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The hippocampal CA3 subregion is a densely connected recurrent circuit that supports memory by generating and storing sequential neuronal activity patterns that reflect recent experience. While theta phase precession is thought to be critical for generating sequential activity during memory encoding, the circuit mechanisms that support this computation across hippocampal subregions are unknown. By analyzing CA3 network activity in the absence of each of its theta-modulated external excitatory inputs, we show necessary and unique contributions of the dentate gyrus (DG) and the medial entorhinal cortex (MEC) to phase precession. DG inputs are essential for preferential spiking of CA3 cells during late theta phases and for organizing the temporal order of neuronal firing, while MEC inputs sharpen the temporal precision throughout the theta cycle. A computational model that accounts for empirical findings suggests that the unique contribution of DG inputs to theta-related spike timing is supported by targeting precisely timed inhibitory oscillations. Our results thus identify a novel and unique functional role of the DG for sequence coding in the CA3 circuit.

A hallmark of fetal alcohol spectrum disorders (FASD) is neurobehavioral deficits that still do not have effective treatment. Here, we present that reduction of Apolipoprotein E (APOE) is critically involved in neurobehavioral deficits in FASD. We show that prenatal alcohol exposure (PAE) changes chromatin accessibility of Apoe locus, and causes reduction of APOE levels in both the brain and peripheral blood in postnatal mice. Of note, postnatal administration of an APOE receptor agonist (APOE-RA) mitigates motor learning deficits and anxiety in those mice. Several molecular and electrophysiological properties essential for learning, which are altered by PAE, are restored by APOE-RA. Our human genome-wide association study further reveals that the interaction of PAE and a single nucleotide polymorphism in the APOE enhancer which chromatin is closed by PAE in mice is associated with lower scores in the delayed matching-to-sample task in children. APOE in the plasma is also reduced in PAE children, and the reduced level is associated with their lower cognitive performance. These findings suggest that controlling the APOE level can serve as an effective treatment for neurobehavioral deficits in FASD.

BackgroundVolatile anesthetic exposure during development leads to long-term cognitive deficits in rats which are dependent on age and sex. Female rats are protected relative to male rats for the same exposure on postnatal day 7. Here we test our hypothesis that androgens can modulate chloride cotransporter expression to alter the susceptibility to neurotoxicity from GABAergic drugs using female rats with exogenous testosterone exposure.MethodsFemale rats were injected with testosterone (100 μg/animal) or vehicle on postnatal days 1 to 6. On postnatal day 7, the animals were randomized to either isoflurane exposure or sham. Spatial memory was assessed with the Barnes maze starting on postnatal day 41. Western blots were run from testosterone treated postnatal day 7 animals to measure levels of chloride cotransporters sodium-potassium-chloride symporter (NKCC1) and chloride-potassium symporter 5 (KCC2).ResultsExogenous testosterone modulated isoflurane anesthetic neurotoxicity in female rats based on poor performance in the probe trial of the Barnes Maze. By contrast, females with vehicle and isoflurane exposure were able to differentiate the goal position. These behavioral differences corresponded to differences in the protein levels of NKCC1 and KCC2 after exogenous testosterone exposure, with NKCC1 increasing ( P

TERT promoter mutations are commonly associated with 1p/19q codeletion in IDH-mutated gliomas. However, whether these mutations have an impact on patient survival independent of 1p/19q codeletion is unknown. In this study, we investigated the impact of TERT promoter mutations on survival in IDH-mutated glioma cases. Detailed clinical information and molecular status data were collected for a cohort of 560 adult patients with IDH-mutated gliomas. Among these patients, 279 had both TERT promoter mutation and 1p/19q codeletion, while 30 had either TERT promoter mutation (n = 24) or 1p/19q codeletion (n = 6) alone. A univariable Cox proportional hazard analysis for survival using clinical and genetic factors indicated that a Karnofsky performance status score (KPS) of 90 or 100, WHO grade II or III, TERT promoter mutation, 1p/19q codeletion, radiation therapy, and extent of resection (90-100%) were associated with favorable prognosis (p

BackgroundCognitive deficits after perinatal anesthetic exposure are well established outcomes in animal models. This vulnerability is sex-dependent and associated with expression levels of the chloride transporters NKCC1 and KCC2. The hypothesis was that androgen signaling, NKCC1 function, and the age of isoflurane exposure are critical for the manifestation of anesthetic neurotoxicity in male rats.MethodsFlutamide, an androgen receptor antagonist, was administered to male rats on postnatal days 2, 4, and 6 before 6 h of isoflurane on postnatal day 7 (ntotal = 26). Spatial and recognition memory were subsequently tested in adulthood. NKCC1 and KCC2 protein levels were measured from cortical lysates by Western blot on postnatal day 7 (ntotal = 20). Bumetanide, an NKCC1 antagonist, was injected immediately before isoflurane exposure (postnatal day 7) to study the effect of NKCC1 inhibition (ntotal = 48). To determine whether male rats remain vulnerable to anesthetic neurotoxicity as juveniles, postnatal day 14 animals were exposed to isoflurane and assessed as adults (ntotal = 30).ResultsFlutamide-treated male rats exposed to isoflurane successfully navigated the spatial (Barnes maze probe trial F[1, 151] = 78; P < 0.001; mean goal exploration ± SD, 6.4 ± 3.9 s) and recognition memory tasks (mean discrimination index ± SD, 0.09 ± 0.14; P = 0.003), unlike isoflurane-exposed controls. Flutamide changed expression patterns of NKCC1 (mean density ± SD: control, 1.49 ± 0.69; flutamide, 0.47 ± 0.11; P < 0.001) and KCC2 (median density [25th percentile, 75th percentile]: control, 0.23 [0.13, 0.49]; flutamide, 1.47 [1.18,1.62]; P < 0.001). Inhibiting NKCC1 with bumetanide was protective for spatial memory (probe trial F[1, 162] = 6.6; P = 0.011; mean goal time, 4.6 [7.4] s). Delaying isoflurane exposure until postnatal day 14 in males preserved spatial memory (probe trial F[1, 140] = 28; P < 0.001; mean goal time, 6.1 [7.0] s).ConclusionsVulnerability to isoflurane neurotoxicity is abolished by blocking the androgen receptor, disrupting the function of NKCC1, or delaying the time of exposure to at least 2 weeks of age in male rats. These results support a dynamic role for androgens and chloride transporter proteins in perinatal anesthetic neurotoxicity.Editor’s perspective

