Short Relapse Research Articles

Superfast Lombard response in free-flying, echolocating bats

Acoustic cues are crucial to communication, navigation, and foraging in many animals, which hence face the problem of detecting and discriminating these cues in fluctuating noise levels from natural or anthropogenic sources. Such auditory dynamics are perhaps most extreme for echolocating bats that navigate and hunt prey on the wing in darkness by listening for weak echo returns from their powerful calls in complex, self-generated umwelts.1,2 Due to high absorption of ultrasound in air and fast flight speeds, bats operate with short prey detection ranges and dynamic sensory volumes,3 leading us to hypothesize that bats employ superfast vocal-motor adjustments to rapidly changing sensory scenes. To test this hypothesis, we investigated the onset and offset times and magnitude of the Lombard response in free-flying echolocating greater mouse-eared bats exposed to onsets of intense constant or duty-cycled masking noise during a landing task. We found that the bats invoked a bandwidth-dependent Lombard response of 0.1-0.2 dB per dB increase in noise, with very short delay and relapse times of 20ms in response to onsets and termination of duty-cycled noise. In concert with the absence call time-locking to noise-free periods, these results show that free-flying bats exhibit a superfast, but hard-wired, vocal-motor response to increased noise levels. We posit that this reflex is mediated by simple closed-loop audio-motor feedback circuits that operate independently of wingbeat and respiration cycles to allow for rapid adjustments to the highly dynamic auditory scenes encountered by these small predators.

Drought Stress Amelioration Attributes of Plant-Associated Microbiome on Agricultural Plants.

The future global food security depends on the availability of water for agriculture. Yet, the ongoing rise in nonagricultural uses for water, such as urban and industrial uses, and growing environmental quality concerns have increased pressure of irrigation water demand and posed danger to food security. Nevertheless, its severity and duration are predicted to rise shortly. Drought pressure causes stunted growth, severe damage to photosynthesis activity, loss in crop yield, reduced seed germination, and reduced nutrient intake by plants. To overcome the effects of a devastating drought on plants, it is essential to think about the causes, mechanisms of action, and long-term agronomy management and genetics. As a result, there is an urgent need for long-term medication to deal with the harmful effects of drought pressure. The review focuses on the adverse impact of drought on the plant, physiological, and biochemical aspects, and management measures to control the severity of drought conditions. This article reviews the role of genome editing (GE) technologies such as CRISPR 9 (CRISPR-Cas9) related spaces and short palindromic relapse between proteins in reducing the effects of phytohormones, osmolytes, external compounds, proteins, microbes (plant growth-promoting microorganism [PGPM]), approach omics, and drought on plants that support plant growth. This research is to examine the potential of using the microbiome associated with plants for drought resistance and sustainable agriculture. Researchers also advocate using a mix of biotechnology, agronomic, and advanced GE technologies to create drought-tolerant plant varieties.

Identification of potential resistance mechanisms and therapeutic targets for the relapse of BCMA CAR-T therapy in relapsed/refractory multiple myeloma through single-cell sequencing

BackgroundBCMA CAR-T is highly effective for relapsed/refractory multiple myeloma(R/R-MM) and significantly improves the survival of patients. However, the short remission time and high relapse rate of MM patients treated with BCMA CAR-T remain bottlenecks that limit long-term survival. The immune microenvironment of the bone marrow (BM) in R/R-MM may be responsible for this. The present study aims to present an in-depth analysis of resistant mechanisms and to explore potential novel therapeutic targets for relapse of BCMA CAR-T treatment via single-cell RNA sequencing (scRNA-seq) of BM plasma cells and immune cells.MethodsThis study used 10X Genomic scRNA-seq to identify cell populations in R/R-MM CD45+ BM cells before BCMA CAR-T treatment and relapse after BCMA CAR-T treatment. Cell Ranger pipeline and CellChat were used to perform detailed analysis.ResultsWe compared the heterogeneity of CD45+ BM cells before BCMA CAR-T treatment and relapse after BCMA CAR-T treatment. We found that the proportion of monocytes/macrophages increased, while the percentage of T cells decreased at relapse after BCMA CAR-T treatment. We then reclustered and analyzed the alterations in plasma cells, T cells, NK cells, DCs, neutrophils, and monocytes/macrophages in the BM microenvironment before BCMA CAR-T treatment and relapse after BCMA CAR-T treatment. We show here that the percentage of BCMA positive plasma cells increased at relapse after BCMA CAR-T cell therapy. Other targets such as CD38, CD24, SLAMF7, CD138, and GPRC5D were also found to be expressed in plasma cells of the R/R-MM patient at relapse after BCMA CAR-T cell therapy. Furthermore, exhausted T cells, TIGIT+NK cells, interferon-responsive DCs, and interferon-responsive neutrophils, increased in the R/R-MM patient at relapse after BCMA CAR-T cell treatment. Significantly, the proportion of IL1βhi Mφ, S100A9hi Mφ, interferon-responsive Mφ, CD16hi Mφ, MARCO hi Mφ, and S100A11hi Mφ significantly increased in the R/R-MM patient at relapse after BCMA CAR-T cell therapy. Cell–cell communication analysis indicated that monocytes/macrophages, especially the MIF and APRIL signaling pathway are key players in R/R-MM patient at relapse after BCMA CAR-T cell therapy.ConclusionTaken together, our data extend the understanding of intrinsic and extrinsic relapse of BCMA CAR-T treatment in R/R-MM patient and the potential mechanisms involved in the alterations of antigens and the induced immunosuppressive microenvironment, which may provide a basis for the optimization of BCMA CAR-T strategies. Further studies should be performed to confirm these findings.

