Homologous Recombination Deficiency and Platinum-Based Therapy Outcomes in Advanced Breast Cancer

Purpose: Recent studies have identified mutation signatures of homologous recombination deficiency (HRD) in over 20% of breast cancers, as well as pancreatic, ovarian, and gastric cancers. There is an urgent need to understand the clinical implications of HRD signatures. Whereas BRCA1/2 mutations confer sensitivity to platinum-based chemotherapies, it is not yet clear whether mutation signatures can independently predict platinum response.

Experimental Design: In this observational study, we sequenced tumor whole genomes (100x depth) and matched normals (60x) of 93 advanced-stage breast cancers (33 platinum-treated). We computed a published metric called HRDetect, independently trained to predict BRCA1/2 status, and assessed its capacity to predict outcomes on platinum-based chemotherapies. Clinical endpoints were overall survival (OS), total duration on platinum-based therapy (TDT), and radiographic evidence of clinical improvement (CI).

Results: HRDetect predicted BRCA1/2 status with an area under the curve (AUC) of 0.94 and optimal threshold of 0.7. Elevated HRDetect was also significantly associated with CI on platinum-based therapy (AUC = 0.89; P = 0.006) with the same optimal threshold, even after adjusting for BRCA1/2 mutation status and treatment timing. HRDetect scores over 0.7 were associated with a 3-month extended median TDT (P = 0.0003) and 1.3-year extended median OS (P = 0.04).

Conclusions: Our findings not only independently validate HRDetect, but also provide the first evidence of its association with platinum response in advanced breast cancer. We demonstrate that HRD mutation signatures may offer clinically relevant information independently of BRCA1/2 mutation status and hope this work will guide the development of clinical trials. Clin Cancer Res; 23(24); 7521–30. ©2017 AACR.

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Acknowledgment to Reviewers

http://ift.tt/2jWhkqi

Head and Neck Squamous Cell Carcinomas Are Characterized by a Stable Immune Signature Within the Primary Tumor Over Time and Space

Purpose: Genetic and morphologic heterogeneity is well-documented in solid cancers. Immune cells are also variably distributed within the tumor; this heterogeneity is difficult to assess in small biopsies, and may confound our understanding of the determinants of successful immunotherapy. We examined the transcriptomic variability of the immunologic signature in head and neck squamous cell carcinoma (HNSCC) within individual tumors using transcriptomic and IHC assessments.

Experimental Design: Forty-four tumor biopsies from 16 HNSCC patients, taken at diagnosis and later at resection, were analyzed using RNA-sequencing. Variance filtering was used to identify the top 4,000 most variable genes. Principal component analysis, hierarchical clustering, and correlation analysis were performed. Gene expression of CD8A was correlated to IHC analysis.

Results: Analysis of immunologic gene expression was highly consistent in replicates from the same cancer. Across the cohort, samples from the same patient were most similar to each other, both spatially (at diagnosis) and, notably, over time (diagnostic biopsy compared with resection); comparison of global gene expression by hierarchical clustering (P ≤ 0.0001) and correlation analysis [median intrapatient r = 0.82; median interpatient r = 0.63]. CD8A gene transcript counts were highly correlated with CD8 T-cell counts by IHC (r = 0.82).

Conclusions: Our data demonstrate that in HNSCC the global tumor and adaptive immune signatures are stable between discrete parts of the same tumor and also at different timepoints. This suggests that immunologic heterogeneity may not be a key reason for failure of immunotherapy and underpins the use of transcriptomics for immunologic evaluation of novel agents in HNSCC patients. Clin Cancer Res; 23(24); 7641–9. ©2017 AACR.

http://ift.tt/2jWa65H

The Driver Mutational Landscape of Ovarian Squamous Cell Carcinomas Arising in Mature Cystic Teratoma

Purpose: We sought to identify the genomic abnormalities in squamous cell carcinomas (SCC) arising in ovarian mature cystic teratoma (MCT), a rare gynecological malignancy of poor prognosis.

Experimental design: We performed copy number, mutational state, and zygosity analysis of 151 genes in SCC arising in MCT (n = 25) using next-generation sequencing. The presence of high-/intermediate-risk HPV genotypes was assessed by quantitative PCR. Genomic events were correlated with clinical features and outcome.

Results: MCT had a low mutation burden with a mean of only one mutation per case. Zygosity analyses of MCT indicated four separate patterns, suggesting that MCT can arise from errors at various stages of oogenesis. A total of 244 abnormalities were identified in 79 genes in MCT-associated SCC, and the overall mutational burden was high (mean 10.2 mutations per megabase). No SCC was positive for HPV. The most frequently altered genes in SCC were TP53 (20/25 cases, 80%), PIK3CA (13/25 cases, 52%), and CDKN2A (11/25 cases, 44%). Mutation in TP53 was associated with improved overall survival. In 8 of 20 cases with TP53 mutations, two or more variants were identified, which were bi-allelic.

Conclusions: Ovarian SCC arising in MCT has a high mutational burden, with TP53 mutation the most common abnormality. The presence of TP53 mutation is a good prognostic factor. SCC arising in MCT share similar mutation profiles to other SCC. Given their rarity, they should be included in basket studies that recruit patients with SCC of other organs. Clin Cancer Res; 23(24); 7633–40. ©2017 AACR.

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Inhibiting PI3K{beta} with AZD8186 Regulates Key Metabolic Pathways in PTEN-Null Tumors

Purpose: PTEN-null tumors become dependent on the PI3Kβ isoform and can be targeted by molecules such as the selective PI3Kβ inhibitor AZD8186. However, beyond the modulation of the canonical PI3K pathway, the consequences of inhibiting PI3Kβ are poorly defined.

Experimental Design: To determine the broader impact of AZD8186 in PTEN-null tumors, we performed a genome-wide RNA-seq analysis of PTEN-null triple-negative breast tumor xenografts treated with AZD8186. Mechanistic consequences of AZD8186 treatment were examined across a number of PTEN-null cell lines and tumor models.

Results: AZD8186 treatment resulted in modification of transcript and protein biomarkers associated with cell metabolism. We observed downregulation of cholesterol biosynthesis genes and upregulation of markers associated with metabolic stress. Downregulation of cholesterol biosynthesis proteins, such as HMGCS1, occurred in PTEN-null cell lines and tumor xenografts sensitive to AZD8186. Therapeutic inhibition of PI3Kβ also upregulated PDHK4 and increased PDH phosphorylation, indicative of reduced carbon flux into the TCA cycle. Consistent with this, metabolomic analysis revealed a number of changes in key carbon pathways, nucleotide, and amino acid biosynthesis.

Conclusions: This study identifies novel mechanistic biomarkers of PI3Kβ inhibition in PTEN-null tumors supporting the concept that targeting PI3Kβ may exploit a metabolic dependency that contributes to therapeutic benefit in inducing cell stress. Considering these additional pathways will guide biomarker and combination strategies for this class of agents. Clin Cancer Res; 23(24); 7584–95. ©2017 AACR.

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A First-in-Human Phase I Study of the Anticancer Stem Cell Agent Ipafricept (OMP-54F28), a Decoy Receptor for Wnt Ligands, in Patients with Advanced Solid Tumors

Purpose: Wnt signaling is implicated in tumor cell dedifferentiation and cancer stem cell function. Ipafricept (OMP-54F28) is a first-in-class recombinant fusion protein with the extracellular part of human frizzled 8 receptor fused to a human IgG1 Fc fragment that binds Wnt ligands. This trial evaluated ipafricept in patients with solid tumors.

Experimental design: A 3+3 design was used; ipafricept was given intravenously every 3 weeks. The objectives were determination of dose-limiting toxicities (DLTs), recommended phase 2 dose (RP2D), safety, pharmacokinetics (PK), immunogenicity, pharmacodynamics (PD), and preliminary efficacy.

Results: 26 patients were treated in seven dose-escalation cohorts (0.5, 1, 2.5, 5, 10, 15, and 20 mg/kg). No further dose escalation was pursued as PK modeling indicated that the target efficacious dose was reached at 10 mg/kg, and fragility fractures occurred at 20 mg/kg. Most common related grade 1 and 2 adverse events (AEs; ≥20% of patients) were dysgeusia, decreased appetite, fatigue, and muscle spasms. Ipafricept-related grade 3 TEAEs included hypophosphatemia and weight decrease (1 subject each, 3.8%). Ipafricept half-life was ~4 days and had low incidence of antidrug antibody formation (7.69%) with no impact on drug exposure. Six patients had β-C-terminal telopeptide (β-CTX) doubling from baseline, which was reversible. PD modulation of Wnt pathway genes in hair follicles occurred ≥2.5 mg/kg. Two desmoid tumor and a germ cell cancer patient experienced stable disease for >6 months.

Conclusions: Ipafricept was well tolerated, with RP2D of 15 mg/kg Q3W. Prolonged SD was noted in desmoid tumor and germ cell cancer patients. Clin Cancer Res; 23(24); 7490–7. ©2017 AACR.

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Modulation of Navitoclax Sensitivity by Dihydroartemisinin-Mediated MCL-1 Repression in BCR-ABL+ B-Lineage Acute Lymphoblastic Leukemia

Purpose: BCR-ABL⁺ B-ALL leukemic cells are highly dependent on the expression of endogenous antiapoptotic MCL-1 to promote viability and are resistant to BH3-mimetic agents such as navitoclax (ABT-263) that target BCL-2, BCL-X_L, and BCL-W. However, the survival of most normal blood cells and other cell types is also dependent on Mcl-1. Despite the requirement for MCL-1 in these cell types, initial reports of MCL-1–specific BH3-mimetics have not described any overt toxicities associated with single-agent use, but these agents are still early in clinical development. Therefore, we sought to identify approved drugs that could sensitize leukemic cells to ABT-263.

Experimental Design: A screen identified dihydroartemisinin (DHA), a water-soluble metabolite of the antimalarial artemisinin. Using mouse and human leukemic cell lines, and primary patient-derived xenografts, the effect of DHA on survival was tested, and mechanistic studies were carried out to discover how DHA functions. We further tested in vitro and in vivo whether combining DHA with ABT-263 could enhance the response of leukemic cells to combination therapy.

Results: DHA causes the downmodulation of MCL-1 expression by triggering a cellular stress response that represses translation. The repression of MCL-1 renders leukemic cells highly sensitive to synergistic cell death induced by ABT-263 in a mouse model of BCR-ABL⁺ B-ALL both in vitro and in vivo. Furthermore, DHA synergizes with ABT-263 in human Ph⁺ ALL cell lines, and primary patient-derived xenografts of Ph⁺ ALL in culture.

Conclusions: Our findings suggest that combining DHA with ABT-263 can improve therapeutic response in BCR-ABL⁺ B-ALL. Clin Cancer Res; 23(24); 7558–68. ©2017 AACR.

http://ift.tt/2kuxEhK

Monocytes and Granulocytes Reduce CD38 Expression Levels on Myeloma Cells in Patients Treated with Daratumumab

Purpose: Daratumumab treatment results in a marked reduction of CD38 expression on multiple myeloma cells. The aim of this study was to investigate the clinical implications and the underlying mechanisms of daratumumab-mediated CD38 reduction.

Experimental Design: We evaluated the effect of daratumumab alone or in combination with lenalidomide-dexamethasone, on CD38 levels of multiple myeloma cells and nontumor immune cells in the GEN501 study (daratumumab monotherapy) and the GEN503 study (daratumumab combined with lenalidomide-dexamethasone). In vitro assays were also performed.