BackgroundEarly life anesthesia exposure results in long-term cognitive deficits in rats. Environmental enrichment consisting of social housing, a stimulating environment, and voluntary exercise can rescue this deficit. We hypothesized that exercise alone is sufficient to rescue the cognitive deficit associated with perinatal anesthesia.MethodsPostnatal day 7 male rats (P7) underwent isoflurane (Iso) or sham exposure and were subsequently weaned at P21. They were then singly housed in a cage with a running wheel or a fixed wheel. After 3 weeks of exercise, animals underwent behavioral testing for spatial and recognition memory assessments. Animals were killed at various time points to accomplish either bromodeoxyuridine (BrdU) labeling or quantitative real-time polymerase chain reaction (qRT-PCR) to quantify brain-derived neurotrophic factor (BDNF) messenger ribonucleic acid (mRNA) levels.ResultsPostweaning voluntary exercise rescued the long-term spatial memory deficit associated with perinatal Iso exposure. Iso-sedentary animals did not discriminate the goal quadrant, spending no more time than chance during the Barnes maze probe trial (1-sample t test, P = .524) while all other groups did (1-sample t test, PIso-exercise = .033; Pcontrol [Con]-sedentary = .004). We did not find a deficit in recognition memory tasks after Iso exposure as we observed previously. BrdU incorporation in the adult hippocampus of Iso-sedentary animals was decreased compared to sedentary controls (Tukey P = .005). Exercise prevented this decrease, with Iso-exercise animals having more proliferation than Iso-sedentary (Tukey P < .001). There was no effect of exercise or Iso on BDNF mRNA in either the cortex or hippocampus (cortex: FExercise[1,32] = 0.236, P = .631; FIso [1,32] = 0.038, P = .847; FInteraction [1,32] = 1.543, P = .223; and hippocampus: FExercise[1,33] = 1.186, P = .284; FIso [1,33] = 1.46, P = .236; FInteraction[1,33] = 1.78, P = .191).ConclusionsExercise restores BrdU incorporation and rescues a spatial memory deficit after early life anesthesia exposure. This demonstrates sufficiency of exercise alone in the context of environmental enrichment to recover a behavioral phenotype after a perinatal insult.

BackgroundPreclinical investigations of the effects of general anesthesia on the young brain show differences in vulnerability of males and females to anesthetic exposure at different times during development. However, the mechanism underlying this sex difference is poorly understood. Perinatal testosterone is the primary determinant of sexual differentiation and likely plays an important role in defining the period of susceptibility to anesthetic injury. We investigated whether the removal of testosterone through gonadectomy shortly after birth would improve cognitive outcomes in male rodents after early anesthesia exposure.MethodsMale Sprague Dawley rats underwent gonadectomy at postnatal day 2 (P2), followed by exposure to 6 hours of isoflurane at P7. A control cohort of gonad-intact male littermates was simultaneously exposed. All rats were subjected to a series of object recognition and association tasks beginning at P42. Cell death in the thalamus and hippocampus was assessed in a separate cohort.ResultsAll groups performed similarly on the Novel Object Recognition task; however, the gonad-intact isoflurane group exhibited decreased performance in the more difficult tasks. This deficit was ameliorated in the gonadectomized group. Cell death was similar between both isoflurane-exposed groups, regardless of gonadectomy.ConclusionsThe absence of testosterone does not block cell death after anesthesia in specific brain regions of interest; however, does provide some neuroprotection as evidenced by the improved cognitive test performance during adulthood. These findings suggest that testosterone may be mechanistically involved in the sex-specific effects of anesthetic injury on the developing brain by extending the vulnerable period in male rats.

BACKGROUND: The outcome of older patients with newly diagnosed, Philadelphia chromosome (Ph)-negative acute lymphoblastic leukemia (ALL) is poor. The combination of targeted therapy with low-intensity chemotherapy is safe and effective. The objective of the current analysis was to compare the outcome of patients who received a combination of inotuzumab ozogamicin plus low-intensity chemotherapy (mini-hyperfractionated cyclophosphamide, vincristine, and dexamethasone [mini-HCVD]) with or without blinatumomab versus the outcome of those who received the standard, intensive, hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (HCVAD) regimen. METHODS: The authors analyzed 135 older patients with newly diagnosed, Ph-negative ALL who were treated prospectively with standard HCVAD (n = 77) or with the combination of inotuzumab ozogamicin plus mini-HCVD with or without blinatumomab (n = 58). A propensity score analysis was conducted using 1:1 matching using the nearest neighbor matching method. RESULTS: Propensity score matching identified 38 patients in each cohort. The antibody plus low-intensity chemotherapy combination induced higher response rates (98% vs 88%), with lower rates of early death (0% vs 8%) and lower rates of death in complete remission (5% vs 17%). With propensity score matching, the 3-year event-free survival rates for patients who received HCVAD and those who received the combination of inotuzumab ozogamicin plus mini-HCVD with or without blinatumomab were 34% and 64%, respectively (P = .003), and the 3-year overall survival rates were 34% and 63%, respectively (P = .004). By multivariate analysis, age (P = .019; hazard ratio, 1.045) and the combination of inotuzumab plus mini-HCVD with or without blinatumomab (P = .020; hazard ratio, 0.550) were identified as independent prognostic factors for survival. CONCLUSIONS: The combination of inotuzumab ozogamicin plus mini-HCVD with or without blinatumomab is safe and effective in older patients with newly diagnosed, Ph-negative ALL and confers a better outcome compared with standard HCVAD chemotherapy.

Patients with chronic myeloid leukemia (CML) treated with tyrosine kinase inhibitors (TKIs) have near-normal life expectancies. With this comes the possibility of developing second cancers; we aimed to evaluate the incidence of second malignancies in patients with CML using Surveillance, Epidemiology, and End Results Program data. We identified 13,276 patients with CML newly diagnosed in 2001-2014. Patients who had prior history of cancer, a concurrent diagnosis of other malignancies in the same diagnostic year, or a second leukemia after CML diagnosis were excluded. Second malignancies were observed in 597 patients (4%) with a median follow-up of 69 months. The 5- and 10-year cumulative incidences of death for all patients were 30.5% and 41.8%. The 5- and 10-year cumulative incidences of second malignancies were 4.4% and 7.2%, respectively. The overall standardized incidence ratio (SIR) was 1.204. Increased SIRs compared to the general population were observed for the male genital system, 1.593; digestive system, 1.291; skin, 1.588; and urinary system, 1.366. Overall excess absolute risk was 1.714 per 1000 person-years at risk. Our results suggest that relative incidence of overall second malignancies in CML is slightly higher than that of the general population, with minimal increase in the excess absolute risk.

BackgroundThe factors determining peak susceptibility of the developing brain to anaesthetics are unclear. It is unknown why postnatal day 7 (P7) male rats are more vulnerable to anaesthesia-induced memory deficits than littermate females. Given the precocious development of certain regions in the female brain during the neonatal critical period, we hypothesised that females are susceptible to anaesthetic brain injury at an earlier time point than previously tested.MethodsFemale rats were exposed to isoflurane (Iso) 1 minimum alveolar concentration or sham anaesthesia at P4 or P7. Starting at P35, rats underwent a series of behavioural tasks to test their spatial and recognition memory. Cell death immediately after anaesthesia was quantified by Fluoro-Jade C staining in select brain regions, and developmental expression of the chloride transporters KCC2 and NKCC1 was analysed by immunoblotting in male and female rats at P4 and P7.ResultsFemale rats exposed to Iso at P4 displayed impaired spatial, object-place, -context, and social recognition memory, and increased cell death in the hippocampus and laterodorsal thalamus. Female rats exposed at P7 exhibited only decreased performance in object-context compared with control. The ratio of NKCC1/KCC2 expression in cerebral cortex was higher in P4 females than in P7 females, and similar to that in P7 males.ConclusionsFemale rats exposed to Iso at P4 are sensitive to anaesthetic injury historically observed in P7 males. This is consistent with a comparably immature developmental state in P4 females and P7 males. The window of anaesthetic vulnerability correlates with sex-specific cortical expression of chloride transporters NKCC1 and KCC2. These findings suggest that both sex and developmental age play important roles in determining the outcome after early anaesthesia exposure.