Glioblastoma Stem Cells-Useful Tools in the Battle against Cancer.

Glioblastoma stem cells (GSCs) are cells with a self-renewal ability and capacity to initiate tumors upon serial transplantation that have been linked to tumor cell heterogeneity. Most standard treatments fail to completely eradicate GSCs, causing the recurrence of the disease. GSCs could represent one reason for the low efficacy of cancer therapy and for the short relapse time. Nonetheless, experimental data suggest that the presence of therapy-resistant GSCs could explain tumor recurrence. Therefore, to effectively target GSCs, a comprehensive understanding of their biology and the survival and developing mechanisms during treatment is mandatory. This review provides an overview of the molecular features, microenvironment, detection, and targeting strategies of GSCs, an essential information required for an efficient therapy. Despite the outstanding results in oncology, researchers are still developing novel strategies, of which one could be targeting the GSCs present in the hypoxic regions and invasive edge of the glioblastoma.

Inhibition of Carbonic Anhydrase-IX As a Novel Strategy to Overcome Hypoxia Mediated Drug Resistance in FLT3/ITD Mutated Acute Myeloid Leukemia

Background: FLT3/ITD mutated (FLT3/ITD+) acute myeloid leukemia (AML) is an aggressive form of blood cancer that carries a poor prognosis due to short remission durations and high relapse rates. Several studies suggest that this poor outcome is due to a small fraction of leukemic cells (LCs) that elude treatment and survive in hypoxic niches of the bone marrow (BM) where they lead to relapse. The identification of molecules capable to target LCs under hypoxic conditions is therefore of utmost importance on the way to find a cure for AML. Our study addresses the effects of pharmacological inhibition of carbonic anhydrase-IX (CA9), a transmembrane protein which functions to maintain a neutral intracellular pH - a key survival mechanism for tumor cells to escape cell death in the hypoxic environment - on AML cells. Targeting CA9 is of particular interest as its expression is confined to only a few normal tissues. CA9 inhibition may therefore show relatively few side effects compared to standard chemotherapies. Methods: Molm14 (M14), M13, OCI-AML3, THP-1 and primary cells (PC) from FLT3/ITD+ AML patients were incubated under normoxic (21% O2) and hypoxic (1% O2) conditions in the presence or absence of Quizartinib (Quiz), Cytarabine (Cy) or the CA9 inhibitors FC531 (FC) or SLC-0111 (SLC). After 48h proliferation and apoptosis assays were performed using MTT assays, annexin V/PI staining and FACS analysis. Cells were also assessed for CA9 and CA12 mRNA expression as well as intracellular pH levels via RT-PCR and fluorescent imaging, respectively. FLT3/ITD+ AML xenografts were generated by injecting M14 cells in the tail vein of NSG mice. Tissue samples were fixed in 10% NBF, embedded in paraffin and stained with H&E and CA9 for pathologic evaluation. Results: CA9 mRNA was upregulated in M14 cells (3.8±1.1-fold; n=3, p<.05) and FLT3/ITD+ AML PCs (215.4±142.7-fold, n=7, p=NS) under 1% compared to 21% O2. Consistently, immunohistochemical staining of M14 xenograft tissues showed multifocal CA9 staining of LCs in the BM and spleen. In M14 cells, inhibition of CA9 with FC conferred substantial, dose-dependent growth inhibitory effects under 1% O2 (IC50=4.04µM) and was significantly more effective than clinically achievable doses of Quiz or Cy in this regard. Under 1% O2, flow cytometry revealed significant induction of apoptosis in FC, but not in Quiz or Cy treated cells (p<.01 vs Cy, p<.01 vs Quiz; n=3). Similar results were obtained in M13 cells. Treatment of M14 cells with 5µM FC under 1% O2 resulted in substantial intracellular pH acidification (ΔpH=-2.7±0.6, p<.05 vs 1% O2, n=3) within 48h. FC synergistically inhibited M14 cell growth when combined with Cy (CI=0.78). To investigate the effects of CA9 inhibition against non-FLT3 mutated cells we incubated OCI-AML3 and THP-1 cells to increasing doses of FC (1-10µM) under 1% O2. We observed that both cell lines were less sensitive to FC (IC50>10µM) compared to M14 and M13 cells. Interestingly, these cell lines displayed higher levels of CA12 mRNA (CA9/12 ratio=0.68 [OCI-AML3] and 0.54 [THP-1]) compared to the FC sensitive cell lines M14 and M13 (CA-9/12 ratio=2.5 and 4.6, respectively). Next, we assessed the effects Cy (1µM), Quiz (100nM) and FC (200µM) against FLT/ITD+ PCs. As expected, Cy and Quiz did not confer cytotoxic effects under 1% O2. Surprisingly, FC was only mildly effective against FLT/ITD+ PCs, which harbored low CA9/12 ratios (<0.5). In contrast, treatment with equimolar doses of SLC, a different class CA9 inhibitor, exhibited substantial anti-leukemic activity under 1% O2 conditions (78.8±1.9% growth inhibition, n=3, p<.05 vs FC, p<.001 vs Cy or Quiz). Conclusions: 1. CA9 is upregulated in FLT3/ITD+ cell lines and PCs under hypoxic conditions. 2. CA9 is expressed in LCs residing in the BM and spleen of FLT/ITD+ AML xenografts. 3. The CA9 inhibitor FC531 confers marked anti-leukemic activity against FLT3/ITD+ AML cells under hypoxic conditions via intracellular pH acidification and acts synergistically with cytarabine. 4. Upregulation of other carbonic anhydrase isoforms, such as CA12, might represent a resistance mechanism against FC531 that can be overcome by different class CA9 inhibitors. 5. Our data suggests that CA9 inhibition has the potential to specifically target LCs residing in hypoxic niches and may be of value as an adjunct to chemotherapy for FLT3/ITD+AML treatment. 6. Our ongoing work evaluates the effects of CA9 inhibition in AML xenografts. DisclosuresNo relevant conflicts of interest to declare.