Results: In both trials, daratumumab reduced CD38 expression on multiple myeloma cells within hours after starting the first infusion, regardless of depth and duration of the response. In addition, CD38 expression on nontumor immune cells, including natural killer cells, T cells, B cells, and monocytes, was also reduced irrespective of alterations in their absolute numbers during therapy. In-depth analyses revealed that CD38 levels of multiple myeloma cells were only reduced in the presence of complement or effector cells, suggesting that the rapid elimination of CD38^high multiple myeloma cells can contribute to CD38 reduction. In addition, we discovered that daratumumab–CD38 complexes and accompanying cell membrane were actively transferred from multiple myeloma cells to monocytes and granulocytes. This process of trogocytosis was also associated with reduced surface levels of some other membrane proteins, including CD49d, CD56, and CD138.

Conclusions: Daratumumab rapidly reduced CD38 expression levels, at least in part, through trogocytosis. Importantly, all these effects also occurred in patients with deep and durable responses, thus excluding CD38 reduction alone as a mechanism of daratumumab resistance.

The trials were registered at http://ift.tt/PmpYKN as NCT00574288 (GEN501) and NCT1615029 (GEN503). Clin Cancer Res; 23(24); 7498–511. ©2017 AACR.

http://ift.tt/2kw07n9

Mutational Analysis of Gene Fusions Predicts Novel MHC Class I-Restricted T-Cell Epitopes and Immune Signatures in a Subset of Prostate Cancer

Purpose: Gene fusions are frequently found in prostate cancer and may result in the formation of unique chimeric amino acid sequences (CASQ) that span the breakpoint of two fused gene products. This study evaluated the potential for fusion-derived CASQs to be a source of tumor neoepitopes, and determined their relationship to patterns of immune signatures in prostate cancer patients.

Experimental Design: A computational strategy was used to identify CASQs and their corresponding predicted MHC class I epitopes using RNA-Seq data from The Cancer Genome Atlas of prostate tumors. In vitro peptide-specific T-cell expansion was performed to identify CASQ-reactive T cells. A multivariate analysis was used to relate patterns of in silico–predicted tumor-infiltrating immune cells with prostate tumors harboring these mutational events.

Results: Eighty-seven percent of tumors contained gene fusions with a mean of 12 per tumor. In total, 41% of fusion-positive tumors were found to encode CASQs. Within these tumors, 87% gave rise to predicted MHC class I–binding epitopes. This observation was more prominent when patients were stratified into low- and intermediate/high-risk categories. One of the identified CASQ from the recurrent TMPRSS2:ERG type VI fusion contained several high-affinity HLA-restricted epitopes. These peptides bound HLA-A*02:01 in vitro and were recognized by CD8⁺ T cells. Finally, the presence of fusions and CASQs were associated with expression of immune cell infiltration.

Conclusions: Mutanome analysis of gene fusion-derived CASQs can give rise to patient-specific predicted neoepitopes. Moreover, these fusions predicted patterns of immune cell infiltration within a subgroup of prostate cancer patients. Clin Cancer Res; 23(24); 7596–607. ©2017 AACR.

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Gene Expression Signatures and Immunohistochemical Subtypes Add Prognostic Value to Each Other in Breast Cancer Cohorts

Purpose: Gene signatures and Ki67 stratify the same breast tumor into opposing good/poor prognosis groups in approximately 20% of patients. Given this discrepancy, we hypothesized that the combination of a clinically relevant signature and IHC markers may provide more prognostic information than either classifier alone.

Experimental Design: We assessed Ki67 alone or combined with ER, PR and HER2 (forming IHC subtypes), and the research versions of the Genomic Grade Index, 70-gene, cell-cycle score, recurrence score (RS), and PAM50 signatures on matching TMA/whole tumor sections and microarray data in two Swedish breast cancer cohorts of 379 and 209 patients, with median follow-up of 12.4 and 12.5 years, respectively. First, we fit Cox proportional hazards models and used the change in likelihood ratio ( LR) to determine the additional prognostic information provided by signatures beyond that of (i) Ki67 and (ii) IHC subtypes. Second and uniquely, we then assessed whether signatures could compete well with pathology-based IHC classifiers by calculating the additional prognostic information of Ki67/IHC subtypes beyond signatures.

Results: In cohort 1, only RS and PAM50 provided additional prognostic information beyond Ki67 and IHC subtypes ( LR-² Ki67: RS = 12.8, PAM50 = 20.7, IHC subtypes: RS = 12.9, PAM50 = 11.7). Conversely, IHC subtypes added prognostic information beyond all signatures except PAM50. Similar results were observed in cohort 2.

Conclusions: RS and PAM50 provided more prognostic information than the IHC subtypes in all breast cancer patients; however, the IHC subtypes did not add any prognostic information to PAM50. Clin Cancer Res; 23(24); 7512–20. ©2017 AACR.

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Common TDP1 Polymorphisms in Relation to Survival among Small Cell Lung Cancer Patients: A Multicenter Study from the International Lung Cancer Consortium

Purpose: DNA topoisomerase inhibitors are commonly used for treating small-cell lung cancer (SCLC). Tyrosyl-DNA phosphodiesterase (TDP1) repairs DNA damage caused by this class of drugs and may therefore influence treatment outcome. In this study, we investigated whether common TDP1 single-nucleotide polymorphisms (SNP) are associated with overall survival among SCLC patients.

Experimental Design: Two TDP1 SNPs (rs942190 and rs2401863) were analyzed in 890 patients from 10 studies in the International Lung Cancer Consortium (ILCCO). The Kaplan–Meier method and Cox regression analyses were used to evaluate genotype associations with overall mortality at 36 months postdiagnosis, adjusting for age, sex, race, and tumor stage.

Results: Patients homozygous for the minor allele (GG) of rs942190 had poorer survival compared with those carrying AA alleles, with a HR of 1.36 [95% confidence interval (CI): 1.08–1.72, P = 0.01), but no association with survival was observed for patients carrying the AG genotype (HR = 1.04, 95% CI, 0.84–1.29, P = 0.72). For rs2401863, patients homozygous for the minor allele (CC) tended to have better survival than patients carrying AA alleles (HR = 0.79; 95% CI, 0.61–1.02, P = 0.07). Results from the Genotype Tissue Expression (GTEx) Project, the Encyclopedia of DNA Elements (ENCODE), and the ePOSSUM web application support the potential function of rs942190.

Conclusions: We found the rs942190 GG genotype to be associated with relatively poor survival among SCLC patients. Further investigation is needed to confirm the result and to determine whether this genotype may be a predictive marker for treatment efficacy of DNA topoisomerase inhibitors. Clin Cancer Res; 23(24); 7550–7. ©2017 AACR.

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CAR T Therapy Targeting ICAM-1 Eliminates Advanced Human Thyroid Tumors

Purpose: Poorly differentiated thyroid cancer and anaplastic thyroid cancer (ATC) are rare yet lethal malignancies with limited treatment options. Many malignant tumors, including papillary thyroid cancer (PTC) and ATC, are associated with increased expression of ICAM-1, providing a rationale for utilizing ICAM-1–targeting agents for the treatment of aggressive cancer. We developed a third-generation chimeric antigen receptor (CAR) targeting ICAM-1 to leverage adoptive T-cell therapy as a new treatment modality.

Experimental Design: ICAM-1 CAR T cells were applied to multiple malignant and nonmalignant target cells to investigate specific target cell death and "off-tumor" toxicity in vitro. In vivo therapeutic efficacy of ICAM-1 CAR T cells was examined in ATC mouse models established from a cell line and patient-derived tumors that rapidly develop systemic metastases.

Results: ICAM-1 CAR T cells demonstrated robust and specific killing of PTC and ATC cell lines in vitro. Interestingly, although certain ATC cell lines showed heterogeneous levels of ICAM-1 expression, addition of cytotoxic CAR T cells induced increased ICAM-1 expression such that all cell lines became targetable. In mice with systemic ATC, a single administration of ICAM-1 CAR T cells mediated profound tumor killing that resulted in long-term remission and significantly improved survival. Patient-derived ATC cells overexpressed ICAM-1 and were largely eliminated by autologous ICAM-1 CAR T cells in vitro and in animal models.

Conclusions: Our findings are the first demonstration of CAR T therapy against both a metastatic, thyroid cancer cell line and advanced ATC patient-derived tumors that exhibit dramatic therapeutic efficacy and survival benefit in animal studies. Clin Cancer Res; 23(24); 7569–83. ©2017 AACR.

http://ift.tt/2jVUtLH

Cocaine-induced pseudo-Wellens syndrome: a Wellens phenocopy

Wellens' syndrome represents critical occlusion of the proximal left anterior descending coronary artery. Electrocardiographic changes similar to Wellens' wave are not exceptional to acute coronary occlusion and can also be seen in cardiac and non-cardiac conditions, such as left ventricular hypertrophy, persistent juvenile T wave, bundle branch blocks, cerebral haemorrhage, pulmonary oedema, pulmonary embolism, pheochromocytoma, Takotsubo syndrome, digitalis and cocaine-induced coronary vasospasm. Cocaine-induced pseudo-Wellens' syndrome should be considered as one of the differentials, since cocaine is used frequently by young adults and can cause left anterior descending coronary vasospasm mimicking Wellens' syndrome. Initiation of the beta-blocking agent in pseudo-Wellens' syndrome as a part of acute coronary syndrome management can be disastrous. We illustrated a case of cocaine-induced pseudo-Wellens' syndrome presented with typical chest pain associated with Wellenoid ECG.

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Iatrogenic propagation of coronary dissection during diagnostic coronary angiography: an uncommon but important procedural consideration

Spontaneous coronary artery dissection is an uncommon cause of acute myocardial infarction in the general population but is relatively more common in the peripartum period. Regardless of clinical setting, the management strategy is individualised, ranging from conservative to invasive. We report a case of peripartum myocardial infarction due to spontaneous coronary dissection that propagated during diagnostic angiography and ultimately required emergent bypass surgery.

http://ift.tt/2B36k23

Congenital scoliosis: an anomalous association with endosulfan

Endosulfan is an organochlorine pesticide that is used extensively across the world to kill insects. Incidence of acute and chronic toxicity with endosulfan poisoning has been reported, and nearly 80 countries have banned its use. However, it is still being used in many low-income/middle-income countries. One of the most severe tragedies because of endosulfan poisoning has taken place in the Indian state of Kerala due to persistent aerial spraying of endosulfan. Even though there are reports of skeletal and other congenital abnormalities in humans and experimental animals following exposure to endosulfan, very few have been documented. We report two cases of congenital scoliosis in siblings living in a community affected by high levels of endosulfan in the environment. High index of suspicion is essential during the screening of school children exposed to endosulfan. Congenital scoliosis is a progressive deformity that leads to severe disability, unless detected and corrected at an early stage.

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Stent extrusion on the external surface of the transplanted kidney: unusual occurrence

Here we present the case of a 40-year-old man, who underwent deceased donor renal transplantation. Towards the end of this operation, open-ended double J stent was inserted in the transplanted kidney. Modified Lich–Gregoir ureterovesical anastomosis was performed. Prior to the abdominal closure, it was discovered that proximal end of the stent had pierced the renal parenchyma and extruded on the external surface of the transplanted kidney. We contemplated removing the stent and reinserting it but decided against that due to various reasons. The stent was left as such. The patient was managed conservatively with satisfactory outcome in the postoperative period. To the best of our knowledge, this is first such report of conservative management of stent extrusion in transplanted kidney in the literature.

