Cause Of Relapse Research Articles

Impact of the 18F- PET/CT scan in the management of patients with high-risk or intermediate-risk prostate cancer at initial diagnosis or at recurrence.

87 Background: It is reported that a Fcholine Positron Emission Tomography (PET/CT) scan can change the management of the patients with prostate cancer up to 20% of the cases. The aim of this study was to evaluate the impact of 18FCholine PET/CT when its indication was taken by a multi-disciplinary staff in case of initial diagnosis or in case of recurrence. Methods: This retrospective study involved 84 patients between May 2013 and July 2014. After a selective approach 86 18F-PET/CT were performed consecutively: 37 (43%) for the initial staging and 49 (57%) in biochemical failure. The acquisition protocol included a pelvic dynamic scan after injection of 4 MBq/kg of 18FCholine followed by a whole-body scan. Mean age, PSA level and Gleason score were respectively in relapse and initial staging: 71 years (59-82), 4.9 (0.12-32.8), 7 (6-9) and 63 years (48-76), 16 (2.42-55) and 8 (6-10). Results: In initial diagnosis, prostate cancer was identified in all the patients on PET/CT. Local disease was seen in 23/37 scans (62.2%); loco-regional node involvement in 8 (21.6%) and metastatic disease in 6 (16.2%). PET/CT confirmed the therapeutic decision in 48.6% of cases and led to a therapeutic modification in 43.2% of cases,avoiding radical prostatectomy and lymphadenectomy in 25% of cases or modifying the extend of radiotherapy (25%) . In biochemical recurrence, PET/CT showed relapse in the prostatic area in 14 patients (28.6%); abnormal pelvic lymph nodes in 10 cases (20.4%) and distant metastases in 18 patients (36.7%). It failed to identify the cause of relapse in 7 cases (14.3%). PET/CT confirmed the therapeutic approach in 24.5% and led to a therapeutic change in 61.2% of cases The diagnostic performance of the FCholine PET/CT scan on nodes, according to the pathological results were: sensitivity 80 %, specificity 84.6%, positive predictive value 66.7% and negative predictive value 91.7 % Conclusions: A rigorous selection of the patients before the realization of a FCholine PET/CT scan in the management of a prostate cancer can increase the diagnostic performance and provide a better impact. In this study the treatment modification affected 54.8% of the patients.

Rewired Metabolism in Drug-resistant Leukemia Cells: A METABOLIC SWITCH HALLMARKED BY REDUCED DEPENDENCE ON EXOGENOUS GLUTAMINE

Cancer cells that escape induction therapy are a major cause of relapse. Understanding metabolic alterations associated with drug resistance opens up unexplored opportunities for the development of new therapeutic strategies. Here, we applied a broad spectrum of technologies including RNA sequencing, global untargeted metabolomics, and stable isotope labeling mass spectrometry to identify metabolic changes in P-glycoprotein overexpressing T-cell acute lymphoblastic leukemia (ALL) cells, which escaped a therapeutically relevant daunorubicin treatment. We show that compared with sensitive ALL cells, resistant leukemia cells possess a fundamentally rewired central metabolism characterized by reduced dependence on glutamine despite a lack of expression of glutamate-ammonia ligase (GLUL), a higher demand for glucose and an altered rate of fatty acid β-oxidation, accompanied by a decreased pantothenic acid uptake capacity. We experimentally validate our findings by selectively targeting components of this metabolic switch, using approved drugs and starvation approaches followed by cell viability analyses in both the ALL cells and in an acute myeloid leukemia (AML) sensitive/resistant cell line pair. We demonstrate how comparative metabolomics and RNA expression profiling of drug-sensitive and -resistant cells expose targetable metabolic changes and potential resistance markers. Our results show that drug resistance is associated with significant metabolic costs in cancer cells, which could be exploited using new therapeutic strategies.

