A graph placement methodology for fast chip design.

Chip floorplanning is the engineering task of designing the physical layout of a computer chip. Despite five decades of research1, chip floorplanning has defied automation, requiring months of intense effort by physical design engineers to produce manufacturable layouts. Here we present a deep reinforcement learning approach to chip floorplanning. In under six hours, our method automatically generates chip floorplans that are superior or comparable to those produced by humans in all key metrics, including power consumption, performance and chip area. To achieve this, we pose chip floorplanning as a reinforcement learning problem, and develop an edge-based graph convolutional neural network architecture capable of learning rich and transferable representations of the chip. As a result, our method utilizes past experience to become better and faster at solving new instances of the problem, allowing chip design to be performed by artificial agents with more experience than any human designer. Our method was used to design the next generation of Google's artificial intelligence (AI) accelerators, and has the potential to save thousands of hours of human effort for each new generation. Finally, we believe that more powerful AI-designed hardware will fuel advances in AI, creating a symbiotic relationship between the two fields.

Applying a risk prediction model for bloodstream infection in a febrile, nonseverely neutropenic cohort of pediatric stem cell transplant patients.

BACKGROUND: The optimal management of febrile stem cell transplant (SCT) patients presenting without severe neutropenia (absolute neutrophil count [ANC] ≥ 500/µL) is unclear. The authors have developed iterative risk prediction models (Esbenshade Vanderbilt [EsVan] models) that reliably predict bloodstream infections (BSIs) in the febrile general pediatric oncology population without severe neutropenia, but SCT-specific data are limited. METHODS: All SCTs occurring from May 2005 to November 2019 at a single institution were identified. Episodes of fever with a central venous catheter and ANC values ≥ 500/µL were abstracted. All previous versions of the EsVan model were applied to the SCT data, and c-statistics were generated. The models were additionally applied to each type of transplant (autologous/allogeneic), and a new allogeneic model that further adjusted for metrics of immunosuppression, Esbenshade Vanderbilt Allogeneic SCT Model (EsVanAlloSCT), was developed and internally validated. RESULTS: For 429 SCT episodes (221 autologous and 208 allogeneic), the BSI incidence was 19.6% (84 of 429), and it was higher in allogeneic transplant patients (25.5%) than autologous transplant patients (14.0%; p < .01). All versions of the EsVan model performed well for the overall SCT cohort (c-statistics, 0.759-0.795). The EsVan models performed better for the autologous episodes (c-statistics, 0.869-0.881) than the allogeneic SCT episodes (c-statistics, 0.678-0.717). The new allogeneic transplant-specific model, EsVanAlloSCT, which added an adjustment for the extent of immunosuppression, yielded a c-statistic of 0.792 (bootstrap-corrected, 0.750). CONCLUSIONS: The EsVan models work exceptionally well when they are applied to autologous SCT, but they work less well for allogeneic SCT. EsVanAlloSCT appears to improve the predictive ability in allogeneic SCT, but it will need additional external validation.

Muybridge, Dercum, and the Early Use of Photography in the Study of Psychogenic Non-Epileptic Seizures.

The impact of the collaboration between photographer Eadweard Muybridge and neurologist Francis Dercum is detailed within the context of a photographic study of an artificially induced psychogenic non-epileptic seizure. Their contribution served as inspiration to other contemporary European neurologists and photographers to use motion photography to further understand psychogenic neurological disorders, such as seizures.

CYP2C9, VKORC1, and CYP4F2 polymorphisms and pediatric warfarin maintenance dose: a systematic review and meta-analysis.