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Periosteal desmoid tumour: a rare finding in the oral cavity

A 55-year-old female patient reported with an intraoral well-localised asymptomatic swelling on the right side of the mandible in relation to the right mandibular first molar along with a history of trauma 6 months back. Panoramic radiograph revealed normal trabecular bone pattern in relation to the lesion. The lesion was excised along with the associated buccal cortical plate and tooth. The microscopic examination revealed a well-circumscribed lesion consisting of spindle cells arranged in storiform pattern associated with the buccal cortical plate. The key feature to note was presence of reactive periosteum, which was in continuum with the lesion. Immunohistochemistry (IHC) revealed faint nuclear positivity for β-catenin. The above findings led to our diagnosis of periosteal desmoid, which is rarely reported in the head-and-neck region. The major challenge in the diagnosis of such lesions is good clinicopathological correlation as the differential diagnosis of spindle-cell lesions is vast and needs IHC confirmation.

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Left ventricular pseudoaneurysm formation in a patient presenting with a subacute myocardial infarction

Left ventricular pseudoaneurysm is a rare mechanical complication of acute myocardial infarction. In the present case, an 80-year-old man presenting with a subacute non-ST segment elevation myocardial infarction was found to have an occluded second obtuse marginal branch of the left circumflex coronary artery. Following the implantation of two drug-eluting stents, the patient developed no-reflow phenomenon. Coronary angiography 6 weeks later revealed persistence of the no-reflow phenomenon. During the left ventriculogram, a massive pseudoaneurysm was diagnosed and the patient successfully underwent emergency surgery. The persistence of no-reflow was likely due to the fact that the myocardial territory supplied by the infarct-related artery was completely necrosed resulting in persistent flow impairment through the vessel.

http://ift.tt/2B35Fh3

Pneumatosis intestinalis with extensive intrahepatic portal venous gas secondary to intra-abdominal sepsis: a rare occurrence

Description

A 32-year-old man presented with a 3-day history of abdominal pain, vomiting and diarrhoea. He was afebrile and haemodynamically stable (saturating at 97% on air with a respiratory rate of 15, his blood pressure was 117/65 with a heart rate of 78 bpm). Clinical examination revealed right iliac fossa tenderness with localised guarding. His inflammatory markers were raised (white cell count 21 x10⁹/L , neutrophils 16 and C-reactive protein 26). He was diagnosed with acute appendicitis and had an emergency open appendectomy. The operative findings were a periappendicular mass with a necrotic tip of appendix and pus within the abdomen.

Unfortunately he had a complex postoperative course. He developed paralytic ileus by day 3 and was managed conservatively via insertion of a nasogastric tube, rehydration with intravenous fluid and correction of his electrolyte imbalance. By day 6 he became febrile (39°), increasingly short of breath with a grossly distended non-tender...

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Sarcoidosis-lymphoma syndrome: a diagnostic dilemma

Sarcoidosis and lymphoma are generally thought of as being two mutually exclusive diseases that need to be considered in the differential diagnosis of patients with hilar/mediastianal lymphadenopathy. However, there are rare patients in whom both of these diseases coexist. These patients constitute a diagnostic challenge because their presentation (ie, clinical symptoms, imaging abnormalities and even pathology) may all be atypical when each individual disease is considered separately. In this report, we describe a patient who presented with such atypical features and was eventually diagnosed as having both sarcoidosis and a B-cell lymphoma with features of splenic marginal zone lymphoma (SMZL) simultaneously. To our knowledge, this is only the second reported case of SMZL and sarcoidosis in the same patient.

http://ift.tt/2Ca6wM9

[18F]fluorothymidine PET Informs the Synergistic Efficacy of Capecitabine and Trifluridine/Tipiracil in Colon Cancer

In cancer therapy, enhanced thymidine uptake by the salvage pathway can bypass dTMP depletion, thereby conferring resistance to thymidylate synthase inhibition. We investigated whether sequential combination therapy of capecitabine and trifluridine/tipiracil (TAS-102) could synergistically enhance antitumor efficacy in colon cancer xenograft models. We also examined 3'-deoxy-3′-[18F]fluorothymidine ([18F]FLT) PET as a means to predict therapeutic response to a sequential combination of capecitabine and trifluridine/tipiracil. [3H]FLT uptake after 5-fluorouracil treatment in vitro and [18F]FLT uptake after capecitabine (360 mg/kg/day) in athymic nude mice (Balb/c-nu) with xenografts (n = 10–12 per group) were measured using eight human colon cancer cell lines. We determined the synergistic effects of sequential combinations of 5-fluorouracil and trifluridine in vitro as well as the sequential combination of oral capecitabine (30–360 mg/kg) and trifluridine/tipiracil (trifluridine 75 or 150 mg/kg with tipiracil) in six xenograft models (n = 6–10 per group). We observed significant increases in [3H]FLT uptake in all cell lines and [18F]FLT uptake in five xenograft models after 5-fluorouracil and capecitabine treatment, respectively. Increased [18F]FLT uptake after capecitabine followed by extinction of uptake correlated strongly with tumor growth inhibition (ρ = −0.81, P = 0.02). The effects of these combinations were synergistic in vitro. A synergy for sequential capecitabine and trifluridine/tipiracil was found only in mouse xenograft models showing increased [18F]FLT uptake after capecitabine. Our results suggest that the sequential combination of capecitabine and trifluridine/tipiracil is synergistic in tumors with an activated salvage pathway after capecitabine treatment in mice, and [18F]FLT PET imaging may predict the response to capecitabine and the synergistic antitumor efficacy of a sequential combination of capecitabine and trifluridine/tipiracil. Cancer Res; 77(24); 7120–30. ©2017 AACR.

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Acknowledgment to Reviewers

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Correction: JARID1B Enables Transit between Distinct States of the Stem-like Cell Population in Oral Cancers

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A Systems Approach to Prostate Cancer Classification—Letter

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Distinct Angiogenic Changes during Carcinogenesis Defined by Novel Label-Free Dark-Field Imaging in a Hamster Cheek Pouch Model

There remain gaps in knowledge concerning how vascular morphology evolves during carcinogenesis. In this study, we imaged neovascularization by label-free dark-field microscopy of a 7,12-Dimethylbenz[a]anthracene (DMBA)-induced hamster cheek pouch model of oral squamous cell carcinoma (SCC). Wavelength-dependent imaging revealed distinct vascular features at different imaging depths and vessel sizes. Vascular tortuosity increased significantly in high-risk lesions, whereas diameter decreased significantly in hyperplastic and SCC lesions. Large vessels preserved the same trends seen in the original images, whereas small vessels displayed different trends, with length and diameter increasing during carcinogenesis. On the basis of these data, we developed and validated a classification algorithm incorporating vascular features from different vessel masks. Receiver operator curves generated from the classification results demonstrated high accuracies in discriminating normal and hyperplasia from high-grade lesions (AUC > 0.94). Overall, these results provided automated imaging of vasculature in the earliest stages of carcinogenesis from which one can extract robust endpoints. The optical toolbox described here is simple, low-cost and portable, and can be used in a variety of health care and research settings for cancer prevention and pharmacology research. Cancer Res; 77(24); 7109–19. ©2017 AACR.

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TLR4-Mediated Inflammation Promotes KSHV-Induced Cellular Transformation and Tumorigenesis by Activating the STAT3 Pathway

Toll-like receptors (TLR) are conserved immune sensors mediating antimicrobial and antitumoral responses, but recent evidence implicates them in promoting carcinogenesis in certain cancers. Kaposi sarcoma is caused by infection of Kaposi sarcoma–associated herpesvirus (KSHV) and is characterized by uncontrolled neoangiogenesis and inflammation. Here, we show that TLR4 is upregulated in KSHV-infected spindle tumor cells in human Kaposi sarcoma lesions. In a model of KSHV-induced cellular transformation, KSHV upregulated expression of TLR4, its adaptor MyD88, and coreceptors CD14 and MD2. KSHV induction of TLR4 was mediated by multiple viral miRNAs. Importantly, the TLR4 pathway was activated constitutively in KSHV-transformed cells, resulting in chronic induction of IL6, IL1β, and IL18. Accordingly, IL6 mediated constitutive activation of the STAT3 pathway, an essential event for uncontrolled cellular proliferation and transformation. TLR4 stimulation with lipopolysaccharides or live bacteria enhanced tumorigenesis while TLR4 antagonist CLI095 inhibited it. These results highlight an essential role of the TLR4 pathway and chronic inflammation in KSHV-induced tumorigenesis, which helps explain why HIV-infected patients, who frequently suffer from opportunistic bacterial infections and metabolic complications, frequently develop Kaposi sarcoma. Cancer Res; 77(24); 7094–108. ©2017 AACR.

http://ift.tt/2B4r3lK

Emergence of High-Avidity Melan-A-Specific Clonotypes as a Reflection of Anti-PD-1 Clinical Efficacy

Therapeutic strategies using anti–PD-1–blocking antibodies reported unparalleled effectiveness for melanoma immunotherapy, but deciphering immune responses modulated by anti–PD-1 treatment remains a crucial issue. Here, we analyzed the composition and functions of the large Melan-A–specific T-cell repertoire in the peripheral blood of 9 melanoma patients before and after 2 months of treatment with anti–PD-1. We observed amplification of Melan-A–specific Vß subfamilies undetectable before therapy (thereafter called emerging Vß subfamilies) in responding patients, with a predominant expansion in patients with a complete response. These emerging Vß subfamilies displayed a higher functional avidity for their cognate antigen than Vß subfamilies not amplified upon anti–PD-1 therapy and could be identified by a sustained coexpression of PD-1 and TIGIT receptors. Thus, in addition to the emergence of neoantigen-specific T cells previously documented upon anti–PD-1 therapy, our work describes the emergence of high-avidity Melan-A–specific clonotypes as a surrogate marker of treatment efficacy. Cancer Res; 77(24); 7083–93. ©2017 AACR.

http://ift.tt/2C9Qyl2

Paxillin Binding to the Cytoplasmic Domain of CD103 Promotes Cell Adhesion and Effector Functions for CD8+ Resident Memory T Cells in Tumors

CD8+/CD103+ tissue-resident memory T cells (TRM cells) accumulate in several human solid tumors, where they have been associated with a favorable prognosis. However, the role of CD103, the α subunit of the integrin αEβ7 (also known as CD103), in the retention and functions of these TRM is undefined. In this report, we investigated the role of CD103 cytoplasmic domain and the focal adhesion-associated protein paxillin (Pxn) in downstream signaling and functional activities triggered through αE/CD103 chain. Binding to immobilized recombinant (r)E-cadherin-Fc of CD103 integrin expressed on tumor-specific CTL clones promotes phosphorylation of Pxn and Pyk2 and binding of Pxn to the αE/CD103 subunit tail. Inhibition of Pxn phosphorylation by the Src inhibitor saracatinib or its knockdown via shRNA dramatically altered adhesion and spreading of freshly isolated CD8+/CD103+ lung tumor–infiltrating lymphocytes and CD103+ tumor-specific CTL clones. Inhibition of Pxn phosphorylation with saracatinib in these CTL clones also severely compromised their functional activities toward autologous tumor cells. Using Jurkat T cells as a model to study CD103 integrin activation, we demonstrated a key role of serine residue S1163 of the αE chain intracellular domain in polarization of CD103 and recruitment of lysosomes and Pxn at the contact zone of T lymphocytes with rE-cadherin-Fc–coated beads. Overall, our results show how Pxn binding to the CD103 cytoplasmic tail triggers αEβ7 integrin outside-in signaling that promotes CD8+ T-cell migratory behavior and effector functions. These results also explain the more favorable prognosis associated with retention of TRM cells in the tumor microenvironment. Cancer Res; 77(24); 7072–82. ©2017 AACR.