Abstract B52: A novel personalized therapeutic management in multiple myeloma

Abstract Introduction: Multiple Myeloma (MM) is an incurable hematological malignancy affecting plasma cells marked by highly heterogeneous survival rate. Relapse is a significant impediment to the successful treatment of MM clinically. One of the main causes for relapse is drug resistance to cancer chemotherapy. Currently risk stratification to MM sub -groups and categorization of complete response to therapy are assessed based on molecular, cytogenetic markers using bone marrow biopsy as available systemic markers are incompetent in this regard. We are exploring the clinical significance of our recent in vitro and in vivo findings of a novel non-genetic basis to MDR whereby tiny vesicles called microparticles (MPs) shed from cancer cell's surface transfer MDR phenotype intercellularly. MP isolated from the blood of patients who suffer from Multiple Myeloma will be phenotyped for resistance, adhesion and dissemination markers and assessed whether these characteristics are predictive of treatment outcome. Materials and Methods: We have analysed 44 de-identified Multiple Myeloma patients. The platelet free plasma was ultracentrifuged, MM- derived microparticles were identified and quantified with flow cytometry using Annexin V450, CD138 APC, P-glycoprotein -FITC in BD TruCount tubes. Also platelet derived MPs were identified and excluded using CD41a PE and compared to age-matched healthy volunteers. Western blot analysis was conducted on microparticle lysate probing for the presence of Lung-resistance related protein (LRP). Results: Plasma cell derived MPs were identified based on the CD138 expression from the peripheral blood plasma of MM patients. The number of systemic microparticles was found to be significantly higher in MM patients compared to the healthy volunteers. Also the systemic microparticles carried the drug resistance markers. Conclusions: There are elevated numbers of microparticles in MM that potentially correlate with tumour aggressiveness and they carried MDR phenotypes systemically. Phenotyping MM –derived microparticles holds the potential for a non-invasive personalised systemic biomarker to predict therapeutic response. Citation Format: Rajeev S. Krishnan, Frederick Luk, R. D. Brown, Y. L. Kwan, Mary Bebawy. A novel personalized therapeutic management in multiple myeloma. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Drug Sensitivity and Resistance: Improving Cancer Therapy; Jun 18-21, 2014; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(4 Suppl): Abstract nr B52.

Are changes in HLA Ags responsible for leukemia relapse after HLA-matched allogeneic hematopoietic SCT?

Loss of heterozygosity (LOH) has been shown to be associated with leukemia relapse after haploidentical transplantation. Whether such changes are an important cause of relapse after HLA-matched transplantation remains unclear. We retrospectively HLA-typed leukemic blasts for 71 patients with AML/myelodysplastic syndrome obtained from stored samples, and the results were compared with those obtained at diagnosis and/or before the transplant. No LOH or any other changes in HLA Ag were found in any of the samples tested post transplant as compared with pretransplant specimens. One patient had LOH in HLA class I Ag (HLA-A,-B and -C); however, these changes were present in the pretransplant sample indicating that they occurred before the transplant. We concluded that, in contrast with haploidentical transplantation, HLA loss does not have a major role as a mechanism of relapse after allogeneic transplantation with a closely HLA-matched donor.

Discordance between patients and parents regarding the perceived causes of clinical relapse in young inflammatory bowel disease patients.

Relapse in inflammatory bowel disease (IBD) is not predictable, although several factors have been suggested. The aims of the current study were to assess and compare the possible causes of clinical relapse as perceived by patients and parents. Of 107 young (<35 years old) IBD patients, 26 patients who experienced recent (<3 month) relapse and their parents completed a questionnaire at the same time. Baseline characteristics and clinical manifestations were reviewed and the most common causes of relapse as perceived by patients and parents were compared. Median patient age was 22.5 years and the male to female ratio was 17 : 9. Crohn's disease was diagnosed in 23 patients and ulcerative colitis in the other three patients. Mean disease duration was 39.8±30.3 months. Eighteen (69.2%) patients experienced stress before relapse. Fifteen (57.7%) parents thought that their children experienced stress before relapse. Agreement between patients and parents for non-adherence to medication and stress was 100% and 73.1%, respectively. Stress was considered the most likely cause of relapse in both groups. Discordance rate between parents and patients with respect to main causes of relapse was 40.4%. Stress was perceived to be the most common condition noted before clinical relapse in young IBD patients and their parents. However, the discordance rate between patients and parents with respect to the main causes of relapse was 40.4%. This result suggests a considerable difference in terms of disease understanding between young IBD patients and parents.

Effects of laser-aided circumferential supracrestal fiberotomy on relapse of orthodontically treated teeth: A pilot study

A significant cause of relapse of orthodontically treated teeth is thought to be the gingival and transseptal fibers of the periodontium, which are stretched and twisted as the tooth is rotated. To relieve the rotated tooth from forces exerted by the stretched fibers, circumferential supracrestal fiberotomy (CSF) was introduced. In simple CSF using a scalpel blade, intergingival, transgingival, transseptal, and semicircular fibers are transected. CSF helps the tissue remodelling and decreases relapse of orthodontically treated teeth. Laser offers numerous advantages compared with surgery. Laser CSF is expected to prevent relapse of orthodontically treated teeth. This study was conducted to evaluate the effectiveness and periodontal side effects of laser CSF on orthodontically rotated tooth. The aims were to compare the: amount of relapse and sulcus depth.The study involves 10 patients between age group of 14- 30 years. Patients with extraction site closure were included with the teeth adjacent to the extracted tooth involved in the study. A split mouth design was made with the maxillary right side as control whereas laser CSF was performed only on the maxillary left side. Laser diode of 980nm wavelength will be used. Evaluation after CSF was done after 4 weeks.

