Predictors of Local Recurrence in Patients With Myxofibrosarcoma

Objectives: Myxofibrosarcoma (MFS) is reported to have a higher risk of local recurrence (LR) following definitive surgical excision relative to other soft tissue sarcomas. We reviewed our clinical experience treating MFS to investigate predictors of LR. Materials and Methods: We retrospectively reviewed treatment outcomes for MFS patients treated at our institution between 1999 and 2015. A total of 52 patients were identified. Median age was 65 years (range, 21 to 86 y). Site of disease was: upper extremity (27%), lower extremity (46%), trunk (15%), pelvic (8%), and head and neck (4%). Patients had low, intermediate, high-grade, and unknown grade in: 23%, 8%, 67%, and 2% of tumors, respectively. Tumors were categorized as ≤5 cm (35%), >5 cm (56%), or unknown size (9%). In total, 71% received radiotherapy: 19% preoperative, 50% postoperative, and 2% both. All patients underwent surgery. Margins were negative in 71%, close/positive in 21%, and unknown in 8%. In total, 27% of patients received chemotherapy. Univariate Cox regression analysis was utilized to determine associations between clinical and treatment factors with LR. Results: Median follow-up time was 2.9 years (range, 0.4 to 14.3 y). The 3-year actuarial LR, distant metastasis, and overall survival were: 31%, 15%, and 87%, respectively. Predictors of LR were patient age greater than or equal to the median of 65 years (hazard ratio, 13.46, 95% confidence interval, 1.71-106.18, P=0.013), and having close/positive tumor margins (hazard ratio, 3.4, 95% confidence interval, 1-11.53, P=0.049). Conclusions: In this institutional series of MFS older age and positive/close margins were significantly associated with a higher risk of LR.

https://ift.tt/2w977gB

Extraskeletal Osteosarcoma: Outcomes and the Role of Chemotherapy

Objectives: Extraskeletal osteosarcoma (EO) is a malignant neoplasm that produces osteoid, bone, and chondroid material without direct attachment to bone or periosteum. Surgical resection is the mainstay of treatment; the role of chemotherapy is not well defined. Therefore, we evaluated the impact of chemotherapy in the survival of patients with EO. Methods: All EO patients seen at Mayo Clinic between 1990 and 2014 were assessed. Forty-three patients were included after all archived pathology slides were reviewed to confirm the diagnosis of EO. Results: Of 43 patients, 37 patients had localized disease and 6 patients had metastatic disease at diagnosis. Chemotherapy was used in 73% and 75% of patients, respectively. Chemotherapy was predominantly anthracycline based, and included platinum in 22 patients (84%). Median overall survival (OS) and progression-free survival (PFS) were 50 months (95% confidence interval, 25-99), and 21 months (95% confidence interval, 13-not reached), respectively. There was a trend towards longer OS and PFS in patients who received chemotherapy. Those who received platinum-based therapy had remarkably prolonged OS (median, 182 vs. 18 mo; 5-year, 61% vs. 0%; P=0.01) and PFS (median, not reached vs. 10 mo; 5-year, 56% vs. 0%; P=0.005). Baseline characteristics were similar in the platinum and nonplatinum group. In patients who received chemotherapy, relapse/recurrence rate was lower in the platinum-based group (41%) as opposed to the nonplatinum-based group (100%; P=0.02). In the neoadjuvant setting, the overall response rate of platinum-containing regimens was 27%. Conclusions: Our results suggest a clinical benefit when platinum-based chemotherapy is incorporated in the management of patients with EO. We plan to validate this further with an expanded multicenter analysis.

https://ift.tt/2LlTcZn

Impact of the Primary Information Source Used for Decision Making on Treatment Perceptions and Regret in Prostate Cancer

Objective: To assess the impact of the primary source of information used by prostate cancer patients to select a radiation treatment on their overall treatment experience and on treatment regret. Methods: Patients with low to favorable intermediate-risk prostate cancer treated with stereotactic body radiation therapy, intensity-modulated radiation therapy, or high-dose rate brachytherapy were surveyed. The questionnaire explored the decision-making experience, treatment experience, and treatment regret. Results: In total, 322 consecutive patients were surveyed with an 86% (n=276) response rate. In total, 48% (n=132) selected their radiation oncologist as the primary information source, 23% (n=62) selected their urologist, 16% (n=44) selected the Internet, 6% (n=17) selected other patients, and 8% (n=21) selected other. In total, 39% of patients who selected the Internet as their primary information source reported their actual treatment experience to be worse than expected versus 13% of respondents who selected their urologist, 12% who selected other patients, and 2% who selected their radiation oncologist (P

https://ift.tt/2w8UbHv

Clinical Use and Optimal Cutoff Value of Ca15-3 in Evaluation of Adnexal Mass: Retrospective Cohort Study and Review of the Literature

Objective: To estimate the diagnostic performance and reference values of serum cancer antigen (Ca)15-3 levels in the triage of adnexal masses. Materials and Methods: This retrospective cohort study was carried out in 481 patients referred to the Gynecology Department at Carmel Medical Center due to adnexal mass between years 2005 and 2012. All patients underwent surgery with histopathologically confirmed diagnosis and routine preoperative measurements of serum Ca125 and Ca15-3. Results: Combination of Ca125 with Ca15-3 elevated the sensitivity of Ca125 alone (from 86.9% to 93.2%; P=0.029), along with reduction of its specificity (from 80.5% to 69.5%; P=0.005) in differentiation between malignant and benign cases. According to receiver operating characteristic curve, Ca15-3 level of 21 U/mL was shown to be the optimal reference value for malignancy detection. All cases with Ca15-3 levels above 44.5 U/mL were malignant, mostly of primary ovarian source. Conclusions: As Ca15-3 assessment allowed detection of significantly more malignancy cases, we believe that measurement of this marker in combination with Ca125 is worthwhile in patients presenting with adnexal masses. The cutoff of 21 U/mL seems to be the optimal value in this specific population. High Ca15-3 levels (above 44.5 U/mL) strongly direct to a diagnosis of malignancy, mostly of primary ovarian tumors rather than breast malignancy.

https://ift.tt/2LlTaAJ

Concurrent Chemoradiotherapy in the Adjuvant Treatment of High-risk Primary Salivary Gland Malignancies

Objectives: Adjuvant radiation therapy (RT) is indicated for patients with salivary gland malignancies with risk factors for recurrence following resection. We analyzed patients treated with adjuvant RT with or without concurrent chemotherapy to determine the impact of prognostic and treatment factors. Materials and Methods: Retrospective analysis was performed of 128 patients treated with surgical resection followed by intensity-modulated radiotherapy. In total, 31 (24.2%) patients were treated with concurrent chemoradiotherapy. The Kaplan-Meier method was used to estimate rates of progression-free survival (PFS), local-regional control, distant control, overall survival. Multivariable Cox regression was performed to evaluate factors significant on univariate analysis. Results: The 5-year rates of PFS, local-regional control, freedom-from distant metastasis, and overall survival were 61.2%, 85.8%, 76.5%, and 73.7%, respectively. Predictors of decreased PFS on univariate analyses were age, tumor stage, nodal stage, positive surgical margins, histology, high grade, perineural invasion, lymphovascular space invasion, extranodal extension, and use of chemoradiotherapy. On multivariable analysis, elevated T-stage, positive surgical margins, and presence of extranodal extension were predictive of decreased PFS. The acute toxicity rates were 30.3% grade 1, 51.5% grade 2, 11.4% grade 3, and 0.8% grade 4. There was no difference in rates of grade 3 or higher acute toxicity with use of RT alone versus chemoradiotherapy (P=0.183). Conclusions: Use of chemoradiotherapy for adjuvant treatment of salivary gland malignancies was well-tolerated, but no improvement in survival was seen with the use of chemoradiotherapy in both the overall study population and a subset with high-risk features. Caution should be used when using this modality until randomized evidence becomes available.

https://ift.tt/2waD9IX

Survival Benefit of Adjuvant Radiation Therapy in Node-positive Vulvar Cancer

Background: Adjuvant radiation therapy improves overall survival in patients with vulvar cancer with 2+ positive lymph nodes, but its benefit remains uncertain for 1 positive lymph node. Methods: Using the Surveillance, Epidemiology, and End Results (SEER) database, we identified node-positive, American Joint Committee on Cancer version 6-staged women with squamous cell vulvar carcinoma treated with and without radiation following surgery. The Kaplan-Meier approach assessed overall and cause-specific survival. Propensity score-based, multiply imputed Cox modeling accounted for missing data and selection bias. Results: From 2004 to 2013, 488 versus 206 women did and did not receive adjuvant radiation after surgery. Patient characteristics were well balanced, including home county, index tumor diameter, number of nodes excised, provider type, race, and surgery type (P>0.05). Unbalanced covariates—including median age, grade, number of positive nodes, N-stage—were adjusted using Cox regression. At a median follow-up of 36 months, adjuvant radiation was associated with improved median overall survival across all node-positive patients (54 vs. 24 mo; P

https://ift.tt/2LnEcdd

Prevention of Trastuzumab and Anthracycline-induced Cardiotoxicity Using Angiotensin-converting Enzyme Inhibitors or β-blockers in Older Adults With Breast Cancer

Purpose: Although clinical trials have provided some data on the benefit of angiotensin-converting enzyme inhibitors (ACEIs) or β-blockers (BBs) in patients with chemotherapy-induced cardiotoxicity, evidence of ACEIs/BBs on prevention of trastuzumab and/or anthracycline-induced cardiotoxicity outside trials is limited. Materials and Methods: A cohort study of 142,990 women (66 y and above) newly diagnosed with breast cancer from 2001 to 2009 was conducted using the Surveillance, Epidemiology, and End Results-Medicare–linked database. The ACEI/BB exposure was defined as filled prescription(s) before or after the initiation of trastuzumab/anthracyclines. The nonexposed group was defined as those who had never been prescribed ACEIs/BBs. Cumulative rates of cardiotoxicity and all-cause mortality were estimated and marginal structural Cox models were used to determine factors associated with cardiotoxicity and all-cause mortality adjusting for baseline covariates and use of chemotherapy. All statistical tests were 2 sided. Results: The final sample included 6542 women. Adjusted hazard ratio for cardiotoxicity and all-cause mortality for the ACEI/BB exposed group were 0.77 (95% confidence interval, 0.62-0.95) and 0.79 (95% confidence interval, 0.70-0.90) compared with the nonexposed group, respectively. Starting ACEIs/BBs≤6 months after the initiation of trastuzumab/anthracyclines and having exposed duration≥6 months were also associated with decreased risk of cardiotoxicity and all-cause mortality. Baseline characteristics, including age, non-Hispanic black, advanced cancer, region, comorbidity, preexisting cardiovascular conditions, lower socioeconomic status, and concomitant treatment were significantly associated with an elevated risk of all-cause mortality and/or cardiotoxicity (all P

https://ift.tt/2w8SN7I

Efficacy of Modified Dose-dense Paclitaxel in Recurrent Cervical Cancer

Objective: To examine survival outcomes of women with recurrent cervical cancer who received salvage chemotherapy with modified dose-dense paclitaxel (MDDP) monotherapy (paclitaxel 80 mg/m2, administered on day 1, 8, and 15 without day 22). Materials and Methods: A retrospective study was conducted to evaluate cause-specific survival after the first recurrence (SAR) of women with recurrent cervical cancer diagnosed between 2006 and 2014. Pooled analyses were performed to examine SAR in women who received MDDP monotherapy (n=17) for any treatment line, compared with those who received salvage chemotherapy with paclitaxel-doublet (n=18) and nonpaclitaxel regimens (n=52). Results: In the whole cohort, median SAR was 13.7 months including 63 (72.4%) events. MDDP monotherapy regimen was most commonly used in the second-line setting (35.3%) followed by the third/fourth lines (both, 23.5%). Among the women who received MDDP regimen, there were 6 (35.3%) women who received ≥6 cycles; there was 1 (5.9%) women who discontinued the regimen due to adverse effects (grade 3 transaminitis); regimen postponement was seen in 2 (1.4%) of 140 total cycles; and the response rate after the sixth cycle of this regimen was 29.4% (1 complete and 4 partial responses). On univariate analysis, MDDP usage had the highest 2-year SAR rate (MDDP 54.1%, paclitaxel-doublet 43.6%, and nonpaclitaxel regimens 28.1%; Ptrend=0.044). On multivariate analysis, MDDP monotherapy remained an independent prognostic factor for improved SAR compared with the nonpaclitaxel regimen (adjusted-hazard ratio, 0.50; 95% confidence interval, 0.26-0.95; P=0.036). Conclusion: Our results suggested that MDDP monotherapy is a tolerable and relatively effective regimen for recurrent cervical cancer.