http://ift.tt/2B3uclY

Subtype-Specific Tumor-Associated Fibroblasts Contribute to the Pathogenesis of Uterine Leiomyoma

Recent genomic studies have identified subtypes of uterine leiomyoma (LM) with distinctive genetic alterations. Here, we report the elucidation of the biological characteristics of the two most prevalent uterine leiomyoma subtypes, MED12-mutant (MED12-LM) and HMGA2-overexpressing (HMGA2-LM) uterine leiomyomas. Because each tumor carries only one genetic alteration, both subtypes are considered to be monoclonal. Approximately 90% of cells in HMGA2-uterine leiomyoma were smooth muscle cells (SMC) with HMGA2 overexpression. In contrast, MED12-LM consisted of similar numbers of SMC and non-SMC, which were mostly tumor-associated fibroblasts (TAF). Paradoxically, TAF carried no mutations in MED12, suggesting an interaction between SMC and TAF to coordinate their growth. The higher amount of extracellular matrix in MED12-LM than HMGA2-LM was partially due to the high concentration of collagen-producing TAF. SMC growth in a xenograft assay was driven by progesterone in both uterine leiomyoma subtypes. In contrast, TAF in MED12-LM proliferated in response to estradiol, whereas progesterone had no effect. The high concentration of estrogen-responsive TAF in MED12-LM explains the inconsistent discoveries between in vivo and in vitro studies on the mitogenic effect of estrogen and raises questions regarding the accuracy of previous studies utilizing MED12-LM cell culture. In addition, the differential effects of estradiol and progesterone on these uterine leiomyoma subtypes emphasize the importance of subtypes and genotypes in designing nonsurgical therapeutic strategies for uterine leiomyoma. Cancer Res; 77(24); 6891–901. ©2017 AACR.

http://ift.tt/2CaaYdO

Cathepsin B Is Dispensable for Cellular Processing of Cathepsin B-Cleavable Antibody-Drug Conȷugates

Antibody–drug conjugates (ADC) are designed to selectively bind to tumor antigens via the antibody and release their cytotoxic payload upon internalization. Controllable payload release through judicious design of the linker has been an early technological milestone. Here, we examine the effect of the protease-cleavable valine-citrulline [VC(S)] linker on ADC efficacy. The VC(S) linker was designed to be cleaved by cathepsin B, a lysosomal cysteine protease. Surprisingly, suppression of cathepsin B expression via CRISPR-Cas9 gene deletion or shRNA knockdown had no effect on the efficacy of ADCs with VC(S) linkers armed with a monomethyl auristatin E (MMAE) payload. Mass spectrometry studies of payload release suggested that other cysteine cathepsins can cleave the VC(S) linker. Also, ADCs with a nonprotease-cleavable enantiomer, the VC(R) isomer, mediated effective cell killing with a cysteine-VC(R)-MMAE catabolite generated by lysosomal catabolism. Based on these observations, we altered the payload to a pyrrolo[2,1-c][1,4]benzodiazepine dimer (PBD) conjugate that requires linker cleavage in order to bind its DNA target. Unlike the VC-MMAE ADCs, the VC(S)-PBD ADC is at least 20-fold more cytotoxic than the VC(R)-PBD ADC. Our findings reveal that the VC(S) linker has multiple paths to produce active catabolites and that antibody and intracellular targets are more critical to ADC efficacy. These results suggest that protease-cleavable linkers are unlikely to increase the therapeutic index of ADCs and that resistance based on linker processing is improbable. Cancer Res; 77(24); 7027–37. ©2017 AACR.

http://ift.tt/2B2ZjhJ

miR-6883 Family miRNAs Target CDK4/6 to Induce G1 Phase Cell-Cycle Arrest in Colon Cancer Cells

CDK4/6 targeting is a promising therapeutic strategy under development for various tumor types. In this study, we used computational methods and The Cancer Genome Atlas dataset analysis to identify novel miRNAs that target CDK4/6 and exhibit potential for therapeutic development in colorectal cancer. The 3′UTR of CDK4/6 mRNAs are targeted by a family of miRNAs, which includes miR-6883-5p, miR-149*, miR-6785-5p, and miR-4728-5p. Ectopic expression of miR-6883-5p or miR-149* downregulated CDK4 and CDK6 levels in human colorectal cancer cells. RNA-seq analysis revealed an inverse relationship between the expression of CDK4/6 and miR-149* and intronic miRNA-6883-5p encoding the clock gene PER1 in colorectal cancer patient samples. Restoring expression of miR-6883-5p and miR-149* blocked cell growth leading to G0–G1 phase cell-cycle arrest and apoptosis in colorectal cancer cells. CDK4/6 targeting by miR-6883-5p and miR-149* could only partially explain the observed antiproliferative effects. Notably, both miRNAs synergized with the frontline colorectal cancer chemotherapy drug irinotecan. Further, they resensitized mutant p53-expressing cell lines resistant to 5-fluorouracil. Taken together, our results established the foundations of a candidate miRNA-based theranostic strategy to improve colorectal cancer management. Cancer Res; 77(24); 6902–13. ©2017 AACR.

http://ift.tt/2CaaWCI

Protein Acyltransferase DHHC3 Regulates Breast Tumor Growth, Oxidative Stress, and Senescence

DHHC-type protein acyltransferases may regulate the localization, stability, and/or activity of their substrates. In this study, we show that the protein palmitoyltransferase DHHC3 is upregulated in malignant and metastatic human breast cancer. Elevated expression of DHHC3 correlated with diminished patient survival in breast cancer and six other human cancer types. ZDHHC3 ablation in human MDA-MB-231 mammary tumor cell xenografts reduced the sizes of both the primary tumor and metastatic lung colonies. Gene array data and fluorescence dye assays documented increased oxidative stress and senescence in ZDHHC3-ablated cells. ZDHHC3-ablated tumors also showed enhanced recruitment of innate immune cells (antitumor macrophages, natural killer cells) associated with clearance of senescent tumors. These antitumor effects were reversed upon reconstitution with wild-type, but not enzyme-active site-deficient DHHC3. Concomitant ablation of the upregulated oxidative stress protein TXNIP substantially negated the effects of ZDHHC3 depletion on oxidative stress and senescence. Diminished DHHC3-dependent palmitoylation of ERGIC3 protein likely played a key role in TXNIP upregulation. In conclusion, DHHC3-mediated protein palmitoylation supports breast tumor growth by modulating cellular oxidative stress and senescence. Cancer Res; 77(24); 6880–90. ©2017 AACR.

http://ift.tt/2CaaPXO

A Synthetic CD8{alpha}:MyD88 Coreceptor Enhances CD8+ T-cell Responses to Weakly Immunogenic and Lowly Expressed Tumor Antigens

T cell–based immunotherapies are a promising approach for patients with advanced cancers. However, various obstacles limit T-cell efficacy, including suboptimal T-cell receptor (TCR) activation and an immunosuppressive tumor environment. Here, we developed a fusion protein by linking CD8α and MyD88 (CD8α:MyD88) to enhance CD8+ T-cell responses to weakly immunogenic and poorly expressed tumor antigens. CD8α:MyD88–engineered T cells exhibited increased proliferation and expression of effector and costimulatory molecules in a tumor antigen–dependent manner. These effects were accompanied by elevated activation of TCR and Toll-like receptor signaling-related proteins. CD8α:MyD88–expressing T cells improved antitumor responses in mice. Enhanced antitumor activity was associated with a unique tumor cytokine/chemokine signature, improved T-cell infiltration, reduced markers of T-cell exhaustion, elevated levels of proteins associated with antigen presentation, and fewer macrophages with an immunosuppressive phenotype in tumors. Given these observations, CD8α:MyD88 represents a unique and versatile approach to help overcome immunosuppression and enhance T-cell responses to tumor antigens. Cancer Res; 77(24); 7049–58. ©2017 AACR.

http://ift.tt/2B4oGiQ

SGK1 Is a Critical Component of an AKT-Independent Pathway Essential for PI3K-Mediated Tumor Development and Maintenance

Activation of the PI3K–AKT signaling cascade is a common critical event during malignant transformation. In this study, we used thyroid gland epithelial cells and a series of genetically engineered mouse strains as model systems to demonstrate that, although necessary, AKT activation is not sufficient for PI3K-driven transformation. Instead, transformation requires the activity of the PDK1-regulated AGC family of protein kinases. In particular, SGK1 was found to be essential for proliferation and survival of thyroid cancer cells harboring PI3K-activating mutations. Notably, cotargeting SGK1 and AKT resulted in significantly higher growth suppression than inhibiting either PI3K or AKT alone. Overall, these findings underscore the clinical relevance of AKT-independent pathways in tumors driven by genetic lesions targeting the PI3K cascade. Cancer Res; 77(24); 6914–26. ©2017 AACR.

http://ift.tt/2C9YenD

NF{kappa}B Promotes Ovarian Tumorigenesis via Classical Pathways That Support Proliferative Cancer Cells and Alternative Pathways That Support ALDH+ Cancer Stem-like Cells

Understanding the mechanisms supporting tumor-initiating cells (TIC) is vital to combat advanced-stage recurrent cancers. Here, we show that in advanced ovarian cancers NFκB signaling via the RelB transcription factor supports TIC populations by directly regulating the cancer stem-like associated enzyme aldehyde dehydrogenase (ALDH). Loss of RelB significantly inhibited spheroid formation, ALDH expression and activity, chemoresistance, and tumorigenesis in subcutaneous and intrabursal mouse xenograft models of human ovarian cancer. RelB also affected expression of the ALDH gene ALDH1A2. Interestingly, classical NFκB signaling through the RelA transcription factor was equally important for tumorigenesis in the intrabursal model, but had no effect on ALDH. In this case, classical signaling via RelA was essential for proliferating cells, whereas the alternative signaling pathway was not. Our results show how NFκB sustains diverse cancer phenotypes via distinct classical and alternative signaling pathways, with implications for improved understanding of disease recurrence and therapeutic response. Cancer Res; 77(24); 6927–40. ©2017 AACR.

http://ift.tt/2B42GF3

Genomic Activation of PPARG Reveals a Candidate Therapeutic Axis in Bladder Cancer

The PPARG gene encoding the nuclear receptor PPARγ is activated in bladder cancer, either directly by gene amplification or mutation, or indirectly by mutation of the RXRA gene, which encodes the heterodimeric partner of PPARγ. Here, we show that activating alterations of PPARG or RXRA lead to a specific gene expression signature in bladder cancers. Reducing PPARG activity, whether by pharmacologic inhibition or genetic ablation, inhibited proliferation of PPARG-activated bladder cancer cells. Our results offer a preclinical proof of concept for PPARG as a candidate therapeutic target in bladder cancer. Cancer Res; 77(24); 6987–98. ©2017 AACR.