Comprehensive Analysis of Surface Antigens on Adult T-Cell Leukemia/Lymphoma (ATL) Cells and Search for ATL-Initiating Cell Markers

Adult T-cell leukemia/lymphoma (ATL) is highly aggressive malignancy caused by human T-cell leukemia virus type 1 (HTLV1). Intensive combination chemotherapy can initially reduce ATL cells, but relapses are common. Today many kinds of tumors are considered to be organized in a hierarchy of heterogeneous cell populations, with only a small proportion of cancer initiating cells (CICs) capable of sustaining tumor formation and growth. Even if most of tumor cells are killed, remaining chemo-resistant CICs can be causes of relapses. However, CICs of ATL have not been identified yet. Our first goal is to identify ATL-initiating cells using in-vitro and in-vivo models.Because co-culture of HTLV1-infected ATL cells and normal lymphocytes results in extraordinarily high HTLV1 integration into normal lymphocytes, which is not seen in the bodies of patients, purification of ATL cells is necessary for evaluation of tumor-specific proliferation. We reported that HTLV1-infected ATL cells could be specifically enriched in the CD4+CADM1+ fraction, while the HTLV-1 basic leucine zipper (HBZ) gene was not detected in CD4+CADM1- cells by PCR analysis. To purify ATL cells, CD4+CADM1+ gating was used.First, we performed comprehensive analysis of surface antigens specifically on ATL cells. Peripheral blood mononuclear cells (PBMCs) were isolated from typical acute-type ATL patients and healthy volunteers. Using flow cytometry and gating, surface expression of 105 antigens, including activated T-cell markers, cell adhesive molecules, and lineage markers, was analyzed. The expression on ATL cells was compared with other CD4-positive non-ATL lymphocytes. Statistical hierarchical clustering analysis of 10 sample groups showed that ATL cells were all grouped into the same cluster, and markers specific for acute-type ATL cells were therefore picked up as candidate markers.Second, CD4+CADM1+ cells were classified by differences in expression of those candidate markers and sorted using 12-color flow cytometry. Although growing primary ATL cells in vitro is very difficult, it was reported that only a small proportion of ATL cells can survive and proliferate on the murine MS-5 stromal cell line, which also allows the proliferation of some ALL and hematopoietic progenitor cells. We repeated these 14-days in-vitro assays and tried to identify the cells capable of surviving and proliferating on MS-5, which we consider to be ATL-initiating cells. Although most of picked-up markers didn’t have any impacts on survival and proliferation of ATL cells, several surface antigens affected the results. After confirmation and prioritization, CD25+ and CD71- fractions were finally picked up. Combining these two fractions, we found that CD71-CD25+CD4+CADM1+ cells could survive and proliferate on MS-5, while other CD4+CADM1+ cells died off in many cases. Even in a case where CD71-CD25+ cells accounted only for 1.1% among the CD4+CADM1+ fraction, CD71-CD25+ cells exclusively survived and proliferated in vitro (figure 1). Moreover, CD71-CD25+ cells could generate CD71+ and CD25- cells on MS-5. In serial culture models, the CD71-CD25+ cells could serially generate other CD4+CADM1+ cells in vitro.Then, we focused on the clinical course of actual ATL patients, and followed up the CD71-CD25+ ATL cells before and after chemotherapy. After chemotherapy, the frequency of CD71-CD25+ cells among CD4+CADM1+ cells became obviously higher, and they therefore seemed to be resistant to chemotherapy. In a case where robust reduction of ATL cells was achieved, more than 90% of remaining ATL cells were in the CD71-CD25+ fraction.Lastly, we compared the in-vivo proliferation of CD71-CD25+ ATL cells and other CD4+CADM1+ cells. Both cells were transplanted intravenously into neonatal NOD/Shi-scid/IL-2Rγnull (NOG) mice within 48 hours from birth. CD71-CD25+CD4+CADM1+ cells could proliferate in vivo while others couldn’t as far as we tried. Moreover, flow cytometric analysis of murine peripheral blood in 70 days after transplantation showed that CD71-CD25+CD4+CADM1+ cells could generate ATL cells with other phenotype seen in primary ATL patients.In summary, we successfully found that CD71-CD25+CD4+CADM1+ cells could generate other ATL cells in vitro and in vivo. This research suggested ATL-initiating cells could be in the CD71-CD25+CD4+CADM1+ fraction. [Display omitted] DisclosuresTojo:Novartis: Research Funding, Speakers Bureau.