https://ift.tt/2LrCAiY

Surgical Intervention in Gastric Carcinoid is Associated With Improved Survival in Local and Regional Disease

Introduction: Gastric carcinoid is a rare entity with complex management options. This study aims to determine if surgical intervention in patients with local, regional, and metastatic gastric carcinoid is associated with prolonged survival. Materials and Methods: The California Cancer Registry merged with the California Office of Statewide Health Planning and Development was queried for patients with a diagnosis of gastric carcinoid (2000 to 2011). Clinicopathologic characteristics, management, and outcomes were evaluated. Results: There were 1012 patients with a diagnosis of gastric carcinoid identified. The median age was 63 (range, 18 to 99) and the majority of patients were women (615, 60.7%). Most patients had localized disease (644, 64%), whereas 9.4% (95) had regional and 13.4% (133) had distant metastases at diagnosis. The majority of patients underwent gastric surgery (56.7%, n=574 vs. 43.2%, n=438). Prolonged survival was associated with gastric surgery in patients with both local (median survival not reached; P

https://ift.tt/2wgHRoP

Assessment of the Albumin-Bilirubin (ALBI) Grade as a Prognostic Indicator for Hepatocellular Carcinoma Patients Treated With Radioembolization

Objective: As the utility of Child-Pugh (C-P) class is limited by the subjectivity of ascites and encephalopathy, we evaluated a previously established objective method, the albumin-bilirubin (ALBI) grade, as a prognosticator for yttrium-90 radioembolization (RE) treatment for patients with hepatocellular carcinoma (HCC). Materials and Methods: A total of 117 patients who received RE for HCC from 2 academic centers were reviewed and stratified by ALBI grade, C-P class, and Barcelona Clinic Liver Cancer stage. The overall survival (OS) according to these 3 criteria was evaluated by Kaplan-Meier survival analysis. The utilities of C-P class and ALBI grade as prognostic indicators were compared using the log-rank test. Multivariate Cox regression analysis was performed to identify additional predictive factors. Results: Patients with ALBI grade 1 (n=49) had superior OS than those with ALBI grade 2 (n=65) (P=0.01). Meanwhile, no significant difference was observed in OS between C-P class A (n=100) and C-P class B (n=14) (P=0.11). For C-P class A patients, the ALBI grade (1 vs. 2) was able to stratify 2 clear and nonoverlapping subgroups with differing OS curves (P=0.03). Multivariate Cox regression test identified alanine transaminase, Barcelona Clinic Liver Cancer stage, and ALBI grade as the strongest prognostic factors for OS (P

https://ift.tt/2LlPLlf

Radiotherapy Alone or With Chemotherapy in the Management of Carcinoma of the Supraglottic Larynx: A 25-Year Community Hospital Experience

Objectives: The purpose of this study was to retrospectively review outcomes for patients treated with definitive radiotherapy for carcinoma of the supraglottic larynx at a community hospital and to compare our results with the literature. Materials and Methods: Treatment records of 46 patients with localized carcinoma of the supraglottic larynx treated from January 1987 through January 2012 were reviewed. Overall, 18 (39%) presented with stage I or II disease, whereas 28 (61%) presented with stage III to IV. In total, 30 patients (65%) were treated using hyperfractionation, whereas 16 (35%) received once-daily fractionation. Twelve patients (26%) received concurrent chemotherapy with weekly cisplatin. The Kaplan-Meier method was used to assess outcomes. Results: The median follow-up for the living patients was 6.7 years (range, 1.7 to 23.1 y). At 5 years, the local-regional control (LRC), ultimate LRC, laryngeal preservation, and overall survival (OS) rates were 70%, 82%, 65%, and 53%, respectively. At 5 years, disease-free survival and cause-specific survival rates were 75% and 76%, respectively. The 5-year OS rates by American Joint Committee on Cancer stage were as follows: I to II, 61%; III, 51%; and IV, 44%. For those receiving concurrent chemotherapy, there was no improvement in 5-year LRC (83% vs. 66%; P=0.4081) or OS (55% vs. 50%; P=0.7697). For those receiving hyperfractionation, there was no improvement in 5-year LRC (75% vs. 63%; P=0.3369) or OS (55% vs. 50%; P=0.4161). Conclusions: Our outcomes are similar to those reported in the literature. Neither hyperfractionation nor chemotherapy appeared to confer a benefit for disease control or OS possibly owing to small sample size and the inherent bias of a retrospective review.

https://ift.tt/2w7x28o

Predictive Impact of Clinical Benefit in Chemotherapy-treated Advanced Pancreatic Cancer Patients in Northern Alberta

Objectives: Patients with advanced pancreatic cancer (APC) have a poor prognosis and experience a large burden of disease-related symptoms. Despite advancements in the treatment of APC, survival is dismal and controlling disease-related symptoms and maintaining quality of life is paramount. We hypothesize that an improvement in disease-related symptoms, and therefore, a clinical benefit, while on chemotherapy is a predictive marker in APC. Materials and Methods: Patients 18 and older with APC diagnosed between January 1, 2005 and December 31, 2010 and treated at the Cross Cancer Institute were identified using the provincial cancer registry. Disease symptoms were assessed at baseline and clinical benefit while on chemotherapy was defined using a composite endpoint of improvement in patient-reported pain, opioid consumption, Eastern Cooperative Oncology Group performance status, and/or weight. Best radiologic response, progression-free survival (PFS), and overall survival (OS) were recorded. Results: Of 103 patients, the median age was 64, 58% were male and 66% had metastatic disease. At baseline, the majority of patients reported pain (80%), opioid use (61%), or weight loss (71%). In total, 35 (34%) patients received a clinical benefit with treatment but only 6 (17%) of these patients experienced a radiologic response. The median PFS and OS were improved in patients who experienced a clinical benefit (6.6 vs. 4.6 mo; P=0.03 and 11.7 vs. 6.1 mo; P

https://ift.tt/2LnOgD2

Treatment and Outcomes of Primary Urethra Cancer

Background: Urethral cancer is a rare malignancy, representing

https://ift.tt/2w8SKJ4

Obesity is Independently Associated With Increased Risk of Hepatocellular Cancer–related Mortality: A Systematic Review and Meta-Analysis

Objective: Excess body weight is associated with increased risk of developing hepatocellular cancer (HCC), but its effect on HCC-related mortality remains unclear. We performed a systematic review and meta-analysis to assess the association between premorbid obesity and HCC-related mortality. Materials and Methods: Through a systematic literature search-up to March 2016, we identified 9 observational studies (1,599,453 individuals, 5705 HCC-related deaths) reporting the association between premorbid body mass index (BMI), and HCC-related mortality. We estimated summary adjusted hazard ratio (aHR) with 95% confidence intervals (CIs), comparing obese (BMI>30 kg/m2) and overweight (BMI, 25 to 29.9 kg/m2) individuals with normal BMI individuals using random-effects model. Results: On meta-analysis, compared with individuals with normal BMI, obese (aHR, 1.95; 95% CI, 1.46-2.46), but not overweight individuals (aHR, 1.08; 95% CI, 0.97-1.21), had higher HCC-related mortality, with moderate heterogeneity. On subgroup analysis, magnitude of increased mortality was higher in obese men (aHR, 2.50; 95% CI, 2.02-3.09; 3 studies) as compared with obese women (aHR, 1.45; 95% CI, 1.08-1.97; 2 studies). The impact of premorbid obesity on HCC-related mortality was observed only in western populations (aHR, 2.10; 95% CI, 1.77-2.48; 4 studies), but not Asian populations (aHR, 1.10; 95% CI, 0.63-1.92; 1 study). There was limited assessment of competing risk because of advanced liver disease. Conclusions: On the basis of this meta-analysis, premorbid obesity may be independently associated with a 2-fold risk of HCC-related mortality. This association was more pronounced in men and western populations. Strategies targeting obesity-associated metabolic abnormalities may provide novel pathways for HCC therapy.

https://ift.tt/2LnE4KL

Advanced Age is Not a Contraindication for Treatment With Curative Intent in Esophageal Cancer

Objectives: The objective of this study is to compare long-term outcomes between younger and older (70 y and above) esophageal cancer patients treated with curative intent. Materials and Methods: Overall survival (OS), disease-free survival (DFS), and locoregional recurrence-free interval were compared between older (70 y and above) and younger (below 70 y) esophageal cancer patients treated between 1998 and 2013. Treatment consisted of neoadjuvant chemoradiotherapy with surgery or definitive chemoradiotherapy: 36 to 50.4 Gy in 18 to 28 fractions combined with 5-fluorouracil/cisplatin or carboplatin/paclitaxel. Results: The study comprised 253 patients, of whom 76 were 70 years and older. Median age was 64 years (range, 41 to 83). Most patients had stage II-IIIA disease (83%). Planned treatment was neoadjuvant chemoradiotherapy with surgery for 169 patients (41 patients aged 70 y and older) and definitive chemoradiotherapy for 84 patients (31 patients aged 70 y and older). The compliance to radiotherapy was 92%, with no difference between older and younger patients. In 33 patients (13 patients aged 70 y and older) planned surgery was not performed. Median follow-up was 4.9 years. Three-year OS was 42%. The multivariable analysis showed no statistical difference in OS or in DFS comparing older and younger patients: OS (hazard ratio [HR], 0.88; 95% confidence interval [CI], 0.61-1.28), DFS (HR, 0.87; 95% CI, 0.60-1.25). Elderly showed a longer locoregional recurrence-free interval; HR, 0.53 (95% CI, 0.30-0.92; P=0.02) and a higher pathologic complete response rate (50% vs. 25%; P=0.02). Conclusions: Long-term outcomes of older esophageal cancer patients (70 y and above) selected for treatment with neoadjuvant chemoradiotherapy followed by surgery or definitive chemoradiotherapy were comparable with the outcomes of their younger counterparts. Advanced age alone should not be a contraindication for potentially curative chemoradiotherapy-based treatment in esophageal cancer patients.

https://ift.tt/2w9ccFw

Targeted Therapies in the Treatment of Sarcomas

Abstract

About 50% of sarcomas have specific pathology-defining molecular alterations including mutations, fusion genes, and gene amplifications. Some of these alterations appear to be oncogenic drivers, and a subset can be utilized as targets for standard or experimental molecularly targeted agents in the clinic. In addition, immunotherapies may have a growing role in the treatment of sarcomas in the future.

https://ift.tt/2Ngg9ia

International Conference on Lymphocyte Engineering Abstract Author Index

Human Gene Therapy, Ahead of Print.


https://ift.tt/2o3kgmG

International Conference on Lymphocyte Engineering; September 13–15, 2018; Madrid, Spain

Human Gene Therapy, Ahead of Print.