http://ift.tt/2C9YcMx

Mitochondrial Haplotype Alters Mammary Cancer Tumorigenicity and Metastasis in an Oncogenic Driver-Dependent Manner

Using a novel mouse model, a mitochondrial-nuclear exchange model termed MNX, we tested the hypothesis that inherited mitochondrial haplotypes alter primary tumor latency and metastatic efficiency. Male FVB/N-Tg(MMTVneu)202Mul/J (Her2) transgenic mice were bred to female MNX mice having FVB/NJ nuclear DNA with either FVB/NJ, C57BL/6J, or BALB/cJ mtDNA. Pups receiving the C57BL/6J or BALB/cJ mitochondrial genome (i.e., females crossed with Her2 males) showed significantly (P < 0.001) longer tumor latency (262 vs. 293 vs. 225 days), fewer pulmonary metastases (5 vs. 7 vs. 15), and differences in size of lung metastases (1.2 vs. 1.4 vs. 1.0 mm diameter) compared with FVB/NJ mtDNA. Although polyoma virus middle T–driven tumors showed altered primary and metastatic profiles in previous studies, depending upon nuclear and mtDNA haplotype, the magnitude and direction of changes were not the same in the HER2-driven mammary carcinomas. Collectively, these results establish mitochondrial polymorphisms as quantitative trait loci in mammary carcinogenesis, and they implicate distinct interactions between tumor drivers and mitochondria as critical modifiers of tumorigenicity and metastasis. Cancer Res; 77(24); 6941–9. ©2017 AACR.

http://ift.tt/2B2yjyz

ATR Is a Therapeutic Target in Synovial Sarcoma

Synovial sarcoma (SS) is an aggressive soft-tissue malignancy characterized by expression of SS18–SSX fusions, where treatment options are limited. To identify therapeutically actionable genetic dependencies in SS, we performed a series of parallel, high-throughput small interfering RNA (siRNA) screens and compared genetic dependencies in SS tumor cells with those in >130 non–SS tumor cell lines. This approach revealed a reliance of SS tumor cells upon the DNA damage response serine/threonine protein kinase ATR. Clinical ATR inhibitors (ATRi) elicited a synthetic lethal effect in SS tumor cells and impaired growth of SS patient-derived xenografts. Oncogenic SS18–SSX family fusion genes are known to alter the composition of the BAF chromatin–remodeling complex, causing ejection and degradation of wild-type SS18 and the tumor suppressor SMARCB1. Expression of oncogenic SS18–SSX fusion proteins caused profound ATRi sensitivity and a reduction in SS18 and SMARCB1 protein levels, but an SSX18–SSX1 Δ71–78 fusion containing a C-terminal deletion did not. ATRi sensitivity in SS was characterized by an increase in biomarkers of replication fork stress (increased γH2AX, decreased replication fork speed, and increased R-loops), an apoptotic response, and a dependence upon cyclin E expression. Combinations of cisplatin or PARP inhibitors enhanced the antitumor cell effect of ATRi, suggesting that either single-agent ATRi or combination therapy involving ATRi might be further assessed as candidate approaches for SS treatment. Cancer Res; 77(24); 7014–26. ©2017 AACR.

http://ift.tt/2Ca9MqQ

CDH1 promoter methylation in patients with cervical carcinoma: a systematic meta-analysis with trial sequential analysis

Future Oncology, Ahead of Print.


http://ift.tt/2yw4HGV

Protocol for a randomised pilot multiple centre trial of conservative versus liberal oxygenation targets in critically ill children (Oxy-PICU)

Introduction

Optimal targets for systemic oxygenation in paediatric critical illness are unknown. Observational data indicate that high levels of arterial oxygenation are associated with poor outcomes in resuscitation of the newborn and in adult critical illness. Within paediatric intensive care units (PICUs), staff prevent severe hypoxia wherever possible, but beyond this there is no consensus. Practice varies widely with age, diagnosis, treating doctor and local or national guidelines followed, though peripheral blood oxygen saturations (SpO₂) of >95% are often targeted. The overall aim of this pilot study is to determine the feasibility of performing a randomised trial in critically ill children comparing current practice of liberal SpO₂ targets with a more conservative target.

Methods and analysis

Oxy-PICU is a pragmatic, open, pilot randomised controlled trial in infants and children requiring mechanical ventilation and receiving supplemental oxygen for abnormal gas exchange accepted for emergency admission to one of three participating UK PICUs. The study groups will be either a conservative SpO₂ target of 88%–92% (inclusive) or a liberal SpO₂ target of >94%. Infants and children who fulfil all inclusion criteria and none of the exclusion criteria will be randomised 1:1 by a secure web-based system to one of the two groups. Baseline demographics and clinical status will be recorded as well as daily measures of oxygenation and organ support. Discharge outcomes will also be recorded. In addition to observational data, blood and urine samples will be taken to identify biochemical markers of oxidative stress. Outcomes are targeted at assessing study feasibility with a primary outcome of adequate study recruitment (target: 120 participants).

Ethics and dissemination

The trial received Health Research Authority approval on 1 June 2017 (16/SC/0617). Study findings will be disseminated in national and international conferences and peer-reviewed journals.

Trial registration number

NCT03040570.

http://ift.tt/2kw3Q4h

Healthcare resource availability and cardiovascular health in the USA

Objectives

Cardiovascular disease (CVD) remains the leading cause of death in the USA. Reducing the population-level burden of CVD disease will require a better understanding and support of cardiovascular health (CVH) in individuals and entire communities. The objectives for this study were to examine associations between community-level healthcare resources (HCrRes) and CVH in individuals and entire communities.

Setting

This study consisted of a retrospective, cross-sectional study design, using multivariable epidemiological analyses.

Participants

All participants in the 2011 Behavioral Risk Factor Surveillance System (BRFSS) survey were examined for eligibility. CVH, defined using the American Heart Association CVH Index (CVHI), was determined using self-reported responses to 2011 BRFSS questions. Data for determining HCrRes were obtained from the Area Health Resource File. Regression analysis was performed to examine associations between healthcare resources and CVHI in communities (linear regression) and individuals (Poisson regression).

Results

Mean CVHI was 3.3±0.005 and was poorer in the Southeast and Appalachian regions of the USA. Supply of primary care physicians and physician assistants were positively associated with individual and community-level CVHI, while CVD specialist supply was negatively associated with CVHI. Individuals benefiting most from increased supply of primary care providers were: middle aged; female; had non-Hispanic other race/ethnicity; those with household income <$25 000/year; and those in non-urban communities with insurance coverage.

Conclusions

Our results support the importance of primary care provider supply for both individual and community CVHI, though not all sociodemographic groups benefited equally from additional primary care providers. Further research should investigate policies and factors that can effectively increase primary care provider supply and influence where they practice.

http://ift.tt/2kvkNvL

Comparing four service delivery models for adolescent girls and young women through the 'Girl Power study: protocol for a multisite quasi-experimental cohort study

Introduction

In sub-Saharan Africa, adolescent girls and young women (AGYW) face a range of sexual and reproductive health (SRH) challenges. Clinical, behavioural and structural interventions have each reduced these risks and improved health outcomes. However, combinations of these interventions have not been compared with each other or with no intervention at all. The 'Girl Power' study is designed to systematically make these comparisons.

Methods and analysis

Four comparable health facilities in Malawi and South Africa (n=8) were selected and assigned to one of the following models of care: (1) Standard of care: AGYW can receive family planning, HIV testing and counselling (HTC), and sexually transmitted infection (STI) syndromic management in three separate locations with three separate queues with the general population. No youth-friendly spaces, clinical modifications or trainings are offered, (2) Youth-Friendly Health Services (YFHS): AGYW are meant to receive integrated family planning, HTC and STI services in dedicated youth spaces with youth-friendly modifications and providers trained in YFHS, (3) YFHS+behavioural intervention (BI): In addition to YFHS, AGYW can attend 12 monthly theory-driven, facilitator-led, interactive sessions on health, finance and relationships, (4) YFHS+BI+conditional cash transfer (CCT): in addition to YFHS and BI, AGYW receive up to 12 CCTs conditional on monthly BI session attendance.

At each clinic, 250 AGYW 15–24 years old (n=2000 total) will be consented, enrolled and followed for 1 year. Each participant will complete a behavioural survey at enrolment, 6 months and 12 months . All clinical, behavioural and CCT services will be captured. Outcomes of interest include uptake of each package element and reduction in HIV risk behaviours. A qualitative substudy will be conducted.

Ethics/dissemination

This study has received ethical approval from the University of North Carolina Institutional Review Board, the University of Cape Town Human Research Ethics Committee and Malawi's National Health Sciences Research Committee. Study plans, processes and findings will be disseminated to stakeholders, in peer-reviewed journals and at conferences.

http://ift.tt/2kv1zpQ

Study protocol for a randomised controlled trial of Allen Carrs Easyway programme versus Lambeth and Southwark NHS for smoking cessation

Introduction

Smoking is a major cause of ill health and is associated with several diseases including cancer, coronary heart disease and stroke. Many psychological and pharmacological smoking cessation treatments are available and although they are undoubtedly the most cost-effective health interventions available, many people still fail to maintain cessation in the longer term. Recently, National Institute for Health and Care Excellence called for comparative studies to determine the short-term and long-term effectiveness of Allen Carr's Easyway (ACE) method of stopping smoking. This study will compare the efficacy of the ACE programme and a 1–1 counselling service available via the National Health Service.

Methods and analysis

A two-arm, parallel-group, blinded, randomised controlled trial will be conducted with people who smoke tobacco cigarettes, are aged ≥18 years and are motivated to quit. Exclusion criteria comprise self-reported mental health condition, pregnancy or respiratory disease such as chronic obstructive pulmonary disease or emphysema. The primary treatment outcome is smoking cessation 26 weeks after treatment. Participants will be analysed on an intention to treat basis at the point of randomisation. Before being randomised, the research team will not inform participants which two treatments are being compared. Once randomised researchers will be blinded to participant condition, and participants will be blinded to the condition they are not assigned to. Logistic regression will be used to estimate the effectiveness of the treatment condition on smoking cessation at 26 weeks. The following covariates will be included: baseline quit efficacy (at inclusion), age (at inclusion), gender and baseline nicotine dependency.

Ethics and dissemination

Approval was granted by London–Fulham Research Ethics Committee (ref: 16/LO/1657). The study's findings will be published in peer-reviewed journals and disseminated at national and international conferences.

Trial registration number

ClinicalTrials.gov identifier number: NCT02855255. ISRCTN registration number: ISRCTN23584477; Pre-results.

http://ift.tt/2CjmSmp

Protocol of a single group prospective observational study on the diagnostic value of 3T susceptibility weighted MRI of nigrosome-1 in patients with parkinsonian symptoms: the N3iPD study (nigrosomal iron imaging in Parkinsons disease)

Introduction

Parkinson's disease (PD) is the most common movement disorder in the elderly and is characterised clinically by bradykinesia, tremor and rigidity. Diagnosing Parkinson's can be difficult especially in the early stages. High-resolution nigrosome MRI offers promising diagnostic accuracy of patients with established clinical symptoms; however, it is unclear whether this may help to establish the diagnosis in the early stages of PD, when there is diagnostic uncertainty. In this scenario, a single photon emission CT scan using a radioactive dopamine transporter ligand can help to establish the diagnosis, or clinical follow-up may eventually clarify the diagnosis. A non-invasive, cost-effective diagnostic test that could replace this would be desirable. We therefore aim to prospectively test whether nigrosome MRI is as useful as DaTSCAN to establish the correct diagnosis in people with minor or unclear symptoms suspicious for PD.