Phase II Study of Combination of Hypercvad with Ponatinib in Front Line Therapy of Patients (pts) with Philadelphia Chromosome (Ph) Positive Acute Lymphoblastic Leukemia (ALL)

▪Background: Combination of cytotoxic chemotherapy with tyrosine kinase inhibitors (TKIs) is effective in the treatment of Ph+ ALL. Ponatinib is a more potent BCR-ABL inhibitor. It also suppresses the T315I clones, a common cause of relapse in pts with Ph+ ALL. The combinations of chemotherapy and ponatinib may be associated with better response rates and higher likelihood of eradication of minimal residual disease (MRD) than those reported with other TKIs.Methods: Pts with newly diagnosed Ph+ ALL received 8 cycles of hyper-CVAD (fractionated cyclophosphamide, vincristine [VCR], doxorubicin, dexamethasone) alternating with high dose methotrexate (MTX) and cytarabine every 21 days. Ponatinib was given at 45 mg po daily for the first 14 days of cycle 1 then continuously for the subsequent 7 cycles. Pts in CR received maintenance with ponatinib 45 mg po daily and vincristine and prednisone monthly for 2 years followed by ponatinib indefinitely. MRD monitoring was conducted.Results: To date, 34 pts with untreated Ph+ ALL and 3 pts previously treated (1 previous course) have received a median of 6 cycles (2-8); 10 pts are receiving maintenance in CR. 3 pts have completed the 2 years of maintenance and they are receiving single agent TKI. Median WBC at diagnosis was 8 x 109/L (0.9 -629 x 109/L). CD20 expression was reported positive in 11 pts (30%). 3 (8%) had concomitant CNS disease at diagnosis. All pts were in CR after cycle 1. 30/32 pts (94%) with Ph+ metaphases by CG analysis at baseline achieved CCyR after 1 cycle; 1 had mCyR only and 1 had no CG analysis at CR, both of them achieved CCyR after cycle 2. To date, 35 pts (95%) achieved MMR and 26 (70%) CMR. The median time to MMR and CMR were 3 and 10 weeks, respectively. MRD is negative in 35/36 (97%) pts, in whom a sample was sent for assessment. 9 (24%) received an allogeneic stem cell transplantation (ASCT) after a median of 4 cycles (3-10). Median time to neutrophil and platelet recovery for cycle 1 was 18 and 23 days, and 16 and 22 days for subsequent cycles, respectively. Grade ≥ 3 toxicity included infections during induction in 18 pts (49%), increased LFT’s in 12 (32%), thrombotic events in 3 (8%), myocardial infarction (MI) in 3 (8%, 2 unexplained, 1 in the context of sepsis ), skin rash in 4 (11%), and pancreatitis in 6 (16%). With a median follow up of 18 months (9-31), 31 pts are alive, 6 died in CR. 1 pt died in CR from an unrelated cardiac event after being taken off therapy and placed on imatinib, 1 from MOF (C2D13), 1 from NSTEMI (C2D41), 1 from potential MI (C4D42), 1 from head injury sustained after a fall (C4D13), and 1 from sepsis post ASCT. At the last follow-up, 8 pts (19%) are alive post ASCT; 13 pts remain on ponatinib at the dose of 15 mg daily in 14 and 30 mg daily in 1; Of the other 9 alive patients, 7 were switched to dasatinib, two were switched to imatinib and nilotinib (one each); 1 was lost of follow-up. All but one pt who switched to dasatinib remained in CR; the latter relapsed after a first remission of 10 months; she is receiving salvage therapy in combination with dasatinib. The 1-year progression-free and overall survival rates were 96% and 86%, respectively.Conclusion: The combination of hyperCVAD with ponatinib is highly effective in pts with Ph+ ALL. Due to the vascular events observed, some pts switched to alternative TKI; in the remaining, ponatinib dose was modified to 30 mg daily during consolidation with subsequent reduction to 15 mg in pts in CMR. DisclosuresKantarjian:ARIAD: Research Funding; Pfizer: Research Funding; Amgen: Research Funding. Kadia:GSK: Research Funding; ARIAD: Honoraria.

Environmental factors in the relapse and recurrence of inflammatory bowel disease: a review of the literature.