https://ift.tt/2BQg6bU

Selected Abstracts from the American Aging Association 47th Annual Meeting “Improving Resilience to Delay Aging” Philadelphia, 2018

https://ift.tt/2MOvMQZ

Facilitating implementation of the Decision-Making Capacity Assessment (DMCA) Model: senior leadership perspectives on the use of the National Implementation Research Network (NIRN) Model and frameworks

Dementia and other chronic conditions can compromise a person's ability to make independent personal and financial decisions. In the wake of an ageing population and rising incidence of chronic conditions, the...

https://ift.tt/2P4gPI9

Powerful moments: The rollercoaster of life in EMS

Making connections with the patients you treat and transport can allow you to feel the magic

https://ift.tt/2LmUCmj

Clinical and pharmacogenetics associated with recovery time from general anesthesia

Pharmacogenomics, Ahead of Print.


https://ift.tt/2LouxDh

Powerful moments: The rollercoaster of life in EMS

Making connections with the patients you treat and transport can allow you to feel the magic

https://ift.tt/2LmUCmj

Daratumumab and its use in the treatment of relapsed and/or refractory multiple myeloma

Future Oncology, Ahead of Print.


https://ift.tt/2PzCXv6

Viable Triploid Honey Bees (Apis mellifera capensis) Are Reliably Produced in the Progeny of CO2 Narcotised Queens

The haplodiploid system of sex determination of Hymenoptera acts as an exaptation for species to evolve novel forms of asexual reproduction including thelytoky (clonal offspring of the mother). During normal reproduction in Hymenoptera, three of the four products of meiosis that are present in newly-laid eggs are lost as polar bodies, while the remaining pronucleus either develops as a haploid male or fuses with a sperm nucleus to produce a diploid zygote. In contrast, in thelytokous reproduction, which is uncommon but taxonomically widespread, two of the four products of meiosis fuse, as if one acted as a sperm. Queenless workers of Apis mellifera capensis, a subspecies of honey bee from South Africa, routinely reproduce thelytokously. Unmated A. m. capensis queens can also be induced to lay thelytokously by narcosis with carbon dioxide, but mated queens are never thelytokous. We artificially inseminated A. m. capensis queens using CO₂ narcosis. Up to 1/3 of offspring workers carried two maternal alleles and an allele of one father whereas no three-allele progeny were seen in control queens of the arrhenotokous (unfertilized eggs result in males) subspecies A. m. scutellata. Flow cytometry of three-allele individuals revealed that they were triploid and arose from the fertilization of a thelytokous fusion nucleus. We then reared six queens from a narcotized A. m. capensis queen and determined the ploidy of the offspring queens based on microsatellites. One of the five daughters was triploid. Following artificial insemination, this queen produced unfertilized thelytokous diploid eggs at high frequency, and unfertilized triploid eggs at much lower frequency. If fertilized, thelytokous diploid eggs were non-viable, even though triploidy in itself does not impede normal development. In contrast, when the rarer triploid eggs were fertilized, a proportion developed into viable tetraploids. Our study highlights the extraordinary developmental flexibility of haplo-diploid systems.

https://ift.tt/2w67vwo

Comparative Genomics Approaches Accurately Predict Deleterious Variants in Plants

Recent advances in genome resequencing have led to increased interest in prediction of the functional consequences of genetic variants. Variants at phylogenetically conserved sites are of particular interest, because they are more likely than variants at phylogenetically variable sites to have deleterious effects on fitness and contribute to phenotypic variation. Numerous comparative genomic approaches have been developed to predict deleterious variants, but the approaches are nearly always assessed based on their ability to identify known disease-causing mutations in humans. Determining the accuracy of deleterious variant predictions in nonhuman species is important to understanding evolution, domestication, and potentially to improving crop quality and yield. To examine our ability to predict deleterious variants in plants we generated a curated database of 2,910 Arabidopsis thaliana mutants with known phenotypes. We evaluated seven approaches and found that while all performed well, their relative ranking differed from prior benchmarks in humans. We conclude that deleterious mutations can be reliably predicted in A. thaliana and likely other plant species, but that the relative performance of various approaches does not necessarily translate from one species to another.

https://ift.tt/2LlD4XP

PSMA ligand PET/MRI for primary prostate cancer: Staging performance and clinical impact

Purpose: Primary staging of prostate cancer (PC) relies on modalities, which are limited. We evaluate simultaneous [⁶⁸Ga]Ga-PSMA-11positron emission tomography (PSMA-PET)/magnetic resonance imaging (MRI) as a new diagnostic method for primary TNM-staging compared to histology and its impact on therapeutic decisions. Patients and Methods: We investigated 122 patients with PSMA-PET/MRI prior to planned radical prostatectomy (RP). Primary endpoint was the accuracy of PSMA-PET/MRI in tumor staging as compared to staging-relevant histology. Additionally, a multidisciplinary team reassessed the initial therapeutic approach to evaluate its impact on the therapeutic management. Results: PSMA-PET/MRI correctly identified PC in 119 of 122 patients (97.5%). 81 patients were treated with RP and pelvic lymphadenectomy. The accuracy for T-staging was 82.5% (95%CI 73-90; P<0.001), for T2-stage: 85% (95%CI 71-94; P<0.001), T3a-stage: 79% (95%CI 43-85; P<0.001), T3b-stage: 94% (95%CI 73-100; P<0.001) and 93% (95%CI 84-98) for N1-stage (P<0.001). PSMA-PET/MRI changed the therapeutic strategy in 28.7% of the patients with either the onset of systemic therapy/radiotherapy (n=16) or active surveillance (n=19). Conclusion: PSMA-PET/MRI can provide an accurate staging of newly diagnosed PC. Additionally, treatment strategies were changed in almost a third of the patients due to the information of this hybrid imaging technique.

https://ift.tt/2w8IznM

Functional ex vivo assay reveals homologous recombination deficiency in breast cancer beyond BRCA gene defects

PURPOSE: Tumors of germline BRCA1/2 mutated carriers show homologous recombination (HR) deficiency (HRD), resulting in impaired DNA double strand break (DSB) repair and high sensitivity to Poly-(ADP-Ribose)-Polymerase (PARP) inhibitors. Although this therapy is expected to be effective beyond germline BRCA1/2 mutated carriers, a robust validated test to detect HRD tumors is lacking. In the present study we therefore evaluated a functional HR assay exploiting the formation of RAD51 foci in proliferating cells after ex vivo irradiation of fresh breast cancers (BrC) tissue: the RECAP test. METHODS: Fresh samples of 170 primary BrC were analyzed using the RECAP test. The molecular explanation for the HRD phenotype was investigated by exploring BRCA deficiencies, mutational signatures, tumor infiltrating lymphocytes (TILs) and microsatellite instability (MSI). RESULTS: RECAP was completed successfully in 148 out of 170 samples (87%). 24 tumors showed HRD (16%), while 6 tumors were HR intermediate (HRi) (4%). HRD was explained by BRCA deficiencies (mutations, promoter hypermethylation, deletions) in 16 cases, whereas 7 HRD tumors were non-BRCA related. HRD tumors showed an increased incidence of high TIL counts (p=0.023) compared to HR proficient (HRP) tumors and MSI was more frequently observed in the HRD group (2/20, 10%) than expected in BrC (1%) (p=0.017). CONCLUSION: RECAP is a robust functional HR assay detecting both BRCA1/2 deficient and BRCA1/2 proficient HRD tumors. Functional assessment of HR in a pseudo-diagnostic setting is achievable and produces robust and interpretable results.

https://ift.tt/2LoL22t

Pathobiologic Pseudohypoxia as a Putative Mechanism Underlying Myelodysplastic Syndromes [Research Articles]

Myelodysplastic syndromes (MDS) are heterogeneous hematopoietic disorders that are incurable with conventional therapy. The incidence is increasing with global population ageing. Although many genetic, epigenetic, splicing, and metabolic aberrations have been identified in MDS patients, their clinical features are quite similar. Here we show that hypoxia-independent activation of hypoxia-inducible factor 1α (HIF1A) signaling is both necessary and sufficient to induce dysplastic and cytopenic MDS phenotypes. The HIF1A transcriptional signature is generally activated in MDS-patient bone-marrow stem/progenitors. Major MDS-associated mutations (Dnmt3a, Tet2, Asxl1, Runx1, and Mll1) activate the HIF1A signature. While inducible activation of HIF1A signaling in hematopoietic cells is sufficient to induce MDS phenotypes, both genetic and chemical inhibition of HIF1A signaling rescues MDS phenotypes in a mouse model of MDS. These findings reveal HIF1A as a central pathobiologic mediator of MDS, and as an effective therapeutic target for a broad spectrum of MDS patients.

https://ift.tt/2OXQfjQ

Cytotoxicity of the Aqueous Extract and Organic Fractions from Origanum majorana on Human Breast Cell Line MDA-MB-231 and Human Colon Cell Line HT-29

The toxicity of the aqueous extract of Origanum majorana was tested (5 and 10 g/kg) in albino mice. No symptoms of toxicity or mortality were observed. The mice survived being active and healthy during all 14 days of observation. In addition, the weight measurement of the left and right kidneys, heart, and liver shows no significant difference between the control, 5 g/kg, and 10 g/kg. All extracts (aqueous, petroleum ether, dichloromethane, ethyl acetate, methanolic, and depleted aqueous extracts) of Origanum majorana tested against both types of cancer cells showed a more pronounced cytotoxic effect against breast cell line MDA-MB-231 than colon cells line HT-29 cells. The most marked effect is that of the ethyl acetate extract with IC50 30.90 ± 1.39 and 50.11 ± 1.44 (µg/ml), respectively. HPLC analysis of extracts from Origanum majorana showed that this plant contained polyphenols and flavonoids, which may be responsible for the biological activities found.

https://ift.tt/2NdFxVZ

YouTube Videos May Provide Biased Info on Facial Plastic Sx

THURSDAY, Aug. 23, 2018 -- Some YouTube videos that provide information about facial plastic surgery procedures present biased information, and many do not include qualified medical professionals, according to a research letter published online Aug....

https://ift.tt/2MSai60

Frailty in Middle-Aged With Multimorbidity Tied to Mortality

THURSDAY, Aug. 23, 2018 -- For middle-aged individuals with multimorbidity, frailty is significantly associated with mortality, according to a study published in the July issue of The Lancet Public Health. Peter Hanlon, from the University of...

https://ift.tt/2MMXY6V

Increased First-Trimester HbA1c Predicts Gestational Diabetes

THURSDAY, Aug. 23, 2018 -- First-trimester glycated hemoglobin (HbA1c) may aid in early identification of women at risk for gestational diabetes mellitus (GDM), according to a study published online Aug. 16 in Scientific Reports. Stefanie N. Hinkle,...

https://ift.tt/2Ndzvob

FDA Approves First Drug for Neurotrophic Keratitis

THURSDAY, Aug. 23, 2018 -- Oxervate (cenegermin) has been approved by the U.S. Food and Drug Administration to treat neurotrophic keratitis, a rare degenerative disease of the cornea. This application received priority review by the FDA and was...

https://ift.tt/2MJKJUw

Environmental risk factors for Toxoplasma gondii infections and the impact of latent infections on allostatic load in residents of Central North Carolina

Toxoplasma gondii infection can be acquired through ingestion of infectious tissue cysts in undercooked meat or environmental oocysts excreted by cats. This cross-sectional study assessed environmental risk facto...

https://ift.tt/2OYPM0I

Pasteurella multocida line infection: a case report and review of literature

There are as many as 300,000 visits to the emergency department in the USA with animal bites every year. The most common infection after cat or dog bite is with Pasteurella Multocida. Many people infected will al...

https://ift.tt/2Mw61FW

Spectrum of disease in HIV-positive patients presenting to a tertiary care hospital: a retrospective, cross-sectional review in Kumasi, Ghana

