Different Phases Of Treatment Research Articles

Impact of Rituximab-Based Immunochemotherapy Induction and Maintenance on the Immunisation Rate Against Tetanus Toxin in Follicular Lymphoma Treated Patients : A Subanalysis of the PRIMA Study

BackgroundCD20 is a cell surface antigen commonly expressed on B-cell lineage, but is absent on hematopoïetic stem cells and plasma cells. Therefore, it has been postulated that its targeting should not significantly affect immunoglobulin serum concentrations. However, due to rapid and prolonged B-cell depletion, rituximab-based therapy has been shown to impair humoral response. In addition, protective serologic response to influenza vaccination in lymphoma patients in the 6 months following rituximab-containing regimen has been found to be particularly low1. Because the vast majority of adults individuals have been previously vaccinated against tetanus, we decided to analyse the impact of prolonged rituximab-based therapy on the immune protection rate against tetanus toxin in patients, and conducted in this aim a sub-analysis in follicular lymphoma (FL) patients treated into the PRIMA study.MethodsThe PRIMA study is a multicentre, phase III, randomized study in patients with advanced FL evaluating the benefit of maintenance therapy with rituximab after induction of response with chemotherapy plus rituximab in comparison with no maintenance therapy, whose results have been previously published2. In a subset of patients, serum samples were prospectively collected and antitetanus toxin antibodies were measured at baseline, end of immunochemotherapy induction and end of maintenance period. Protective titer was defined as > 0.1 UI/mL according to standards. Statistical analysis aimed to determine if serum antitetanus antibodies titers significantly changed over time according to different phases of treatment, and if rituximab maintenance arm had a significant impact as compared to observation arm.ResultsOverall, 104 patients were evaluable for this subanalysis. Fifty-five percent were male. Median age was 57 (range, 27-80), 88.5% had Ann-Arbor stage III-IV disease. All patients had received R-CHOP induction. Among those patients, 56 were randomised into rituximab arm, 48 into observation arm. At baseline, median serum antitetanus antibodies titers in the overall population was 0.8 UI/mL (range, 0–8) and 89.4% of patients had protective titers. At the end of induction, among the 70 evaluable subjects, 90% had still a protective titer with a median of 0.7 UI/mL (range, 0-4), and at the end of maintenance period, among the 62 evaluable patients, 93% had still protective titer with a median of 0.8 (range, 0-3). When comparing the two arms, at the end of maintenance period, median serum antitetanus antibodies titer was 0.8 UI/mL in the rituximab arm, not significantly different from that in the observation arm (0.6 UI/mL) (p=0.17). At the end of the maintenance period, 100% of subjects had still protective titer in the rituximab arm versus 84.6% in the observation arm.ConclusionIn this subanalysis of 104 FL treated patients issued from the PRIMA study, rituximab-based induction and maintenance therapy did not significantly affect the immunisation rate against tetanus toxin in previously immunized patients. These results are in contrast with the poor serologic response rate obtained following rituximab-based therapy, emphasizing that common serum vaccinal titers should be controlled, and vaccination updated, when possible, before treatment initiation and the first rituximab administration.References1-Yri O, Torfoss D, Hungnes O, et al. Rituximab blocks protective serologic response to influenza A (H1N1) 2009 vaccination in lymphoma patients during or within 6 months after treatment. Blood 2011, 118 (6769 – 6771).2-Salles G, Seymour J, Offner F, et al. Rituximab maintenance for 2 years in patient with high tumour burden follicular lymphoma responding to rituximab plus chemotherapy (PRIMA): a phase 3, randomised controlled trial. Lancet 2011, 377 (42-51). DisclosuresKarlin:Sandoz: Consultancy; celgene: Consultancy, Honoraria; Janssen: Honoraria. Delmer:Roche: Honoraria. Brice:Seattle Genetics, Inc.: Research Funding; Takeda Pharmaceuticals International Co.: Honoraria, Research Funding; Roche: Honoraria.

New dosages and therapies in oncology: Don’t underestimate the subcutaneous route

While “new therapies” are currently causing disruptions when it comes to standard cancer treatment procedures, a pharmacologist and a psychiatrist are questioning the resulting changes when it comes to the quality of care relationship. The various dosage forms are a component, in particular the subcutaneous format, which may provide an opportunity to improve the quality of life for patients during the different phases of treatment, but which will affect the rate and the timings in the structure of the care given.

Medical therapy for pediatric vascular anomalies.

Vascular anomalies (VAs) comprise a large variety of individual diagnoses that in different phases of treatment require a diverse number of medical specialists to provide optimal care. Medical therapies include agents usually associated with cancer chemotherapy, such as vincristine, as well more immunomodulatory types of drugs, such as glucocorticoids and sirolimus. These immunomodulating drugs are being successfully applied in cases that are typically categorized as vascular tumors, including kaposiform hemangioendothelioma (KHE) and tufted angioma (TA), as well as some of the more invasive types of vascular malformations (i.e., microcystic lymphatic malformations and blue rubber bleb nevus syndrome (BRBNS). These therapies need to be combined with good supportive care, which often involves anticoagulation, antimicrobial prophylaxis, and comprehensive pain and symptom-relief strategies, as well as appropriate drug monitoring and management of side effects of medical treatment. The optimal care of these patients frequently involves close collaboration between surgeons, interventional and conventional radiologists, medical subspecialists, and nurses.