The causes of relapse in patients with Crohn's disease (CD) and ulcerative colitis (UC) are largely unknown. This paper reviews the epidemiological and clinical data on how medications (non-steroidal anti-inflammatory drugs, estrogens and antibiotics), lifestyle factors (smoking, psychological stress, diet and air pollution) may precipitate clinical relapses and recurrence. Potential biological mechanisms include: increasing thrombotic tendency, imbalances in prostaglandin synthesis, alterations in the composition of gut microbiota, and mucosal damage causing increased permeability. The clinical epidemiological data consistently reports positive associations between smoking and relapses in CD, and inverse ones with UC. For NSAIDs and estrogens, the epidemiological findings are inconsistent, although general antibiotic use was associated with a reduced risk of relapse in CD. High levels of stress were positively associated with relapse, although psychological interventions did not have therapeutic benefits. The limited work on diet has reported sulphur-containing foods are positively associated with relapse in UC, but there is no work in CD. Ecological data reported positive correlations between air pollution levels and IBD hospitalisations. In the future, to clarify this area, more clinical epidemiological work is required where detailed drug types and doses, and complete dietary intakes are measured, in specific forms of IBD. Such work could provide guidance to both patients and doctors to help maintain remission.

AB03. Intermittent androgen suppression: current status

Hormone therapy has been a major treatment for advanced prostate cancer. This therapy aims at inhibiting growth of prostate tumor cells by deprivation of male hormones which stimulate prostate cells to grow. However, in spite of its temporally high effectiveness for tumor regression, most patients suffer from a relapse within a few years after initiation of treatment. The main cause of relapse is that cancer cells become resistant to hormone suppression. The toxicities of androgen deprivation have been well described, with a number of potential adverse effects on quality of life, including sexual dysfunction, hot flashes, fatigue, anemia, decreased bone density and muscle mass, altered blood lipid profile, depression, cognitive dysfunction, and worsening of the metabolic syndrome with effects on glucose metabolism and cardiovascular morbidity. The introduction of PSA testing into clinical practice in the early 1990’s provided an objective evaluation of the efficacy of definitive treatment and biochemical failure became an accepted end point. This ability to determine early treatment failure created a clinical dilemma for the practitioner. The justification for lifelong androgen deprivation is more apparent in the face of obvious clinical disease than in an asymptomatic individual with a slowly rising PSA, either with or without primary therapy aimed at the prostate.A possible clinical strategy to prevent or delay hormone-refractoriness of prostate tumor is intermittent hormone therapy. This treatment is also effective in reduction of side effects during off-treatment periods and thereby quality of life of patients can be improved. Bruchovsky and Goldenberg used the androgen-dependent Shionogi carcinoma to demonstrate that castration followed by re-exposure to androgens prior to tumor progression caused surviving stem cells to remain androgen-dependent, and thus amenable to further treatment by repeated androgen withdrawal. Successive castration and re-exposure to androgens in the mouse model produced multiple apoptotic regressions, resulting in a 3-fold delay in development of androgen independence. Cycles of androgen deprivation followed by re-exposure to testosterone form the basis of intermittent androgen deprivation (IAD).Multiple phase 2 clinical studies and 3 definitive phase-III trials of IAS have been published and will be reviewed. All phase 2 studies, including a meta-analysis strongly suggested that IAS is not inferior to continuous therapy and offers the potentials of QOL improvement and financial savings. The optimal protocol of IAS therapy, that is, how to determine the appropriate lower and upper thresholds of the serum PSA level for switching on- and off-treatment periods is quite varied but the most common approach is to treat for 6 to 8 months and resume at a predetermined PSA level. In clinical practice, a tailor-made patient-specific regimen is usually adopted because the best protocol of hormone therapy must depend upon individual patients.The multicentre randomized, prospective studies (NCIC PR8, SWOG 9346 and SEUG 9901) have been somewhat controversial. The large PR7 trial of IAS for men suffering PSA relapse after radiation strongly suggests non-inferiority. However, the PR8 study of men with metastatic cancer was not definitive in its conclusions and actually reported as “not non-inferior”. Many, but not all intermittent patients showed significant improvements in global QOL.A recently published metaanalysis of 5,508 patients in 9 RCT’s confirmed a cost savings of 48% with a pooled hazard ration for overall survival of 1.02 in favour of IAS (95% CI, 0.94 to 1.11). The HR for cancer specific survival was 1.08 for IAS vs. CAS (95% CI, 0.85 to 1.38). The authors pointed out some limitations of their metaanalysis but concluded that there was no notable compromise in health outcomes in eligible men treated with IAS as all showed either superiority or equivalence. They do caution the use of IAS in men with asymptomatic non-metastatic disease which reflects the question of appropriate timing of therapy along this disease’s continuum. Future work in this field includes the question of exogenous testosterone replacement for men in whom endogenous levels do not recover, the role of mathematical modeling in predicting an individual’s likely response to cycled therapy, choline PET scanning and the layering on of novel agents with low toxicity during the off-treatment interval.