FLT3 ITD AML Outcomes Are Impacted By Exposure to One Cycle of Cytarabine Based Consolidation, Pre- and Post-Transplant TKI Therapy, and Presence of Minimal Residual Disease (MRD) Prior to Allogeneic Blood or Marrow Transplant

Background:FLT3 ITD AML is associated with high rates of relapse and short relapse free survival. Prognosis after relapse is extremely poor, making optimization of initial therapy for this group of patients important. Most data now suggest allogeneic transplant should be the standard consolidation for FLT3 ITD AML. Although peri-transplant tyrosine kinase inhibitor (TKI) use is common, there is no consensus on the best way to incorporate TKIs into the management of these patients. A comprehensive review of treatment outcomes is needed to determine which strategies reduce the risk of relapse and prolong survival.Methods:We conducted a retrospective chart review for 112 patients with FLT3 ITD mutations seen at JHH between 2005 and 2016 who underwent bone marrow transplantation to collect demographic, diagnostic, transplant and survival data. Differences in the distribution of demographic, clinical, and biological characteristics were analyzed for significance using Fisher's exact test. Consolidation was defined as any cytarabine-based regimen after remission induction therapy. MRD positivity included the presence of >0 to 5% abnormal blasts by morphology or flow cytometry and/or persistence of genetic abnormalities (cytogenetics, mutation panels) prior to transplant. Overall survival (OS) was defined as the time interval from date of transplant to date of death from any cause or to last follow up visit. Relapse free survival (RFS) was defined as the time interval from date of transplant to date of relapse or death from any cause. Survival was censored at 2 years post-transplant. Time was censored at the last follow-up visit if relapse or death were not observed. Survival estimates were calculated using Kaplan-Meier method and comparison of survival distributions were done using log-rank test. TKI included are quizartinib, sorafenib, and gilteritinib.Results:Patient characteristics are summarized in Table 1.Outcomes based on disease characteristics including NPM1 status, allelic ratio and cytogenetics are listed in Table 2. Patients with NPM1 mutations had improved RFS (HR=0.4165, p=0.0193). Patients with no detectable MRD prior to transplant have improved RFS (HR=0.4394, p=0.0023) and OS (HR=0.5526, p=0.0437).Outcomes related to treatment strategies are also summarized in Table 2. Patients with at least 1 cycle of post remission consolidation had lower rates of MRD (p=0.0046) (Table 3), and improved RFS (HR=0.5191, p=0.0228) and OS (HR=0.4728, p=0.0143) (Figure 2). Patients who received consolidation and pre-transplant TKI had the best outcomes (Figure 1). In the absence of consolidation, pre-transplant TKI usage was associated with longer RFS (median 1.819 years versus 0.8548 years, p = 0.2105) and OS (median 1.995 years versus 1.249 years, p=0.4384) compared to those with no pre-transplant TKI use. Patients who received either consolidation or pre-transplant TKI had similar outcomes. Non-myeloablative conditioning regimens trended toward favorable outcomes over myeloablative regimens despite older patients and lower rates of NPM1 mutations (HR=.6358, p=0.1346 for OS, HR=0.6471, p=0.1231 for RFS). There was no difference in OS or RFS between matched and haploidentical donors. Post-transplant TKI use improves RFS (HR=0.5503, p=0.0339) and OS for all patients (HR=0.4679, p=0.0102). For patients who had MRD prior to transplant, TKI use post-transplant was associated with median RFS of 1.499 years versus 0.7425 years for those who did not use post-transplant TKI (Figure 2). Post-transplant TKI use also improved OS (HR=0.3737, p =0.0308) for patients without MRD prior to transplant.Discussion:Remission status at time of transplant is key to outcomes. Consolidation, as well as use of TKI pre- and post-transplant are associated with favorable outcomes. Although patients who were given consolidation had more favorable outcomes, it is unclear if patient characteristics (higher NPM1 %, lower AR>50%, and younger age) confounded their outcomes. Matched and haploidentical donors confer similar outcomes. This data supports treatment of FLT3 ITD AML patients to include induction, 1 cycle of post remission consolidation, TKI use prior to transplant, and transplant with post-transplant TKI maintenance. [Display omitted] DisclosuresSmith:Celgene: Consultancy; Curis: Consultancy; Ariad/Takeda: Consultancy; Novartis: Consultancy; Pfizer: Consultancy. Swinnen:Genentech: Consultancy; Pharmacyclics: Consultancy. Levis:Astellas Pharma Us: Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Research Funding; FujiFilm: Research Funding; Daiichi Sankyo, Inc.: Consultancy, Honoraria.