P0118 Early cardiac changes due to doxorubicin-based chemotherapy and radiotherapy in early stage and locally advanced breast carcinoma patients: A descriptive study

Background The aim of this study was to determine early cardiac changes from doxorubicin-based chemotherapy and radiotherapy in patients with early and locally advanced carcinoma of the breast and to assess cardiac changes in relation to radiation dose received by heart. Methods In this a single centre descriptive study, 56 patients with either early or locally advanced breast cancer were analysed. ECG, ECHO, and ERV were done at baseline, after chemotherapy, after radiotherapy, and after 6 months of follow up. Changes in ECG, ECHO, and ERV were recorded at different time periods during the study. Left ventricular ejection fraction (LVEF) was recorded using both ECHO and ERV. Patients were divided into four groups. Group 1 patients completed all six cycles of chemotherapy before starting radiation. Group 2 patients received all six cycles of chemotherapy after completion of radiotherapy. In group 3 patients underwent neoadjuvant chemotherapy followed by mastectomy. In these patients radiotherapy was completed before adjuvant chemotherapy. Group 4 patients received only six cycles of chemotherapy. Findings The most common ECG change was T wave inversion in the pre-cordial leads. One patient had ST depression in V4 and V5 leads and two had physiological T wave inversion in lead III. In group 1, mean LVEF (ECHO) at baseline was 66.79 ± 3.73. It decreased to 63.45 ± 3.54 after chemotherapy. It further decreased to 61.64 ± 4.26 after radiotherapy. On follow up there was a further decline to 61.42 ± 3.27. In group 2, baseline mean LVEF was 66.67 ± 4.33. Post radiotherapy, it slightly decreased to 66 ± 4.975, while post chemotherapy it further declined to 62.7 ± 2.92. During follow up mean LVEF further decreased to 61.89 ± 2.934. In group 4, baseline mean LVEF was 67.25 ± 4.33, which decreased after chemotherapy to 64.75 ± 2.062. During follow up it further decreased to 63.25 ± 2.363. LVEF was also measured by MUGA/ERV. In group 1 mean LVEF at baseline was 58.14 ± 2.997. After chemotherapy it decreased to 56.15 ± 3.144. After radiotherapy it increased to 56.21 ± 3.81 and during follow up mean LVEF decreased to 55.21 ± 2.913. In group 2 mean LVEF at baseline was 59.11 ± 1.41 which decreased to 58.67 ± 2.872 after radiotherapy and post chemotherapy it decreased to 54.44 ± 1.81. During follow up it increased to 55.22 ± 1.787. In group 4 mean LVEF at baseline was 60 ± 1.63, which decreased to 58.75 ± 1.89 after chemotherapy. During follow up it further decreased to 56.25 ± 2.63. Interpretation Our prospective study shows that a significant number of patients can develop a transient depression in ventricular function after chemotherapy and radiotherapy. ECG changes in our study were not specific. T wave inversion was the most common abnormality, suggestive of ventricular repolarisation abnormality. Decrease in LVEF was seen in our patients both by conventional ECHO and MUGA/ERV scan during different phases of treatment. These changes indicate that doxorubicin-based chemotherapy and radiotherapy produce acute abnormalities in left ventricular function. Whether these results are predictive of the development of chronic cardiac toxicity can only be answered by serially investigating these patients for a longer duration.

Effects of Different Steps in Gender Reassignment Therapy on Psychopathology: A Prospective Study of Persons with a Gender Identity Disorder

At the start of gender reassignment therapy, persons with a gender identity disorder (GID) may deal with various forms of psychopathology. Until now, a limited number of publications focus on the effect of the different phases of treatment on this comorbidity and other psychosocial factors. The aim of this study was to investigate how gender reassignment therapy affects psychopathology and other psychosocial factors. This is a prospective study that assessed 57 individuals with GID by using the Symptom Checklist-90 (SCL-90) at three different points of time: at presentation, after the start of hormonal treatment, and after sex reassignment surgery (SRS). Questionnaires on psychosocial variables were used to evaluate the evolution between the presentation and the postoperative period. The data were statistically analyzed by using SPSS 19.0, with significance levels set at P < 0.05. The psychopathological parameters include overall psychoneurotic distress, anxiety, agoraphobia, depression, somatization, paranoid ideation/psychoticism, interpersonal sensitivity, hostility, and sleeping problems. The psychosocial parameters consist of relationship, living situation, employment, sexual contacts, social contacts, substance abuse, and suicide attempt. A difference in SCL-90 overall psychoneurotic distress was observed at the different points of assessments (P = 0.003), with the most prominent decrease occurring after the initiation of hormone therapy (P < 0.001). Significant decreases were found in the subscales such as anxiety, depression, interpersonal sensitivity, and hostility. Furthermore, the SCL-90 scores resembled those of a general population after hormone therapy was initiated. Analysis of the psychosocial variables showed no significant differences between pre- and postoperative assessments. A marked reduction in psychopathology occurs during the process of sex reassignment therapy, especially after the initiation of hormone therapy.

A day-by-day investigation of changes in criminal convictions before and after entering and leaving opioid maintenance treatment: a national cohort study.