Establishing Clinical Research in a Limited Resource Setting, "Acute Lymphoblastic Leukemia Model"

ABSTRACT Aim: One of the most important challenges that face Children's Cancer Hospital-57357 since its start, is establishing on Childhood Acute Lymphoblastic Leukemia (ALL) in a limited resource country like Egypt. Methods: Research Department was established in November-2008. it was the first time in Egypt to introduce the concept of forming team for each disease. A multidisplenary team of was formed. Team is composed of pediatric oncologist, Radiologist, clinical pathologists, flow cytometry specialist, cytogenetics specialist, basic researcher, radiologist, radiotherapist, psychologists, pharmacist, epidemiologist and clinical researchers. In parallel, and with the help of clinical researchers, a database of patients was established. Training curriculum for clinical researchers included 1- Scientific writing workshop, 2- The principles and practice of clinical research course from Harvard medical school, 3- Cancer Registry training. Results: above mentioned steps had a marvelous impact on childhood ALL. Initially, a genetic epidemiology grant in funded by US-NIH was obtained. Based on the results of this grant we applied to another grant on Genome wide Association Study in ALL to get fund and complete our to identify the cause of in Egyptian population and was obtained.The presence of database and statistical analysis of the survival, allow them to 1- hold collaboration with St Jude Research Hospital in special risk protocol that allow both check quality of flow cytometry results, cytogentics results so enhance the quality and allow rapid consultation on complicated cases, 2- the presence of hospital based-cancer registry for ALL,3- Supplying biobank with samples that help in future research, 4- rapid statistics of the number of relapsed and died patients. In addition to Production of patient education booklet. challenges become clear and the future plan to make strategy become mandatory: 1- Identifying the cause of relapse, 2- Route-cause analysis for patient died during induction and in complete remission, 3- plan to make translational and individualized treatment. 4- Using isimple audio-visual materials for education. Conclusions: presence of clinical has an impact on the childhood patients, staff and the institution. Disclosure: All authors have declared no conflicts of interest.

Récidives et dégradations de résultats en chirurgie orthognathique

Orthognathic surgery is a surgical technique that provides normalization of the face and occlusion. Some malocclusions are particularly unstable, such as maxillary transversal deficits, and anterior open bite. Many factors are implicated in the stability of surgical results. Indeed, facial balance largely depends on functions that could be the cause of unstable results, despite a good anatomical correction. Breathing, swallowing, chewing disorders and more largely alteration of the functional matrix may be sources of instability. These dysfunctions are the first cause of relapse. Others constitutional factors can also be involved in relapse. Understanding oro-facial functions and rules determining cranial and maxillo-facial balance is mandatory for the surgeon to ensure a long-term stability of procedures.

Distinct mu, delta, and kappa opioid receptor mechanisms underlie low sociability and depressive-like behaviors during heroin abstinence.

Addiction is a chronic disorder involving recurring intoxication, withdrawal, and craving episodes. Escaping this vicious cycle requires maintenance of abstinence for extended periods of time and is a true challenge for addicted individuals. The emergence of depressive symptoms, including social withdrawal, is considered a main cause for relapse, but underlying mechanisms are poorly understood. Here we establish a mouse model of protracted abstinence to heroin, a major abused opiate, where both emotional and working memory deficits unfold. We show that delta and kappa opioid receptor (DOR and KOR, respectively) knockout mice develop either stronger or reduced emotional disruption during heroin abstinence, establishing DOR and KOR activities as protective and vulnerability factors, respectively, that regulate the severity of abstinence. Further, we found that chronic treatment with the antidepressant drug fluoxetine prevents emergence of low sociability, with no impact on the working memory deficit, implicating serotonergic mechanisms predominantly in emotional aspects of abstinence symptoms. Finally, targeting the main serotonergic brain structure, we show that gene knockout of mu opioid receptors (MORs) in the dorsal raphe nucleus (DRN) before heroin exposure abolishes the development of social withdrawal. This is the first result demonstrating that intermittent chronic MOR activation at the level of DRN represents an essential mechanism contributing to low sociability during protracted heroin abstinence. Altogether, our findings reveal crucial and distinct roles for all three opioid receptors in the development of emotional alterations that follow a history of heroin exposure and open the way towards understanding opioid system-mediated serotonin homeostasis in heroin abuse.

