Background Measures of socioeconomic disadvantage may enable improved targeting of programs to prevent rehospitalizations, but obtaining such information directly from patients can be difficult. Measures of US neighborhood socioeconomic disadvantage are more readily available, although rarely employed clinically. Objective To evaluate the association between neighborhood socioeconomic disadvantage at the census block-group level, as measured by Singh’s validated Area Deprivation Index (ADI), and 30-day rehospitalization. Design Retrospective cohort study Setting United States Patients Random 5% national sample of fee-for-service Medicare patients discharged with congestive heart failure, pneumonia or myocardial infarction, 2004–2009 (N = 255,744) Measurements 30-day rehospitalizations. Medicare data were linked to 2000 Census data to construct an ADI for each patient’s census block-group, which were then sorted into percentiles by increasing ADI. Relationships between neighborhood ADI grouping and rehospitalization were evaluated using multivariate logistic regression models, controlling for patient sociodemographics, comorbidities/severity, and index hospital characteristics. Results The 30-day rehospitalization rate did not vary significantly across the least disadvantaged 85% of neighborhoods, which had an average rehospitalization rate=21%. However, within the most disadvantaged 15% of neighborhoods, rehospitalization rates rose from 22% to 27% with worsening ADI. This relationship persisted after full adjustment, with the most disadvantaged neighborhoods having a rehospitalization risk (adjusted risk ratio = 1.09, confidence interval 1.05–1.12) similar to that of chronic pulmonary disease (1.06, 1.04–1.08) and greater than that of diabetes (0.95, 0.94–0.97). Limitations No direct markers of care quality, access Conclusions Residence within a disadvantaged US neighborhood is a rehospitalization predictor of magnitude similar to chronic pulmonary disease. Measures of neighborhood disadvantage, like the ADI, could potentially be used to inform policy and post-hospital care. Primary Funding Source National Institute on Aging

SUMMARY Interactions between tumorigenic cells and their surrounding microenvironment are critical for tumor progression yet remain incompletely understood. Germline mutations in the NF1 tumor suppressor gene cause neurofibromatosis type 1 (NF1), a common genetic disorder characterized by complex tumors called neurofibromas. Genetic studies indicate that biallelic loss of Nf1 is required in the tumorigenic cell of origin in the embryonic Schwann cell lineage. However, in the physiologic state, Schwann cell loss of heterozygosity is not sufficient for neurofibroma formation and Nf1 haploinsufficiency in at least one additional nonneoplastic lineage is required for tumor progression. Here, we establish that Nf1 heterozygosity of bone marrow-derived cells in the tumor microenvironment is sufficient to allow neurofibroma progression in the context of Schwann cell Nf1 deficiency. Further, genetic or pharmacologic attenuation of c-kit signaling in Nf1+/− hematopoietic cells diminishes neurofibroma initiation and progression. Finally, these studies implicate mast cells as critical mediators of tumor initiation.

Luminal- and basal-like prostate cancers demonstrate divergent clinical behavior, and patients with luminal B tumors respond better to postoperative ADT than do patients with non–luminal B tumors. These findings contribute novel insight into prostate cancer biology, providing a potential clinical tool to personalize ADT treatment for prostate cancer by predicting which men may benefit from ADT after surgery.

Summary Coactivator-associated arginine methyltransferase 1 (CARM1), a coactivator for various cancer-relevant transcription factors, is overexpressed in breast cancer. To elucidate the functions of CARM1 in tumorigenesis, we knocked out CARM1 from several breast cancer cell lines using Zinc-Finger Nuclease technology, which resulted in drastic phenotypic and biochemical changes. The CARM1 KO cell lines enabled identification of CARM1 substrates, notably the SWI/SNF core subunit BAF155. Methylation of BAF155 at R1064 was found to be an independent prognostic biomarker for cancer recurrence and to regulate breast cancer cell migration and metastasis. Furthermore, CARM1-mediated BAF155 methylation affects gene expression by directing methylated BAF155 to unique chromatin regions (e.g., c-Myc pathway genes). Collectively, our studies uncover a mechanism by which BAF155 acquires tumorigenic functions via arginine methylation.