Cardiovascular or arteriothrombotic adverse events (CV- or AT-AEs) are reported in chronic myeloid leukemia (CML) patients treated with tyrosine kinase inhibitors (TKIs). The incidence and characteristics across different TKI have not been systematically analyzed. We analyzed 531 patients treated with frontline TKIs in different prospective trials: imatinib 400 mg (n = 71) and 800 mg (n = 203), nilotinib (n = 108), dasatinib (n = 106), and ponatinib (n = 43). Characteristics and incidence of new-onset CV-AEs and AT-AEs were analyzed. Poisson regression models assessed factors associated with AE incidence. Median follow-up was 94 months (range, 2-195). Overall, 237 patients (45%) developed CV-AEs and 46 (9%) developed AT-AEs. Hypertension was the most common AE seen in 175 patients (33%; grade 3/4 in 17%). CV-AE and AT-AE incidence ratios (IRs) with 95% confidence intervals (CIs) were 8.6 (7.6-9.8) and 1.7 (1.2-2.2) per 100 person-years. Among the TKIs, ponatinib showed the highest IR (95% CI) for CV-AEs and AT-AEs at 40.7 (27.9-59.4) and 9.0 (4.1-20.1). In multivariate analysis, ponatinib therapy was associated with increased incidence rate ratio (IRR) for CV-AEs (4.62; 95% CI, 2.7-7.7; P < .0001) and AT-AEs (6.38; 95% CI, 1.8-21.8; P < .0001) compared with imatinib 400. In summary, there is an increased risk of CV-AEs (except hypertension) and AT-AEs in CML patients treated with newer TKIs, particularly with ponatinib. Patients on TKIs must be informed and closely monitored for vascular AEs. These studies were registered at www.clinicaltrials.gov as #NCT00048672, #NCT00038649, #NCT00050531, #NCT00254423, #NCT00129740, and #NCT01570868.

Titanium (Ti) biomaterials have been applied to a wide range of implantable medical devices. When placed in bone marrow, Ti-biomaterials integrate to the surrounding bone tissue by mechanisms that are not fully understood. We have previously identified an unexpected upregulation of circadian clock molecule neuronal PAS domain 2 (Npas2) in successfully integrated implant with a rough surface. This study aimed to elucidate the molecular mechanism of osseointegration through determining the role of Npas2. Human bone marrow stromal cells (BMSC) that were cultured on a Ti disc with SLA surface exhibited increased NPAS2 expression compared to BMSC cultured on a machined surface. A mouse model was developed in which miniature Ti implants were surgically placed into femur bone marrow. The implant push-out test and bone-to-implant contact measurements demonstrated the establishment of osseointegration in 3 weeks. By contrast, in Npas2 functional knockout (KO) mice, the implant push-out value measured for SLA surface Ti implant was significantly decreased. Npas2 KO mice demonstrated normal femur bone structure surrounding the Ti implant; however, the recovered implants revealed abnormal remnant mineralized tissue, which lacked dense collagen architecture typically found on recovered implants from wild type mice. To explore the mechanisms leading to the induced Npas2 expression, an unbiased chemical genetics analysis was conducted using mouse BMSC carrying an Npas2-reporter gene for high throughput screening of Library of Pharmacologically Active Compounds. Npas2 modulating compounds were found clustered in regulatory networks of the α2-adrenergic receptor and its downstream cAMP/CREB signaling pathway. Mouse primary BMSC exposed to SLA Ti disc significantly increased the expression of α2-adrenergic receptors, but the expression of β2-adrenergic receptor was unaffected. Our data provides the first evidence that peripheral clock gene component Npas2 plays a role in facilitating the enhanced osseointegration through neuroskeletal regulatory pathways induced by BMSC in contact with rough surface Ti implant.

BackgroundThe combination of chemotherapy and ponatinib in Philadelphia chromosome-positive acute lymphoblastic leukaemia has the potential to be a new standard of care for the disease; however, long-term efficacy and safety data are needed. Our aim was to evaluate the long-term efficacy and safety of this regimen in patients with newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukaemia in this ongoing phase 2 trial.MethodsIn our single-centre, phase 2, single-arm trial in the USA, adult patients with previously untreated Philadelphia chromosome-positive acute lymphoblastic leukaemia were sequentially enrolled. Eligible patients had newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukaemia, were aged 18 years or older, had an Eastern Cooperative Oncology Group performance status of 2 or less, a left ventricular ejection fraction above 50%, and adequate hepatic and renal function (serum bilirubin ≤3·0 mg/dL and serum creatinine ≤3·0 mg/dL, unless higher levels were believed to be due to leukaemia at the discretion of the investigator). Patients received eight cycles of 21 days, alternating between two drug combinations: hyper-fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (hyper-CVAD) and high-dose methotrexate and cytarabine. Ponatinib was given orally at 45 mg per day for the first 14 days of cycle 1 then continuously at 45 mg per day for the subsequent cycles. After 37 patients were treated, the protocol was amended to reduce the dose of ponatinib to 30 mg per day at cycle 2, with further reduction to 15 mg once a complete molecular response (defined as absence of quantifiable BCR-ABL1 transcripts) was achieved. Patients in complete remission received maintenance with ponatinib daily (30 mg or 15 mg) indefinitely, and with vincristine (2 mg intravenously on day 1) and prednisone (200 mg orally on days 1-5) monthly for 2 years. The primary endpoint was 3-year event-free survival in the intention-to-treat population. The trial is registered at ClinicalTrials.gov, number NCT01424982, and is ongoing and still enrolling patients.Findings76 patients with a median age of 47 years (IQR 39-61) were enrolled and treated between Nov 19, 2011, and April 4, 2018. The 3-year event-free survival was 70% (95% CI 56-80). The most common grade 3 or 4 adverse events were infection (n=65, 86%), increased transaminases (n=24, 32%), increased bilirubin (n=13, 17%), pancreatitis (n=13, 17%), hypertension (n=12, 16%), bleeding (n=10, 13%), and skin rash (n=9, 12%). Six patients died while still on study treatment. Three patients (4%) died from infection and one (1%) from haemorrhage. Two patients died from myocardial infarction related to early ponatinib use; neither death occurred after protocol revision.InterpretationThe combination of chemotherapy with ponatinib is effective in achieving long-term remission in patients with newly diagnosed Philadelphia chromosome-positive  acute lymphoblastic leukaemia. This regimen could represent a new standard of care for this population. A randomised, phase 3 study to evaluate the efficacy of this combination compared with chemotherapy plus earlier-generation tyrosine-kinase inhibitors is warranted.FundingTakeda Oncology.