Methods and analysis

In a prospective study we will recruit 145 patients with unclear symptoms possibly caused by Parkinson's from three movement disorder centres in the UK to take part in the study. We will record the Movement Disorder Society - Unified Parkinson's Disease Rating Scale, and participants will undergo DaTSCAN and high-resolution susceptibility weighted MRI at a field strength of 3T. DaTSCANs will be assessed visually and semiquantitatively; MRI scans will be visually assessed for signal loss in nigrosome-1 by blinded investigators. We will compare how the diagnosis suggested by MRI compares with the diagnosis based on DaTSCAN and will also validate the diagnosis based on the two tests with a clinical examination performed at least 1 year after the initial presentation as a surrogate gold standard diagnostic test.

Ethics and dissemination

The local ethics commission (Health Research Authority East Midlands – Derby Research Ethics Committee) has approved this study (REC ref.: 16/EM/0229). The study is being carried out under the principles of the Declaration of Helsinki (64th, 2013) and Good Clinical Practice standards. We have included a number of 15 research-funded DaTSCAN in the research protocol. This is to compensate for study site-specific National Health Service funding for this investigation in affected patients. We therefore have also obtained approval from the Administration of Radioactive Substances Administration Committee (ARSAC Ref 253/3629/35864). All findings will be presented at relevant scientific meetings and published in peer-reviewed journals, on the study website, and disseminated in lay and social media where appropriate.

Trial registration number

NCT03022357; Pre-results.

http://ift.tt/2kvkMId

Informatics competencies for nurse leaders: protocol for a scoping review

Introduction

Globally, health information technologies are now being used by nurses in a variety of settings. However, nurse leaders often do not have the necessary strategic and tactical informatics competencies to adequately ensure their effective adoption and use. Although informatics competencies and competency frameworks have been identified and developed, to date there has not been review or consolidation of the work completed in this area. In order to address this gap, a scoping review is being conducted. The objectives of this scoping review are to: (1) identify informatics competencies of relevance to nurse leaders, (2) identify frameworks or theories that have been used to develop informatics competencies for nurse leaders, (3) identify instruments used to assess the informatics competencies of nurse leaders and (4) examine the psychometric properties of identified instruments.

Methods

Using the Arksey and O'Malley five-step framework, a literature review will be conducted using a scoping review methodology. The search will encompass academic and grey literature and include two primary databases and five secondary databases. Identified studies and documents will be independently screened for eligibility by two reviewers. Data from the studies and documents will be extracted and compiled into a chart. Qualitative data will be subject to a thematic analysis and descriptive statistics applied to the quantitative data.

Ethics and dissemination

Ethical approval was not required for this study. Results will be used to inform a future study designed to validate an instrument used to evaluate informatics competencies for nurse leaders within a Canadian context.

http://ift.tt/2ktAF1T

Temporal trend in socioeconomic inequalities in the uptake of cancer screening programmes in France between 2005 and 2010: results from the Cancer Barometer surveys

Objectives

Cancer screening is a form of secondary prevention for a disease which is now the leading cause of death in France. Various socioeconomic indicators have been identified as potential factors for disparities in breast, cervical and colorectal cancer screening uptake. We aimed to identify the socioeconomic inequalities, which persisted in screening uptake for these cancers, and to quantify these disparities over a 5-year period.

Setting

The Cancer Barometer was a population-based-survey carried out in 2005 and 2010 in France.

Participants

A randomly selected sample of participants aged 15–85 years (n=3820 in 2005 and n=3727 in 2010) were interviewed on their participation in breast, cervical and colorectal cancer screening-programmes and their socioeconomic profile.

Primary and secondary outcome measures

For each type of screening programme, we calculated participation rates, OR and relative inequality indices (RII) for participation, derived from logistic regression of the following socioeconomic variables: income, education, occupation, employment and health insurance. Changes in participation between 2005 and 2010 were then analysed.

Results

Participation rates for breast and colorectal screening increased significantly among the majority of socioeconomic categories, whereas for cervical cancer screening there were no significant changes between 2005 and 2010. RIIs for income remained significant for cervical smear in 2005 (RII=0.25, 95% CI 0.13 to 0.48) and in 2010 (RII=0.31, 95% CI 0.15 to 0.64). RIIs for education in mammography (RII=0.43, 95% CI 0.19 to 0.98) and cervical smear (RII=0.36, 95% CI 0.21 to 0.64) were significant in 2005 and remained significant for cervical smear (RII=0.40, 95% CI 0.22 to 0.74) in 2010.

Conclusions

There was a persistence of socioeconomic inequalities in the uptake of opportunistic cervical cancer screening. Conversely, organised screening programmes for breast and colorectal cancer saw a reduction in relative socioeconomic inequalities, even though the results were not statistically significant. The findings suggest that organised cancer screening programmes may have the potential to reduce socioeconomic disparities in participation.

http://ift.tt/2CjmJiR

Temporal changes in the documentation of neurological findings among patients with acute ischaemic stroke in a single centre in Japan: a retrospective cross-sectional study

Objective

To evaluate temporal differences in the documentation of neurological findings by the same physicians in patients with ischaemic stroke while in hospital. We also investigated differences in the rate of documentation of neurological findings in patients with stroke between internists and neurosurgeons.

Design

A retrospective medical chart review.

Participants

Hospitalised adult patients with acute ischaemic stroke who stayed 7 or more days in our hospital. Neurosurgeons (n=8) and internists (n=19) caring for these patients (including up to 10 patients per physician).

Main outcome measures

The documentation rate of any neurological finding in the patients on each day (from day 1 to 7 and on discharge). The documentation rates of eight neurological finding components (consciousness, mental status, cranial nerves, motor function, sensory function, coordination, reflexes and gait). We included only documentation by the same physician. Fisher's exact test was used to evaluate differences in outcomes between neurosurgeons and internists.

Results

During the study period, we identified 172 patients with stroke who were cared for by 27 physicians. The documentation rates of any neurological findings were 94% (day 1), 58% (day 2), 35% (day 3), 40% (day 4), 32% (day 5), 30% (day 6) and 23% (day 7). On discharge, all eight neurological finding components were documented in less than 10% of all cases. The documentation rate was significantly higher by internists than that by neurosurgeons on each day but not on discharge.

Conclusions

The documentation rate of neurological findings by physicians during usual stroke care decreased to less than 50% after the third hospital day. Given the importance of temporal changes in the neurological symptoms of patients with stroke, further study is needed to determine whether this low documentation rate after the third hospital day was due to a lack of physician interest in neurological findings or other factors.

http://ift.tt/2ktoD8H

Risk of high-grade lesions after atypical glandular cells in cervical screening: a population-based cohort study

Objectives

To determine how human papillomavirus (HPV) positivity of atypical glandular cells (AGCs) affects the predictive values for the presence of high-grade cervical lesions.

Design

Population-based cohort study.

Setting

Stockholm-Gotland region, Sweden.

Participants

Between 17 February 2014 and 30 June 2016, there were 562 women with AGC detected in a cervical sample. Registry linkages up to 30 June 2016 identified 392 women with an associated HPV test and a histopathological follow-up.

Main outcome measure

Presence of a high-grade cervical lesion in the cervical biopsy taken after the AGC smear, in relation to the HPV status of the AGC-containing index smear.

Results

The proportion of HPV-positive AGC was 56% (n=222). In this group, there were six cases of invasive cervical adenocarcinoma, 33 cases of cervical adenocarcinoma in situ and 93 cases of high-grade squamous intraepithelial lesion (HSIL), giving a positive predictive value (PPV) for a cervical high-grade lesion of 60% (132/222). Among the 170 women with HPV-negative AGC, there was one invasive cervical squamous cell cancer and four HSIL, giving an PPV for a cervical high-grade lesion of 2.9% (5/170). This group also contained five endometrial cancers and one breast cancer.

Conclusions

HPV triaging of AGC will greatly increase the predictive ability for identifying cervical high-grade lesions (OR: 48.4 (95% CI 19.1 to122.6)) and the high sensitivity (96%; 132/137 women) implies safety of primary HPV screening strategies, with regard to this subset of patients. The measurable risk for endometrial cancer among women with HPV-negative AGC (2.9%) suggests that research on screening for endometrial cancer is needed.

http://ift.tt/2ktTjqc

Influence of overstated abstract conclusions on clinicians: a web-based randomised controlled trial

Objectives

To investigate whether overstatements in abstract conclusions influence primary care physicians' evaluations when they read reports of randomised controlled trials (RCTs)

Design

RCT setting: This study was a parallel-group randomised controlled survey, conducted online while masking the study hypothesis.

Participants

Volunteers were recruited from members of the Japan Primary Care Association in January 2017. We sent email invitations to 7040 primary care physicians. Among the 787 individuals who accessed the website, 622 were eligible and automatically randomised into 'without overstatement' (n=307) and 'with overstatement' (n=315) groups.

Interventions

We selected five abstracts from published RCTs with at least one non-significant primary outcome and overstatement in the abstract conclusion. To construct a version without overstatement, we rewrote the conclusion sections. The methods and results sections were standardised to provide the necessary information of primary outcome information when it was missing in the original abstract. Participants were randomly assigned to read an abstract either with or without overstatements and asked to evaluate the benefit of the intervention.

Outcome measures

The primary outcome was the participants' evaluation of the benefit of the intervention discussed in the abstract, on a scale from 0 to 10. A secondary outcome was the validity of the conclusion.

Results

There was no significant difference between the groups with respect to their evaluation of the benefit of the intervention (mean difference: 0.07, 95% CI –0.28 to 0.42, p=0.69). Participants in the 'without' group considered the study conclusion to be more valid than those in the 'with' group (mean difference: 0.97, 95% CI 0.59 to 1.36, P<0.001).

Conclusion

The overstatements in abstract conclusions did not significantly influence the primary care physicians' evaluations of the intervention effect when necessary information about the primary outcomes was distinctly reported.

Trial registration number

UMIN000025317; Pre-results.

http://ift.tt/2ktAFyV

Accuracy of recall of musculoskeletal injuries in elite military personnel: a cross-sectional study

Background

Self-reported data are often used in research studies among military populations.

Objective

The accuracy of self-reported musculoskeletal injury data among elite military personnel was assessed for issues with recall.

Design

Cross-sectional study.

Setting

Applied research laboratory at a military installation.

Participants

A total of 101 subjects participated (age 28.5±5.6 years). Study participants were active duty military personnel, with no conditions that precluded them from full duty.

Primary and secondary outcome measures

Self-reported and medical record reviewed injuries that occurred during a 1-year period were matched by anatomic location, injury side (for extremity injuries), and injury year and type. The accuracy of recall was estimated as the per cent of medical record reviewed injuries correctly recalled in the self-report. The effect of injury anatomic location, injury type and severity and time since injury, on recall, was also assessed. Injuries were classified as recent (≤4 years since injury) or old injuries (>4 years since injury). Recall proportions were compared using Fisher's exact tests.

