serum level < 10 ng/ml, Gleason score < 7 and clinical stage T1c, T2a-b). We defined 2 groups of patients who would be either adequately treated or not treated by focal therapy. The primary endpoint was the evaluation of preoperative features in order to identify which parameters should be considered when choosing good candidates for focal therapy. Results: Fifty-six out of 599 patients met our criteria. The mean age was 59 years, and the mean number of biopsy cores was 14.4. Forty-seven (83.9%) were staged T1c, and 9 (16.1%) were staged T2a-b. Forty-four (78.6%) patients could be considered to have been adequately treated by focal therapy, and 12 (21.4%) could not. There was no statistical difference between the 2 groups considering age, clinical stage, PSA levels, Gleason score, and tumor volume in the biopsy. All 12 patients who could be considered inadequately treated had a bilateral, significant secondary tumor, 58.3% had Gleason >= 7, and 25% were staged pT3. Conclusion: Although focal therapy might be a good option for patients with localized prostate cancer, we are so far unable to select which of them would benefit from it based on preoperative data, even using very restricted criteria, and a considerable proportion of men would still be left undertreated. (c) 2012 Elsevier Inc. All rights reserved.

Audiological findings in patients treated with radio- and concomitant chemotherapy for head and neck tumors

Abstract Objective To evaluate the functionality of the auditory system in patients who underwent radiotherapy and chemotherapy treatment with cisplatin to treat head and neck tumors. Study Design Case series with planned data collection. Setting From May 2007 to May 2008 by the Department of Otorhinolaryngology and the Department of Oncology/Radiotherapy at Faculdade de Medicina de Marília. Subjects and Methods Audiological evaluation (Pure Tone Audiometry (air and bone conduction), Speech Audiometry, Tympanometry, Acoustic Reflex testing and Distortion Product Otoacoustic Emissions) was performed in 17 patients diagnosed with head and neck neoplasia and treated with chemotherapy, using cisplatin, and radiotherapy. Results 12 left ears (70.5%) and 11 right ears (64.7%) presented bilateral decreased hearing soon after the treatment for the frequency 1 kHz (mild auditory damage) and for the frequency 8 kHz (more significant auditory damage). Conclusion Patients with head and neck cancer submitted to the conventional radiotherapy treatment, combined with the chemotherapy with cisplatin, presented a high incidence of decreased hearing by the end of treatment. Strong evidence was observed linking auditory alteration to the amount of radiotherapy treatment.

Functional independence in patients with chronic kidney disease being treated with haemodialysis¹

PURPOSE: This study has described and analysed the functional independence of the patients served in the haemodialysis services of a countryside town in the State of São Paulo, Brazil, using the Functional Independence Measure (FIM). METHOD: The population considered was that of 214 patients being treated with haemodialysis, assessed in 2011, by means of a social, demographic and clinical report, a Mini-Mental State Examination (MMSE) and also the FIM. RESULTS: The mean age of the population under study was 58.01 years, while the mean FIM point score was 118.38 points, showing a level of complete or modified independence within this population. Even though the level of dependence found has been low, this can be highlighted, within the locomotion domain, in the activity of going up and down stairs (10.28%). Age, complications arising from haemodialysis, and comorbidities show a negative correlation with FIM. CONCLUSION: Awareness of the level of functional independence of the patients being subjected to treatment with haemodialysis is essential in order to back up intervention for the improvement of nursing assistance provided to this population.

Maxillary incisors mesiodistal angulation changes in patients with orthodontically treated anterior superior diastemas

OBJECTIVE: The aims of this study were to describe the patterns of maxillary incisor angulation in patients with upper interincisive diastemas, to evaluate angulation changes with treatment and posttreatment period, and to assess whether there are association between incisor angulation and interincisive diastema relapse. METHODS: The sample comprised 30 Class I or Class II patients with at least one pretreatment anterior diastema of 0.77 mm or greater after eruption of maxillary permanent canines. Data were obtained from panoramic radiographs at pretreatment, posttreatment and at least 2 years post-retention. RESULTS: Incisors presented a mesial tipping tendency after treatment, but only lateral incisors showed significant changes between pre and posttreatment stages. CONCLUSION: Regarding post-retention period, no changes were found. Finally, no relation was found between diastema relapse and maxillary incisor axial angulation.