HIV remains a significant public health dilemma in West and Central Africa. HIV-related morbidity and mortality are unjustly high, yet little is known about the spectrum of complicating comorbidities in HIV-po...

https://ift.tt/2P1y2BN

DFW Airport emergency room takes off with innovative communication platform

BOZEMAN, MT — The world's first fully-equipped airport emergency room opened recently at the Dallas Fort Worth International Airport. Using state-of-the-art communication platform, Pulsara, the ED will be able to quickly exchange patient information, estimated time of arrival, and other data with local EMS to get critical patients treated sooner. These medical care facility projects...

https://ift.tt/2o5EY5D

Effects of shared decision making on distress and healthcare utilization among patients with lung cancer: a systematic review

Lung cancer is associated with significant distress, poor quality of life, and a median prognosis of less than one year. Benefits of shared decision making (SDM) have been described for multiple diseases, either by the use of decisions aids or as part of supportive care interventions.

https://ift.tt/2o3OXIz

Development of a Standard for Hospital-based Palliative Care Consultation Teams in Japan Using a Modified Delphi Method

Hospital-based palliative care consultation teams (PCCTs) are rapidly being disseminated throughout Japan. The roles of PCCTs have changed over the past decade, particularly with the introduction of a modified national cancer care act to promote early palliative care and integrated oncology and palliative care.

https://ift.tt/2BCLnyA

Caregivers’ experiences with medical aid-in-dying in Vermont: a qualitative study

Eight jurisdictions in the United States currently permit medical aid-in-dying (AID), yet little is known about the direct experience of caregivers in supporting a loved one through the process.

https://ift.tt/2o6nIxe

Dyspnea in amyotrophic lateral sclerosis (ALS): Rasch-based development and validation of a patient-reported outcome (DALS-15)

Dyspnea is a cardinal but often underestimated symptom in amyotrophic lateral sclerosis (ALS). The lack of a satisfying assessment tool leads to diagnostic uncertainty and bears the risk that established life-prolonging and symptom relieving therapeutic options will not be adequately applied.

https://ift.tt/2BNpIUq

Hospital acquired vancomycin resistant enterococci in surgical intensive care patients – a prospective longitudinal study

Vancomycin resistant enterococci (VRE) occur with enhanced frequency in hospitalised patients. This study elucidates the prevalence of VRE on admission among surgical intensive care unit (SICU) patients, wheth...

https://ift.tt/2Px0Nrf

Chronic pancreatitis changes in high-risk individuals for pancreatic ductal adenocarcinoma

Pancreatic intraepithelial neoplasia is associated with chronic pancreatitis (CP) changes on EUS. The objective of this study was to determine whether CP changes were more common in high-risk individuals (HRIs) than in controls and whether these changes differed among higher-risk subsets of HRIs.

https://ift.tt/2woE6fU

Comparison of the Effects of Antithrombotic Therapy on Delayed Bleeding after Gastric Endoscopic Resection: A Propensity Score-Matched Case-Control Study

Antithrombotic therapy has been known to increase post-endoscopic resection (ER) bleeding risk; however, there are few studies quantifying the effect of antithrombotic agents. This study aimed to analyze the incidence of delayed bleeding (DB) based on antithrombotic agents administered and to identify the proper timing of drug cessation.

https://ift.tt/2PCNrKa

Comparison of mucosal impedance measurements throughout the esophagus and mucosal eosinophil counts in endoscopic biopsies in eosinophilic esophagitis

Assessing eosinophilic esophagitis (EoE) activity from limited esophageal mucosal biopsy samples has been questioned. Compare mucosal impedance (MI) throughout the esophagus and eosinophil counts in endoscopic biopsies in EoE.

https://ift.tt/2wkDZlH

Accreditation, setting and experience as indicators to assure quality in oncology biomarker testing laboratories

https://ift.tt/2OX32D5

Automated robust proton planning using dose-volume histogram-based mimicking of the photon reference dose and reducing organ at risk dose optimization

An automated approach to robust pencil beam scanning proton planning has been presented by first mimicking the dose-volume histograms of the photon dose and secondly reducing the dose to non-target tissues. This 'mimicking and reducing' algorithm was evaluated in head and neck cancer patients and successfully embedded into a framework to automatically select patients for proton therapy based on normal tissue complication probabilities.

https://ift.tt/2w7BrZ1

The clinical and dosimetric impact of real-time target tracking in pancreatic SBRT

Motion is a major source of uncertainty and error in ablative treatment of pancreatic tumors. We retrospectively analyzed a large cohort of patients treated with Stereotactic Body Radiotherapy under real-time, fiducial-based kV image guidance. We found that using these real-time images to make corrections to the tumor position resulted in significant dosimetric benefits to the tumor. We also characterized the workflow changes required to implement real-time target tracking.

https://ift.tt/2LjgGhv

Hypofractionated Whole Breast Irradiation in Large-Breasted Women – Is There A Dosimetric Predictor for Acute Skin Toxicities?

Underutilization of hypofractionated whole breast irradiation (HF-WBI) in large-breasted women may be partially explained by concerns about dose heterogeneity and lack of validated dosimetric guidelines. We examined acute grade 3 dermatitis rates with HF-WBI in large-breasted patients when our institutionally-designed dosimetric guidelines are followed and evaluated predictors for skin toxicity. Whole breast CTV V105 >10% was a significant predictor of grade 3 dermatitis and is a useful parameter to guide optimization of breast radiation plans.

https://ift.tt/2LlfdaL

Association of non-alcoholic fatty liver disease with thyroid function: a systematic review and meta-analysis

Nonalcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases. The relationship of NAFLD with thyroid function parameters and hypothyroidism remains controversial.

https://ift.tt/2wmjtBn

Renin-Angiotensin-Aldosterone system in cirrhosis: there’s room to try!

https://ift.tt/2PuM549

Diagnostic Imaging in Emergency Medicine: How Much Is Too Much?

Few topics are as pertinent to the current emergency medicine climate as the debate surrounding the overuse of diagnostic imaging. Use of advanced diagnostic imaging has increased in the United States exponentially since the advent of computed tomography (CT) and magnetic resonance imaging (MRI). CT use has increased from 3 million scans in 1980 to greater than 60 million in 2005, and is still increasing.1 Although this growth stretches across the care continuum, it includes the emergency department (ED).

https://ift.tt/2MJzdsa

Evaluation of US Federal Guidelines (Primary Response Incident Scene Management [PRISM]) for Mass Decontamination of Casualties During the Initial Operational Response to a Chemical Incident

The aim of this study was to evaluate the clinical and operational effectiveness of US federal government guidance (Primary Response Incident Scene Management [PRISM]) for the initial response phase to chemical incidents.

https://ift.tt/2MKvWsG

Subarachnoid Mirage: A Case of Pseudosubarachnoid Hemorrhage

A 22-year-old man with a history of intravenous methamphetamine use presented with severe headache for 5 days, was afebrile, and had nuchal rigidity. Computed tomography and magnetic resonance imaging results were interpreted as revealing acute subarachnoid hemorrhage. Twenty-four hours later, he developed acute neurologic deterioration. A lumbar puncture was performed, revealing the presence of Staphylococcus aureus. The false-positive image mimicking blood was potentially a result of an extremely high protein concentration present in the cerebrospinal fluid, provoked by an intense inflammatory reaction leading to disruption of the blood-brain barrier.

https://ift.tt/2NbQirQ

Normal Saline Solution and Lactated Ringer’s Solution Have a Similar Effect on Quality of Recovery: A Randomized Controlled Trial

The purpose of this study is to test the hypothesis that balanced crystalloids improve quality of recovery more than normal saline solution (0.9% sodium chloride) in stable emergency department (ED) patients. Secondary outcomes measured differences in health care use.

https://ift.tt/2NiDvUg

Optimized Reference Intervals for Plasma Free Metanephrines in Patients With CKD

The diagnostic work-up of pheochromocytoma/paraganglioma (PPGL) among patients with chronic kidney disease (CKD) is a clinical challenge. Impaired renal elimination of catecholamines and their metabolites confounds urinary tests, while increased plasma concentrations of free metanephrines in patients with CKD also complicate interpretation of plasma tests.1-3 We therefore aimed to establish optimal reference intervals for plasma free metanephrines and 3-methoxytyramine in patients with CKD stages 3 and 4 or receiving hemodialysis (HD).

https://ift.tt/2wketx6

Risk of ESRD and Mortality in Kidney and Bladder Stone Formers

Kidney stones have been associated with increased risk for end-stage renal disease (ESRD). However, it is unclear whether there is also an increased risk for mortality and if these risks are uniform across clinically distinct categories of stone formers.

https://ift.tt/2wjzFmN

Emerging Concepts in Hematopoietic Stem Cell Transplantation–Associated Renal Thrombotic Microangiopathy and Prospects for New Treatments

Thrombotic microangiopathy associated with hematopoietic stem cell transplantation (HSCT-TMA) is a well-recognized complication of HSCT that has a high risk for death. Even in patients who survive, HSCT-TMA is associated with long-term morbidity and chronic organ injury. HSCT-TMA is a multisystem disease that often affects the kidneys. Renal manifestations of HSCT-TMA include reduced glomerular filtration rate, proteinuria, and hypertension. Understanding of the pathophysiology of HSCT-TMA has expanded in the last decade.

https://ift.tt/2Pzhimt

Missed Hemodialysis Treatments: International Variation, Predictors, and Outcomes in the Dialysis Outcomes and Practice Patterns Study (DOPPS)

Missed hemodialysis (HD) treatments not due to hospitalization have been associated with poor clinical outcomes and related in part to treatment nonadherence. Using data from the Dialysis Outcomes and Practice Patterns Study (DOPPS) phase 5 (2012-2015), we report findings from an international investigation of missed treatments among patients prescribed thrice-weekly HD.

https://ift.tt/2wmjMMx

Innovations in Wearable and Implantable Artificial Kidneys

More than 2 million people worldwide receive treatment for end-stage renal disease (ESRD). Current modalities of renal replacement therapy include in-center hemodialysis, peritoneal dialysis, home hemodialysis, and kidney transplantation. Patient survival has gradually increased during the past 2 decades and efforts continue to improve mortality and quality of life for patients with ESRD. Developments in sorbent technology, nanotechnology, and cell culture techniques provide promise for new innovations in ESRD management.

https://ift.tt/2Pzh0Mp

Early Life Adversity with Height Stunting Is Associated with Cardiometabolic Risk in Adolescents Independent of Body Mass Index

To evaluate cardiovascular and metabolic function in youths adopted internationally from orphanages/institutions (postinstitutionalized) who were height-stunted at adoption.

https://ift.tt/2w85IqB

Echocardiographic estimation of elevated right ventricular afterload in preterm infants at risk for pulmonary hypertension: next steps

We read with interest the report by Levy et al,1 in which the authors use sophisticated echocardiographic variables as surrogates for right ventricular (RV) afterload (or pulmonary hemodynamic measures) and provide data on RV abnormalities in a cohort of infants born preterm with or without bronchopulmonary dysplasia (BPD) vs healthy infants born at term, at age 1 year. They report that right heart Doppler-derived echocardiographic indices of pulmonary vascular disease (PVD) (eg, pulmonary artery acceleration time [PAAT]) are inversely correlated with gestational age.

https://ift.tt/2w2RsPR

Body Mass Index Changes in Early Childhood

To longitudinally investigate body mass index (BMI) in young children in Ireland and identify factors and critical time points associated with changes in BMI.

https://ift.tt/2Lq0qLI

Inhibition of casein kinase 2 disrupts differentiation of myeloid cells in cancer and enhances the efficacy of immunotherapy in mice