Longitudinal CITE-Seq profiling of chronic lymphocytic leukemia during ibrutinib treatment: evolution of leukemic and immune cells at relapse

BackgroundIbrutinib, an irreversible Bruton Tyrosine Kinase (BTK) inhibitor, has revolutionized Chronic Lymphocytic Leukemia (CLL) treatment, but resistances to ibrutinib have emerged, whether related or not to BTK mutations. Patterns of CLL evolution under ibrutinib therapy are well characterized for the leukemic cells but not for their microenvironment.MethodsHere, we addressed this question at the single cell level of both transcriptome and immune-phenotype. The PBMCs from a CLL patient were monitored during ibrutinib treatment using Cellular Indexing of Transcriptomes and Epitopes by sequencing (CITE-Seq) technology.ResultsThis unveiled that the short clinical relapse of this patient driven by BTK mutation is associated with intraclonal heterogeneity in B leukemic cells and up-regulation of common signaling pathways induced by ibrutinib in both B leukemic cells and immune cells. This approach also pinpointed a subset of leukemic cells present before treatment and highly enriched during progression under ibrutinib. These latter exhibit an original gene signature including up-regulated BCR, MYC-activated, and other targetable pathways. Meanwhile, although ibrutinib differentially affected the exhaustion of T lymphocytes, this treatment enhanced the T cell cytotoxicity even during disease progression.ConclusionsThese results could open new alternative of therapeutic strategies for ibrutinib-refractory CLL patients, based on immunotherapy or targeting B leukemic cells themselves.

Longitudinal monitoring of circulating tumour DNA improves prognostication and relapse detection in gastroesophageal adenocarcinoma

BackgroundGastroesophageal adenocarcinoma (GOA) has poor clinical outcomes and lacks reliable blood markers. Here we present circulating tumour DNA (ctDNA) as an emerging biomarker.MethodsForty patients (17 palliative and 23 curative) were followed by serial plasma monitoring. Primary tumour DNA was analysed by targeted next-generation sequencing to identify somatic single-nucleotide variants (SNVs), and Nanostring nCounter® to detect copy number alterations (CNAs). Patient-specific SNVs and CNA amplifications (CNAamp) were analysed in plasma using digital droplet PCR and quantitative PCR, respectively.ResultsThirty-five patients (13 palliative, 22 curative) had ≥1 SNVs and/or CNAamp detected in primary tumour DNA suitable for tracking in plasma. Eighteen of 35 patients (nine palliative, nine curative) had ≥1 ctDNA-positive plasma sample. Detection of postoperative ctDNA predicted short RFS (190 vs 934 days, HR = 3.7, p = 0.028) and subsequent relapse (PPV for relapse 0.83). High ctDNA levels (>60.5 copies/ml) at diagnosis of metastatic disease predicted poor OS (90 vs 372 days, HR = 11.7 p < 0.001).ConclusionSensitive ctDNA detection allows disease monitoring and prediction of short OS in metastatic patients. Presence of ctDNA postoperatively predicts relapse and defines a ‘molecular relapse’ before overt clinical disease. This lead time defines a potential therapeutic window for additional anticancer therapy.