Results

A total of 374 injuries were extracted from the subjects' medical records. Recall was generally low (12.0%) and was not different between recent and old injuries (P=0.206). Injury location did not affect recall (P=0.418). Recall was higher for traumatic fractures as compared with less severe non-fracture injuries (P values 0.001 to <0.001). Recall for non-fracture injuries was higher for recent as compared with old injuries (P=0.033). This effect of time since injury on recall was not observed for fractures (P=0.522).

Conclusions

The results of this study highlight the importance of weighing the advantages and disadvantages of self-reported injury data before their use in research studies in military populations and the need for future research to identify modifiable factors that influence recall.

http://ift.tt/2CkoigF

Sharing and reuse of individual participant data from clinical trials: principles and recommendations

Objectives

We examined major issues associated with sharing of individual clinical trial data and developed a consensus document on providing access to individual participant data from clinical trials, using a broad interdisciplinary approach.

Design and methods

This was a consensus-building process among the members of a multistakeholder task force, involving a wide range of experts (researchers, patient representatives, methodologists, information technology experts, and representatives from funders, infrastructures and standards development organisations). An independent facilitator supported the process using the nominal group technique. The consensus was reached in a series of three workshops held over 1 year, supported by exchange of documents and teleconferences within focused subgroups when needed. This work was set within the Horizon 2020-funded project CORBEL (Coordinated Research Infrastructures Building Enduring Life-science Services) and coordinated by the European Clinical Research Infrastructure Network. Thus, the focus was on non-commercial trials and the perspective mainly European.

Outcome

We developed principles and practical recommendations on how to share data from clinical trials.

Results

The task force reached consensus on 10 principles and 50 recommendations, representing the fundamental requirements of any framework used for the sharing of clinical trials data. The document covers the following main areas: making data sharing a reality (eg, cultural change, academic incentives, funding), consent for data sharing, protection of trial participants (eg, de-identification), data standards, rights, types and management of access (eg, data request and access models), data management and repositories, discoverability, and metadata.

Conclusions

The adoption of the recommendations in this document would help to promote and support data sharing and reuse among researchers, adequately inform trial participants and protect their rights, and provide effective and efficient systems for preparing, storing and accessing data. The recommendations now need to be implemented and tested in practice. Further work needs to be done to integrate these proposals with those from other geographical areas and other academic domains.

http://ift.tt/2kuXYYQ

Sex differences in non-communicable disease prevalence in China: a cross-sectional analysis of the China Health and Retirement Longitudinal Study in 2011

Objectives

To describe the sex differences in the prevalence of non-communicable diseases (NCDs) in adults aged 45 years or older in China.

Design

Cross-sectional study.

Setting

Nationally representative sample of the Chinese population 2011.

Participants

8401 men and 8928 women over 45 years of age who participated in the first wave of the China Health and Retirement Longitudinal Study (CHARLS).

Outcome measures

Self-reported data on overall health and diagnosis of hypertension, dyslipidaemia, diabetes, heart disease, stroke, chronic lung disease, cancer or arthritis. Sex differences in NCDs were described using logistic regression to generate odds ratios (OR) with adjustment for sociodemographic factors and health-related behaviours. All analyses were stratified by age group for 45–64-year-old and ≥65-year-old participants.

Results

In both age groups, men reported better overall health than women. The crude prevalence of heart disease, cancer and arthritis was higher while that of stroke and chronic lung disease was lower in women than in men. After adjustment, ORs (95% CI) for the 45–64 and ≥65 year age groups were 0.70 (0.58 to 0.84) and 0.66 (0.54 to 0.80), respectively, for arthritis for men compared with women. In contrast, ORs were 1.66 (1.09 to 2.52) and 2.12 (1.36 to 3.30) for stroke and 1.51 (1.21 to 1.89) and 1.43 (1.09 to 1.88) for chronic lung disease for men compared with women. ORs for heart disease (0.65 (0.52 to 0.80)) were lower in men than in women only in the 45–64 year age group.

Conclusions

Odds of arthritis were lower while those of stroke and chronic lung disease were higher in men than in women in both age groups. However, odds of heart disease were lower in men than in women, but only in the group of individuals aged 45–64 years.

http://ift.tt/2kxyaLE

Prospective economic evaluation of an electronic discharge communication tool: analysis of a randomised controlled trial

Objective

To complete an economic evaluation within a randomised controlled trial (RCT) comparing the use of an electronic discharge communication tool (eDCT) compared with usual care.

Setting

Patients being discharged from a single tertiary care centre's internal medicine Medical Teaching Units.

Participants

Between January 2012 and December 2013, 1399 patients were randomised to a discharge mechanism. Forty-five patients were excluded from the economic evaluation as they did not have data for the index hospitalisation cost; 1354 patients contributed to the economic evaluation.

Intervention

eDCT generated at discharge containing structured content on reason for admission, details of the hospital stay, treatments received and follow-up care required. The control group was discharged via traditional dictation methods.

Primary and secondary outcome measures

The primary economic outcome was the cost per quality-adjusted life year (QALY) gained. Secondary outcomes included the cost per death avoided and the cost per readmission avoided.

Results

The average transcription cost was $C22.28 per patient, whereas the estimated cost of the eDCT was $C13.33 per patient. The cost per QALY gained was $C239 933 in the eDCT arm compared with usual care due to the very small gains in effectiveness and approximately $C800difference in resource utilisation costs. The bootstrap analyses resulted in eDCT being more effective and more costly in 29.2% of samples, less costly and more effective in 29.2% of samples, less effective and more costly in 23.9% of samples and finally, less costly and less effective in 17.7% of samples.

Conclusions

The eDCT reduced per patient costs of the generation of discharge summaries. The bootstrap estimates demonstrate considerable uncertainty supporting the finding of neutrality reported in the clinical component of the RCT. The immediate transcription cost savings and previously documented provider and patient satisfaction may increase the impetus for organisations to invest in such systems, provided they have a foundation of eHealth infrastructure and readiness.

Trial registration number

NCT01402609.

http://ift.tt/2kuOwEU

Study protocol for Smartphone Monitoring for Atrial fibrillation in Real-Time in India (SMART-India): a community-based screening and referral programme

Introduction

Atrial fibrillation (AF), the world's most common arrhythmia, often goes undetected and untreated in low-resource communities, including India, where AF epidemiology is undefined. AF is an important risk factor for stroke, which plagues an estimated 1.6 million Indians annually. As such, early detection of AF and management of high-risk patients is critically important to decrease stroke burden in individuals with AF. This study aims to describe the epidemiology of AF in Anand District, Gujarat, India, characterise the clinical profile of individuals who are diagnosed with AF and determine the performance of two mobile technologies for community-based AF screening.

Methods

This observational study builds on findings from a previous feasibility study and leverages two novel technologies as well as an existing community health programme to perform door-to-door AF screening for 2000 people from 60 villages of Anand District, Gujarat, India using local health workers. A single-lead ECG and a pulse-based application is used to screen each individual for AF three times over a period of 5 days. Participants with suspected arrhythmias are followed up by study cardiologist who makes final diagnoses. Participants diagnosed with AF are initiated on treatment based on current anticoagulation guidelines and clinical reasoning.

Analytical plan

Age-stratified and sex-stratified prevalence of AF in the Anand District will be calculated for sample and estimated for Anand distribution using survey design weights. Sociodemographic and clinical factors associated with AF will be evaluated using multivariable regression methods. Performance of each mobile technology in detecting AF will be evaluated using a 12-lead ECG interpretation as the gold standard.

Ethics and dissemination

This protocol was approved separately by the Institutional Review Board of University of Massachusetts Medical School and the Human Research Ethics Committee at Charutar Arogya Mandal. The findings of this study will be disseminated through peer-reviewed journals and scientific conferences.

http://ift.tt/2Cnb0Qr

Protocol for the ROBUST (Registry Of type B aortic dissection with the Utility of STent graft) study: an ambispective, multicentre, open cohort study

Introduction

Thoracic endovascular aortic repair (TEVAR) is widely used for type B aortic dissection, although with satisfactory outcome in a limited proportion of patients. To better inform patient prognostication, the Registry Of type B aortic dissection with the Utility of STent graft (ROBUST) study aims to identify imaging-based predictors of post-TEVAR adverse outcomes up to 10-year follow-up.

Methods and analysis

ROBUST is designed as an ambispective, multicentre, open cohort study. All patients undergoing TEVAR from 1 January 2008 to 1 July 2027 at participating centres will be invited to join the study. It is conservatively estimated that over 2000 patients will join the study. Data on demographics, disease history, procedural details, imaging features and follow-up will be collected after discharge. Cox proportional-hazards analysis will be used to identify independent predictors of primary outcomes. Stratification analysis will be performed to identify which subgroup of patients would benefit the most from TEVAR.

Ethics and dissemination

The protocol has been approved by the ethics committee of the coordinating centre. Findings will be disseminated in professional peer-reviewed journals to promote understanding of the rehabilitation process.

Trial registration number

ChiCTR-POC-17011726; Pre-results.

http://ift.tt/2kvQ1Th

Health inequity on access to services in the ethnic minority regions of Northeastern Myanmar: a cross-sectional study

Objectives

To evaluate health inequity on access to services in the ethnic regions of Northeastern Myanmar from three points of analysis: geographic barrier, gender-based disparity and financial burden of health services.

Setting

A multistage-stratified random cluster survey was conducted in Shan State Special Region 2 and Eastern Shan State Special Region 4 of Northeastern Myanmar in 2016, including a total number of 774 households.

Participants

A total number of 4235 participants were recruited during the survey.

Primary and secondary outcome measures

Geographic distance, gender, household income and inpatient/outpatient service utilisation.

Results

The study results showed that residents living within 5 km of any form of healthcare facilities paid more outpatient visits (90.06 visits per thousand population) in the past 2 weeks, compared with those living 5–20 km and over 20 km (54.84 and 54.02 per thousand population, respectively) from healthcare facilities. A similar trend with little significant differences was found for inpatient service use. Regarding household income, adults with an annual household income of above US$720 were more likely to seek outpatient service (OR=1.43, 95% CI 0.98 to 2.10) compared with those with an annual income of <US$360. After adjusting for other covariates, female adults were less likely to seek inpatient treatment (OR=0.55, 95% CI 0.35 to 0.84) and outpatient services (OR=0.86, 95% CI 0.64 to 1.15) than male adults.

Conclusions

Geographic barrier, gender-based disparity and financial burdens were identified as key causes that significantly restrict ethnic people's access to healthcare facilities. The study concludes that tackling health inequity in Northeastern Myanmar ethnic regions requires an improved primary healthcare system, proper financial protection mechanisms and a special focus on women.

http://ift.tt/2kxgNuO

Cohort profile: the Healthy Life in an Urban Setting (HELIUS) study in Amsterdam, The Netherlands

Purpose

Ethnic minority groups usually have a more unfavourable disease risk profile than the host population. In Europe, ethnic inequalities in health have been observed in relatively small studies, with limited possibilities to explore underlying causes. The aim of the Healthy Life in an Urban Setting (HELIUS) study is to investigate the causes of (the unequal burden of) diseases across ethnic groups, focusing on three disease categories: cardiovascular diseases, mental health and infectious diseases.

Participants

The HELIUS study is a prospective cohort study among six large ethnic groups living in Amsterdam, the Netherlands. Between 2011 and 2015, a total 24 789 participants (aged 18–70 years) were included at baseline. Similar-sized samples of individuals of Dutch, African Surinamese, South-Asian Surinamese, Ghanaian, Turkish and Moroccan origin were included. Participants filled in an extensive questionnaire and underwent a physical examination that included the collection of biological samples (biobank).