The role of myeloid cells as regulators of tumor progression that significantly impact the efficacy of cancer immunotherapies makes them an attractive target for inhibition. Here we explore the effect of a novel, potent, and selective inhibitor of serine/threonine protein kinase CK2 on modulating myeloid cells in the tumor microenvironment. Although inhibition of CK2 caused only a modest effect on dendritic cells in tumor-bearing mice, it substantially reduced the amount of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSC) and tumor-associated macrophages (TAM). This effect was not caused by the induction of apoptosis, but rather by a block of differentiation. Our results implicated downregulation of CCAAT-enhancer binding protein-α (C/EBPα) in this effect. Although CK2 inhibition did not directly affect tumor cells, it dramatically enhanced the antitumor activity of immune checkpoint receptor blockade using anti-CTLA-4 antibody. These results suggest a potential role of CK2 inhibitors in combination therapies against cancer.

https://ift.tt/2w87nMD

Virtual Machines and Real Implementations

Abstract

What does it take to implement a computer? Answers to this question have often focused on what it takes for a physical system to implement an abstract machine. As Joslin (Minds Mach 16:29–41, 2006) observes, this approach neglects cases of software implementation—cases where one machine implements another by running a program. These cases, Joslin argues, highlight serious problems for mapping accounts of computer implementation—accounts that require a mapping between elements of a physical system and elements of an abstract machine. The source of these problems is the complexity introduced by common design features of ordinary computers, features that would be relevant to any real-world software implementation (e.g., virtual memory). While Joslin is focused on contemporary views, his discussion also suggests a counterexample to recent mapping accounts which hold that genuine implementation requires simple mappings (Millhouse in Br J Philos Sci, 2017. https://ift.tt/2wlCl3k; Wallace in The emergent multiverse, Oxford University Press, Oxford, 2014). In this paper, I begin by clarifying the nature of software implementation and disentangling it from closely related phenomena like emulation and simulation. Next, I argue that Joslin overstates the degree of complexity involved in his target cases and that these cases may actually give us reasons to favor simplicity-based criteria over relevant alternatives. Finally, I propose a novel problem for simplicity-based criteria and suggest a tentative solution.

https://ift.tt/2PzF8yE

Isolation and Identification of Extravascular Immune Cells of the Heart

This protocol presents a simple and efficient method to isolate, identify and quantify immune cells residing in the myocardium of mice during steady state or inflammation. The protocol combines enzymatic and mechanical digestion for the generation of a single cell suspension that can be further analyzed by flow cytometry.

https://ift.tt/2PuwPUV

Functional Characterization of Carboxylesterases in Insecticide Resistant House Flies, Musca Domestica

Here, we present a protocol to produce house fly carboxylesterase proteins in vitro with a baculovirus mediated insect cell expression system and later functionally characterize their roles in metabolizing permethrin, thereby, conferring pyrethroid resistance by conducting cell-based MTT assay and in vitro metabolic studies.

https://ift.tt/2wkJ79l

Enhancements to NCI’s SEER Program Creating New Research Opportunities

NCI's SEER program is expanding in size and operating a series of innovative pilot studies. As Dr. Lynne Penberthy explains, these studies are setting the stage for the routine collection of more clinical and genomic data that will help researchers better understand cancer and its impact.

https://ift.tt/2BBLWJb

Biomarkers for predicting efficacy of PD-1/PD-L1 inhibitors

Abstract

Programmed cell death protein 1/programmed cell death ligand 1 (PD-1/PD-L1) is a negative modulatory signaling pathway for activation of T cell. It is acknowledged that PD-1/PD-L1 axis plays a crucial role in the progression of tumor by altering status of immune surveillance. As one of the most promising immune therapy strategies, PD-1/PD-L1 inhibitor is a breakthrough for the therapy of some refractory tumors. However, response rate of PD-1/PD-L1 inhibitors in overall patients is unsatisfactory, which limits the application in clinical practice. Therefore, biomarkers which could effectively predict the efficacy of PD-1/PD-L1 inhibitors are crucial for patient selection. Biomarkers reflecting tumor immune microenvironment and tumor cell intrinsic features, such as PD-L1 expression, density of tumor infiltrating lymphocyte (TIL), tumor mutational burden, and mismatch-repair (MMR) deficiency, have been noticed to associate with treatment effect of anti-PD-1/anti-PD-L1 therapy. Furthermore, gut microbiota, circulating biomarkers, and patient previous history have been found as valuable predictors as well. Therefore establishing a comprehensive assessment framework involving multiple biomarkers would be meaningful to interrogate tumor immune landscape and select sensitive patients.

https://ift.tt/2BId09G

Exosomal double-stranded DNA as a biomarker for the diagnosis and preoperative assessment of pheochromocytoma and paraganglioma

Abstract

Pheochromocytomas (PCCs) and paragangliomas (PGLs) are the most heritable endocrine tumors. Genetic testing for 12 driver susceptibility genes is recommended in all PCC and PGL cases. However, detection of somatic mutations in PCC and PGL remains unrealizable for genetic diagnosis and preoperative assessment. We compared the serum exosomal DNA and tumor tissue DNA from patients or mice with PCC or PGL and found double-stranded DNA (dsDNA) fragments in the circulating exosomes of patients with PCC or PGL. Exosomal dsDNA shared the same mutations in the susceptibility genes with that of the parent tumor cells. Moreover, our research showed that serum-derived exosomal dsDNA in PCC and PGL was highly consistent with the paired tumor genome. Our findings provide the first definitive evidence of the presence of exosomal dsDNA that can be used as a noninvasive genetic marker in one of the most effective somatic mutation screens for the diagnosis and preoperative assessment of PCCs and PGLs.

https://ift.tt/2o69Zq8

Heterogeneous Removal of Water-Soluble Ruthenium Olefin Metathesis Catalyst from Aqueous Media Via Host-Guest Interaction

A removable water-soluble N-heterocyclic carbene (NHC) ligand in aqueous media via host-guest interaction has been developed. We demonstrated representative olefin metathesis reactions in water as well as in dichloromethane. Via either host-guest interaction or extraction, the residual ruthenium (Ru) catalyst was as low as 0.14 ppm after the reaction.

https://ift.tt/2BOg7Nw

Synthesis of Bimetallic Pt/Sn-based Nanoparticles in Ionic Liquids

A protocol for the synthesis of bimetallic nanoparticles in ionic liquids and the procedure of their catalytic testing in the selective hydrogenation of unsaturated aldehydes are described.

https://ift.tt/2o65iN4

Long-Term PPI Use Linked to Pneumonia Risk in Older Adults

THURSDAY, Aug. 23, 2018 -- Among older adults in primary care, use of proton pump inhibitors (PPIs) is associated with greater risk of pneumonia in the second year of treatment, according to a study published in the July issue of the Journal of the...

https://ift.tt/2MSHj1X

Dual Effects of Melanoma Cell-derived Factors on Bone Marrow Adipocytes Differentiation

Here, we present a reliable and straightforward two-dimensional (2D) coculture system for studying the interaction between tumor cells and bone marrow adipocytes, which reveals a dual effect of melanoma cell-derived factors on the bone marrow adipocytes differentiation and also poses a classic method for the mechanistic study of bone metastasis.

https://ift.tt/2LngRsb

Doctors' Intuition Linked to Number of Imaging Tests Ordered

THURSDAY, Aug. 23, 2018 -- Doctors' intuition plays a role in determining how many imaging tests are ordered for a patient, according to research presented at the 40th International Conference of the IEEE Engineering in Medicine and Biology Society,...

https://ift.tt/2MSHmLb

Time to Stop Cancer Screenings: What Do Patients Want to Hear?

THURSDAY, Aug. 23, 2018 -- Older adults prefer explanations about stopping cancer screening that emphasize the shift to focus on other health issues, according to a research letter published in the August issue of JAMA Oncology. Nancy L. Schoenborn,...

https://ift.tt/2Nc3IUH

Automated Flight Systems Associated With Health Costs

THURSDAY, Aug. 23, 2018 -- Health costs associated with noise from changing flight patterns over populated areas outweigh the benefits of reduced flight times, according to a study published in the August issue of the International Journal of...

https://ift.tt/2MNjwjN

Non-Medical Costs Burden Families of Hospitalized Children

THURSDAY, Aug. 23, 2018 -- The non-medical cost burden, which includes lost earnings plus expenses, is considerable among families of children who are hospitalized, according to a study published online Aug. 13 in Pediatrics. Lenisa V. Chang, Ph.D.,...

https://ift.tt/2N8KRd1

1997 to 2015 Saw Increase in HIV Viral Suppression Rates

THURSDAY, Aug. 23, 2018 -- From 1997 to 2015 there was a considerable increase in HIV viral suppression rates among people living with HIV (PLWH), according to a study published online Aug. 21 in the Annals of Internal Medicine. Robin M. Nance, from...

https://ift.tt/2MN5HSf

High Prevalence of Diabetes in Those With Severe Mental Illness

THURSDAY, Aug. 23, 2018 -- Antipsychotic-treated patients with severe mental illnesses (SMI) have a high prevalence of diabetes and prediabetes, according to a research letter published recently in Diabetes Care. Christina V. Mangurian, M.D., from...

https://ift.tt/2NfsfZb

Most Surgical Residents Want Financial Education

THURSDAY, Aug. 23, 2018 -- Surgical residents feel strongly that personal financial education should be offered during medical training, according to a study published in the August issue of the Journal of the American College of Surgeons. Sarah E....

https://ift.tt/2MMKOGU

Information Lacking on Effect of Prenatal Use of Marijuana

THURSDAY, Aug. 23, 2018 -- More information is needed on marijuana use in pregnancy, according to an Ideas and Opinions piece published online Aug. 21 in the Annals of Internal Medicine. Nancy Goler, M.D., from Kaiser Permanente Northern California...

https://ift.tt/2NevOyK

Sodium Intake, BP Linked in Communities With Highest Intake

THURSDAY, Aug. 23, 2018 -- Mean systolic blood pressure is increased with increasing sodium intake only in communities in the highest tertile of sodium intake, according to a study published online Aug. 9 in The Lancet. Andrew Mente, Ph.D., from...

https://ift.tt/2N7Z3D8

Study protocol for a controlled trial of an eHealth system utilising patient reported outcome measures for personalised treatment and care: PROMPT-Care 2.0

Abstract

Background

Routine assessment and clinical utilisation of patient-reported outcome (PRO) measures can lead to improved patient outcomes. The PROMPT-Care eHealth system facilitates PRO data capture from cancer patients, data linkage and retrieval to support clinical decisions, patient self-management, and shared care. Pilot testing demonstrated acceptability and feasibility of PROMPT-Care Version 1.0. This study aims to implement PROMPT-Care Version 2.0 and determine its efficacy in reducing emergency department (ED) presentations, and improving chemotherapy delivery and health service referrals, compared to usual care.

Methods

Groups eligible to participate in the intervention arm of this controlled trial are patients receiving cancer care (including follow-up). PROMPT-Care patients will complete monthly assessments (distress, symptoms, unmet needs) until voluntary withdrawal or death. In Version 1.0, the care team accessed patients' clinical feedback reports in 'real time' to guide their care, and patients received links to support their self-management, tailored to their PRO responses. Version 2.0 was extended to include: i) an additional alert system notifying the care team of ongoing unresolved clinical issues, ii) patient self-management resources, and iii) an auto-populated Treatment Summary and Survivorship Care Plan (SCP). The control population will be patients extracted from hospital databases of the general cancer patient population who were seen at the participating cancer therapy centres during the study period, with a ratio of 1:4 of intervention to control patients.

A minimum sample size of 1760 (352 intervention and 1408 control) patients will detect a 14% reduction in the number of ED presentations (primary outcome) in the PROMPT-Care group compared with the control group. Intervention patients will provide feedback on system usability and value of the self-management materials; oncology staff will provide feedback on usefulness of PROMPT-Care reports, response to clinical alerts, impact on routine care, and usefulness of the SCPs; and GPs will provide feedback on the usefulness of the SCPs and attitudes towards shared-care models of survivorship care planning.