BackgroundOpioid maintenance treatment (OMT) is associated with reduced crime among heroin users, but little is known about how crime changes during different phases of treatment. The aim of this study was to investigate changes in criminal convictions on a day-to-day basis before and after entry or discharge from OMT.MethodsNational cohort study of all patients (n = 3221) in OMT in Norway 1997-2003. Patients were followed over a 9-year period, before, during, and after treatment. Criminal convictions were studied on a day-to-day basis in relation to treatment status. A time-continuous estimate of the probability of convictions within the population for all days during observation was calculated.ResultsChanges in convictions were evident before changes of treatment status. During the 3 years prior to OMT, the convictions rate was approximately 0.4% per day. Prior to OMT, convictions decreased to about 0.2% per day on the day of treatment initiation. During the weeks before dropping out of treatment, convictions increased. The patterns during periods of transition were the same across gender, age and pre-treatment conviction-levels.ConclusionsChanges in convictions often occurred prior to changes in treatment status. Reductions in criminal convictions were found in the period before entry (or re-entry) to OMT, and increases in criminal activity were found in the months prior to treatment interruption.

Délinéation des volumes cibles anatomocliniques pour la radiothérapie des cancers du col utérin

Concurrent chemoradiation followed by brachytherapy is currently the standard treatment for locally advanced cervix carcinomas. Modern radiation techniques require planning based on 3D images, and therefore an accurate delineation of target volumes. The clinical target volume (CTV) used for the different phases of treatment are now well defined, but are not always easy to delineate on a CT scan which is currently the standard examination for simulation in radiotherapy. MRI and PET-CT are routinely performed at diagnosis, and can be used to improve the accuracy of the delineation. The objective of this review is to describe the definitions and recommendations of CTV in the treatment of cervical cancer.

Adherence to antidepressant medications: an evaluation of community pharmacists&amp;#39; counseling practices

BackgroundRecent studies have shown that pharmacists have a role in addressing antidepressant nonadherence. However, few studies have explored community pharmacists’ actual counseling practices in response to antidepressant adherence-related issues at various phases of treatment. The purpose of this study was to evaluate counseling practices of community pharmacists in response to antidepressant adherence-related issues.MethodsA simulated patient method was used to evaluate pharmacist counseling practices in Sydney, Australia. Twenty community pharmacists received three simulated patient visits concerning antidepressant adherence-related scenarios at different phases of treatment: 1) patient receiving a first-time antidepressant prescription and hesitant to begin treatment; 2) patient perceiving lack of treatment efficacy for antidepressant after starting treatment for 2 weeks; and 3) patient wanting to discontinue antidepressant treatment after 3 months due to perceived symptom improvement. The interactions were recorded and analyzed to evaluate the content of consultations in terms of information gathering, information provision including key educational messages, and treatment recommendations.ResultsThere was variability among community pharmacists in terms of the extent and content of information gathered and provided. In scenario 1, while some key educational messages such as possible side effects and expected benefits from antidepressants were mentioned frequently, others such as the recommended length of treatment and adherence-related messages were rarely addressed. In all scenarios, about two thirds of pharmacists explored patients’ concerns about antidepressant treatment. In scenarios 2 and 3, only half of all pharmacists’ consultations involved questions to assess the patient’s medication use. The pharmacists’ main recommendation in response to the patient query was to refer the patient back to the prescribing physician.ConclusionThe majority of pharmacists provided information about the risks and benefits of antidepressant treatment. However, there remains scope for improvement in community pharmacists’ counseling practice for patients on antidepressant treatment, particularly in providing key educational messages including adherence-related messages, exploring patients’ concerns, and monitoring medication adherence.

Family-centred care during midface advancement with a rigid external device: What do families need?

Midface advancement with distraction osteogenesis using the rigid external device (RED) is an effective but invasive treatment to correct the hypoplastic midface. This study draws up an inventory of the stressors, needs and coping strategies of families during this treatment, to determine the best conditions for family-centred care. Data were collected by reviewing the patients' files and administering semi-structured interviews. The data were analysed using the software program Atlas.ti and were re-analysed by an independent researcher. Parents and patients were interviewed separately. Fourteen families participated. Four patients had an absolute indication for surgery. All families were eager to have the patient's facial appearance improved. Nevertheless, despite psychological counselling, they experienced stress when confronted with the changed facial appearance. Another stressor was weight loss. Six patients were in a state of acute malnutrition and needed supplementary feeding. We conclude that the best conditions for family-centred care should be aligned to the different phases of treatment. Leading up to surgery it is important to screen families' expectations regarding aesthetic, functional and social outcomes and to assess their capacity to cope with the long treatment and effects of changed facial appearance. Peer contact and psychosocial training to increase self-esteem are tools to enhance co-operation and satisfaction. During the distraction and stabilisation phase, we advise the monitoring of nutritional intake and weight. During all phases of treatment easy accessibility to the team is recommended.