BACKGROUND: The outcomes of patients with relapsed or refractory (R-R) acute lymphoblastic leukemia (ALL) are poor. Inotuzumab ozogamicin and blinatumomab have single-agent activity in R-R ALL. Their addition to low-intensity chemotherapy may further improve the outcomes of patients with ALL in their first relapse. METHODS: The chemotherapy was lower in intensity than conventional hyperfractionated cyclophosphamide, vincristine, adriamycin, and dexamethasone and was called mini-hyperfractionated cyclophosphamide, vincristine, and dexamethasone (or mini-HCVD). Inotuzumab was given on day 3 of each of the first 4 cycles at 1.8 to 1.3 mg/m2 for cycle 1, and this was followed by 1.3 to 1.0 mg/m2 for subsequent cycles. From patient 39 onward, the inotuzumab dose was reduced and fractionated into weekly doses (0.6 and 0.3 mg/m2 during cycle 1 and 0.3 and 0.3 mg/m2 during subsequent cycles), and blinatumomab was administered for up to 4 cycles after inotuzumab therapy. RESULTS: Forty-eight patients with Philadelphia chromosome-negative ALL with a median age of 39 years were treated during their first relapse. Overall, 44 patients (92%) responded, with 35 of them (73%) achieving a complete response. The overall minimal residual disease negativity rate among the responders was 93%. Twenty-four patients (50%) underwent allogeneic stem cell transplantation (ASCT). Veno-occlusive disease of any grade occurred in 5 patients (10%). With a median follow-up of 31 months, the median progression-free survival (PFS) and the median overall survival (OS) were 11 and 25 months, respectively. The 2-year PFS and OS rates were 42% and 54%, respectively. Of the 24 patients (50%) who underwent ASCT, 14 patients were alive at the last follow-up (13 [54%] in remission). Of the remaining 20 responding patients who did not undergo subsequent ASCT, 6 (30%) remained in remission at the last follow-up. According to propensity score matching, the combination of mini-HCVD and inotuzumab with or without blinatumomab conferred better outcomes than intensive salvage chemotherapy or inotuzumab alone. CONCLUSIONS: The combination of inotuzumab and low-intensity mini-HCVD chemotherapy with or without blinatumomab shows encouraging results in patients with ALL in first salvage.

BACKGROUND:Front-line therapy for elderly or unfit patients with acute myeloid leukaemia (AML) remains unsatisfactory with poor outcomes and excessive toxicity. We studied a new low-intensity regimen of cladribine combined with low-dose cytarabine alternating with decitabine, aimed at improving outcomes in this population. Based on our previous experience, we hypothesised that this combination would be safe and more effective than current approaches with hypomethylating agents. METHODS:In this single-arm, open-label, single-centre phase 2 study, we enrolled patients aged 60 years or older with previously untreated AML or high-risk myelodysplastic syndrome who had adequate organ function and an Eastern Cooperative Oncology Group performance status of 2 or less. Patients were treated with cladribine plus low-dose cytarabine for two 28-day cycles alternating with decitabine for two 28-day cycles, for up to 18 cycles. Induction therapy (cycle 1) consisted of cladribine 5 mg/m2 intravenously over 1-2 h on days 1-5 and cytarabine 20 mg subcutaneously twice daily on days 1-10. Patients who had remission during this induction regimen moved on to consolidation therapy (cladribine 5 mg/m2 intravenously over 1-2 h on days 1-3 and cytarabine 20 mg twice daily on days 1-10, alternating with decitabine 20 mg/m2 intravenously on days 1-5). The primary outcome measure was disease-free survival. Secondary outcomes were overall survival, proportion of patients achieving complete response, proportion of patients achieving response, toxicity, and induction mortality. All treated patients were included in the analyses. This trial is ongoing and is registered with ClinicalTrials.gov, number NCT01515527. FINDINGS:Between Feb 17, 2012, and July 6, 2017, 118 patients were enrolled and treated, among whom 48 (41%) had an adverse karyotype, 20 (17%) had therapy-related AML, 18 (15%) had treated secondary AML, and 20 (17%) had TP53 mutations. Median disease-free survival was 10·8 months (IQR 5·4-25·9). 80 (68%) patients achieved objective response: 69 (58%) achieved a complete response and 11 (9%) patients had complete response with incomplete count recovery. The median overall survival was 13·8 months (6·9-28·6). The regimen was well tolerated, with one (1%) death within the first 4 weeks and eight (7%) deaths within the first 8 weeks. The most common non-haematological adverse events of grade 3 or worse were infection (88 [75%] patients), elevated total bilirubin (26 [22%] patients), rash (13 [11%] patients), and nausea (13 [11%] patients). INTERPRETATION:The combination of cladribine and low-dose cytarabine alternating with decitabine appears to be a safe and highly effective regimen for the treatment of elderly or unfit patients with newly diagnosed AML. Further testing of this regimen is warranted, and could help to provide a new, effective option for reduced-intensity therapy in this population. FUNDING:Part supported by the National Institutes of Health.

Repressive H3K27me3 and active H3K4me2/3 together form bivalent chromatin domains, molecular hallmarks of developmental potential. In the male germline, these domains are thought to persist into sperm to establish totipotency in the next generation. However, it remains unknown how H3K27me3 is established on specific targets in the male germline. Here, we demonstrate that a germline-specific Polycomb protein, SCML2, binds to H3K4me2/3-rich hypomethylated promoters in undifferentiated spermatogonia to facilitate H3K27me3. Thus, SCML2 establishes bivalent domains in the male germline of mice. SCML2 regulates two major classes of bivalent domains: Class I domains are established on developmental regulator genes that are silent throughout spermatogenesis, while class II domains are established on somatic genes silenced during late spermatogenesis. We propose that SCML2-dependent H3K27me3 in the male germline prepares the expression of developmental regulator and somatic genes in embryonic development.

BACKGROUND: The achievement of a sustained deep molecular response is a goal of increasing relevance because it opens the possibility of treatment discontinuation. The objective of this analysis was to develop a prediction model for a sustained molecular response with BCR-ABL1 level

BACKGROUND:The achievement of a sustained deep molecular response is a goal of increasing relevance because it opens the possibility of treatment discontinuation. The objective of this analysis was to develop a prediction model for a sustained molecular response with BCR-ABL1 level

BACKGROUND: Inotuzumab ozogamicin, an anti-CD22 monoclonal antibody bound to a toxin, calicheamicin, has shown single-agent activity in relapsed or refractory acute lymphoblastic leukaemia. We aimed to assess the activity and safety of inotuzumab ozogamicin in combination with low-intensity chemotherapy in older patients with acute lymphoblastic leukaemia. METHODS: We did a single-arm, phase 2 study at the MD Anderson Cancer Center (Houston, TX, USA). Eligible patients were aged 60 years or older and had newly diagnosed, Philadelphia chromosome-negative, acute lymphoblastic leukaemia, and an Eastern Cooperative Oncology Group performance status of 3 or lower. The induction chemotherapy regimen used was mini-hyper-CVD (a lower intensity version of the conventional hyper-CVAD). Odd-numbered cycles (1,3, 5, and 7) comprised intravenous cyclophosphamide (150 mg/m2 every 12 h on days 1-3) and oral or intravenous dexamethasone (20 mg per day on days 1-4 and days 11-14); no anthracycline was administered. Intravenous vincristine (2 mg flat dose) was given on days 1 and 8. Even-numbered cycles comprised intravenous methotrexate (250 mg/m2 on day 1) and intravenous cytarabine (0·5 g/m2 given every 12 h on days 2 and 3). Intravenous inotuzumab ozogamicin was given on day 3 of the first four cycles at the dose of 1·3-1·8 mg/m2 at cycle 1, followed by 1·0 -1·3 mg/m2 in subsequent cycles. Maintenance therapy with dose-reduced POMP (purinethol [6-mercaptopurine], oncovin [vincristine sulfate], methotrexate, and prednisone) was given for 3 years. The primary endpoint of this study was progression-free survival at 2 years. Analyses were by intention to treat. The study is ongoing, recruiting patients for an approved expansion phase with a modified treatment plan by protocol amendment. The trial is registered with ClinicalTrials.gov, number NCT01371630. FINDINGS: Between Nov 12, 2011, and April 22, 2017, 52 patients with a median age of 68 years (IQR 64-72) were enrolled. With a median follow-up of 29 months (IQR 13-48), 2-year progression-free survival was 59% (95% CI 43-72). The most frequent grade 3-4 adverse events were prolonged thrombocytopenia (42 [81%] patients), infections during induction (27 [52%]) and consolidation chemotherapy (36 [69%]), hyperglycaemia (28 [54%]), hypokalaemia (16 [31%]), increased aminotransferases (ten [19%]), hyperbilirubinaemia (nine [17%]), and haemorrhage (seven [15%]). Veno-occlusive disease occurred in four (8%) patients. Six (12%) patients died from adverse events that were deemed treatment related (five [10%] from sepsis and one [2%] from veno-occlusive disease). INTERPRETATION: Inotuzumab ozogamicin plus mini-hyper-CVD chemotherapy is a safe and active first-line therapy option in older patients with newly diagnosed acute lymphoblastic leukaemia and could represent a new therapy for this population. Randomised, phase 3 trials to evaluate the efficacy of this combination compared with the current standard of care in this setting, combination chemotherapy without inotuzumab ozogamicin, are warranted. FUNDING: MD Anderson Cancer Center.