Studies on the effect of cytochrome P450 2C9 (CYP2C9), vitamin K epoxide reductase complex subunit 1 (VKORC1), and cytochrome P450 4F2 (CYP4F2) polymorphisms on warfarin maintenance dose in children are conflicting. We conducted a systematic review and meta-analysis to evaluate the effect of these polymorphisms on warfarin maintenance dose in children. We searched relevant literature using the MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trial libraries without any language restrictions from their inception to 23 July 2017. Dose differences are expressed as standardized mean difference (SMD) or mean difference (MD) with 95% confidence intervals (CI). This review was registered in the PROSPERO prospective register of systematic reviews (CRD42015016172). We included a total of nine studies (745 participants) in the meta-analysis. Patients with CYP2C9 *1/*2, *1/*3, *2/*2, *2/*3, or *3/*3 required a lower warfarin maintenance dose compared with patients with CYP2C9 *1/*1 (SMD = -0.610, 95% CI: -0.802 to -0.419, I2 = 0%). Patients with VKORC1-1639GA or AA required a lower warfarin maintenance dose compared with patients with VKORC1-1639GG (SMD = -0.666, 95% CI: -0.887 to -0.445, I2 = 33%). However, no associations were observed between CYP4F2 polymorphisms and warfarin maintenance dose (MD = 0.005 mg/kg/day, 95% CI: -0.006 to 0.015, I2 = 0%). These results were not affected by a sensitivity analysis. Our meta-analysis provides evidence that CYP2C9 and VKORC1 variant statuses affect warfarin maintenance dose in children, but not CYP4F2.

Obesity as a Potential Risk Factor for Vincristine-induced Peripheral Neuropathy.

Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer. Vincristine is a core chemotherapeutic agent for patients with ALL; unfortunately, ∼78% will develop vincristine-induced peripheral neuropathy (VIPN). VIPN can result in vincristine dose reductions that decrease therapeutic efficacy: making it important to understand which children are at highest risk for VIPN. We hypothesized that pediatric ALL patients who were obese at diagnosis would develop worse VIPN than healthy weight children with ALL within the first year. Our results confirmed that obese pediatric patients have significantly (P=0.03) worse VIPN than patients of healthy weight.

Organic Anion Transporting Polypeptides: Emerging Roles in Cancer Pharmacology.

The organic anion transporting polypeptides (OATPs) are a superfamily of drug transporters involved in the uptake and disposition of a wide array of structurally divergent endogenous and exogenous substrates, including steroid hormones, bile acids, and commonly used drugs, such as anti-infectives, antihypertensives, and cholesterol lowering agents. In the past decade, OATPs, primarily OATP1A2, OATP1B1, and OATP1B3, have emerged as potential mediators of chemotherapy disposition, including drugs such as methotrexate, doxorubicin, paclitaxel, docetaxel, irinotecan and its important metabolite 7-ethyl-10-hydroxycamptothecin, and certain tyrosine kinase inhibitors. Furthermore, OATP family members are polymorphic and numerous studies have shown OATP variants to have differential uptake, disposition, and/or pharmacokinetics of numerous drug substrates with important implications for interindividual differences in efficacy and toxicity. Additionally, certain OATPs have been found to be overexpressed in a variety of human solid tumors, including breast, liver, colon, pancreatic, and ovarian cancers, suggesting potential roles for OATPs in tumor development and progression and as novel targets for cancer therapy. This review focuses on the emerging roles for selected OATPs in cancer pharmacology, including preclinical and clinical studies suggesting roles in chemotherapy disposition, the pharmacogenetics of OATPs in cancer therapy, and OATP overexpression in various tumor tissues with implications for OATPs as therapeutic targets.

Presentation of psychogenic nonepileptic seizures in Hawaii's ethnoracially diverse population.