Comparative efficacy and acceptability of antidepressants in the long-term treatment of major depression: protocol for a systematic review and networkmeta-analysis

IntroductionPharmacotherapy plays an important role in the treatment of major depression. At the initiation of antidepressant treatment, both improvement of symptoms in the short term and relapse prevention in the...

Risk of Plasmodium vivax parasitaemia after Plasmodium falciparum infection: a systematic review and meta-analysis

SummaryBackgroundA 14-day course of primaquine is used for radical cure of Plasmodium vivax and Plasmodium ovale malaria only. We quantified the risk of P vivax parasitaemia after treatment of Plasmodium falciparum with commonly used antimalarial drugs to assess the potential benefits of radical cure for all patients with uncomplicated malaria in co-endemic regions.MethodsIn this systematic review and meta-analysis, we searched MEDLINE, Embase, Web of Science, and the Cochrane Database of Systematic Reviews for prospective clinical studies in any language, published between Jan 1, 1960, and Jan 5, 2018, assessing drug efficacy in patients with uncomplicated P falciparum malaria in countries co-endemic for P vivax. Studies were included if the presence or absence of P vivax parasitaemia was recorded after treatment. The primary outcome was the risk of P vivax parasitaemia between day 7 and day 42 after initiation of antimalarial treatment for P falciparum, with the pooled risk calculated by random-effects meta-analysis. We compared the risk of P vivax parasitaemia after treatment with different artemisinin-based combination therapies (ACTs). This study is registered with PROSPERO, number CRD42017064838.Findings153 of 891 screened studies were included in the analysis, including 31 262 patients from 323 site-specific treatment groups: 130 (85%) studies were from the Asia-Pacific region, 16 (10%) from the Americas, and seven (5%) from Africa. The risk of P vivax parasitaemia by day 42 was 5·6% (95% CI 4·0–7·4; I2=92·0%; 117 estimates). The risk of P vivax parasitaemia was 6·5% (95% CI 4·6–8·6) in regions of short relapse periodicity compared with 1·9% (0·4–4·0) in regions of long periodicity, and was greater after treatment with a more rapidly eliminated ACT: 15·3% (5·1–29·3) for artemether-lumefantrine compared with 4·5% (1·2–9·3) for dihydroartemisinin-piperaquine and 5·2% (2·9–7·9) for artesunate-mefloquine. Recurrent parasitaemia was delayed in patients treated with ACTs containing mefloquine or piperaquine compared with artemether-lumefantrine, but by day 63 the risk of vivax parasitaemia was more than 15% for all ACTs assessed.InterpretationOur findings show a high risk of vivax parasitaemia after treatment of falciparum malaria, particularly in areas with short relapse periodicity and after rapidly eliminated treatment. In co-endemic regions, universal radical cure for all patients with uncomplicated malaria has the potential to substantially reduce recurrent malaria.FundingAustralian National Health and Medical Research Council, Royal Australasian College of Physicians, Wellcome Trust, and Bill & Melinda Gates Foundation.

Randomized Trial of Two Dosages of Rabbit Antithymocyte Globulin in Patients with Aplastic Anemia

Randomized Trial of Two Dosages of Rabbit Antithymocyte Globulin in Patients with Aplastic Anemia

Fecal calprotectin measurement is a marker of short-term clinical outcome and presence of mucosal healing in patients with inflammatory bowel disease.

AIMTo evaluate the utility of fecal calprotectin (FC) in predicting relapse and endoscopic activity during follow-up in an inflammatory bowel disease (IBD) cohort.METHODSAll FC measurements that were obtained during a 3-year period from patients with inflammatory bowel disease in clinical remission were identified. Data regarding the short-term (6 mo) course of the disease were extracted from the medical files. Exclusion criteria were defined as: (1) An established flare of the disease at the time of FC measurement, (2) Loss to follow up within 6 mo from baseline FC measurement, and, (3) Insufficient data on file. Statistical analysis was performed to evaluate whether baseline FC measurement could predict the short term clinical relapse and/or the presence of mucosal healing.RESULTSWe included 149 [Crohn’s disease (CD) = 113, Ulcerative colitis (UC) = 36, male = 77] IBD patients in our study. Within the determined 6-month period post-FC measurement, 47 (31.5%) had a disease flare. Among 76 patients who underwent endoscopy, 39 (51.3%) had mucosal healing. Baseline FC concentrations were significantly higher in those who had clinical relapse compared to those who remained in remission during follow up (481.0 μg/g, 286.0-600.0 vs 89.0, 36.0-180.8, P < 0.001). The significant predictive value of baseline median with IQR FC for clinical relapse was confirmed by multivariate Cox analysis [HR for 100μg/g: 1.75 (95%CI: 1.28-2.39), P = 0.001]. Furthermore, lower FC baseline values significantly correlated to the presence of mucosal healing in endoscopy (69.0 μg/g, 30.0-128.0 vs 481.0, 278.0-600.0, in those with mucosal inflammation, median with IQR, P < 0.001). We were able to extract cut-off values for FC concentration with a high sensitivity and specificity for predicting clinical relapse (261 μg/g with AUC = 0.901, sensitivity 87.2%, specificity 85.3%, P < 0.001) or mucosal healing (174 μg/g with AUC = 0.956, sensitivity 91.9%, specificity 87.2%, P < 0.001). FC was better than CRP in predicting either outcome; nevertheless, having a pathological CRP (> 5 mg/L) in addition to the cut-offs for FC, significantly enhanced the specificity for predicting clinical relapse (95.1% from 85.3%) or endoscopic activity (100% from 87.2%).CONCLUSIONSerial FC measurements may be useful in monitoring IBD patients in remission, as FC appears to be a reliable predictor of short-term relapse and endoscopic activity.