MVP expression in the prediction of clinical outcome of locally advanced oral squamous cell carcinoma patients treated with radiotherapy

[EN] Objective: To explore the role of Major Vault Protein (MVP) in oral cavity squamous cell carcinoma patients. Subjects and Methods: 131 consecutive patients suffering from oral cavity squamous cell carcinoma were included in the study. In the whole series, the mean follow-up for survivors was 123.11 ± 40.36 months. Patients in tumour stages I and II were referred to surgery; patients in stage III-IV to postoperative radiotherapy (mean dose = 62.13 ± 7.74 Gy in 1.8–2 Gy/fraction). MVP expression was studied by immunohistochemistry in paraffin-embedded tumour tissue. Results: MVP expression was positive in 112 patients (85.5%) and no relation was found with clinic pathological variables. MVP overexpression (those tumours with moderate or strong expression of the protein) was related to insulin-like growth factor receptor-1 (IGF-1R) expression (P = 0.014). Tumour stage of the disease was the most important prognostic factor related to survival. Tumours overexpressing MVP and IGF-1R were strongly related to poor disease-free survival (P = 0.008, Exp(B) = 2.730, CI95% (1.302-5.724)) and cause-specific survival (P = 0.014, Exp(B) = 2.570, CI95% (1.215-5.437)) in patients achieving tumour stages III-IV, in multivariate analysis. Conclusions: MVP and IGF-1R expression were related in oral squamous cell carcinoma and conferred reduced long-term survival in patients suffering from advanced stages of the disease.

Combined low initial DNA damage and high radiation-induced apoptosis confers clinical resistance to long-term toxicity in breast cancer patients treated with high-dose radiotherapy

[EN] Background: Either higher levels of initial DNA damage or lower levels of radiation-induced apoptosis in peripheral blood lymphocytes have been associated to increased risk for develop late radiation-induced toxicity. It has been recently published that these two predictive tests are inversely related. The aim of the present study was to investigate the combined role of both tests in relation to clinical radiation-induced toxicity in a set of breast cancer patients treated with high dose hyperfractionated radical radiotherapy. Methods: Peripheral blood lymphocytes were taken from 26 consecutive patients with locally advanced breast carcinoma treated with high-dose hyperfractioned radical radiotherapy. Acute and late cutaneous and subcutaneous toxicity was evaluated using the Radiation Therapy Oncology Group morbidity scoring schema. The mean follow-up of survivors (n = 13) was 197.23 months. Radiosensitivity of lymphocytes was quantified as the initial number of DNA double-strand breaks induced per Gy and per DNA unit (200 Mbp). Radiation-induced apoptosis (RIA) at 1, 2 and 8 Gy was measured by flow cytometry using annexin V/propidium iodide. Results: Mean DSB/Gy/DNA unit obtained was 1.70 ± 0.83 (range 0.63-4.08; median, 1.46). Radiation-induced apoptosis increased with radiation dose (median 12.36, 17.79 and 24.83 for 1, 2, and 8 Gy respectively). We observed that those "expected resistant patients" (DSB values lower than 1.78 DSB/Gy per 200 Mbp and RIA values over 9.58, 14.40 or 24.83 for 1, 2 and 8 Gy respectively) were at low risk of suffer severe subcutaneous late toxicity (HR 0.223, 95%CI 0.073-0.678, P = 0.008; HR 0.206, 95%CI 0.063-0.677, P = 0.009; HR 0.239, 95%CI 0.062-0.929, P = 0.039, for RIA at 1, 2 and 8 Gy respectively) in multivariate analysis. Conclusions: A radiation-resistant profile is proposed, where those patients who presented lower levels of initial DNA damage and higher levels of radiation induced apoptosis were at low risk of suffer severe subcutaneous late toxicity after clinical treatment at high radiation doses in our series. However, due to the small sample size, other prospective studies with higher number of patients are needed to validate these results.