PURPOSE: This exploratory study compared the semiology of psychogenic nonepileptic seizures (PNES) between a diverse group of patients in the state of Hawaii. This study may expand understanding of PNES across different ethnocultural and gender groups. METHODS: A retrospective chart review of patients admitted to our Epilepsy Monitoring Unit (EMU) over a 4-year period was performed to compare semiology in different ethnic groups and gender. RESULTS: A total of 139 patients were included in this study, 37% (n = 51) with PNES, 34% (n = 47) with epilepsy only, and 29% (n = 41) with other non-PNES, nonepilepsy diagnosis. The number of Asians with PNES were found to differ when compared with the patients with epilepsy and the patients with non-PNES, nonepilepsy diagnosis. A positive trend was found in the number of Native Hawaiians and Caucasians with PNES in comparison with patients with non-PNES, nonepilepsy diagnosis. In addition, three semiology of PNES in Native Hawaiians were found to differ in comparison with other ethnic groups with PNES: rhythmic motor, mixed semiology, and nonepileptic aura. There is a significant difference in all motor manifestation between males and females in Native Hawaiians. Between patients with PNES, patients with epilepsy, and patients with non-PNES, nonepilepsy diagnosis, significant correlation was found in psychiatric disorders including posttraumatic stress disorder (PTSD), anxiety, and any psychiatric disorder. CONCLUSION: This cross-cultural study found significant differences in the expression of PNES across key ethnoracial groups for the Islands of Hawaii. These findings have implications to the diagnosis and treatment of PNES for Native Hawaiians and other Pacific Islanders in the United States.

The bromodomain protein Brd4 insulates chromatin from DNA damage signalling.

DNA damage activates a signalling network that blocks cell-cycle progression, recruits DNA repair factors and/or triggers senescence or programmed cell death. Alterations in chromatin structure are implicated in the initiation and propagation of the DNA damage response. Here we further investigate the role of chromatin structure in the DNA damage response by monitoring ionizing-radiation-induced signalling and response events with a high-content multiplex RNA-mediated interference screen of chromatin-modifying and -interacting genes. We discover that an isoform of Brd4, a bromodomain and extra-terminal (BET) family member, functions as an endogenous inhibitor of DNA damage response signalling by recruiting the condensin II chromatin remodelling complex to acetylated histones through bromodomain interactions. Loss of this isoform results in relaxed chromatin structure, rapid cell-cycle checkpoint recovery and enhanced survival after irradiation, whereas functional gain of this isoform compacted chromatin, attenuated DNA damage response signalling and enhanced radiation-induced lethality. These data implicate Brd4, previously known for its role in transcriptional control, as an insulator of chromatin that can modulate the signalling response to DNA damage.

Interobserver Variation of Colonic Polyp Measurement at Computed Tomography Colonography.

BACKGROUND: The concept of "advanced polyps" is well accepted and is defined as polyps ≥10 mm and/or those having a villous component and/or demonstrating areas of dysplasia. Of these parameters, computed tomography colonography (CTC) can only document size. The accepted management of CTC-detected "advanced polyps" is to recommend excision if feasible, whereas the management of "intermediate" (6-9 mm) polyps is more controversial, and interval surveillance may be acceptable. Therefore, distinction between 6-9 mm and ≥10 mm is important. METHODS: Datasets containing 26 polyps originally reported as between 8-12 mm in diameter were reviewed independently by 4 CTC-accredited radiologists. Observers tabulated the largest measurement for each polyp on axial, coronal, sagittal, and endoluminal views at lung-window settings. These measurements were also compared to those determined by the computer-aided detection (CAD) software. RESULTS: The interobserver reliability intra-class correlation coefficient (ICC) for sagittal projection was 0.80 ("excellent" category of Hosmer and Lemeshow [2004]), 0.71 for axial ("acceptable"), 0.69 for coronal, and 0.41 for endoluminal ("unacceptable"). The largest of sagittal/axial/coronal measurement gave the best reliability with the smallest variance (ICC = 0.80; 95% CI 0.67-0.89). For 8 of 26 polyps, at least one radiologist's measurement placed the polyp in a different category compared to a colleague. For the majority of the polyps, the CAD significantly overestimated the readings compared to the largest of the manual measurements with an average difference of 1.6 mm (P < .0001 for sagittal/axial/coronal). This resulted in 33% of polyps falling into a different category-10% were lower and 23% were higher (P < .034). CONCLUSION: It is apparent that around the cutoff point of 10 mm between "advanced" and "intermediate" polyps, interobserver performance is variable.

Chaotic Properties of a Turbulent Isotropic Fluid.