Invasive Pleomorphic Lobular Histology is an Adverse Prognostic Factor on Survival in Patients with Breast Cancer

Invasive pleomorphic lobular carcinoma (IPLC) is defined to be an uncommon and different subtype of classical invasive lobular carcinoma (ILC). This special variant is characterized by significant cytological atypia and pleomorphism which differs from the cytological uniformity of ILC. IPLC has been shown to have some poor prognostic factors such as axillary node metastasis and higher histological grade which may lead to poor clinical courses including a short relapse time, increased risk of recurrence and a decreased survival. The aim of this study is to investigate the clinicopathological characteristics and prognosis of IPLC in comparison with ILC and also to evaluate if IPLC is a different clinical entity compared to ILC. A total number of 4418 breast cancer patients treated between 1996 and 2015 in Hacettepe University Cancer Institute, were retrospectively analyzed. Among 4418 patients, 210 were diagnosed with ILC and 23 patients diagnosed with pure IPLC. In this present study, clinicopathological characteristics, disease free survival (DFS) and overall survival (OS) of patients with ILC and IPLC were compared. This study design is one of the rare face to face comparison of pure IPLC and ILC. Patients with IPLC had an increased rate of higher histologic grade, extracapsular extension, lymphovascular invasion and lower percentage of hormone positivity than those of patients with ILC. During the follow-up time, IPLC group experienced 4 cases (17.3%) of recurrence, 5 cases (21.7%) of death and 2 cases (8.7%) of progression in 3 metastatic patients compared to that of 27 cases (12.9%) of recurrence, 29 cases (13,8%) of death and 14 cases (6.7%) of progression in 19 metastatic patients in the ILC group. Patients with IPLC had a worse DFS and OS duration than patients with ILC (P = 0.02 for OS, P = 0.04 for DFS). In conclusion, IPLC is a different and a special breast cancer subtype. This study suggests that IPLC is a distinct clinical entity with an advanced stage and more aggressive clinical course. Patients with IPLC reveal poorer prognostic factors such as higher histological grade, relative lower percentages of hormone positivity, and increased rate of recurrences resulting in poor clinical outcomes and worse survival. Nowadays, it is observed that current treatment methods for IPLC do not seem as successful as in ILC and failed to be effective. Thence, individual therapies including more aggressive surgery and adjuvant or neoadjuvant chemotherapy even in the earlier stages of breast cancer should be performed for this distinct variant.

Self-Reported Reasons for Smoking: Predicting Abstinence and Implications for Smoking Cessation Treatments Among Those With a Psychotic Disorder

ABSTRACTObjectives: People living with a psychotic illness have higher rates of cigarette smoking and face unique barriers to quitting compared to the general population. We examined whether self-reported reasons for smoking are useful predictors of successful quit attempts among people with psychosis. Methods: As part of a randomized controlled trial addressing smoking and cardiovascular disease risk behaviors among people with psychosis, self-reported reasons for smoking were assessed at baseline (n = 235), 15 weeks (n = 151), and 12 months (n = 139). Three factors from the Reasons for Smoking Questionnaire (Coping, Physiological, and Stimulation/Activation) were entered into a model to predict short- and long-term abstinence. The relationship between these factors and mental health symptoms were also assessed. Results: Participants scoring higher on the Stimulation/Activation factor (control of weight, enjoyment, concentration, and “peps me up”) at baseline were just less than half as likely to be abstinent at 15 weeks. Female participants were five times more likely to abstinent at 15 weeks, and those with a higher global functioning at baseline were 5% more likely to be abstinent. There was a positive correlation between changes over time in the Stimulation/Activation factor from baseline to 12-month follow-up and the Brief Psychiatric Rating Scale total score at 12-month follow-up. This indicates that increasingly higher endorsement of the factor was associated with more psychological symptoms. There was also a negative correlation between the change over time in the Stimulation/Activation factor and global functioning at 12 months, indicating that increasingly higher endorsement of the factor led to lower global assessment of functioning. Conclusions: The Stimulation/Activation factor may be particularly important to assess and address among smokers with psychosis. It is recommended that further research use the Reasons for Smoking Questionnaire among smokers with psychosis as a clinical tool to identify specific quit barriers. Further research into why females have higher smoking cessation rates in the short term and relapse prevention interventions seem worthy of further investigation.