Sonication of Antibiotic Spacers Predicts Failure during Two-stage Revision for Prosthetic Knee and Hip Infections

Periprosthetic joint infection is a leading cause of failure after two-stage reimplantation. One cause of relapse may be persistent subclinical infection. Difficulty exists in detecting biofilm-forming infections. Sonication disrupts biofilm and has led to higher rates of positive intraoperative cultures. Our aims in this study were to determine (1) if sonication results were predictive of failure, including reinfection, at 2-year followup; and (2) whether sonication of antibiotic spacers at the time of reimplantation improves sensitivity of intraoperative cultures. We prospectively followed 36 consecutive patients undergoing two-stage reimplantation for periprosthetic hip or knee infection. Minimum followup was 19 months (mean, 29.9 months; range, 19–38 months). Results of intraoperative cultures and sonicated antibiotic spacers were analyzed. Positive sonication results were predictive of failure as defined by reinfection at 2-year followup. Among the 18 patients who had positive sonication results, reinfection developed in nine patients (50%) compared with two of 18 patients (11%) with negative sonication results (odds ratio, 8.0; 95% CI, 1.2–69.0). Sonication of antibiotic spacers improved the sensitivity of intraoperative cultures from 45% to 82%. [corrected]. Sonication of antibiotic spacers appears to be useful in predicting failure attributable to recurrent infection after two-stage reimplantation. For patients with positive sonication cultures during reimplantation, more aggressive antimicrobial treatment may be indicated after reimplantation. Level III, diagnostic study. See the Instructions for Authors for a complete description of levels of evidence.

Inhibition of histone methyltransferase EZH2 depletes leukemia stem cell of mixed lineage leukemia fusion leukemia through upregulation of p16

Leukemia stem cells (LSC) are resistant to conventional chemotherapy and persistent LSC after chemotherapy are supposed to be a major cause of relapse. However, information on genetic or epigenetic regulation of stem cell properties is still limited and LSC-targeted drugs have scarcely been identified. Epigenetic regulators are associated with many cellular processes including maintenance of stem cells. Of note are polycomb group proteins, because they potentially control stemness, and can be pharmacologically targeted by a selective inhibitor (DZNep). Therefore, we investigated the therapeutic potential of EZH2 inhibition in mixed lineage leukemia (MLL) fusion leukemia. Intriguingly, EZH2 inhibition by DZNep or shRNA not only suppressed MLL fusion leukemia proliferation but also reduced leukemia initiating cells (LIC) frequency. Expression analysis suggested that p16 upregulation was responsible for LICs reduction. Knockdown of p16 canceled the survival advantage of mice treated with DZNep. Chromatin immunoprecipitation assays demonstrated that EZH2 was highly enriched around the transcription-start-site of p16, together with H3K27 methylation marks in MLL/ENL and Hoxa9/Meis1 transduced cells but not in E2A/HLF transduced cells. Although high expression of Hoxa9 in MLL fusion leukemia is supposed to be responsible for the recruitment of EZH2, our data also suggest that there may be some other mechanisms independent of Hoxa9 activation to suppress p16 expression, because expression levels of Hoxa9 and p16 were not inversely related between MLL/ENL and Hoxa9/Meis1 transduced cells. In summary, our findings show that EZH2 is a potential therapeutic target of MLL fusion leukemia stem cells.

Identification of small molecules that support human leukemia stem cell activity ex vivo

Leukemic stem cells (LSCs) are considered a major cause of relapse in acute myeloid leukemia (AML). Defining pathways that control LSC self-renewal is crucial for a better understanding of underlying mechanisms and for the development of targeted therapies. However, currently available culture conditions do not prevent spontaneous differentiation of LSCs, which greatly limits the feasibility of cell-based assays. To overcome these constraints we conducted a high-throughput chemical screen and identified small molecules that inhibit differentiation and support LSC activity in vitro. Similar to reports with cord blood stem cells, several of these compounds suppressed the aryl-hydrocarbon receptor (AhR) pathway, which we show to be inactive in vivo and rapidly activated ex vivo in AML cells. We also identified a compound, UM729, that collaborates with AhR suppressors in preventing AML cell differentiation. Together, these findings provide newly defined culture conditions for improved ex vivo culture of primary human AML cells.

Resveratrol Modulates Expression of ABC Transporters in Non-Small Lung Cancer Cells: Molecular Docking and Gene Expression Studies