By tracking the divergence of two initially close trajectories in phase space in an Eulerian approach to forced turbulence, the relation between the maximal Lyapunov exponent λ and the Reynolds number Re is measured using direct numerical simulations, performed on up to 2048^{3} collocation points. The Lyapunov exponent is found to solely depend on the Reynolds number with λ∝Re^{0.53} and that after a transient period the divergence of trajectories grows at the same rate at all scales. Finally a linear divergence is seen that is dependent on the energy forcing rate. Links are made with other chaotic systems.

Contribution of Organic Anion-Transporting Polypeptides 1A/1B to Doxorubicin Uptake and Clearance.

The organic anion-transporting polypeptides represent an important family of drug uptake transporters that mediate the cellular uptake of a broad range of substrates including numerous drugs. Doxorubicin is a highly efficacious and well-established anthracycline chemotherapeutic agent commonly used in the treatment of a wide range of cancers. Although doxorubicin is a known substrate for efflux transporters such as P-glycoprotein (P-gp; MDR1, ABCB1), significantly less is known regarding its interactions with drug uptake transporters. Here, we investigated the role of organic anion transporting polypeptide (OATP) transporters to the disposition of doxorubicin. A recombinant vaccinia-based method for expressing uptake transporters in HeLa cells revealed that OATP1A2, but not OATP1B1 or OATP1B3, and the rat ortholog Oatp1a4 were capable of significant doxorubicin uptake. Interestingly, transwell assays using Madin-Darby canine kidney II cell line cells stably expressing specific uptake and/or efflux transporters revealed that OATP1B1, OATP1B3, and OATP1A2, either alone or in combination with MDR1, significantly transported doxorubicin. An assessment of polymorphisms in SLCO1A2 revealed that four variants were associated with significantly impaired doxorubicin transport in vitro. In vivo doxorubicin disposition studies revealed that doxorubicin plasma area under the curve was significantly higher (1.7-fold) in Slco1a/1b-/- versus wild-type mice. The liver-to-plasma ratio of doxorubicin was significantly decreased (2.3-fold) in Slco1a/1b2-/- mice and clearance was reduced by 40% compared with wild-type mice, suggesting Oatp1b transporters are important for doxorubicin hepatic uptake. In conclusion, we demonstrate important roles for OATP1A/1B in transporter-mediated uptake and disposition of doxorubicin.

Identification and Characterization of Trimethylamine-N-oxide Uptake and Efflux Transporters.

Trimethylamine-N-oxide (TMAO) is a recently identified predictor of cardiovascular and chronic kidney disease. TMAO is primarily generated through gut-microbiome mediated conversion of dietary choline and carnitine to TMA, which is converted to TMAO by hepatic flavin monooxygenase 3 (FMO3) and subsequently undergoes renal elimination. We investigated the role of uptake and efflux drug transporters in TMAO disposition in vitro and in vivo. After screening a large array of uptake transporters, we show organic cation transporter 2 (OCT2) is the key transporter for TMAO cellular uptake. In Oct1/2 knockout mice, we observed increased plasma TMAO levels with reduced renal retention, suggesting the importance of Oct2 in facilitating the uptake of TMAO into renal tubular cells in vivo. Multiple transporters of the ATP-binding cassette (ABC) family, including ABCG2 (BCRP) and ABCB1 (MDR1), were capable of TMAO efflux. In human subjects, clinical, dietary, and pharmacogenetic covariates were evaluated for contribution to TMAO levels in a cohort of dyslipidemic patients (n = 405). Interestingly, genetic variation in ABCG2, but not other transporters, appeared to play a role in modulating TMAO exposure.

Interindividual and interethnic variability in drug disposition: polymorphisms in organic anion transporting polypeptide 1B1 (OATP1B1; SLCO1B1).