Sociodemographic and clinical predictors of compliance with antidepressants for depressive disorders: systematic review of observational studies

BackgroundThe literature shows that compliance with antidepressant treatment is unsatisfactory. Several personal and disease-related variables have been shown to be related to compliance behavior. The objective of this study was to review the literature about sociodemographic and clinical predictors of compliance in patients with depressive disorders.MethodsThe Medline, Embase, Cochrane Central, PsycInfo, and Cinahl databases were searched until May 2012. Studies that analyzed sociodemographic and clinical predictors or correlates of compliance in patients with depressive disorder were included. A quantitative synthesis was not performed because of the heterogeneity and availability of the data reported. For similar reasons, the results were not classified according to the different phases of treatment. The search was limited to studies published in English and Spanish.ResultsThirty-two studies fulfilled the inclusion criteria. The most consistent associations with compliance were found for age (older patients showed more compliance) and race (white patients were more likely to adhere to treatment than minority ethnic groups). Few studies assessed clinical factors, and the most plausible predictors of compliance were certain comorbidities and substance abuse. Severity of depression did not play an important role in predicting compliance.ConclusionThe impact of the variables studied on compliance behavior appeared to be inconsistent. Identifying potential predictors of compliance with antidepressant treatment is important, both for the routine practice of the mental health professional and for refining interventions to enhance adherence and target them to specific populations at risk of noncompliance.

Dose-Intensity Impacts On Survival of Adolescents and Young Adults with Acute Lymphoblastic Leukemia Treated in Adult Departments by a Pediatric Protocol (FRALLE 2000BT)

AbstractAbstract ▪3561▪This icon denotes a clinically relevant abstract Background:Adolescents (15–19y) with acute lymphoblastic leukemia (ALL) markedly benefit from pediatric rather than adult chemotherapy regimens, as highlighted by many retrospective studies (Boissel et al., JCO 2001). In young adults with ALL, there are now strong evidences that pediatric or pediatric-inspired protocols may also improve long-term outcome (Huguet et al., JCO 2009). However, whether care environment (adult vs pediatric unit) may impact this outcome remains an open issue. To address this question, we explored the outcome of adolescents and young adults (AYA, 15–29y) treated in adult hematology departments by the pediatric FRALLE 2000-BT protocol. Methods:From February 2001 to June 2011, 89 AYAs with Ph-negative ALL including 60 adolescents (15–19y) and 29 YAs (20–29y) were treated according to the pediatric FRALLE 2000-BT protocol in 13 French and Belgian adult hematology units (median follow-up, 5 years). After a prednisone prephase and a four-drug induction (prednisone, daunorubicin, vincristine and L-asparaginase), patients achieving CR received four 8-week phases of treatment: consolidation, 1st delayed intensification (DI), interphase, 2nd DI, and maintenance. According to FRALLE protocol recommendations, each phase should begin after hematological recovery of previous phase (ANC>1 G/L, Platelets>100 G/L). Twenty-five patients (18 adolescents and 7 YAs) underwent allogeneic transplantation after consolidation phase or 1stDI. Results:Apart age (median age, 18 vs 23y; p<.0001), adolescent and YAs cohorts had similar characteristics, including WBC, B/T lineage distribution, and high-risk karyotype (t(4;11)/MLL-AF4, hypodiploidy)), except for initial CNS involvement (1/60 vs 4/29 respectively, p=.02). Initial peripheral response to prednisone (PDN) at D7 and bone marrow response to chemotherapy at D21 were better in the adolescent subgroup, without reaching significance (slow PDN-responders: 30% vs 38%, p=.42; slow chemo-responders: 13% vs 21%, p=.37). Overall CR rate was 99% and did not differ between both cohorts (98% in adolescents, 100% in YAs). 5y-OS and 5y-EFS were estimated respectively at 66% and 61%. Despite similar CR rates, 5-year EFS was significantly shorter in adolescents than in YAs (47% vs 79%, p=.02). A non significant shorter 5y-OS was also observed in adolescents (58% vs 81%, p=.11). To explain this difference, we looked at dose-intensity disparities between both subgroups. During induction phase, no differences in drug cumulative doses were observed. To further explore potent difficulties to respect protocol schedules in younger patients, we compared intervals from induction D1 to start of different trial phases between both subgroups. In comparison to YAs, intervals from induction D1 to consolidation, 1st DI, 2nd DI and maintenance phases were progressively delayed in adolescents: 4 days for consolidation (p=.24), 6 days for 1st DI (p=.19), 9 days for 2nd DI (p=.005), and finally 25 days for maintenance phase (p=.0002). In univariate analysis, among age (adolescents vs YAs), B/T lineage, WBC, cytogenetics, and time to 1st DI, only age and time to 1st DI significantly affected EFS (p=.05 and p=.001 respectively). In bivariate analysis, age and time to 1st DI were identified as independent prognostic factors for EFS (p=.03 and p=.004, respectively). The same observation was done with interval time to 2ndDI. Conclusion:The outcome of AYAs treated in adult units with the pediatric FRALLE 2000 protocol is encouraging, particularly in YAs. The poorer outcome observed in adolescents may be related to increasing intervals from initial induction to the different phases of treatment. Prospective trials are required to register individual reasons that lead physicians and patients to progressively delay therapy. This study suggests that trial itself is not sufficient to improve the outcome in adolescents with cancer and that AYA programs are needed to explore the difficulties encountered by patients and care teams to adhere to therapy. Disclosures:No relevant conflicts of interest to declare.