Summary Many statistical methods have recently been developed for identifying subgroups of patients who may benefit from different available treatments. Compared with the traditional outcome-modeling approaches, these methods focus on modeling interactions between the treatments and covariates while by-pass or minimize modeling the main effects of covariates because the subgroup identification only depends on the sign of the interaction. However these methods are scattered and often narrow in scope. In this paper, we propose a general framework, by weighting and A-learning, for subgroup identification in both randomized clinical trials and observational studies. Our framework involves minimum modeling for the relationship between the outcome and covariates pertinent to the subgroup identification. Under the proposed framework, we may also estimate the magnitude of the interaction, which leads to the construction of scoring system measuring the individualized treatment effect. The proposed methods are quite flexible and include many recently proposed estimators as special cases. As a result, some estimators originally proposed for randomized clinical trials can be extended to observational studies, and procedures based on the weighting method can be converted to an A-learning method and vice versa. Our approaches also allow straightforward incorporation of regularization methods for high-dimensional data, as well as possible efficiency augmentation and generalization to multiple treatments. We examine the empirical performance of several procedures belonging to the proposed framework through extensive numerical studies.

Juvenile myelomonocytic leukemia (JMML) is a lethal disease of young children characterized by hypersensitivity of hematopoietic progenitors to granulocyte-macrophage colony-stimulating factor (GM-CSF). Mutations in PTPN11, which encodes the protein tyrosine phosphatase Shp-2, are common in JMML. We hypothesized that PTPN11 mutations induce hypersensitivity of hematopoietic progenitors to GM-CSF and confer increased GM-CSF-stimulated phosphoextracellular signal-regulated kinase (Erk) levels. To test this hypothesis, the wild-type (WT) and 3 mutant Ptpn11 cDNAs (E76K, D61V, and D61Y) were transduced into mu- IntroductionJuvenile myelomonocytic leukemia (JMML), a childhood leukemia, is a lethal disease of young children characterized by spontaneous growth of peripheral blood hematopoietic progenitors and hypersensitivity of hematopoietic progenitors to the cytokine granulocytemacrophage colony-stimulating factor (GM-CSF). 1,2 Activating mutations of the N-RAS and K-RAS genes and loss of heterozygosity of the tumor suppressor gene NF1 (in individuals with the congenital disorder Neurofibromatosis type 1) have long been recognized as pathogenic in this disease. [3][4][5][6][7] However, recently, somatic mutations within PTPN11, which encodes the protein tyrosine phosphatase Shp-2, have also been found to occur commonly in JMML, 8 as well as in acute myeloid leukemia, myelodysplastic syndrome, and acute lymphoid leukemia. [8][9][10] These findings were elicited based on the initial observation that individuals with the congenital disorder known as Noonan syndrome, 50% of which bear germline PTPN11 mutations, 11,12 have an increased incidence of JMML. 13,14 Shp-2 is a nonreceptor protein tyrosine phosphatase that contains 2 Src homology 2 domains (N-SH2 and C-SH2) at the amino terminus and an enzymatic phosphatase domain at the carboxy terminus of the protein. 15 Shp-2 has been demonstrated repeatedly to play a positive role in growth factor signaling to Ras, [16][17][18][19][20][21] suggesting that normal Shp-2 function is required for Ras-dependent functions, such as cellular proliferation and survival. Germline PTPN11 mutations observed in Noonan syndrome as well as somatic PTPN11 mutations observed in leukemias commonly involve residues within the N-SH2 domain or within the phosphatase domain. 8,11 The affected amino acids disrupt noncovalent interactions between the N-SH2 and phosphatase domains necessary to maintain Shp-2 in a closed, inactive conformation. 22 The current hypothesis is that mutant Shp-2 proteins preferentially remain in the open conformation with constitutively active Shp-2 phosphatase activity, thus inducing the observed disease states. A mouse model bearing a common PTPN11 germline mutation found in Noonan syndrome changing amino acid 61 from aspartate to glycine 11 faithfully mimics the human phenotype of Noonan syndrome, including facial anomalies, short stature, heart malformations, and myelomonocytic hyperplasia 23 ; however, the effect of somatic PTPN11 mutations on primary hematopoietic...