OATP1B1 (SLCO1B1) is predominantly expressed at the basolateral membrane of hepatocytes and is critically important for the hepatic uptake and clearance of numerous drug substrates and endogenous compounds. In general, the organic anion transporting polypeptides (OATP; SLCO) represent a superfamily of uptake transporters that mediate the sodium-independent transport of a diverse range of amphipathic organic compounds including bile salts, steroid conjugates, thyroid hormones, anionic peptides, numerous drugs and other xenobiotic substances. OATP1B1 is highly polymorphic and a number of relevant and ethnically dependent polymorphisms have been identified and functionally characterized. In particular, the SLCO1B1 521T>C and 388A>G polymorphisms are commonly occurring variants in ethnically diverse populations and numerous in vitro and clinical studies have evaluated the consequences of these variants to interindividual differences in drug disposition and response. OATP1B1 is particularly important for the disposition of HMG-CoA reductase inhibitors, or statins, as it is known to efficiently transport most statins to their site of action within hepatocytes. Many studies have focused on the consequences of OATP1B1 variants to statin disposition in vitro and in vivo and would suggest that genetic variability in SLCO1B1 has important implications for statin pharmacokinetics, risk for statin-induced myopathy, and modulation of statin treatment response. This review describes what is currently known regarding SLCO1B1 genotype, OATP1B1 protein expression and interindividual and interethnic consequences to drug disposition, with particular focus on statin pharmacokinetics and implications for drug response and toxicity.

Robot-assisted extravesical vesicovaginal fistula repair utilizing laparoscopically mobilized omental flap interposition.

INTRODUCTION AND HYPOTHESIS: High vesicovaginal fistulas (VVF) in the setting of good apical support are best repaired via a transabdominal approach. Laparoscopic VVF repair was first reported in 1998. Several series of robot-assisted VVF repairs have since been published. The robot-assisted approach allows repair of high apical vaginal fistulas while avoiding the morbidity of laparotomy, shortening convalescence, and facilitating the use of omental interposition flaps. This video presents the technique for robot-assisted extravesical VVF repair utilizing a laparoscopically mobilized omental flap. METHODS: A 43-year-old woman developed a VVF after a total abdominal hysterectomy for fibroids. Pre-operative CT urogram and office cystoscopy confirmed the diagnosis and ruled out ureteral involvement. She underwent a robot-assisted extravesical VVF repair utilizing a laparoscopically mobilized omental flap. RESULTS: The surgery was uncomplicated, and the patient was discharged on post-operative day 1. A cystogram 2 weeks post-operatively revealed no evidence of a fistula. At 3 months follow-up, the patient denied any urinary incontinence. CONCLUSIONS: Robot-assisted extravesical VVF repair avoids the morbidity of a laparotomy, provides excellent exposure, and avoids a large cystotomy. It maintains vaginal length and allows for significantly better visualization compared with the transvaginal approach. This repair offers improved outcomes for certain patients depending on their history, anatomy, and the surgeon's experience.

Prostate Cancer Diagnosis on Repeat Magnetic Resonance Imaging-Transrectal Ultrasound Fusion Biopsy of Benign Lesions: Recommendations for Repeat Sampling.

PURPOSE: Urologists face a dilemma when a lesion identified on multiparametric magnetic resonance imaging is benign on image guided fusion biopsy. We investigated the detection rate of prostate cancer on repeat fusion biopsy in multiparametric magnetic resonance imaging lesions initially found to be pathologically benign on fusion biopsy. MATERIALS AND METHODS: We reviewed the records of all patients from 2007 to 2014 who underwent multiparametric magnetic resonance imaging and image guided fusion biopsy. We identified men who underwent rebiopsy of the same discrete lesion after initial fusion biopsy results were benign. Data were documented on a per lesion basis. We manually reviewed UroNav system (Invivo, Gainesville, Florida) needle tracking to verify accurate image registration. Multivariate analysis was used to identify clinical and imaging factors predictive of prostate cancer detection at repeat fusion biopsy. RESULTS: A total of 131 unique lesions were rebiopsied in 90 patients. Of these 131 resampled lesions 21 (16%) showed prostate cancer, which in 13 (61.9%) was Gleason 3 + 3. On multivariate analysis only lesion growth on repeat multiparametric magnetic resonance imaging was significantly associated with prostate cancer detection at repeat biopsy (HR 3.274, 95% CI 1.205-8.896, p = 0.02). CONCLUSIONS: Pathologically benign multiparametric magnetic resonance imaging lesions on initial image guided fusion biopsy are rarely found to harbor clinically significant prostate cancer on repeat biopsy. When prostate cancer was identified, most disease was low risk. An increase in lesion diameter was an independent predictor of prostate cancer detection. While these data are retrospective, they may provide some confidence in the reliability of negative initial image guided fusion biopsies despite a positive multiparametric magnetic resonance imaging finding.