Discussion

This study will inform the PROMPT-Care system's impact on healthcare utilisation and utility as an alternative model for ongoing supportive care.

Trial registration

Australian New Zealand Clinical Trials Registry (ACTRN12616000615482) on 12th May 2016 (www.anzctr.org.au).

https://ift.tt/2w7ujM6

Opisthorchiasis with proinflammatory cytokines ( IL-1β and TNF-α ) polymorphisms influence risk of intrahepatic cholangiocarcinoma in Thailand: a nested case-control study

Abstract

Background

Chronic inflammation and repeated infection with Opisthorchis viverrini (O. viverrini) induces intrahepatic cholangiocarcinoma (ICC). Inflammatory cytokines such as interleukin (IL) and tumor necrosis factor (TNF) are substances in the immune system that promote inflammation and causes disease to progress. Genes that help express proinflammatory cytokines can affect an individual's susceptibility to disease, especially in cancer-related chronic inflammation. This study aimed to investigate risk factors for ICC with a focus on opisthorchiasis and polymorphisms of proinflammatory cytokines (IL-1β and TNF-α).

Methods

This study was a nested case-control study within a cohort study. 219 subjects who developed a primary ICC were identified and matched with two non-cancer controls from the same cohort based on sex and age at recruitment (±3 years). An O. viverrini-IgG antibody was assessed using enzyme linked immunosorbent assay. IL-1β and TNF-α polymorphisms were analyzed using a polymerase chain reaction with high resolution melting analysis. Associations between variables and ICC were assessed using conditional logistic regression.

Results

Subjects with a high infection intensity had higher risk of ICC than those who had a low level (OR = 2.1; 95% CI: 1.2–3.9). Subjects with all genotypes of TNF-α (GG, GA, AA) and high infection intensity were significantly related to an increased risk of ICC (p < 0.05).

Conclusions

Polymorphisms of IL-1β and TNF-α are not a risk of ICC, but an individual with O. viverrini infection has an effect on all genotypes of the TNF-α gene that might promote ICC. Primary prevention of ICC in high-risk areas is based on efforts to reduce O. viverrini infection.

https://ift.tt/2LkyGIo

Evaluation of postoperative ascites after somatostatin infusion following hepatectomy for hepatocellular carcinoma by laparotomy: a multicenter randomized double-blind controlled trial (SOMAPROTECT)

Abstract

Background

The majority of patients undergoing hepatectomy for hepatocellular carcinoma (HCC) suffer from underlying liver disease and are exposed to the risk of postoperative ascites, which is favored by an imbalance between portal venous inflow and a diminished hepatic volume. Finding a reversible, non-invasive method for modulating the portal inflow would be of interest as it could be used temporarily during the early postoperative course. Somatostatin, a well-known drug already used in several indications, may limit the risk of postoperative ascites and liver failure by decreasing portal pressure after hepatectomy for HCC in patients with underlying liver disease. We aimed to evaluate the impact of somatostatin postoperative infusion on the incidence of ascites following hepatectomy by laparotomy for HCC in patients with underlying liver disease.

Methods/design

The SOMAPROTECT study is a multicenter randomized double-blind placebo controlled phase III trial comparing two arms of patients with underlying liver disease undergoing hepatectomy for HCC by open approach. All patients will have primary abdominal drainage before closure. Patients in the experimental arm will receive a postoperative intravenous infusion of somatostatin during 6 days. Patients in the control group will receive a placebo infusion for the same duration. The primary endpoint will be the presence or absence of postoperative ascites occurring during the 90-day postoperative course, defined as ≥500 ml/24 h of fluid in the drains during at least 3 days or any ascites requiring an invasive procedure comprising percutaneous puncture or drainage. Secondary endpoints will be duration and total volume of ascites, postoperative 90-day mortality and morbidity, liver failure, acute renal failure, length of stay in intensive care unit and hospital stay. The total number of patients to be enrolled was calculated to be 152.

Discussion

Postoperative ascites remains a major issue after hepatectomy for HCC as it is associated with increased morbidity, liver and renal failure, the need for specific treatments and prolonged hospital stay. This study represents the first randomized controlled trial to assess the benefits of somatostatin on the risk of postoperative ascites after surgery for HCC.

Trial registration

NCT02799212 (ClinicalTrials.gov identifier). Registered prior to conducting the research on 9 June 2016.

https://ift.tt/2w2oKyz

Sacral insufficiency fractures after high-dose carbon-ion based radiotherapy of sacral chordomas

Abstract

Background

This study aimed to analyse the frequency and clinical relevance of sacral insufficiency fractures (SIFs) after high-dose carbon-ion based irradiation of sacral chordomas.

Methods

A total of 56 patients were included in this retrospective study. Twenty one patients (37%) were treated with definitive radiotherapy (RT), and 35 patients (63%) received postoperative RT using carbon ions, either in combination with photons or as single-modality treatment (median radiation dose 66 Gy RBE, range 60–74 Gy). Follow-up examinations including MRI of the pelvis were performed at 3-monthly intervals in the first year and consecutively at 6-monthly intervals. Median follow-up was 35.5 months (range 2–83).

Results

SIFs were diagnosed in 29 patients (52%) after a median follow-up of 11 months (range 1–62 months). Most sacral fractures (79%) occurred within 2 years after RT. For the overall study population, the fracture-free survival probability amounted to values of 0.68 (95% CI, 0.53–0.79) after 1 year, 0.46 (95% CI, 0.31–0.60) after 2 years, and 0.31 (95% CI, 0.16–0.47) after 5 years. Statistical analysis showed no significant difference regarding the fracture rates between patients who received an operation and postoperative RT and patients treated with definitive RT. About one third of the patients with SIFs (34%; 10 of 29 patients) had associated clinical symptoms, most notably pain. All patients with symptomatic fractures required strong analgesics and often intensive pain management.

Conclusions

Sacral fractures after high-dose carbon ion-based RT of sacral chordomas were shown to be a considerable radiogenic late effect, affecting about half of the treated patients. However, only one third of these fractures were clinically symptomatic requiring regular medical care and pain therapy.

Further hazard factor analysis in the future with larger patient numbers will possibly enable the identification of high-risk patients for developing SIFs with the ultimate goal to prevent symptomatic fractures.

https://ift.tt/2wnXKJf

The effects of prophylactic cranial irradiation versus control on survival of patients with extensive-stage small-cell lung cancer: a meta-analysis of 14 trials

Abstract

Background

A recent Japanese study suggested prophylactic cranial irradiation (PCI) failed to improve survival of extensive-stage small-cell lung cancer (SCLC). However, previous studies showed that PCI was beneficial in reducing the rate of mortality for extensive-stage SCLC. In this study, we aimed to evaluate the impact of PCI on the survival of patients diagnosed with extensive-stage SCLC by meta-analysis.

Methods

PubMed, Embase, the Cochrane library and Chinese Biomedical Literature database (CBM) were systematically searched to identify eligible clinical studies assessing the efficacy of PCI in extensive-stage SCLC patients. After extracting survival data, brain metastasis, and response rates, the pooled estimates were calculated.

Results

A total of 14 clinical studies were included, involving 1221 cases in the PCI group and 5074 in the control group. The results showed that PCI significantly improved overall survival (Hazard ratio (HR) = 0.57; 95% confidence interval (CI): 0.47, 0.69; p < 0.001) and brain metastasis (risk ratio (RR) =0.47, 95%CI: 0.33, 0.69; p < 0.01). Subgroup analysis along with sensitivity analysis suggested that PCI effects on overall survival were independent of region, pre-PCI brain metastasis status and PCI administration timing.

Conclusion

PCI improves overall survival in extensive-stage SCLC. More randomized controlled trials are needed to verify our findings.

https://ift.tt/2PtiPum

Synergistic Effect of Bupleuri Radix and Scutellariae Radix on Adipogenesis and AMP-Activated Protein Kinase: A Network Pharmacological Approach

Obesity has become a major health threat in developed countries. However, current medications for obesity are limited because of their adverse effects. Interest in natural products for the treatment of obesity is thus rapidly growing. Korean medicine is characterized by the wide use of herbal formulas. However, the combination rule of herbal formulas in Korean medicine lacks experimental evidence. According to Shennong's Classic of Materia Medica, the earliest book of herbal medicine, Bupleuri Radix (BR) and Scutellariae Radix (SR) possess the Sangsoo relationship, which means they have synergistic features when used together. Therefore these two are frequently used together in prescriptions such as Sosiho-Tang. In this study, we used the network pharmacological method to predict the interaction between these two herbs and then investigated the effects of BR, SR, and their combination on obesity in 3T3-L1 adipocytes. BR, SR, and BR-SR mixture significantly decreased lipid accumulation and the expressions of two major adipogenic factors, peroxisome proliferator-activated receptor-gamma (PPARγ) and CCAAT/enhancer-binding protein-alpha (C/EBPα), and their downstream genes, Adipoq, aP2, and Lipin1 in 3T3-L1 cells. In addition, the BR-SR mixture had synergistic effects compared with BR or SR on inhibition of adipogenic-gene expressions. BR and SR also inhibited the protein expressions of PPARγ and C/EBPα. Furthermore, the two extracts successfully activated AMP-activated protein kinase alpha (AMPK α), the key regulator of energy metabolism. When compared to those of BR or SR, the BR-SR mixture showed higher inhibition rates of PPARγ and C/EBPα, along with higher activation rate of AMPK. These results indicate a new potential antiobese pharmacotherapy and also provide scientific evidence supporting the usage of herbal combinations instead of mixtures in Korean medicine.

https://ift.tt/2LiG7Qh

Organic Extract of Justicia pectoralis Jacq. Leaf Inhibits Interferon- Secretion and Has Bacteriostatic Activity against Acinetobacter baumannii and Klebsiella pneumoniae

Justicia pectoralis Jacq. (Acanthaceae) leaves currently found in the Brazilian north-east are widely used to treat diabetes, menstrual pains, asthma, and other disorders. This work aimed to identify the phytochemical characterization and biological activities of J. pectoralis leaf extracts. The plant material was ground and the crude extracts were obtained with water or acetone: water (7:3 v/v), yielding aqueous (JPA), and organic (JPO) extracts. Phytochemical characterization was performed by thin-layer chromatography (TLC) and high-performance liquid chromatography (HPLC). Cytotoxicity was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) (MTT) assay and trypan blue (TB) exclusion assay in peripheral blood mononuclear cells (PBMCs), BALB/c splenocytes, and neoplastic cells (TOLEDO, K562, DU-145, and PANC-1) at 1, 10, and 100 μg/mL. Antibacterial activity was evaluated using the microdilution test to obtain the minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC). Cytokines, IFN-γ, and IL-17A from culture supernatants of BALB/c mice splenocytes were measured by sandwich ELISA. In the TLC analysis, both JPA and JPO extracts presented coumarin and flavonoids. In addition, HPLC was able to identify coumarin, apigenin, and ellagic acid in both extracts. JPO IC50 was 57.59 ± 1.03 μg/mL (MTT) and 69.44 ± 8.08 μg/mL (TB) in TOLEDO. MIC value of JPO against Acinetobacter baumannii and Klebsiella pneumoniae was 500 μg/mL. JPO (100 μg/mL) significantly inhibited IFN-γ levels (p=0.03). J. pectoralis is a potential candidate to be further investigated as an IFN-γ inhibitory agent and against Acinetobacter baumannii and Klebsiella pneumoniae.

https://ift.tt/2w9MroB

Adjuvant sunitinib in patients with high-risk renal cell carcinoma: safety, therapy management, and patient-reported outcomes in the S-TRAC trial

Abstract

Background

Adjuvant sunitinib has significantly improved disease-free survival versus placebo in patients with renal cell carcinoma at high risk of recurrence post-nephrectomy (hazard ratio 0.76; 95% confidence interval, 0.59–0.98; two-sided P=0.03). We report safety, therapy management, and patient-reported outcomes for patients receiving sunitinib and placebo in the S-TRAC trial.