Complex spatial working memory tasks have been shown to require both hippocampal sharp-wave ripple (SWR) activity and dentate gyrus (DG) neuronal activity. We therefore asked whether DG inputs to CA3 contribute to spatial working memory by promoting SWR generation. Recordings from DG and CA3 while rats performed a dentate-dependent working memory task on an eight-arm radial maze revealed that the activity of dentate neurons and the incidence rate of SWRs both increased during reward consumption. We then found reduced reward-related CA3 SWR generation without direct input from dentate granule neurons. Furthermore, CA3 cells with place fields in not-yet-visited arms preferentially fired during SWRs at reward locations, and these prospective CA3 firing patterns were more pronounced for correct trials and were dentate-dependent. These results indicate that coordination of CA3 neuronal activity patterns by DG is necessary for the generation of neuronal firing patterns that support goal-directed behavior and memory.

BackgroundTelemedicine in the intensive care unit (tele-ICU) is expected to address geographic health disparities through more efficient resource allocation. Our previous economic evaluation demonstrated tele-ICU to be cost-effective in most cases and cost saving in some cases, compared to conventional intensive care unit (ICU) care without adequate intensivist coverage.IntroductionThis study's objective is to examine how to optimize the cost-effectiveness of tele-ICU use by selecting highest risk (i.e., both highest mortality and highest cost) subpopulations. We also explore potential cost savings.Materials and methodsWe conducted simulation analyses among a hypothetical adult ICU patient cohort defined by the literature, distinguishing four types of hospitals: urban tertiary (primary analysis), urban community, rural tertiary, and rural community. The selected tele-ICU use was assumed to affect per-patient ICU cost and hospital mortality among highest risk subpopulations (10-100% of all ICU patients), defined by an established illness-severity measure.ResultsWe found a U-shaped relationship between the economic efficiency and selected tele-ICU use among all 4 hospital types. Optimal cost-effectiveness was achieved when tele-ICU was applied to the 30-40% highest risk patients among all ICU patients (incremental cost-effectiveness ratio = $25,392 [2014 U.S. dollars] per extending a quality-adjusted life year) in urban tertiary hospitals (primary analysis). Our break-even analyses indicated that cost saving seems more feasible when reducing ICU medical care cost, rather than lowering the cost to operate telemedicine alone.Discussion and conclusionsA selected use of tele-ICU based on severity of illness is likely to improve tele-ICU cost-effectiveness. To achieve cost saving, tele-ICU must reduce more than just telemedicine-related cost.

BackgroundOutcomes in patients with chronic myeloid leukemia in blast phase (CML-BP) are historically dismal. Herein, the authors sought to analyze the characteristics, prognostic factors, and survival outcomes in patients with CML-BP in the tyrosine kinase inhibitor (TKI) era.MethodsA total of 477 patients with CML-BP were treated with a TKI at some point during the course of their CML. Cox proportional hazard models identified characteristics that were predictive of survival. Overall survival and failure-free survival were assessed. Optimal cutoff points for specific parameters were identified using classification and regression tree (CART) analysis.ResultsThe median age of the patients was 53 years (range, 16-84 years) and 64% were male. Approximately 80% of patients initially were diagnosed in the chronic phase of CML at a median of 41 months (range, 0.7-298 months) before transformation to CML-BP. De novo CML-BP occurred in 71 patients. Approximately 72% of patients received TKI therapy before CML-BP. The initial therapy for CML-BP included a TKI alone (35%), a TKI with chemotherapy (46%), and non-TKI therapies (19%). The median overall survival was 12 months and the median failure-free survival was 5 months. In multivariate analysis, myeloid immunophenotype, prior TKI, age ≥58 years, lactate dehydrogenase level ≥1227 IU/L, platelet count

BACKGROUND: Tumor protein 53 (TP53) mutations are uncommon in adult patients with acute lymphoblastic leukemia (ALL) and predict a poor outcome. METHODS: TP53 mutation analysis was performed in 164 newly diagnosed adult patients with ALL using a combination of targeted amplicon-based next-generation sequencing and Sanger sequencing. RESULTS: TP53 mutations were detected in 25 patients (15%), with a median allelic frequency of 42.2% (range, 5.6%-93.8%). The majority of mutations were single-nucleotide variants of missense type and involved the DNA-binding domain. TP53-mutated (TP53mut ) ALL was found to be significantly associated with older age, lower median white blood cell and platelet counts, lower frequency of Philadelphia chromosome and a higher frequency of low hypodiploid karyotype compared with ALL with wild-type TP53 (TP53wt ). To evaluate the prognostic effect of TP53 mutations, the authors selected 146 patients with B-cell immunophenotype ALL (24 with TP53mut and 122 with TP53wt ) who were uniformly treated with frontline hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (hyper-CVAD)-based regimens; >90% of these individuals also received a monoclonal antibody. Over a median follow-up duration of 15 months, there was no significant difference in the median overall survival, event-free survival, and duration of complete remission noted between patients with TP53mut ALL and those with TP53wt ALL. CONCLUSIONS: Hyper-CVAD-based regimens appear to negate the poor prognostic impact of TP53 mutations in patients with adult B-cell immunophenotype ALL. Cancer 2017;123:3717-24. © 2017 American Cancer Society.

In patients with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) treated with chemotherapy plus a tyrosine kinase inhibitor (TKI), the prognostic impact of additional chromosomal abnormalities (ACAs) is not well-established. We evaluated the prognostic impact of individual ACAs in 152 patients with Ph+ ALL receiving first-line intensive chemotherapy plus either imatinib (n = 36), dasatinib (n = 74), or ponatinib (n = 42). ACAs were identified in 118 patients (78%). Compared to outcomes of patients without ACAs, ACAs were not associated with differences in either relapse-free survival (RFS; P = 0.42) or overall survival (OS; P = 0.51). When individual ACAs were evaluated, +der(22)t(9;22) and/or -9/9p in the absence of high hyperdiploidy (HeH) was present in 16% of patients and constituted a poor-risk ACA group. Patients with one or more poor-risk ACAs in the absence of HeH had significantly shorter RFS (5-year RFS rate 33% versus 59%, P = 0.01) and OS (5-year OS rate 24% versus 63%, P = 0.003). Poor-risk ACAs were prognostic in patients who received imatinib and dasatinib but not in those who received ponatinib. By multivariate analysis, this poor-risk ACA group was independently associated with worse RFS (HR 2.03 [95% CI 1.08-3.30], P = 0.03) and OS (HR 2.02 [95% CI 1.10-3.71], P = 0.02). Patients with Ph+ ALL who have +der(22)t(9;22) and/or -9/9p in the absence of HeH have relatively poor outcomes when treated with chemotherapy plus a TKI.