Findings to date

Data on physical, behavioural, psychosocial and biological risk factors, and also ethnicity-specific characteristics (eg, culture, migration history, ethnic identity, socioeconomic factors and discrimination) were collected, as were measures of health outcomes (cardiovascular, mental health and infections). The first results have confirmed large inequalities in health between ethnic groups, such as diabetes and depressive symptoms, and also early markers of disease such as arterial wave reflection and chronic kidney disease, which can only just partially be explained by inequalities in traditional risk factors, such as obesity and socioeconomic status. In addition, the first results provided important clues for targeting prevention and healthcare.

Future plans

HELIUS will be used for further research on the underlying causes of ethnic differences in health. Follow-up data will be obtained by repeated measurements and by linkages with existing registries (eg, hospital data, pharmacy data and insurance data).

http://ift.tt/2CmsOel

Colorectal cancer Consensus Molecular Subtypes translated to preclinical models uncover potentially targetable cancer-cell dependencies

Purpose: Response to standard oncological treatment is limited in colorectal cancer (CRC). The gene expression-based consensus molecular subtypes (CMS) provide a new paradigm for stratified treatment and drug repurposing, however, drug discovery is currently limited by the lack of translation of CMS to preclinical models. Experimental Design: We analyzed CMS in primary CRCs, cell lines and patient-derived xenografts (PDXs). For classification of preclinical models, we developed an optimized classifier enriched for cancer cell-intrinsic gene expression signals, and performed high-throughput in vitro drug screening (n=459 drugs) to analyze subtype-specific drug sensitivities. Results: The distinct molecular and clinicopathological characteristics of each CMS group were validated in a single-hospital series of 409 primary CRCs. The new, cancer cell-adapted classifier was found to perform well in primary tumors, and applied to a panel of 148 cell lines and 32 PDXs, these CRC models were shown to recapitulate the biology of the CMS groups. Drug screening of 33 cell lines demonstrated subtype-dependent response profiles, confirming strong response to EGFR and HER2 inhibitors in the CMS2 epithelial/canonical group, and revealing strong sensitivity to HSP90 inhibitors in cells with the CMS1 microsatellite instability/immune and CMS4 mesenchymal phenotypes. This association was validated in vitro in additional CMS-predicted cell lines. Combination treatment with 5-fluorouracil and luminespib showed potential to alleviate chemoresistance in a CMS4 PDX model, an effect not seen in a chemosensitive CMS2 PDX model. Conclusions: We provide translation of CMS classification to preclinical models and uncover a potential for targeted treatment repurposing in the chemoresistant CMS4 group.

http://ift.tt/2C8rbQE

Activation of ankle muscles following rapid displacement of a light touch contact during treadmill walking

Abstract

The first exposure of a rapid displacement of a light touch reference induces an inappropriate balance corrective response during standing in a proportion of participants that is extinguished with repeated exposures. We hypothesized that if the spatial touch reference was critical to performing of a task the evoked response would be more consistently expressed across participants and observed with repeated exposures to the disturbance. To test this, 20 participants received either forward (N = 10) or backward right-touch displacements at right-heel strike during motorized treadmill walking without visual feedback. Electromyographic recordings from four arm, four leg and one neck muscle were sampled along with joint kinematic and step cycle data. Rapid displacement of the touch surface elicited responses in all 20 participants. However, the frequency of first trial responses was not different from what was observed during standing. In contrast, responses were observed in all participants with subsequent trials. None of the participants tripped or stumbled as a result of the touch perturbations; however, the step cycle duration was consistently shorter following the first forward-touch displacement. A post-experiment questionnaire revealed that many participants often perceived the touch plate displacement as a disturbance to the treadmill belt speed, suggesting the disturbance was occasionally misinterpreted. The activation of ankle muscles following the unexpected slip of a touch reference during walking suggests that tactile information from the finger is a relevant sensory cue for the regulation and control of stepping and stability.

http://ift.tt/2AqGUtO

Expressed Gene Fusions as Frequent Drivers of Poor Outcomes in Hormone Receptor Positive Breast Cancer [Research Articles]

We sought to uncover novel genetic drivers of hormone-receptor positive (HR+) breast cancer, employing a targeted next-generation sequencing approach for detecting expressed gene rearrangements without prior knowledge of the fusion partners. We identified intergenic fusions involving driver genes including PIK3CA, AKT3, RAF1 and ESR1 in 14% (24/173) of unselected patients with advanced HR+ breast cancer. Fluorescence in situ hybridization (FISH) confirmed the corresponding chromosomal rearrangements in both primary and metastatic tumors. Expression of novel kinase fusions in non-transformed cells deregulates phosphoprotein signaling, cell proliferation and survival in 3-dimensional culture, while expression in HR+ breast cancer models modulates estrogen-dependent growth and confers hormonal therapy resistance in vitro and in vivo. Strikingly, shorter overall survival was observed in patients with rearrangement-positive versus -negative tumors. Correspondingly, fusions were uncommon (<5%) among 300 patients presenting with primary HR+ breast cancer. Collectively, our findings identify expressed gene fusions as frequent and potentially actionable drivers in HR+ breast cancer.

http://ift.tt/2zdBZON

Prior Cancers Common in Patients Newly Diagnosed with Cancer

A new study shows that many patients diagnosed with a new cancer have had one or more cancers in the past, which has potential implications for long-term surveillance and clinical trial enrollment.

http://ift.tt/2ytBc8J

Exploring the Fear of Birth Scale in a mixed population of women of childbearing age—A Swedish pilot study

Publication date: Available online 14 December 2017
Source:Women and Birth
Author(s): Ingegerd Hildingsson, Christine Rubertsson, Annika Karlström, Helen Haines
AimThe aim of this pilot study was to explore the Fear of Birth Scale in a mixed sample of women of childbearing age, by investigating the levels of childbirth fear and the content of women's thoughts when completing the scale.MethodsA cross-sectional mixed method study of 179 women who completed a short questionnaire and a think aloud interview.ResultsThe mean score of the Fear of Birth Scale was 40.80 (SD 27.59) and 28.5% were classified as having fear of childbirth (≥60). The internal consistency showed a Cronbach's α>0.92, and a mean inter-item correlation of 0.85.The highest scores were found in women younger than 25 years (mean 60.10), foreign-born women (mean 54.30) and women who did not have any previous children (48.72). The lowest scores were found in women who had recently given birth (mean 34.82) and women older than 35 years (mean 34.85). The content analysis categorization matrix clearly accommodated all 436 statements into the five pre-existing categories. The largest categories were: the content of fear and worry with 138 statements and strategies to cope with fear or worry (122 statements).ConclusionThe Fear of Birth Scale seems to be a useful instrument for different subgroups of women. The construct of fear of childbirth may be universally understood and experienced by women of childbearing age irrespective of whether they are currently pregnant, have recently given birth or do not have children. Identifying fear of birth is important in clinical practice in order to support women's reproductive needs.



http://ift.tt/2B1NE2s

Differential Regulation of Zfp30 Expression in Murine Airway Epithelia Through Altered Binding of ZFP148 to rs51434084

Neutrophil chemotaxis to the airways is a key aspect of host response to microbes and a feature of multiple pulmonary diseases including asthma. Tight regulation of this recruitment is critical to prevent unwanted host tissue damage and inflammation. Using a mouse (Mus musculus) model of asthma applied to the Collaborative Cross (CC), we previously identified a lung gene expression quantitative trait locus (eQTL) for Zinc finger protein 30 (Zfp30) that was also a QTL for neutrophil recruitment and the hallmark neutrophil chemokine CXCL1. The Zfp30 eQTL is defined by three functionally distinct haplotypes. In this study, we searched for causal genetic variants that underlie the Zfp30 eQTL to gain a better understanding of this candidate repressor's regulation. First, we identified a putative regulatory region spanning 500 bp upstream of Zfp30, which contains 10 SNPs that form five haplotypes. In reporter gene assays in vitro, these haplotypes recapitulated the three previously identified in vivo expression patterns. Second, using site directed mutagenesis followed by reporter gene assays, we identified a single variant, rs51434084, that explained the majority of variation in expression between two out of three haplotype groups. Finally, using a combination of in silico predictions and electrophoretic mobility shift assays, we identified ZFP148 as a transcription factor that differentially binds to the Zfp30 promoter region harboring rs51434084. In conclusion, we provide evidence in support of rs51434084 being a causal variant for the Zfp30 eQTL and have identified a mechanism by which this variant alters Zfp30 expression, namely differential binding of ZFP148.

http://ift.tt/2j7OZwp

Editorial Board

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Table of Contents

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Analysis of correlation between the mild cognitive impairment (MCI) and level of adiponectin in elderly patients with type 2 diabetes mellitus (T2DM)

OBJECTIVE: To investigate the correlation between the mild cognitive impairment (MCI) and serum level of adiponectin in elderly patients with Type II diabetes mellitus (T2DM), so as to provide evidence for early diagnosis of MCI and effective evaluation of the impairment of cognitive functions, thereby preventing the impairment of cognitive function as early as possible.

PATIENTS AND METHODS: Clinical data were collected from 260 T2DM patients (≥ 60 years old) in Endocrine Department and 120 healthy subjects (≥ 60 years old) who underwent physical examination in our hospital between June 2015 and June 2017. According to the evaluation results of MCI, these T2DM patients were further divided into the T2DM + MCI group (n = 138) and the T2DM + NMCI group (n = 122). General data, including gender, age, disease history and body mass index (BMI), and the laboratory indexes, including serum adiponectin, fasting blood glucose (FBG), glycosylated hemoglobin (HbA1c) and blood fat, were collected for statistical analysis in T2DM + MCI group, T2DM + NMCI group and healthy control group.

RESULTS: Comparisons among T2DM + MCI group, T2DM + NMCI group and healthy control group, showed that the serum level of adiponectin in T2DM + MCI group was significantly lower than those in remaining two groups (p < 0.01). Spearman correlation analysis revealed that score of Montreal Cognitive Assessment (MoCA) was positively correlated with the serum level of adiponectin (r = 0.446, p < 0.01). Multivariate linear regression analysis indicated that education (standard β = 0.325, p = 0.003), age (standard β = -0.236, p = 0.016), disease course of hypertension (standard β = -0.242, p = 0.006), disease course of diabetes mellitus (standard β = -0.377, p < 0.001) and the level of adiponectin were correlated with the cognitive impairment. The results of itemized assessment in MoCA scale showed that in T2DM + MCI group, the scores in visuospatial and executive abilities, attention, language and orientation were significantly lower than those in other two groups (p < 0.01). As for the delayed recall, the score in T2DM + MCI group was significantly lower than those in other two groups (p < 0.01), while the score in T2DM + NMCI group was lower than that in the healthy control group (p < 0.01); in terms of the naming ability and abstraction, no statistically significant differences were identified among three groups (p > 0.05).

CONCLUSIONS: Age, poor education, disease course of hypertension, disease course of diabetes mellitus and a low level of adiponectin in serum are the risk factors in MCI of T2DM patients. Besides, the level of adiponectin in serum of T2DM patients is correlated with the development of MCI; elderly T2DM patients are afflicted by cognitive impairment, mainly in visuospatial and executive abilities, attention, language, delayed recall and orientation.

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