Reproducibility of Multiparametric Magnetic Resonance Imaging and Fusion Guided Prostate Biopsy: Multi-Institutional External Validation by a Propensity Score Matched Cohort.

PURPOSE: As the adoption of magnetic resonance imaging/ultrasound fusion guided biopsy expands, the reproducibility of outcomes at expert centers becomes essential. We sought to validate the comprehensive NCI (National Cancer Institute) experience with multiparametric magnetic resonance imaging and fusion guided biopsy in an external, independent, matched cohort of patients. MATERIALS AND METHODS: We compared 620 patients enrolled in a prospective trial comparing systematic biopsy to fusion guided biopsy at NCI to 310 who underwent a similar procedure at Long Island Jewish Medical Center. The propensity score, defined as the probability of being treated outside NCI, was calculated using the estimated logistic regression model. Patients from the hospital were matched 1:1 for age, prostate specific antigen, magnetic resonance imaging suspicion score and prior negative biopsies. Clinically significant disease was defined as Gleason 3 + 4 or greater. RESULTS: Before matching we found differences between the cohorts in age, magnetic resonance imaging suspicion score (each p <0.001), the number of patients with prior negative biopsies (p = 0.01), and the overall cancer detection rate and the cancer detection rate by fusion guided biopsy (each p <0.001). No difference was found in the rates of upgrading by fusion guided biopsy (p = 0.28) or upgrading to clinically significant disease (p = 0.95). A statistically significant difference remained in the overall cancer detection rate and the rate by fusion guided biopsy after matching. On subgroup analysis we found a difference in the overall cancer detection rate and the rate by fusion guided biopsy (p <0.001 and 0.003) in patients with prior negative systematic biopsy but no difference in the 2 rates (p = 0.39 and 0.51, respectively) in biopsy naïve patients. CONCLUSIONS: Improved detection of clinically significant cancer by magnetic resonance imaging and fusion guided biopsy is reproducible by an experienced multidisciplinary team consisting of dedicated radiologists and urologists.

The outcome of allogeneic hematopoietic cell transplantation for children with FMS-like tyrosine kinase 3 internal tandem duplication-positive acute myelogenous leukemia.

FMS-like tyrosine kinase 3 (FLT3) internal tandem duplication (ITD) is a somatic mutation associated with poor outcome when treated with chemotherapy alone. In children, hematopoietic stem cell transplantation (HSCT) is recommended, but very limited data on outcome are reported. We determined the outcome of 29 children with FLT3/ITD-positive acute myelogenous leukemia (AML) who underwent allogeneic HSCT in 4 pediatric centers. Eleven patients (38%) received matched related donor hematopoietic stem cells and 18 (62%) received alternative donors. Eighteen patients (62%) received total body irradiation (TBI)-based regimens. No patients experienced transplantation-related mortality. Eleven patients (38%) experienced relapsed disease. The cumulative incidence of relapse at 2 years was 34.7% (95% confidence interval [CI], 20.4% to 54.9%). Two-year disease-free survival (DFS) and overall survival (OS) were 65.3% (95% CI, 45.1% to 79.6%) and 82.2% (95% CI, 58.5% to 91.3%), respectively. There was no difference in the DFS of patients who received transplants from related donors versus the DFS of those who received transplants from alternative donors (hazard ratio [HR], 2.64; 95% CI, .79 to 8.76; P = .10), using univariate analysis. Patients with higher FLT3/ITD ratio at diagnosis had significantly worse DFS (HR, 1.42; 95% CI, 1.04 to 1.93; P = .03). The use of TBI in the preparative regimen was associated with superior DFS (HR, .29; 95% CI, .08 to .99; P = .04) and OS (HR, .07; 95% CI, .01 to .62; P = .002). We conclude that allogeneic HSCT improves DFS and OS in children with FLT3/ITD-positive AML compared with what has been reported in those treated with chemotherapy alone.