In patients with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) treated with chemotherapy plus a tyrosine kinase inhibitor (TKI), the prognostic impact of additional chromosomal abnormalities (ACAs) is not well-established. We evaluated the prognostic impact of individual ACAs in 152 patients with Ph+ ALL receiving first-line intensive chemotherapy plus either imatinib (n = 36), dasatinib (n = 74), or ponatinib (n = 42). ACAs were identified in 118 patients (78%). Compared to outcomes of patients without ACAs, ACAs were not associated with differences in either relapse-free survival (RFS; P = 0.42) or overall survival (OS; P = 0.51). When individual ACAs were evaluated, +der(22)t(9;22) and/or -9/9p in the absence of high hyperdiploidy (HeH) was present in 16% of patients and constituted a poor-risk ACA group. Patients with one or more poor-risk ACAs in the absence of HeH had significantly shorter RFS (5-year RFS rate 33% versus 59%, P = 0.01) and OS (5-year OS rate 24% versus 63%, P = 0.003). Poor-risk ACAs were prognostic in patients who received imatinib and dasatinib but not in those who received ponatinib. By multivariate analysis, this poor-risk ACA group was independently associated with worse RFS (HR 2.03 [95% CI 1.08-3.30], P = 0.03) and OS (HR 2.02 [95% CI 1.10-3.71], P = 0.02). Patients with Ph+ ALL who have +der(22)t(9;22) and/or -9/9p in the absence of HeH have relatively poor outcomes when treated with chemotherapy plus a TKI.

BackgroundThe introduction of novel prognostic factors such as minimal residual disease (MRD) and genomic profiling has led to the reevaluation of the role of cytogenetics and other conventional factors in risk stratification for acute lymphoblastic leukemia (ALL).MethodsThis study assessed the impact of baseline cytogenetics on the outcomes of 428 adult patients with Philadelphia chromosome-negative ALL who were receiving frontline chemotherapy. Three hundred thirty patients (77%) were treated with hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone-based regimens, and 98 (23%) were treated with the augmented Berlin-Frankfurt-Munster regimen.ResultsThe median age was 40 years (range, 13-86 years). One hundred eighty-six patients (43%) had diploid cytogenetics, 32 (7%) had complex cytogenetics (defined as ≥ 5 chromosomal abnormalities), 27 (6%) had low hypodiploidy/near-triploidy (Ho-Tr), 24 (6%) had high hyperdiploidy, and 24 (6%) had a mixed-lineage leukemia (MLL) rearrangement. Patients with an MLL rearrangement, Ho-Tr, or a complex karyotype had significantly worse relapse-free survival (RFS) and overall survival (OS) than the diploid group. According to a multivariate analysis including all the baseline characteristics and MRD status, Ho-Tr and a complex karyotype were independent predictive factors for worse RFS and OS. Furthermore, survival among all cytogenetic groups was similar, regardless of the treatment received.ConclusionsA complex karyotype and Ho-Tr are adverse prognostic factors for adults with ALL independently of the MRD status. These findings suggest that pretreatment cytogenetics remain a valuable prognostic tool in this population. Cancer 2017;123:459-467. © 2016 American Cancer Society.

BACKGROUND: The role of day 14 (D14) bone marrow (BM) assessment in detecting increased blasts in patients undergoing induction for acute lymphoblastic leukemia (ALL) is not well defined. METHODS: This study evaluated 389 adolescent and adult patients with previously untreated Philadelphia chromosome-negative ALL who received frontline induction chemotherapy and for whom a D14 BM assessment was performed. RESULTS: A D14 BM blast proportion

BACKGROUND: The clinical efficacy of hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (HCVAD) plus ponatinib has not been compared with that of HCVAD plus dasatinib in patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) in a randomized clinical trial. METHODS: The authors analyzed 110 patients with newly diagnosed Ph+ ALL who were enrolled in 2 consecutive, prospective, phase 2 clinical trials of frontline HCVAD with either dasatinib (63 patients) or ponatinib (47 patients). Propensity score analysis with 1:1 matching with the nearest neighbor matching method and inverse probability of treatment weighting (IPTW) analysis based on the propensity scores were performed to assess response rates, event-free survival (EFS), and overall survival (OS) between the cohorts. RESULTS: Propensity score matching identified 41 patients in each cohort. With propensity score matching, the 3-year EFS rates for patients treated with HCVAD plus ponatinib and HCVAD plus dasatinib were 69% and 46%, respectively (P =.04), and the 3-year OS rates were 83% and 56%, respectively (P =.03). IPTW analysis using prematching cohorts demonstrated that patients treated with HCVAD plus ponatinib had significantly higher rates of minimal residual disease negativity by flow cytometry on day 21, complete cytogenetic response at complete response, major molecular response at complete response and at 3 months, and complete molecular response at 3 months. IPTW confirmed that treatment with HCVAD plus ponatinib was associated with longer EFS (P =.003) and OS (P =.001) compared with treatment with HCVAD plus dasatinib. CONCLUSIONS: The clinical outcome of patients treated with HCVAD plus ponatinib appears to be superior to that of patients treated with HCVAD plus dasatinib among individuals with Ph+ ALL. Cancer 2016;122:3650-6. © 2016 American Cancer Society.

PurposeTo learn whether an antecedent hematologic disorder (AHD) is associated with additional risk in patients with therapy-related acute myeloid leukemia (t-AML).Patients and methodsWe reviewed data of 301 patients with newly diagnosed t-AML who sought care from January 2000 to January 2014 (183 t-AML without AHD, 118 t-AML with AHD). Overall, median follow-up was 44 months.ResultsThe primary malignancy was non-Hodgkin lymphoma in 92 (31%), breast cancer in 80 (27%), and prostate cancer in 49 (16%). Median relapse-free survival (RFS) in t-AML without or with AHD was 10 months and 29 months, respectively (P = .032); median overall survival (OS) was 8 months and 8 months, respectively (P = .53). Multivariate analysis for OS identified older age, poor performance status, thrombocytopenia, nonfavorable cytogenetics, and lack of response as adverse factors.ConclusionThe favorable-risk cohort had better RFS and OS compared to the outcomes of patients in the intermediate- and adverse-risk cohorts; the RFS and OS did not differ between intermediate- and adverse-risk cohorts. The presence of AHD did not affect OS.

Studies of individual T cell antigen receptors (TCRs) have shed some light on structural features that underlie self-reactivity. However, the general rules that can be used to predict whether TCRs are self-reactive have not been fully elucidated. Here we found that the interfacial hydrophobicity of amino acids at positions 6 and 7 of the complementarity-determining region CDR3β robustly promoted the development of self-reactive TCRs. This property was found irrespective of the member of the β-chain variable region (Vβ) family present in the TCR or the length of the CDR3β. An index based on these findings distinguished Vβ2(+), Vβ6(+) and Vβ8.2(+) regulatory T cells from conventional T cells and also distinguished CD4(+) T cells selected by the major histocompatibility complex (MHC) class II molecule I-A(g7) (associated with the development of type 1 diabetes in NOD mice) from those selected by a non-autoimmunity-promoting MHC class II molecule I-A(b). Our results provide a means for distinguishing normal T cell repertoires versus autoimmunity-prone T cell repertoires.