Reduced Chemosensitivity of FLT3/ITD Mutated Cells to Cytarabine and Quizartinib Under Hypoxic Conditions

Background: FLT3/ITD mutated AML is characterized by short remission duration and high relapse rates due to the survival of a small fraction of leukemic cells (LCs) that outlive initial therapy. There is compelling evidence that the hypoxic niche in the bone marrow (BM) provides a sanctuary where subpopulations of LCs evade cytotoxic therapy and acquire drug resistance. In order to define the mechanisms involved in this process, multiple studies have focused on the interactions between LCs and the BM microenvironment but less is known about to the role of hypoxia as a modulator of drug resistance. Hence, the effects of standard and investigational therapies under hypoxic conditions are largely unknown. Here, we investigated the cytotoxic response of FLT3/ITD-mutated cells to conventional and targeted therapy under normoxic (21% O2) and hypoxic (1% O2) conditions. Methods: Molm14 (M14) cells and primary cells from relapsed/refractory FLT3/ITD mutated AML patients were incubated in culture medium under normoxic and hypoxic conditions. Cytarabine (Cy) or Quizartinib (Quiz) were added as single agents at the indicated concentrations. After 48 hours proliferation and apoptosis assays were performed using MTT assays, annexin V/PI staining and FACS analysis (M14). Cells were also assessed for FLT3 protein and Hypoxia inducible factor (HIF) target gene expression by western blotting and PCR arrays (RT2 ProfilerTM PCR Array, Human Hypoxia Signaling Pathway Plus, Qiagen) (M14 and primary cells), respectively. Results: We found that M14 cells were significantly less susceptible to treatment under hypoxic conditions, both when exposed to Cy and targeted FLT3 inhibition with Quiz (Growth inhibition, 0.25nM Quiz: 8.5±4.2% (1% O2) vs. 22±2.5% (21% O2), p<.05; 49.6±2.5% (1% O2) vs. 58.1±2.3% (21% O2), n=8, p<.05; 0.25µM Cy: 3.7±2.5% (1% O2) vs. 14.4±1.5% (21% O2), p<.01; 1 µM Cy: 26.3±4.1% (1% O2) vs. 53.3±3.8% (21% O2), n=10-12, p<.001). In line with these findings, the apoptotic response of M14 cells to Cy treatment was significantly blunted under hypoxic conditions (Fold increase in apoptotic cells vs. untreated control, 1 µM: 5.7±0.8 fold [21% O2] vs. 2.7±0.5 fold [1% O2], n=4, p<.05). While not reaching the significance threshold, the trend was similar for the Quiz-treated cells. This effect was extended to primary, relapsed/refractory FLT3/ITD-mutated cells derived from patients (n=2) treated at our institution, where growth inhibition was consistently decreased in hypoxia at all doses of Cy and Quiz tested. Not unexpectedly, these primary cells required significantly higher doses compared to the established M14 cell line (1-10µM for Cy, and 50-200nM for Quiz). Importantly, Quiz appeared to be similarly effective in inactivating FLT3 activity under low and high oxygen tension. Therefore identifying tractable pro-survival genes induced by the low oxygen microenvironment should represent a viable strategy to increase the effectiveness of anti-leukemic agents. In order to identify such target candidates, we surveyed the effects of Quiz and Cy on a panel of 84 hypoxia-regulated genes using PCR arrays. Our preliminary studies revealed that while HIF pathway remains largely functional in the presence of Quiz or Cy, these agents severely blunt induction of several hypoxia genes (including Glucose transporter 1 [Glut1] and Carbonic Anhydrase 9 [CA9]) in both primary cells and M14 cells. Conclusions: 1.Hypoxia limits the cytotoxic effects of conventional and targeted therapeutic agents in primary and established FLT3/ITD mutated AML cells. 2. Quizartinib effectively abrogates FLT3 signaling under both normoxic and hypoxic conditions, indicating that other signaling pathways are critical for leukemic cell survival under reduced oxygen tension. 3. The induction of several potentially druggable HIF targets is disrupted by anti-AML agents, warranting the further investigation of combinational approaches between standard anti-AML agents and HIF targeted strategies. 4. Such therapeutic combinations are likely to be particularly effective undermicro-environmental stress conditions (e.g. severe hypoxia) thus addressing an unmet need in AML therapy. DisclosuresNo relevant conflicts of interest to declare.

MicroRNA-10b and minichromosome maintenance complex component 5 gene as prognostic biomarkers in breast cancer.