Patients and methods

Patients were stratified by the University of California, Los Angeles Integrated Staging System and Eastern Cooperative Oncology Group performance status score, and randomized (1:1) to receive sunitinib (50 mg/day) or placebo. Single dose reductions to 37.5 mg, dose delays, and dose interruptions were used to manage adverse events (AEs). Patients' health-related quality of life, including key symptoms typically associated with sunitinib, were evaluated with the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30).

Results

Patients maintained treatment for 9.5 (mean, SD 4.4) and 10.3 (mean, SD 3.7) months in the sunitinib and placebo arms, respectively. In the sunitinib arm, key AEs occurred ∼1 month (median) after start of treatment and resolved within ∼3.5 weeks (median). Many (40.6%) AEs leading to permanent discontinuation were grade 1/2, and most (87.2%) resolved or were resolving by 28 days after last treatment. Patients taking sunitinib showed a significantly lower EORTC QLQ-C30 overall health status score versus placebo, although this reduction was not clinically meaningful. Patients reported symptoms typically related to sunitinib treatment with diarrhea and loss of appetite showing clinically meaningful increases.

Conclusions

In S-TRAC, AEs were predictable, manageable, and reversible via dose interruptions, dose reductions, and/or standard supportive medical therapy. Patients on sunitinib did report increased symptoms and reduced HRQoL, but these changes were generally not clinically meaningful, apart from appetite loss and diarrhoea, and were expected in the context of known sunitinib effects.

Clinical Trial Registration

ClinicalTrials.gov, NCT00375674.

https://ift.tt/2BEw0G7

Reply to the letter to the editor “Small repeated boluses are unreliable to provide rapid analgesia with intravenous morphine titration and mislead conversion ratio to oral morphine” by Mercadante S.

https://ift.tt/2o2yVyv

Colorectal Premalignancy is Associated with Consensus Molecular Subtypes 1 and 2

Abstract

Background

Gene expression-based profiling of colorectal cancer (CRC) can be used to identify four molecularly homogeneous Consensus Molecular Subtypes (CMS) groups with unique biologic features. However, its applicability to colorectal premalignant lesions remains unknown.

Patients and methods

We assembled the largest transcriptomic premalignancy data set by integrating different public and proprietary cohorts of adenomatous and serrated polyps from sporadic (N = 311) and hereditary (N = 78) patient populations and performed a comprehensive analysis of carcinogenesis pathways using the CMS Random Forest (RF) classifier.

Results

Overall, transcriptomic subtyping of sporadic and hereditary polyps revealed CMS2 and CMS1 subgroups as the predominant molecular subtypes in premalignancy. Pathway enrichment analysis showed that adenomatous polyps from sporadic or hereditary cases (including Lynch syndrome) displayed a CMS2-like phenotype with WNT and MYC activation, whereas hyperplastic and serrated polyps with CMS1-like phenotype harbored prominent immune activation. Rare adenomas with CMS4-like phenotype showed significant enrichment for stromal signatures along with TGFβ activation. There was a strong association of CMS1-like polyps with serrated pathology, right-sided anatomic location and BRAF mutations.

Conclusions

Based on our observations made in premalignancy, we propose a model of pathway activation associated with CMS classification in colorectal carcinogenesis. Specifically, while adenomatous polyps are largely CMS2, most hyperplastic and serrated polyps are CMS1 and may transition into other CMS groups during evolution into carcinomas. Our findings shed light on the transcriptional landscape of premalignant colonic polyps and may help guide the development of future biomarkers or preventative treatments for CRC.

https://ift.tt/2BFkhHh

Induction chemotherapy (IC) followed by radiotherapy (RT) vs. cetuximab plus IC and RT in advanced laryngeal/hypopharyngeal cancer resectable only by total laryngectomy – final results of the larynx organ preservation trial DeLOS-II

Abstract

Background

The German multicenter randomized phase-II larynx-organ preservation (LOP) trial DeLOS-II was performed to prove the hypothesis that cetuximab (E) added to induction chemotherapy (IC) and radiotherapy improves laryngectomy-free survival (LFS; survival with preserved larynx) in locally advanced laryngeal/hypopharyngeal cancer (LHSCC).

Patients and methods

Treatment-naïve patients with stage III/IV LHSCC amenable to total laryngectomy (TL) were randomized to three cycles IC with TPF (docetaxel [T] and cisplatin [P] 75 mg/m²/day 1, 5-FU [F] 750 mg/m²/day days 1-5) followed by radiotherapy (69.6 Gy) without (A) or with (B) standard dose cetuximab for 16 weeks throughout IC and radiotherapy (TPFE). Response to first IC-cycle (IC-1) with ≥30% endoscopically estimated tumor surface shrinkage (ETSS) was used to define early responders; early salvage TL was recommended to non-responders. The primary objective was 24-months LFS above 35% in arm B.

Results

Of 180 patients randomized (7/2007-9/2012), 173 fulfilled eligibility criteria (A/B: larynx 44/42, hypopharynx 41/46). Because of 4 therapy-related deaths among the first 64 randomized patients, 5-FU was omitted from IC in the subsequent 112 patients reducing further fatal toxicities. Thus, IC was TPF in 61 patients and TP in 112 patients, respectively. The primary objective (24-months LFS above 35%) was equally met by arms A (40/85, 47.1%) as well as B (41/88, 46.6%). 123 early responders completed IC+RT; their overall response rates (TPF/TP) were 94.7%/87.2% in A vs. 80%/86.0% in B. The 24-months overall survival (OS) rates were 68.2% and 69.3%.

Conclusions

Despite being accompanied by an elevated frequency in adverse events, the IC with TPF/TP plus cetuximab was feasible but showed no superiority to IC with TPF/TP regarding LFS and OS at 24 months. Both early response and 24-months LFS compare very well to previous LOP trials and recommend effective treatment selection and stratification by ETSS.

Clinical trial information

NCT00508664

https://ift.tt/2o3EDAg

TP53 mutations are predictive and prognostic when co-occurring with ALK rearrangements in lung cancer

https://ift.tt/2BEv8kP

“Optimism Bias” in Contemporary National Clinical Trial Network Phase III Trials: Are We Improving?

Abstract

Background

Previous studies have found that overestimating treatment effects (i.e., "optimism bias") leads to underpowered clinical trials. The prevalence of "optimism bias" in contemporary National Clinical Trials Network (NCTN) cancer clinical trials is unknown.

Methods

We conducted a systematic review of NCTN phase III randomized trials published from January 2007 to January 2017. We compared the hypothesized vs. observed treatment effects in each trial, and examined whether trial-related factors were correlated with the study results. We also reviewed the methods of each protocol to assess whether a rationale for the hypothesized effect size was provided.

Results

We identified 161 clinical trials, of which 130 were eligible for analysis. Original protocols could not be located for 8 trials (5.0%). Twenty-eight trials (21.5%) observed a statistically significant difference in the primary endpoint favoring the experimental treatment. The median ratio of observed-to-expected HRs among trials that observed a statistically significant effect on the primary endpoint was 1.07 (range: 0.33-1.28) vs 1.32 (range: 0.86-2.02) for trials that did not, compared with 1.34 and 1.86, respectively, for National Cancer Institute (NCI) trials published between 1955 to 2006. An effect size at least as large as the one projected in the protocol trials was observed in 9.8% of trials, compared to 17% of NCI trials published from 1955 to 2006. Most trials (64.6%) provided no rationale to support the magnitude of the proposed treatment effect in the protocol.

Conclusions

Despite a reduction in "optimism bias" compared to previous eras, most contemporary NCTN phase III trials failed to establish statistically significant benefits of new cancer therapies. Better rationalization of proposed effect sizes in research protocols is needed.

https://ift.tt/2o5nqXi

SIRT1 Activation Disrupts Maintenance of Myelodysplastic Syndrome Stem and Progenitor Cells by Restoring TET2 Function

An improved understanding of the mechanisms regulating myelodysplastic syndrome (MDS) hematopoietic stem/progenitor cell (HSPC) growth and self-renewal is critical for developing MDS therapy. Sun et al. report that SIRT1 deficiency-induced TET2 hyperacetylation promotes MDS HSPC function and provides an approach to target MDS HSPCs by activating SIRT1 deacetylase.

https://ift.tt/2o1i7bj

Inhibition of Aberrant DNA Re-methylation Improves Post-implantation Development of Somatic Cell Nuclear Transfer Embryos

Gao et al. show that aberrant DNA re-methylation is a critical epigenetic barrier to SCNT embryo development. Inactivation of Dnmts can rescue re-methylation defects and improve post-implantation development of SCNT embryos and overall cloning efficiency, which is further enhanced by simultaneous removal of additional epigenetic barriers.

https://ift.tt/2BEiH8r

The Use of a Novel Tablet Application to Quantify Dysfunction in Cervical Spondylotic Myelopathy Patients

Publication date: Available online 23 August 2018

Source: The Spine Journal

Author(s): Brett D. Rosenthal, Tyler J. Jenkins, Arjun Ranade, Surabhi Bhatt, Wellington K. Hsu, Alpesh A. Patel

Abstract

Background Context

Despite the prevalence and importance of myelopathy, there is a paucity of objective and quantitative clinical measures. The most commonly used diagnostic tools available are nonquantitative physical exam findings (e.g., pathologic reflexes, gait disturbance) and subjective scoring systems (e.g., modified Japanese Orthopaedic Association (mJOA)). A decline in fine motor coordination is a hallmark of early myelopathy, which may be useful for quantitative testing.

Purpose

To identify if a novel tablet application could provide a quantitative measure of upper extremity dysfunction in cervical spondylotic myelopathy.

Study Design/Setting

Prospective cohort study Patient Sample: Adult patients with a diagnosis of cervical spondylotic myelopathy from a board-certified, spine surgeon were compared to agematched, healthy, adult control patients. Outcome Measures: Self-reported function was assessed via the mJOA. Upper extremity function was measured via the fine motor skills (FiMS) tablet test.

Methods

Subjects and controls prospectively completed the mJOA paper survey and the fine motor skills (FiMS) tablet testing, which consisted of four challenges.

Results

After age-matching, 65 controls and 28 myelopathic patients were available for comparison. The mean mJOA was 13.5 ± 2.9 in the myelopathic cohort and 17.3 ± 1.1 in the control cohort (p<0.0001). The average scores for challenges 1-4 in control patients were 24.4, 16.3, 3.2, and 6.6 respectively, whereas the average scores for the myelopathic patients were 16.6, 10.5, 1.4, and 1.8 respectively (p-values for all 4 challenges < 0.001). Based upon the 15 control subjects who repeated FiMS testing four sequential times, intra-rater reliability was excellent, yielding an interclass correlation coefficient of 0.88

Conclusions

The FiMS tablet application produced significantly lower scores in a myelopathic cohort when compared to an age-matched control cohort. This is true for all 4 challenges in the FiMS tablet application. The test can be completed in under 1.5 minutes, producing a reliable, quantitative measure of cervical myelopathy upper extremity function. In summary, the FiMS tablet application is a novel, easily administered, objectively quantifiable test for analyzing cervical spondylotic myelopathy.

https://ift.tt/2MwCICY

The Impact of Obesity on the Effectiveness of Spinal Cord Stimulation in Chronic Spine-Related Pain Patients

Publication date: Available online 22 August 2018

Source: The Spine Journal

Author(s): Nagy Mekhail, Diana Mehanny, Sherif Armanyous, Youssef Saweris, Shrif Costandi

Abstract

Background Context: Chronic pain and obesity are both on the rise. Spinal cord stimulation has gained increasing popularity in the pain management field for the treatment of spine-related chronic pain, however to-date, the correlation between the spinal cord stimulator effectiveness and increasing body mass index (BMI) has not been fully established.