Role of High Dose Methotrexate with Cranial Irradiation for Pediatric T-Cell Lymphoid Malignancies

AbstractAbstract 4310 Introduction:T cell lymphoid malignancies are associated with distinctive clinical and biologic features; however, true lineage-specific treatments have yet to be identified. Recent trials have shown promising results for patients with advanced T-cell malignancies given novel treatment regimens of rotating myelosuppressive agents. Objectives:To evaluate the response of children with advanced stage lymphoblastic lymphoma (T-NHL) and T-cell acute lymphoblastic lymphoma (T-ALL) to high dose methotrexate (HDMTX) (5gm/m2) and cranial radiation (1800 cGy). Estimates of complete response rate (CRR), disease free survival (DFS), event-free survival (EFS), and overall survival (OS) will be analyzed. The administered protocol was modeled after the POG 9404 study, Arm IV, to assess its effectiveness in a developing country's patient population. Methodology:The regimen included 4 doses of HDMTX (5gm/m2) plus leucovorin rescue, given at weeks 4,7, 10, and 13 of therapy. An intensive anthracycline based multidrug regimen (vincristine, doxorubicin, prednisone, methotrexate, and mercaptopurine) combined with high dose asparginase consolidation (25.000 IU/m2) was added by intramuscular injection weekly for 20 weeks starting at week 7. Extended intrathecal chemotherapy (methotrexate and cytarabine) was given as CNS prophylaxis throughout different phases of treatment in addition to central nervous system (CNS) irradiation (1800 cGy) to the brain and meninges given to all patients beginning at week 22. Results:105 patients with newly diagnosed T-Cell lymphoid malignancy presenting to the department of Pediatric Oncology at the National Cancer Institute, Cairo University between November 1st 2004 and August 1st 2008, were considered eligible for the study and enrolled. Sample population had a mean age of 9.75 years (2–18 years) comprised of 72 (68.6%) T-ALL and 33 (31.4%) T-NHL (stage III & IV) subtypes. All patients were started on the novel regimen as described. 94 cases (89.5%) achieved complete remission post induction therapy. At the conclusion of our follow-up period (6–48 months, median 24 months), 58/105 cases (55.2%) maintained complete remission (CR). Three year disease free survival (DFS) was 47.1±8.6% and 93.3±6.4% for T-Cell ALL and NHL groups, respectively (Fig 1). Three year estimated free survival (EFS) was 48.5±6.2% and 59.2 ±9.2% in T- ALL and T-NHL groups, respectively (Fig 2). 22/105 (20.9%) cases relapsed with classification including nodal relapse in 4 cases, hematological relapse (HR) in 3 cases, CNS relapse in 12 cases, both CNS and HR relapse in 2 cases and both hematological and testicular relapse in 1 case. CNS relapse was the most frequent occurrence, recorded in 14 cases (13.3%), 13 cases for T-ALL and 1 case for T-NHL. Time to relapse ranged between 3 months and 24 months, with 12 cases occurring early in the maintenance phase after cranial irradiation and 2 cases occurring early in consolidation phase before cranial prophylaxis. 6/105 (5.7%) cases failed induction, incorrect diagnoses was found in 2 (1.9%) of those cases.12/105 (11.4%) patients died during active treatment with mortality equally distributed amongst each phase of therapy. Most common cause of death was sepsis in febrile neutropenic patients 8/105 (7.6%). 6/105 (5.7%) cases were lost to follow up. Toxicities were tolerable in most cases; however, 1 case (1.1%) developed toxicity not amenable to HDMTX. No secondary malignancies were found and no patients underwent bone marrow transplantation (BMT) during the follow up period. Isolated relapse in sanctuary sites was not effectively prevented in this study. Both CNS prophylaxis and CNS directed therapy were administered through extended intrathecal chemotherapy, high dose methotrexate and cranial irradiation. [Display omitted] [Display omitted] Conclusions:Superior response to extended intrathecal chemotherapy, high dose methotrexate and cranial irradiation was achieved in the T-NHL group compared to the T-ALL group, without significant P value. T-ALL has more significant risk of induction failure (3 of 4 resistant cases), early relapse (<18 months from diagnosis), and isolated CNS relapse when compared to T-NHL. Further studies must be done to delineate the role of CNS directed therapy in improving outcomes for T-cell lymphoid malignancies. Disclosures:No relevant conflicts of interest to declare.

Changes in plasma thiol levels induced by different phases of treatment in breast cancer; the role of commercial extract from black chokeberry

Different low-molecular-weight thiols, including glutathione, cysteine, and cysteinylglycine are physiological free radical scavengers. On the other hand, homocysteine may play a role as an oxidant. The aim of our present study was to establish in vitro the effects of the commercial extract of Aronia melanocarpa (Aronox(®)) on the amount of selected low-molecular-weight thiols and the activity of antioxidative enzymes (superoxide dismutase, glutathione peroxidase, and glutathione reductase) in plasma obtained from patients with invasive breast cancer during different phases of treatment [before or after the surgery and patients after different phases of chemotherapy (doxorubicin and cyclophosphamide)] and from healthy subjects. Patients were hospitalized in Department of Oncological Surgery and Department of Chemotherapy, Medical University of Lodz, Poland. The level of low-molecular-weight thiols was determined by high-performance liquid chromatography. We observed that in the presence of the Aronia extract changes in amount of thiols in plasma from breast cancer patients (at all tested groups) were significantly reduced. Our results showed that tested commercial extract reduced modifications of antioxidative enzymes activity in plasma from patients during different phases of treatment, but this effect was not statistical significant. Our results suggest that the Aronia extract supplementation in breast cancer patients has a beneficial effect on thiols concentration in plasma. Plasma, as reported in this work, could be used as an experimental model to evaluate the beneficial action of plant supplements, including phenolic extracts on thiols or other molecules during different phases of treatment.