Multidrug resistance is one of the most common causes of relapse in cancer chemotherapy. Inhibition of ABC transporters to reverse MDR is a prominent approach to enhance the efficacy of cancer chemotherapy. We investigated the effect of resveratrol (RSV) on the membrane transport function and the expression of proteins involved in the multidrug resistance in NCI-H460 cells. The molecular interactions of RSV with P-gp were analyzed by Schrodinger software. The membrane transport function and cell cycle distribution were measured using flow cytometry. The mRNA expression level of MDR1, LRP, MRP2, ABCC1, ABCC2 and ABCC3 genes were detected by qRT-PCR and BCRP expression was detected by western blot analysis. In silico docking studies revealed that RSV possesses greater binding affinity with TMD region of P-gp. In this study, RSV pretreatment significantly enhanced Paclitaxel (PTX) antiproliferative effect in NCI-H460 cells. The rhodamine 123 drug efflux studies revealed that there was a significant transport function inhibition by RSV treatment and moderate transport function inhibition by PTX. Further, RSV treatment significantly decreased the mRNA expression levels of various ABC transporters genes. Furthermore, expression of BCRP was found to be down-regulated during RSV treatment. It was also found that this enhanced anticancer efficacy of RSV was associated with PTX-induced cell arrest in the G2/M phase of cell cycle. Interestingly, we observed significantly enhanced antiproliferative effect, transport function inhibition and downregulation of ABC transporters in RSV-PTX combination group. This might be due to additive or synergistic effect of RSV with PTX in NCI-H460 cells. Thus, the present findings illustrate the modulatory role of RSV on PTX sensitization in relatively resistant NCI-H460 cells.

Nurses' Roles and Experiences with Enhancing Adherence to Tuberculosis Treatment among Patients in Burundi: A Qualitative Study.

Background. In TB control, poor treatment adherence is a major cause of relapse and drug resistance. Nurses have a critical role in supporting patients in TB treatment process. Yet, very little research has been done to inform policymakers and practitioners on nurses' experiences of treatment adherence among patients with TB. Aim. To describe nurses' experiences of supporting treatment adherence among patients with tuberculosis in Burundi. Method. The study adopted qualitative approach with a descriptive design. A purposive sampling was performed. Eight nurses were selected from two TB treatment centers in Burundi. Content analysis was used to analyze the data. Result. According to the nurses, most patients complete their treatment. Educating patients, providing the medication, observing and following up treatment, and communicating with the patients were the key tasks by nurses to support adherence. Causes for interruption were medication-related difficulties, poverty, and patients' indiscipline. Treatment adherence could also be affected by patients' and nurses' feelings. Providing transportation and meals could enhance treatment compliance. Conclusion. Nurses are critical resources to TB treatment success. In a poverty stricken setting, nurses' work could be facilitated and adherence further could be enhanced if socioeconomic problems (transportation and nutritional support) were alleviated.

The Relevance of Blue Moods and Depression in the Context of Smoking and Natural Quitting Rates in People Living with HIV

Objective: Research suggests that smoking-cessation interventions are less successful among people living with HIV (PLWH). The factors influencing the limited success of evidence-based smoking-cessation interventions in this population are not well understood. Design: Longitudinal analyses (of the first 12-months of an ongoing cohort (“FILTERS”) sociodemographically matched sample of 160 PLWH and 180 without HIVcomprised of both smokers and non-smokers . Methods: Semi-annual visits include a detailed survey of smoking behaviors (e.g., type of cigarette, amounts) and cessation efforts (i.e., prior attempts to quit, interest in quitting). Additionally, a fasting blood sample was obtained to assess serum cotinine, biochemical, and viroimmune parameters. Results: Compared to seronegatives, PLWH were more likely to be smokers (OR=1.4; 95% CI: 1-2.2;p=0.05).The readiness-to-quit-stages assessment showed that only 45% of the participants in the PLWH group were in the preparation or ready-to-action stages.PLWH were less likely to express interest in quitting than HIV negatives (OR=0.6; 95% CI: 0.4-1;p=0.05). Analyses indicated that PLWH were twice more likely to report stress, depression and anxiety as causes of relapse in prior quitting attempts (OR=1.6; 95% CI: 1.5- 2.4;p=0.004). After a natural course of 12 months,subjects receiving antidepressants exhibited larger reductions in number of cigarettes smoked per day (-2.6 CPD, p=0.06), than those without treatment (-0.8 CPD, p=0.2). Conclusions: Our analyses indicated that negative moodsimpact quitting success rates, particularly among PLWH. Our findings suggest that evaluation and treatment of depression may be a critical component of a smoking cessation program.

The functional mechanisms of the white line of the abdomen and their role in the pathogenesis of ventral hernia

The article gives a detailed analysis of the scientific work and their own data for the last ten years devoted to the problem of treatment of patients with umbilical hernias. Covered in detail and summarized the practical experience of various authors on the surgical treatment of patients with this pathology. Identified the causes of relapse and development periomphalic umbilical hernia in the postoperative period . Based on a detailed analysis of morfofuntional and biomechanical properties of the fascial- musculo- aponeurotic complex abdominal wall author justifies the use of prosthetic techniques in closing the defect of the umbilical ring.