Purpose: We aimed to investigate the correlation between patients' BMI and the percentage of pain relief as well as opioid utilization in chronic spine-related pain patients treated with spinal cord stimulation.

Study Design: Retrospective cohort study

Patient Sample: Patients with chronic spine-related pain who were treated with a spinal cord stimulator.

Outcome Measures: Eleven-point numeric rating scale for pain and opioid utilization.

Methods: Following IRB approval, data from all eligible subjects who had undergone a successful SCS-trial defined as ≥50% decrease in pain followed by SCS implant were collected and statistically analyzed. Patients were divided into 4 groups according to BMI. Self-reported pain scores on the 11-point numerical rating scale (NRS) were collected at baseline, 6 months and 12 months post SCS-implant visits. Opioid utilization, if any, was collected at baseline and 12 months post-SCS implant.

Results: In all, 181 patients were included. Thirty-three were under/normal weight (≤24.9 kg/m2), 72 overweight (25.0- 29.9 kg/m2), 63 obese (30.0- 39.9 kg/m2), and 13 morbidly obese (≥40.0 kg/m2). The estimated coefficients from multivariable linear regression analysis were -1.91% (95% CI:-2.82% to -0.991%) and -1.48% (95% CI: -2.30% to -0.660%) reduction in pain improvement per unit increase of BMI for 6 months and 12 months scores, respectively. The estimated coefficient of disability status was -15.3% (95% CI: -22.1% to -8.48%). The estimated coefficient for 12 month opioid equivalence was -0.08% (95% CI: -0.14 to -0.021), per 1 mg unit increase of morphine opioid equivalency. The data showed a statistically significant negative association between increasing BMI and SCS effectiveness at 6 and 12 months post-SCS therapy with a 2% reduction in efficacy for every unit increase of BMI after adjusting for confounding factors and a 20% better response in underweight/normal patients over the morbidly obese individuals which was not related to baseline pain score level. The significant difference in pain scores at 6 months (p=0.0003) and 12 months (p=0.04) post-SCS implant between obese and non-obese patients was not attributable to differences in baseline pain scores. There was no significant change in opioid utilization between baseline and 12 months post-SCS therapy.

Conclusion: A negative association between SCS effectiveness and increasing BMI was found, whereas, no significant difference was noted amongst the various BMI cohorts and the daily opioid consumption.

https://ift.tt/2P0wpnT

Long term Outcome after Spinal Fusion for Isthmic Spondylolisthesis in Adults

Publication date: Available online 22 August 2018

Source: The Spine Journal

Author(s): P Endler, P Ekman, H Ljungqvist, TB Brismar, P Gerdhem, H Möller

Abstract

Background context

Data on the long-term outcome after fusion for isthmic spondylolisthesis is scarce.

Purpose

To study patient-reported outcomes and adjacent segment degeneration (ASD) after fusion for isthmic spondylolisthesis and to compare patient-reported outcomes with a control group.

Study design/Setting

Prospective study including a cross-sectional control group.

Patient sample

Patients with isthmic spondylolisthesis underwent posterior lumbar interbody fusion (PLIF) (n=86) or posterolateral fusion (PLF) (n=77). Patient-reported outcome data was available for 73 patients in the PLIF group and 71 in the PLF group at a mean 11 (range 5-16) years after baseline. Seventy-seven patients in the PLIF group and 54 in the PLF group had radiographs at a mean 14 (range 9-19) years after baseline. One hundred thirty-six randomly selected persons from the population served as controls for the patient-reported outcomes.

Outcome measures

Patient-reported outcomes: global outcome, Oswestry Disability Index (ODI), Disability Rating Index (DRI) and Short Form (SF) 36. ASD was determined from radiographs using the UCLA grading scale.

Methods: The Chi-square test or analysis of covariance (ANCOVA) was used for group comparisons. The ANCOVA was adjusted for follow-up time, smoking, Meyerding slippage grade, teetotaler (yes/no) and, when available, the baseline level of the dependent variable. No funds were received for the conduction of this study.  The authors have no conflicts of interest.

Results

There were no significant patient-reported outcome differences between the posterior lumbar interbody fusion group and the posterolateral fusion group. The prevalence of ASD was 42% (32/77) in the posterior lumbar interbody fusion group and 26% (14/54) in the posterolateral fusion group (p=0.98). The patient-reported outcome data indicated lower physical function and more pain in the individuals with surgically treated isthmic spondylolisthesis compared to the controls.

Conclusion

Posterior lumbar interbody fusion and posterolateral fusion had similar long- term patient reported and radiological outcome. Individuals with isthmic spondylolisthesis have lower physical function and more pain several years after surgery when compared to the general population.

https://ift.tt/2MxykUw

Intervertebral Kinematics of the Cervical Spine Before, During and After High Velocity Low Amplitude Manipulation

Publication date: Available online 22 August 2018

Source: The Spine Journal

Author(s): William J Anderst, Tom Gale, Clarissa LeVasseur, Sandesh Raj, Kris Gongaware, Michael Schneider

Abstract

Background Context

Neck pain is one of the most commonly reported symptoms in primary care settings, and a major contributor to healthcare costs. Cervical manipulation is a common and clinically effective intervention for neck pain. However, the in vivo biomechanics of manipulation are unknown due to previous challenges with accurately measuring intervertebral kinematics in vivo during the manipulation.

Purpose

The objectives were to characterize manual forces and facet joint gapping during cervical spine manipulation and to assess changes in clinical and functional outcomes after manipulation. It was hypothesized that patient-reported pain would decrease and intervertebral range of motion would increase after manipulation.

Study Design/Setting

Laboratory-based prospective observational study. Patient Sample. 12 patients with acute mechanical neck pain (4 M, 8 F; average age 40±15 yrs.).

Outcome Measures

Amount and rate of cervical facet joint gapping during manipulation, amount and rate of force applied during manipulation, change in active intervertebral range of motion from before to after manipulation, numeric pain rating scale (NPRS) to measure change in pain after manipulation.

Methods

Initially, all participants completed a numeric pain rating scale (0-10). Participants then performed full range of motion (ROM) flexion/extension, rotation, and lateral bending while seated within a custom biplane radiography system. Synchronized biplane radiographs were collected at 30 images/second for 3 seconds during each movement trial. Next, synchronized, 2.0 ms duration pulsed biplane radiographs were collected at 160 images/second for 0.8 seconds during the manipulation. The manipulation was performed by a licensed chiropractor using an articular pillar push technique. For the final 5 participants, two pressure sensors placed on the thumb of the chiropractor (Novel pliance system) recorded pressure at 160 Hz. After manipulation, all participants repeated the full ROM movement testing and once again completed the NPRS. A validated volumetric model-based tracking process that matched subjectspecific bone models (from CT) to the biplane radiographs was used to track bone motion with sub-millimeter accuracy. Facet joint gapping was calculated as the average distance between adjacent articular facet surfaces. Pre to post-manipulation changes were assessed using the Wilcoxon signed-rank test. This study was funded in part by a grant of $10,000 from the NCMIC Foundation. The authors have no potential financial conflict of interest biases related to this study.

Results

The facet gap increased 0.9±0.40 mm during manipulation. The average rate of facet gapping was 6.2±3.9 mm/s. The peak force and rate of force application during manipulation were 65±4 N and 440±58 N/s. Pain score improved from 3.7±1.2 before manipulation to 2.0±1.4 after manipulation (p<0.001). Intervertebral range of motion increased after manipulation by 1.2º (p=0.006), 2.1º (p=0.01), and 3.9º (p=0.003) at the C4/C5, C5/C6 and C6/C7 motion segments, respectively, during flexion/extension, by 1.5º (p=0.028),1.9º (p=0.005), and 1.3º (p=0.050) at the C3/C4, C4/C5, and C5/C6 motion segments, respectively, during rotation, and by 1.3º (p=0.034) and 1.1º (p=0.050) at the C4/C5 and C5/C6 motion segments, respectively, during lateral bending. Global head ROM relative to the torso increased after manipulation by 8º (p=0.023), 10º (p=0.002), and 13º (p=0.019) during lateral bending, axial rotation and flexion/extension, respectively, after manipulation.

Conclusions

This study is the first to measure facet gapping during cervical manipulation on live humans. The results demonstrate that target and adjacent motion segments undergo facet joint gapping during manipulation and that intervertebral range of motion is increased in all three planes of motion after manipulation. The results suggest that clinical and functional improvement after manipulation may occur as a result of small increases in intervertebral ROM across multiple motion segments. This study demonstrates the feasibility of characterizing in real-time the manual inputs and biological responses that comprise cervical manipulation, including clinician-applied force, facet gapping, and increased intervertebral ROM. This provides a basis for future clinical trials to identify the mechanisms behind manipulation and to optimize the mechanical factors that reliably and sufficiently impact the key mechanisms behind manipulation.

https://ift.tt/2OWFs9B

Risk factors for cage migration and cage retropulsion following transforaminal lumbar interbody fusion

Publication date: Available online 22 August 2018

Source: The Spine Journal

Author(s): Man-Kyu Park, Kyoung-Tae Kim, Woo-Seok Bang, Dae-Chul Cho, Joo-Kyung Sung, Young-Seok Lee, Chang Kyu Lee, Chi Heon Kim, Brian K. Kwon, Won-Kee Lee, Inbo Han

ABSTRACT

BACKGROUND CONTEXT

Transforaminal lumbar interbody fusion (TLIF) is a widely accepted surgical procedure, but cage migration (CM) and cage retropulsion (CR) are associated with poor outcomes.

PURPOSE

This study seeks to identify risk factors associated with these serious events.

STUDY DESIGN

A prospective observational longitudinal study

PATIENT SAMPLE

Over a 5-year period, 881 lumbar levels in 784 patients were treated using TLIF at 3 spinal surgery centers.

OUTCOME MEASURES

We evaluated the odds ratio of the risk factors for CM with and without subsidence and CR in multivariate analysis.

METHODS

Our study classified CM into two subgroups: CM without subsidence and CM with subsidence. Cases of spinal canal/foramen intrusion of the cage was defined separately as CR. Patient records, operative notes, and radiographs were analyzed for factors potentially related to CM with subsidence, CM without subsidence, and CR.

RESULTS

Of 881 lumbar levels treated with TLIFs, CM without subsidence was observed in 20 (2.3%) and CM with subsidence was observed in 36 (4.1%) patients. Among the CM cases, CR was observed in 17 (17/56, 30.4%). The risk factors of CM without subsidence were osteoporosis (OR 8.73, p<.001) and use of a unilateral single cage (OR 3.57, p<.001). Osteoporosis (OR 5.77, p<.001) and endplate injury (OR 26.87, p<.001) were found to be significant risk factors for CM with subsidence. Risk factors of CR were osteoporosis (OR 7.86, p<.001), pear-shaped disc (OR 8.28, p=.001), endplate injury (OR 18.70, p<.001), unilateral single cage use (OR 4.40, p=.03), and posterior cage position (OR 6.45, p=.04). A difference in overall fusion rates was identified, with a rate of 97.1% (801 of 825) for no CM, 55.0% (11 of 20) for CM without subsidence, 41.7% (15 of 36) for CM with subsidence, and 17.6% (3 of 17) for CR at 1.5 years postoperatively.

CONCLUSIONS

Our results suggest that osteoporosis is significant risk factor for both CM and CR. In addition, a pear-shaped disc, posterior positioning of the cage, the presence of endplate injury and the use of a single cage were correlated with the CM with and without subsidence and CR.

https://ift.tt/2MwStdh