Constitutive gene expression profile segregates toxicity in locally advanced breast cancer patients treated with high-dose hyperfractionated radical radiotherapy

[EN] Breast cancer patients show a wide variation in normal tissue reactions after radiotherapy. The individual sensitivity to x-rays limits the efficiency of the therapy. Prediction of individual sensitivity to radiotherapy could help to select the radiation protocol and to improve treatment results. The aim of this study was to assess the relationship between gene expression profiles of ex vivo un-irradiated and irradiated lymphocytes and the development of toxicity due to high-dose hyperfractionated radiotherapy in patients with locally advanced breast cancer. Raw data from microarray experiments were uploaded to the Gene Expression Omnibus Database http://www.ncbi.nlm.nih.gov/geo/ (GEO accession GSE15341). We obtained a small group of 81 genes significantly regulated by radiotherapy, lumped in 50 relevant pathways. Using ANOVA and t-test statistical tools we found 20 and 26 constitutive genes (0 Gy) that segregate patients with and without acute and late toxicity, respectively. Non-supervised hierarchical clustering was used for the visualization of results. Six and 9 pathways were significantly regulated respectively. Concerning to irradiated lymphocytes (2 Gy), we founded 29 genes that separate patients with acute toxicity and without it. Those genes were gathered in 4 significant pathways. We could not identify a set of genes that segregates patients with and without late toxicity. In conclusion, we have found an association between the constitutive gene expression profile of peripheral blood lymphocytes and the development of acute and late toxicity in consecutive, unselected patients. These observations suggest the possibility of predicting normal tissue response to irradiation in high-dose non-conventional radiation therapy regimens. Prospective studies with higher number of patients are needed to validate these preliminary results.

The impact of polymorphisms in P-gp, DNA repair and folic acid metabolism genes in newly diagnosed multiple myeloma patients treated with thalidomide plus dexamethasone, with or without bortezomib

The principle aim of this study was to investigate biological predictors of response and resistance to multiple myeloma treatment. Two hypothesis had been proposed as responsible of responsiveness: SNPs in DNA repair and Folate pathway, and P-gp dependent efflux. As a first objective, panel of SNPs in DNA repair and Folate pathway genes, were analyzed. It was a retrospective study in a group of 454, previously untreated, MM patients enrolled in a randomized phase III open-label study. Results show that some SNPs in Folate pathway are correlated with response to MM treatment. MTR genotype was associated with favorable response in the overall population of MM patients. However, this relation, disappear after adjustment for treatment response. When poor responder includes very good partial response, partial response and stable/progressive disease MTFHR rs1801131 genotype was associated with poor response to therapy. This relation - unlike in MTR – was still significant after adjustment for treatment response. Identification of this genetic variant in MM patients could be used as an independent prognostic factor for therapeutic outcome in the clinical practice. In the second objective, basic disposition characteristics of bortezomib was investigated. We demonstrated that bortezomib is a P-gp substrate in a bi-directional transport study. We obtain apparent permeability rate values that together with solubility values can have a crucial implication in better understanding of bortezomib pharmacokinetics with respect to the importance of membrane transporters. Subsequently, in view of the importance of P-gp for bortezomib responsiveness a panel of SNPs in ABCB1 gene - coding for P-gp - were analyzed. In particular we analyzed five SNPs, none of them however correlated with treatment responsiveness. However, we found a significant association between ABCB1 variants and cytogenetic abnormalities. In particular, deletion of chromosome 17 and t(4;14) translocation were present in patients harboring rs60023214 and rs2038502 variants respectively.