This study assessed the relevance of 2013 European LeukaemiaNet (ELN) response categories on patients treated with common frontline tyrosine kinase inhibitors (TKI) in chronic myeloid leukaemia in chronic phase (CML-CP). Four hundred and eighty-seven patients treated with imatinib (400 mg; IM 400, n = 70; 800 mg; IM800, n = 201), dasatinib (n = 107) or nilotinib (n = 109) were analysed. Intention to treat (ITT) analysis indicated that the proportion of patients falling into optimal, warning and failure ELN categories were 89%, 6%, 6% at 3 months, 78%, 17% and 6% at 6 months, and 75%, 13% and 13% at 12 months, respectively. Rates of optimal response at 3 months were 75% for IM400, 90% for IM800, 89% for dasatinib and 97% for nilotinib; 41%, 80%, 86% and 89% at 6 months; and 47%, 77%, 76% and 87% at 12 months, respectively. Patients achieving optimal response had longer eventfree (EFS), failurefree (FFS), transformationfree (TFS) and overall survival (OS) compared to warning and failure responses at all-time points. Treatment with imatinib 800, dasatinib or nilotinib predicted for achieving an optimal response. Optimal response predicted for significantly longer EFS, FFS, TFS and OS at 3, 6 and 12 months, irrespective of the TKI modality used. ELN response categories reliably predicted outcomes in CML patients receiving commonly used TKIs.

BackgroundThe safety and efficacy of front-line nilotinib and dasatinib in patients with newly diagnosed chronic-phase chronic myelogenous leukemia (CML-CP) with pre-existing liver and/or renal dysfunction are unknown.Patients and methodsWe analyzed the adverse event rates, response rates, and survival rates of 215 patients with CML-CP with or without renal and/or liver dysfunction who had been treated with front-line nilotinib (n = 108) or dasatinib (n = 107).ResultsThe overall median follow-up period was 49 months. At baseline, 6 dasatinib-treated patients (6%) had mild renal dysfunction and 13 (12%) had mild liver dysfunction. Also, 8 nilotinib-treated patients (7%) had mild renal dysfunction, 1 (1%) moderate renal dysfunction, and 9 (8%) mild liver dysfunction. No significant differences were found in the rate of complete cytogenetic response, major molecular response, or molecular response by a 4.5 log reduction on the international scale between the organ function cohorts. Dasatinib- or nilotinib-treated patients with baseline renal dysfunction had a greater incidence of transient reversible acute kidney injury (P = .011 and P < .001), and nilotinib-treated patients with renal dysfunction had a greater incidence of bleeding (P < .001).ConclusionPatients with CML-CP and mild to moderate renal or liver dysfunction can be safely treated with front-line dasatinib or nilotinib and can achieve response rates similar to those of patients with CML-CP without organ dysfunction.

BackgroundTyrosine kinase inhibitors (TKIs) significantly improve survival in patients with chronic myeloid leukemia in chronic phase (CML-CP). Conditional probability provides survival information in patients who have already survived for a specific period of time after treatment.MethodsCumulative response and survival data from 6 consecutive frontline TKI clinical trials were analyzed. Conditional probability was calculated for failure-free survival (FFS), transformation-free survival (TFS), event-free survival (EFS), and overall survival (OS) according to depth of response within 1 year of the initiation of TKIs, including complete cytogenetic response, major molecular response, and molecular response with a 4-log or 4.5-log reduction.ResultsA total of 483 patients with a median follow-up of 99.4 months from the initiation of treatment with TKIs were analyzed. Conditional probabilities of FFS, TFS, EFS, and OS for 1 additional year for patients alive after 12 months of therapy ranged from 92.0% to 99.1%, 98.5% to 100%, 96.2% to 99.6%, and 96.8% to 99.7%, respectively. Conditional FFS for 1 additional year did not improve with a deeper response each year. Conditional probabilities of TFS, EFS, and OS for 1 additional year were maintained at >95% during the period.ConclusionsIn the era of TKIs, patients with chronic myeloid leukemia in chronic phase who survived for a certain number of years maintained excellent clinical outcomes in each age group. Cancer 2016;122:238-248. © 2015 American Cancer Society.

Registered nurses (RN) who held prior health-related employment in occupations other than licensed practical or vocational nursing (LPN/LVN) are reported to have increased rapidly in the past decades. Researchers examined whether prior health-related employment affects RN workforce supply. A cross-sectional bivariate probit model using the 2008 National Sample Survey of Registered Nurses was esti- mated. Prior health-related employment in relatively lower-wage occupations, such as allied health, clerk, or nursing aide, was positively associated with working s an RN. ~>Prior health-related employ- ment in relatively higher-wage categories, such as a health care manager or LPN/LVN, was positively associated with working full-time as an RN. Policy implications are to promote an expanded career ladder program and a nursing school admission policy that targets non-RN health care workers with an interest in becoming RNs.

BackgroundBody dysmorphic disorder (BDD) and anorexia nervosa (AN) are both characterized by distorted perception of appearance. Previous studies in BDD suggest abnormalities in visual processing of own and others' faces, but no study has examined visual processing of faces in AN, nor directly compared the two disorders in this respect.MethodWe collected functional magnetic resonance imaging data on 60 individuals of equivalent age and gender in each of three groups--20 BDD, 20 weight-restored AN, and 20 healthy controls (HC)--while they viewed images of others' faces that contained only high or low spatial frequency information (HSF or LSF). We tested hypotheses about functional connectivity within specialized sub-networks for HSF and LSF visual processing, using psychophysiological interaction analyses.ResultsThe BDD group demonstrated increased functional connectivity compared to HC between left anterior occipital face area and right fusiform face area (FFA) for LSF faces, which was associated with symptom severity. Both BDD and AN groups had increased connectivity compared to HC between FFA and precuneous/posterior cingulate gyrus for LSF faces, and decreased connectivity between FFA and insula. In addition, we found that LSF connectivity between FFA and posterior cingulate gyrus was significantly associated with thoughts about own appearance in AN.ConclusionsResults suggest similar abnormal functional connectivity within higher-order systems for face processing in BDD and AN, but distinct abnormal connectivity patterns within occipito-temporal visual networks. Findings may have implications for understanding relationships between these disorders, and the pathophysiology underlying perceptual distortions.