Les « fibrosarcomes » de l’enfant et de l’adolescent : un même nom pour différentes entités

Fibrosarcomas (FS) are rare malignant tumors in pediatrics, classified in the heterogeneous non-rhabdomyosarcomas group of malignant mesenchymal tumors. Infantile FS are found typically in children less than 2years of age, and include congenital FS usually occurring in infants in the first 3months of life. Histological diagnosis can be difficult; and confirmed with detection by molecular biology of the ETV6-NTRK3 fusion protein. FS is most often a localized disease at diagnosis, with involvement of an extremity. The management of these patients must be multidisciplinary, to define the different phases of treatment and avoid mutilating surgery. Cellular or atypical mesoblastic nephroma (MN) is a subtype of malignant pediatric renal tumors, most often present in children of less than 3months. Histopathological characteristics of the cellular MN are very close to the congenital FS due to a fusion transcript common to both diseases. Treatment schedule is defined by initial local stage of the disease. FS called “adult-type” found exceptionally in childhood occur most often after 10 years old. Adult FS differ from infantile FS in their clinical presentation because of a strong local aggressiveness and problematic appearance of metastasis in 50% of cases, sometimes late. These three diseases present therefore histological similarities. Both have a common name but different clinical presentation and outcome: infantile FS and adult FS. Two have different names and initial location but similar histology, chromosomal rearrangement, sensitivity to chemotherapy and outcome: the congenital FS and cellular mesoblatic nephroma. Authors present a review of the literature of these entities.

Dynamics of Resistance Development to Imatinib under Increasing Selection Pressure: A Combination of Mathematical Models and In Vitro Data

In the last decade, cancer research has been a highly active and rapidly evolving scientific area. The ultimate goal of all efforts is a better understanding of the mechanisms that discriminate malignant from normal cell biology in order to allow the design of molecular targeted treatment strategies. In individual cases of malignant model diseases addicted to a specific, ideally single oncogene, e.g. Chronic myeloid leukemia (CML), specific tyrosine kinase inhibitors (TKI) have indeed been able to convert the disease from a ultimately life-threatening into a chronic disease with individual patients staying in remission even without treatment suggestive of operational cure. These developments have been raising hopes to transfer this concept to other cancer types. Unfortunately, cancer cells tend to develop both primary and secondary resistance to targeted drugs in a substantially higher frequency often leading to a failure of treatment clinically. Therefore, a detailed understanding of how cells can bypass targeted inhibition of signaling cascades crucial for malignant growths is necessary. Here, we have performed an in vitro experiment that investigates kinetics and mechanisms underlying resistance development in former drug sensitive cancer cells over time in vitro. We show that the dynamics observed in these experiments can be described by a simple mathematical model. By comparing these experimental data with the mathematical model, important parameters such as mutation rates, cellular fitness and the impact of individual drugs on these processes can be assessed. Excitingly, the experiment and the model suggest two fundamentally different ways of resistance evolution, i.e. acquisition of mutations and phenotype switching, each subject to different parameters. Most importantly, this complementary approach allows to assess the risk of resistance development in the different phases of treatment and thus helps to identify the critical periods where resistance development is most likely to occur.

Emotional adjustment in infertile people

Emotional adjustment in infertile people Ramazanzadeh, F. 1 (MD); Noorbala, A. A. 2 (MD); Abedinia, N. 3 * (MS) 1. Professor of Gynecology, Vali-e-Asr Reproduction Health Research Center, Imam Khomeini Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran. 2. Professor of Psychiatry, Psychiatry and Psychology Research Center, Roozbeh Hospital, Tehran University of Medical Sciences, Tehran, Iran. 3. Clinical Psychologist , Vali-e-Asr Reproduction Health Research Center, Imam Khomeini Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran. Abstract Background and aim Infertility has mental, social as well as reproductive consequences, among which depression, anxiety, aggressiveness, feelings of guilt, lack of self-esteem, lack of confidence, psychosomatic complaints, obsessions, relationship difficulties and sexual dissatisfaction are evident. Many authors consider the psychological consequences of infertility as responses to grief. The aim of this study was to assess emotional adjustment of infertile couples and psychological outcomes of infertility (depression, anxiety, relationship as well as sexual problems, and personality disorders) in different phases of treatment. Materials and methods The review of literature included most studies in the past 2 decades. Search terms were infertility, pregnancy, depression, anxiety, psychology disorder, marital satisfaction, psychiatric as well as psychology interventions and personality disorders in such data bases as Pub Med, Scholar, Google, Scopus and Amazon. All data were in agreement with articles published earlier than 2006 and almost all of them are accessible. Findings Most studies have found that more than half of the infertile people (women, men, and couples) learn to some extent cope with this problem. Conclusion High prevalence of psychological disorders (particularly, anxiety and depression) appears as inappropriate emotional adjustment which requires psychiatric and psychotherapeutic interventions. Keywords: Infertility, Emotional adjustment, Depression, Anxiety, In vitro fertilization (IVF). * Corresponding Author: Nasrin Abedinia. Clinical Psychologist , Vali-e-Asr Reproduction Health Research Center, Imam Khomeini Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran. E-mail: abedinia_nasrin@yahoo.com