The aim of this study is to identify micro-ribonucleic acid (microRNA) and its target, in addition to their relationship to the outcome in breast cancer (BC). To achieve this aim, we investigated microRNA-10b (miR-10b) and minichromosome maintenance complex component 5 (MCM5 mRNA) expression in 230 breast tissue samples by real-time PCR and semiquantitative conventional RT-PCR, respectively. Relapse-free survival (RFS) associated with miRNA-10b and MCM5 mRNA were tested by Kaplan-Meier survival analysis. The impact of miRNA-10b andMCM5 mRNA expression on the survival was evaluated by Cox proportional hazard regression model. The expression of miRNA-10b and MCM5 mRNA was positive in 86.4 and 79.7 % breast cancer patients, respectively. The overall concordance rate between miRNA-10b and MCM5 RNA was 90.4 %. The median follow-up period was 50 months. The survival analysis showed that high levels of both miR-10b and MCM5 were associated with short relapse free survival of BC. We identified MCM5 mRNA expression changes consistent with the miRNA-10b target regulation. Thus, we could consider miRNA-10b and MCM5 mRNA as prognostic markers and potential therapeutic targets in breast cancer to be applied to other patient data sets.

Positionnement condylien lors de la chirurgie orthognathique mandibulaire

Sagittal split osteotomy of the mandible is the most frequently used method in orthognatic surgery. Osteosynthesis was performed with wires in the 1970s. The instability of fixation allowed condyle movements and there was no problem of condylar positioning. The drawback of this technique was that it required a strict intermaxillary fixation for 6 weeks. Osteosynthesis evolved in the 1980s to a rigid and semi-rigid fixation, with no longer any need for an intermaxillary fixation. But accurately determining the condyle position in the fossa is essential when using a rigid fixation, because no spontaneous adaptation is possible. Moreover, an improper condyle positioning is known to increase short term skeletal relapse, inadequate corrections, and a high incidence of temporomandibular joint dysfunctions. Many solutions have been proposed to solve the problem of condylar positioning: manual positioning technique at osteosynthesis, and mechanical or computer assisted devices to control condylar positioning. The repositionable and adjustable miniplates have also been designed to improve condyle positioning, with the possibility of peroperative adjustment.

Successful management of early recurrence after surgery for primary rib osteosarcoma in an adult

Primary osteosarcoma is a common malignant bone tumour that principally affects the long bones, but relatively rare in flat bones, in children and adolescents. This study presents a rare case of primary rib osteosarcoma in a 59-year old man. The patient underwent second radical excision of the tumour due to a short time relapse after the first operation. Chest wall reconstruction, neoadjuvant chemotherapy before the second operation and postoperative chemotherapy were also performed. To date, 5 months have passed with no recurrence being observed.

Neuromyelitis Optica in Child: Diagnostic and Therapeutic Challenges

Neuromyelitis optica (NMO) is a rare syndrome of severe inflammatory demyelination of the central nervous system, causing attacks of optic neuritis and transverse myelitis. Although uncommon, attention should be given to the proper identification and management of the affected patients. We present a case of a 13-year-old girl with severe neuromyelitis optica. The patient's initial presentation consisted of encephalopathy and optic neuritis. Approximately 2 months later, coinciding with the weaning of steroid treatment, she presented with ascending paralysis and respiratory failure. She was seropositive for NMO-IgG. Treatment included intravenous immune globulin, steroids, plasmapheresis, and rituximab and was complemented with proper nutrition, vitamins, minerals, and intense rehabilitation. Two years after the initial presentation and one short relapse, the patient has made a remarkable recovery without neurologic deficit. This report underscores the difficulty in making the initial diagnosis, choosing the best treatment, and the need for more streamlined pediatric guidelines for diagnosis, treatment, and prevention of relapses of pediatric NMO.

A Case of De novo Seizures Following a Probable Interaction of High-Dose Baclofen with Alcohol

Baclofen is a promising medication for the treatment of alcohol dependence, and the prescription of high-dose baclofen (HDB) is increasing within the medical community, especially for patients who are unresponsive to approved treatments. Although baclofen is considered to be quite safe at low doses, the possible interactions between HDB and alcohol have not been precisely studied. We report the case of a 46-year-old patient without any history of neurological disorders who experienced two episodes of seizures after a short relapse of alcohol misuse while undergoing treatment with up to 240 mg/day of baclofen. Although both alcohol and baclofen may theoretically induce seizures individually, we discuss and largely rule out the likelihood that either of these two drugs was solely responsible for the patient's seizures. We hypothesize that the seizures resulted from an interaction between alcohol and HDB, and determined that this hypothesis is 'probable' with Horn's Drug Interaction Probability Scale. We encourage our colleagues who prescribe HDB to acquaint their patients with the possible enhanced risk of seizures, notably in persistence of alcohol abuse. Moreover, until data from a large study on the safety of HDB use by alcohol misusers are available, this treatment should be conducted under strict supervision and after having carefully evaluated the benefit-risk ratio.