Long-term use of the thrombopoietin-mimetic romiplostim in children with severe chronic immune thrombocytopenia (ITP).

BACKGROUND: Treatment of chronic severe pediatric ITP is not well studied. In a phase 1/2 12-16-week study, 15/17 romiplostim-treated patients achieved platelet counts ≥50 × 109 /L, and romiplostim treatment was well tolerated. In a subsequent open-label extension (≤109 weeks), 20/22 patients received romiplostim; all achieved platelet counts >50 × 109 /L. Twelve patients continued in a second extension (≤127 weeks). Longitudinal data from start of romiplostim treatment through the two extensions were evaluated to investigate the safety and efficacy of long-term romiplostim treatment in chronic severe pediatric ITP. PROCEDURE: Patients received weekly subcutaneous romiplostim, adjusted by 1 µg/kg/week to maintain platelet counts (50-200 × 109 /L, maximum dose 10 µg/kg). Bone marrow examinations were not required. RESULTS: At baseline, patients were median age 10.0 years; median ITP duration 2.4 years; median platelet count 13 × 109 /L; 73% were male; and 36% had prior splenectomy. Median romiplostim treatment duration was 167 weeks (Q1, Q3: 78,227 weeks), and median average weekly dose was 5.4 µg/kg (Q1, Q3: 4.3, 8.0 µg/kg). Seven patients discontinued treatment: four withdrew consent, two were noncompliant, and one received alternative therapy. None withdrew because of adverse events (AEs). After the first 12 weeks, median platelet counts remained >50 × 109 /L. Eight (36.4%) patients received rescue medication, and 14 (63.6%) used concurrent ITP therapy. Seven patients (31.8%) reported serious AEs, and two (9.1%) reported life-threatening AEs (both thrombocytopenia); there were no serious AEs attributed to treatment and no fatalities. CONCLUSIONS: Long-term romiplostim treatment in this small cohort increased and maintained platelet counts for over 4 years in children with ITP with good tolerability and without significant toxicity. Pediatr Blood Cancer 2015;62:208-213. © 2014. The Authors. Pediatr Blood & Cancer published by Wiley Periodicals, Inc.

Patterns and severity of vincristine-induced peripheral neuropathy in children with acute lymphoblastic leukemia.

Vincristine, a critical component of combination chemotherapy treatment for pediatric acute lymphoblastic leukemia (ALL), can lead to vincristine-induced peripheral neuropathy (VIPN). Longitudinal VIPN assessments were obtained over 12 months from newly diagnosed children with ALL (N = 128) aged 1-18 years who received vincristine at one of four academic children's hospitals. VIPN assessments were obtained using the Total Neuropathy Score-Pediatric Vincristine (TNS©-PV), National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE©), Balis© grading scale, and Pediatric Neuropathic Pain Scale©-Five (PNPS©-5). Of children who provided a full TNS©-PV score, 85/109 (78%) developed VIPN (TNS©-PV ≥4). Mean TNS©-PV, grading scale, and pain scores were low. CTCAE©-derived grades 3 and 4 sensory and motor VIPN occurred in 1.6%/0%, and 1.9%/0% of subjects, respectively. VIPN did not resolve in months 8-12 despite decreasing dose density. VIPN was worse in older children. Partition cluster analysis revealed 2-3 patient clusters; one cluster (n = 14) experienced severe VIPN. In this population, VIPN occurs more commonly than previous research suggests, persists throughout the first year of treatment, and can be severe.