BackgroundCombination of chemotherapy with a tyrosine-kinase inhibitor is effective in the treatment of Philadelphia chromosome-positive acute lymphoblastic leukaemia. Ponatinib is a more potent BCR-ABL1 inhibitor than all other tyrosine-kinase inhibitors and selectively suppresses the resistant T315I clones. We examined the activity and safety of combining chemotherapy with ponatinib for patients with Philadelphia chromosome-positive acute lymphoblastic leukaemia in this continuing phase 2 trial.MethodsIn this single-centre, phase 2, single-arm trial, adult patients with previously untreated Philadelphia chromosome-positive acute lymphoblastic leukaemia were sequentially enrolled. Patients who had received fewer than two courses of previous chemotherapy with or without tyrosine-kinase inhibitors were also eligible. Patients had to be aged 18 years or older, have an Eastern Cooperative Oncology Group performance status of 2 or less, have normal cardiac function (defined by ejection fraction above 50%), and have adequate organ function (serum bilirubin ≤3·0 mg/dL and serum creatinine ≤3·0 mg/dL, unless higher concentrations were believed to be due to a tumour). Patients received eight cycles of hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (hyper-CVAD) alternating with high-dose methotrexate and cytarabine every 21 days. Ponatinib 45 mg was given daily for the first 14 days of cycle 1 then continuously for the subsequent cycles. Patients in complete remission received maintenance with ponatinib 45 mg daily with vincristine and prednisone monthly for 2 years followed by ponatinib indefinitely. The primary endpoint for this study was event-free survival. The trial is registered at ClinicalTrials.gov, number NCT01424982.Findings37 patients were enrolled and treated from Nov 1, 2011, to Sept 1, 2013. 2-year event-free survival rate was 81% (95% CI 64-90). Grade 3 or more toxic effects included infections during induction (20 [54%] patients), increased aspartate aminotransferase and alanine aminotransferase concentration (14 [38%] patients), thrombotic events (three [8%]), myocardial infarction (three [8%]), hypertension (six [16%]), skin rash (eight [22%]), and pancreatitis (six [16%] patients). Two patients died from from myocardial infarction potentially related to treatment; another patient also died from myocardial infarction related to sepsis. Two further patients died, one from bleeding and another from infection, both deemed unrelated to treatment.InterpretationThe first results of this ongoing trial indicate that the combination of chemotherapy with ponatinib is effective in achieving early sustained remissions in patients with newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukaemia. New strategies, including dosing titration of ponatinib and optimised control of vascular risk factors, might further improve outcomes.FundingARIAD Pharmaceuticals Inc.

BackgroundTo assess the differences across continental regions in terms of stroke imaging obtained for making acute revascularization therapy decisions, and to identify obstacles to participating in randomized trials involving multimodal imaging.MethodsSTroke Imaging Repository (STIR) and Virtual International Stroke Trials Archive (VISTA)-Imaging circulated an online survey through its website, through the websites of national professional societies from multiple countries as well as through email distribution lists from STIR and the above mentioned societies.ResultsWe received responses from 223 centers (2 from Africa, 38 from Asia, 10 from Australia, 101 from Europe, 4 from Middle East, 55 from North America, 13 from South America). In combination, the sites surveyed administered acute revascularization therapy to a total of 25,326 acute stroke patients in 2012. Seventy-three percent of these patients received intravenous (i.v.) tissue plasminogen activator (tPA), and 27%, endovascular therapy. Vascular imaging was routinely obtained in 79% (152/193) of sites for endovascular therapy decisions, and also as part of standard IV tPA treatment decisions at 46% (92/198) of sites. Modality, availability and use of acute vascular and perfusion imaging before revascularization varied substantially between geographical areas. The main obstacles to participate in randomized trials involving multimodal imaging included: mainly insufficient research support and staff (50%, 79/158) and infrequent use of multimodal imaging (27%, 43/158) .ConclusionThere were significant variations among sites and geographical areas in terms of stroke imaging work-up used tomake decisions both for intravenous and endovascular revascularization. Clinical trials using advanced imaging as a selection tool for acute revascularization therapy should address the need for additional resources and technical support, and take into consideration the lack of routine use of such techniques in trial planning.

BackgroundTyrosine-kinase inhibitors improve overall survival in patients with chronic myeloid leukaemia in chronic phase (CML-CP). Survival compared with the general population by age, response, and type of tyrosine-kinase inhibitor is not known. With use of data from trials of tyrosine kinase inhibitors, we compared overall survival in patients with newly diagnosed CML-CP to that of general population.MethodsIn this cohort analysis, we included data from patients with CML-CP enrolled in six consecutive or parallel prospective clinical trials of tyrosine-kinase inhibitors at a single institution from July 30, 2000, to Sept 17, 2012. We analysed data for response and survival with the Kaplan-Meier method. For estimated overall survival in the general population, we obtained data from national vital statistics reports and matched to patients with CML-CP by age, sex, ethnicity, and year at diagnosis. We assessed numbers and causes of death within 1 year of beginning treatment by age group and by response to therapy. We then did univariate analysis and multivariate analysis to investigate factors associated with survival probability.FindingsOur analysis included 483 patients, 271 received imatinib, 105 received nilotinib, and 107 received dasatinib. Most patients were younger than 65 years, and no patients were older than 85 years. Median follow-up was 99·4 months (IQR 44·9-121·6), by which time 53 (11%) patients had died. The most common causes of death were progression to advanced disease stage, including complications of stem-cell transplantation (17 [4%] patients), secondary malignancies (nine [2%] patients), and cardiovascular causes (nine [2%] patients). 5-year overall survival in patients with CML-CP decreased in older age categories. For the whole population of patients with CML-CP, 5-year survival was only slightly lower than that of the matched general population (relative survival 94·7% [95% 92·1-97·4]). Individuals of all ages with a report of complete cytogenetic response to treatment or deeper within 1 year had a 5-year survival similar to that of the general population.InterpretationIn the era of treatment with tyrosine-kinase inhibitors, patients diagnosed with CML-CP can expect a 5-year survival that is only slightly lower than that of the general population. With access to tyrosine-kinase inhibitors, most patients with chronic myeloid leukaemia could enjoy a near normal life expectancy.FundingMD Anderson Cancer Center, National Cancer Institute.

Inotuzumab ozogamicin was found to be highly active in patients with refractory-relapsed acute lymphocytic leukemia (ALL), with an overall response rate of 58% and a median survival of 6.3 months. Identifying factors associated with different outcomes on inotuzumab therapy may help select patients for this treatment and advice of prognosis. A total of 89 patients treated with inotuzumab on previous studies were analyzed. Inotuzumab was given at 1.3-1.8 mg/m(2) intravenously (IV) × 1 every 3-4 weeks or weekly (0.8 mg/m(2) day 1, 0.5 mg/m(2) days 8 and 15) every 3-4 weeks. Pretreatment factors associated with achieving marrow complete response (CR) and with survival were analyzed using standard statistical methods. The median survival of patients with at least marrow CR was 9.2 months versus 3.4 months for those without marrow CR (P

Detecting signs that someone is a member of a hostile outgroup can depend on very subtle cues. How do ecology-relevant motivational states affect such detections? This research investigated the detection of briefly-presented enemy (versus friend) insignias after participants were primed to be self-protective or revenge-minded. Despite being told to ignore the objectively nondiagnostic cues of ethnicity (Arab vs. Western/European), gender, and facial expressions of the targets, both priming manipulations enhanced biases to see Arab males as enemies. They also reduced the ability to detect ingroup enemies, even when these faces displayed angry expressions. These motivations had very different effects on accuracy, however, with self-protection enhancing overall accuracy and revenge-mindedness reducing it. These methods demonstrate the importance of considering how signal detection tasks that occur in motivationally-charged environments depart from results obtained in conventionally motivationally-inert laboratory settings.

Dopamine has multiple functions in the modulation of social behavior and promotion of reproduction in eusocial Hymenoptera. In the honey bee, there are sex-specific differences in the regulation of dopamine production in the brain. These different dopaminergic systems might contribute to the maintenance of sex-specific behaviors and physiology. However, it is still not fully understood how the dopaminergic system in the brain is regulated by endocrinal factors and social stimuli in the colony. In this review, we focus on the regulation of dopamine production in queens, workers, and males in the honey bee. Dopamine production can be controlled by queen substance, juvenile hormone, and exogenous tyrosine from food. Queens can control dopamine production in workers via queen substance, whereas workers can manipulate the supply of tyrosine, a precursor of dopamine, to queens and males. The regulation of dopamine production through social interaction might affect the reproductive states of colony members and maintain sex-specific behaviors in unpredictable environments.