Analysis of Infections In Acute Leukemia According to the Different Phases of Treatment Reveals Marked Differences Potentially Useful for Tailored Prophylactic and Empiric Antimicrobial Treatments

AbstractAbstract 2773 Introduction.Infections during chemotherapy-induced aplasia are still a problem in the management of acute leukemia (AL) patients (pts), causing potentially life-threatening consequences and treatment delays. Adequate empiric antibiotic therapy is crucial for a favourable clinical evolution. In order to better define the best antimicrobial management for AL pts during different phases of treatment, we analyzed all infectious events occurring to consecutively treated AL pts at our Institute during a period of six years. Patients and Methods.Since June 2004 a program of active epidemiological surveillance is ongoing at our Institute. Data concerning infections occurring during chemotherapy-induced cytopenia in AL pts were analysed. All pts showing fever or signs/symptoms of infection underwent thorax X-ray and culture of any other fluid/drainage obtained from a suspected infection site. CT scan of thorax was performed when fever persisted >48h. An infection was considered clinically documented (CDI) when pertinent symptoms, objective signs, or diagnostic radiological findings were present and microbiologically documented (MDI) when microorganisms were isolated. Results.From June 2004 to May 2010, 210 cases of AL (154 acute myeloid leukemia [AML], 53 acute lymphoblastic leukemia [ALL], and 3 blastic plasmacytoid dendritic cell leukemia), were diagnosed and treated with at least one induction cycle followed by consolidation and with reinduction cycles in relapsing/refractory pts. Overall, 1014 chemotherapy cycles were delivered, subdivided as induction (I) (210), consolidation (C) (708) and salvage (S) (96) treatment. Overall 309 clinically documented infections (CDI) were observed (30.5%). Incidence of CDI was higher during S therapy in comparison with I or C (77.1% vs 41.9% and 20.7%, p<0.0001). Incidence of pneumonia was similar in S and I phase (18.7% vs 17.6%) and significantly higher than in C (1.8%, p<0.0001). Incidence of bloodstream infections (BSI) was similar during I and C phase (20% and 15%, p=0.09) and significantly lower than in S (54.2%, p<0.0001). MDI were diagnosed in 270/1014 cycles (26.6%). Isolates were Gram negative (G-) in 54.8%, Gram-positive (G+) in 32.6% and fungi (F, moulds only) in 2,6% of cases; in 27 cases (10%) a mixed infection was documented. Frequency of fungal infections was higher during I therapy (6.9%) than in C+S (1%, p=0.016). Epidemiological distribution of G+ and G- infections during different phases was similar, with the exception of a lower frequency of G- during I (41.7%) vs C+S (59.6%, p=0.012). Mixed infections were more frequent during I (16.7%) than C+S (7.6%, p=0.038). Overall, 297 pathogens were isolated. S. aureus (9/270, 3.3%) and coagulase-negative staphylococci (43/270, 15.9%) were more frequent during I than C+S (respectively: 6.9% vs 2%, p=0.059 and 25% vs 12.6%, p=0.02); E. coli infections (92/270, 34.1%) were predominant during C (52.5%) in comparison with I+S (25.7%, p=0.004). Enterococci (30/270, 11.1%) and P. aeruginosa infections (52/270, 19.6%) were uniformly distributed during different phases. Death occurred in 19 cases (6 and 13 during I and S, respectively). At univariate analysis, S phase (p<0.0001), P. aeruginosa and S. aureus, alone or in association with other pathogens, emerged as poor prognostic factors (p=0.002 and 0.016, respectively). Two of the 7 cases of probable aspergillosis died during I. Conclusions.The S phase has the highest infectious risk, particularly for BSI. Both prophylactic and empiric antibiotic therapy guided by epidemiological data seem warranted. In the I phase pneumonia, particularly of mycotic origin, is relatively more frequent, confirming the appropriateness of an effective antifungal prophylaxis. The C phase carries a very limited risk of life-threatening infections and a relatively high incidence of E. coli. Therefore, the need for antimicrobial and antifungal prophylaxis during C may be reconsidered. Overall the frequency of bacterial infections largely outweighs that of fungal infections and is responsible for 84% of infectious deaths. Among bacteria, P. aeruginosa ranks as the second more frequent microorganism after E. coli and carries the highest risk of death. Given its intrinsic ability of developing antibiotic resistance, it should be presently considered as the most threatening infectious agent in AL against which empiric antibiotic therapy should be tailored. Disclosures:No relevant conflicts of interest to declare.