Summary BACKGROUND Plexiform neurofibromas (PN) are slow growing chemoradiotherapy resistant tumours arising in patients with neurofibromatosis type I (NF1). Currently there are no viable therapeutic options for patients whose life-threatening plexiform neurofibromas cannot be surgically removed due to proximity to vital body structures. Based on identification of molecular targets in genetic mouse models of human NF1 tumours, we hypothesized that the oral kinase inhibitor, imatinib mesylate, may be effective in targeted treatment of these chemoradiotherapy-refractory tumours. METHODS An open-label pilot Phase II clinical trial was designed to test whether treatment with imatinib mesylate can decrease volume burden of clinically significant plexiform neurofibromas in NF1 patients. The entry criteria require patients only to have NF1 and a clinically significant plexiform neurofibroma with the specified age limitations (age 3–65). Patients were treated with daily oral imatinib at 440 mg/m2/day for children and 800 mg/day for adults divided twice daily for 6 months. The primary endpoint measure of significant response was a 20% or more reduction in plexiform size by sequential volumetric MRI imaging. Clinical data was analyzed on an intent to treat basis, however to determine the activity of imatinib on NF1-related plexiform tumours, patients able to take imatinib for 6 months were evaluated for their response. Secondary outcomes included evaluation of safety of imatinib mesylate in this group of patients. The trial is registered at http://clinicaltrials.gov/; study number 0512-25. The trial currently is closed to enrollment, however there is a single patient that continues to respond and remains on study. FINDINGS On an intent to treat basis, 6 out of 36 patients or 17% (95% CI: 6 – 33%) experienced objective response to imatinib mesylate. In the evaluable study population of patients (n=23) who received drug for at least six months, six patients (26%; 95% CI: 10 – 48%) experienced ≥ 20% decrease in volume of one or more plexiform tumours and 30% of study patients had symptomatic improvement. We noted significant inter-patient and intra-patient heterogeneity of plexiform neurofibroma response. Toxicity of drug was comparable to previous reports in patients with chronic myelogenous leukemia. The most common adverse events were reversible skin rash (5 patients) and edema with weight gain (6 patients). More serious adverse events included reversible grade 3 neutropenia (2 patients) and grade 4 transaminitis (one patient). INTERPRETATION Imatinib mesylate caused disease regression in 26% of evaluable patients with clinically significant plexiform neurofibromas due to neurofibromatosis type 1. These results warrant confirmation in a larger multi-institutional clinical trial aimed at this patient population. These findings provide the first demonstration of radiographic volumetric tumour reduction in response to medical therapy in patients with NF1 plexiform neurofibromas using imatinib mesylate based on studies...

The purpose of this study was to evaluate the preliminary efficacy and satisfaction/acceptability of training in memory or speed of processing versus wait-list control for improving cognitive function in breast cancer survivors. 82 breast cancer survivors completed a three-group randomized, controlled trial. Primary outcomes were objective neuropsychological tests of memory and speed of processing. Secondary outcomes were perceived cognitive functioning, symptom distress (mood disturbance, anxiety, and fatigue), quality of life, and intervention satisfaction/acceptability. Data were collected at baseline, post-intervention, and 2-month follow-up. Using repeated-measures mixed-linear ANCOVA models, each intervention was compared to wait-list control while adjusting for age, education, and baseline measures. The effect sizes for differences in means and the reliable improvement percentage were reported. The results show that domain-specific effects were seen for both interventions: memory training improved memory performance at 2-month follow-up (p = 0.036, d = 0.59); speed of processing training improved processing speed post-intervention (p = 0.040, d = 0.55) and 2-month follow-up (p = 0.016; d = 0.67). Transfer effects to non-trained domains were seen for speed of processing training with improved memory post-intervention (p = 0.007, d = 0.75) and 2-month follow-up (p = 0.004, d = 0.82). Both interventions were associated with improvements in perceived cognitive functioning, symptom distress, and quality of life. Ratings of satisfaction/acceptability were high for both interventions. It was concluded that while both interventions appeared promising, speed of processing training resulted in immediate and durable improvements in objective measures of processing speed and verbal memory. Speed of processing training may have broader benefits in this clinical population.