Targeting NEK2 Kinase In Drug-Resistant Multiple Myeloma with Small Molecule Inhibitors

AbstractAbstract 788 Background:Treatment failure in malignant diseases, including multiple myeloma (MM), is due to drug resistance of a minor population of cancer cells, already present de novo. Gene expression profiling (GEP) data can be obtained repeatedly during different phases of treatment. Thus, it is possible to monitor newly acquired genetic changes in the drug-resistant MM clone. Materials and Methods:Nineteen primary MM patients enrolled in protocol 25009, provided 59 samples, obtained at baseline, pre-1st, pre-2nd, post-2nd stem cell transplant, and in consolidation. GEP was performed using Affymetrix U133Plus2 chips. In addition, a total of 2552 samples with GEP and clinical data, obtained from published studies, were analyzed. We induced NEK2 over-expression and knockdown using a lentiviral delivery system. A NEK2 inhibitor, NI-2, was identified by screening a kinase inhibitor library including 160 compounds and was used for our in vitro and in vivo studies. Results:By comparing serial GEP samples at baseline versus after treatment or at rapid relapse, we defined 56 genes associated with drug resistance. Ten of the top 20 genes belong to the well established chromosomal instability (CIN) signature. The mean expression levels of CIN genes define a high-risk score present in 10% of newly diagnosed MM patients, which is associated with shorter durations of response, event-free (EFS) (HR = 4.8; P < 0.001), and overall survival (OS)(HR = 5.2; P < 0.001). NEK2 is a serine-threonine kinase and a CIN gene. It was the most significant of the 56 genes related to drug resistance. We found that high expression of NEK2 was associated with a shorter EFS and OS in multiple other cancers, such as breast, lung, AML, mesothelioma, glioma and mantle cell lymphoma. As expected, NEK2 over-expression induced CIN in MM cells evidenced by array-CGH. Over-expressing NEK2 in multiple cancer cell lines resulted in enhanced cell proliferation and increased drug resistance, whereas knockdown of NEK2 by sh RNA induced cancer cell death and growth inhibition. NI-2, a NEK2 kinase inhibitor, significantly suppressed NEK2 activity and induced cancer cell apoptosis, most pronounced in cancer cells with induced NEK2 over-expression. Our in vivo studies in the 5TGM1 C57BL/KaLwRij myeloma mouse model confirm that NI-2 treatment indeed overcomes drug resistance and extends mouse survival also drug-resistant 5GM1 cells were infused (P < 0.01). NI-2 showed a synergistic killing effect on MM cells when combined with bortezomib. Conclusion:We conclude that NEK2 is an important indicator of drug resistance, and therefore, of poor prognosis in MM and many other cancers. It represents a logical target to overcome drug resistance. In combination with other chemotherapies, it may result in the curing of previously incurable neoplasias, including MM. Our future work will aim at modifying NEK2 inhibitors to optimize activity and decrease toxicity of NEK2 kinase inhibitors in collaboration with our medicinal chemistry colleagues. Disclosures:No relevant conflicts of interest to declare.

Psychometric validation of the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Endometrial Cancer Module (EORTC QLQ-EN24)

Aim A validation study was conducted to evaluate the psychometric properties of the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Endometrial Cancer Module (EORTC QLQ-EN24). This module was designed to assess disease and treatment specific aspects of the quality of life (QoL) of patients with endometrial cancer. Methods Two hundred and sixty-eight women with endometrial cancer were recruited in different phases of treatment: after pelvic surgery (Group 1); during adjuvant chemotherapy and/or radiotherapy (Group 2); after completion of treatment (Group 3). Patients completed the EORTC QLQ-C30, the endometrial cancer module and a short debriefing questionnaire. Results Multi-trait scaling analyses confirmed the hypothesised scale structure of the QLQ-EN24. Internal consistency reliability was good with Cronbach’s alpha coefficients ranging from 0.74 to 0.86 (lymphoedema 0.80, urological symptoms 0.75, gastrointestinal symptoms 0.74, body image problems 0.86 and sexual/vaginal problems 0.86). Convergent and discriminant validity did not show any scaling errors for the subscales. The QLQ-EN24 module discriminated well between clinically different groups of patients. All items exhibited a high completion rate with less than 2% missing values except for the sexuality items (19%). Conclusion The validation study supports the reliability, the convergent and divergent validity of the EORTC QLQ-EN24. This newly developed QLQ-EN24 module is a useful instrument for the assessment of the QoL in patients treated for endometrial cancer in clinical trials.

Clinical significance of long-term psychoanalytic treatment

The present study evaluated the clinical significance of long-term psychoanalytic treatment in four groups of about 60 patients in different phases of treatment (before, during, after, follow-up) with normative comparisons on four symptom questionnaires (SCL-90, BDI-II, STAI, IIP-64) and two personality assessment instruments (MMPI-2, Rorschach-CS). In each group, the proportion of patients with clinically elevated scores was calculated by comparing their scores with clinical and nonclinical reference groups for each instrument. The authors also calculated a combined percentage of clinically elevated scores based on the six instruments as a conservative estimate of improvement to nonclinical levels after long-term psychoanalytic treatment. Compared to pretreatment levels, the authors found a significant decrease in the percentage of clinical cases after treatment. For the personality assessment, these results became even more evident at follow-up. It appears that long-term psychoanalytic treatment was clinically significant for patients with chronic mental disorders. In the discussion, the authors point out that the evaluation of clinical significance at group level should be followed by an examination of individual changes over a longer period of time.