Bevacizumab in advanced lung cancer: state of the art

Future Oncology, Ahead of Print.


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Adaptive Global Innovative Learning Environment for Glioblastoma: GBM AGILE

Glioblastoma (GBM) is a deadly disease with few effective therapies. While much has been learned about the molecular characteristics of the disease, this knowledge has not been translated into clinical improvements for patients. At the same time, many new therapies are being developed. Many of these therapies have potential biomarkers to identify responders. The result is an enormous amount of testable clinical questions that must be answered efficiently. The GBM Adaptive Global Innovative Learning Environment (GBM AGILE) is a novel, multi-arm, platform trial designed to address these challenges. It is the result of the collective work of over 130 oncologists, statisticians, pathologists, neurosurgeons, imagers, and translational and basic scientists from around the world. GBM AGILE is comprised of two stages. The first stage is a Bayesian adaptively randomized screening stage to identify effective therapies based on impact on overall survival compared with a common control. This stage also finds the population in which the therapy shows the most promise based on clinical indication and biomarker status. Highly effective therapies transition in an inferentially seamless manner in the identified population to a second confirmatory stage. The second stage uses fixed randomization to confirm the findings from the first stage in order to support registration. Therapeutic arms with biomarkers may be added to the trial over time while others complete testing. The design of GBM AGILE enables rapid clinical testing of new therapies and biomarkers to speed highly effective therapies to clinical practice.

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Personalized Medicine Based Approach to Model Patterns of Chemoresistance and Tumor Recurrence Using Ovarian Cancer Stem Cell Spheroids

Purpose: Chemoresistant ovarian cancers grow in suspension within the ascites fluid. In order to screen the effect of chemotherapeutics and biologics on resistant ovarian cancers with a personalized basis, we developed a 3D hanging drop spheroid platform. Experimental Design: We initiated spheroids with primary ALDH+ CD133+ ovarian cancer stem cells (OvCSCs) from different patient samples, and demonstrated that stem cell progeny from harvested spheroids was similar to the primary tumor. OvCSC spheroids were utilized to initiate tumors in immune-deficient mice. Drug responses to cisplatin and ALDH targeting compound or JAK2 inhibitor determined if the OvCSC population within the spheroids could be targeted. Cells that escaped therapy were isolated and used to initiate new spheroids and model tumor re-emergence in a personalized manner. Results: OvCSC spheroids from different patients exhibited varying, and personalized responses to chemotherapeutics. Xenografts were established from OvCSC spheroids, even with one single spheroid. Distinct responses to therapy were observed in distinct primary tumor xenografts similar to those observed in spheroids. Spheroids resistant to Cisplatin/ALDH inhibitor therapy had persistent, albeit lower ALDH expression and complete loss of CD133 expression while those resistant to cisplatin/JAK2 inhibitor therapy were enriched for ALDH+ cells. Conclusions: Our 3D hanging drop suspension platform can be used to propagate primary OvCSCs that represent individual patient tumors effectively by differentiating in vitro, and initiating tumors in mice. Therefore, our platform can be used to study cancer stem cell biology, and model tumor re-emergence to identify new targeted therapeutics from an effective personalized medicine standpoint.

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Combined CDK4/6 and mTOR inhibition is synergistic against glioblastoma via multiple mechanisms

Purpose: Glioblastoma (GBM) is a deadly brain tumor marked by dysregulated signaling and aberrant cell cycle control. Molecular analyses have identified that the CDK4/6-Rb-E2F axis is dysregulated in about 80% of GBMs. Single-agent CDK4/6 inhibitors have failed to provide durable responses in GBM, suggesting a need to combine them with other agents. We investigate the efficacy of the combination of CDK4/6 inhibition and mTOR inhibition against GBM. Experimental Design: Preclinical in vitro and in vivo assays using primary GBM cell lines were performed. Results: We show that the CDK4/6 inhibitor palbociclib suppresses the activity of downstream mediators of the mTOR pathway, leading to rebound mTOR activation that can be blocked by the mTOR inhibitor everolimus. We further show that mTOR inhibition with everolimus leads to activation of the Ras mediator Erk that is reversible with palbociclib. The combined treatment strongly disrupts GBM metabolism, resulting in significant apoptosis. Further increasing the utility of the combination for brain cancers, everolimus significantly increases the brain concentration of palbociclib. Conclusions: Our findings demonstrate that the combination of CDK4/6 and mTOR inhibition has therapeutic potential against GBM and suggest it should be evaluated in a clinical trial.

http://ift.tt/2whe2oO

Atypical presentation of anti-N-methyl-D-aspartate receptor encephalitis: two case reports

Anti-N-methyl-D-aspartate receptor encephalitis is a rare autoimmune disease characterized by severe neurological and psychiatric symptoms and a difficult diagnosis.

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Alterations in SCAI Expression during Cell Plasticity, Fibrosis and Cancer

Abstract

Suppressor of cancer cell invasion (SCAI) has been originally characterized as a tumor suppressor inhibiting metastasis in different human cancer cells, and it has been suggested that SCAI expression declines in tumors. The expression patterns and role of SCAI during physiological and pathophysiological processes is still poorly understood. Earlier we demonstrated that SCAI is regulating the epithelial-mesenchymal transition of proximal tubular epithelial cells, it is downregulated during renal fibrosis and it is overexpressed in Wilms' tumors. Here we bring further evidence for the involvement of SCAI during cell plasticity and we examine the prognostic value and expression patterns of SCAI in various tumors. SCAI prevented the activation of the SMA promoter induced by angiotensin II. SCAI expression decreased in a model of endothelial-mesenchymal transition and increased during iPS reprogramming of fibroblasts. During renal fibrosis SCAI expression declined, as evidenced in a rat model of renal transplant rejection and in TGF-β1 overexpressing transgenic mice. High expression of SCAI correlated with better survival in patients with breast and lung cancers. Intriguingly, in the case of other cancers (gastric, prostate, colorectal) high SCAI expression correlated with poor survival of patients. Finally, we bring evidence for SCAI overexpression in colorectal cancer patients, irrespective of stage or metastatic status of the disease, suggesting a diverse role of SCAI in various diseases and cancer.

http://ift.tt/2x5WZDo

Alterations in SCAI Expression during Cell Plasticity, Fibrosis and Cancer

Abstract

Suppressor of cancer cell invasion (SCAI) has been originally characterized as a tumor suppressor inhibiting metastasis in different human cancer cells, and it has been suggested that SCAI expression declines in tumors. The expression patterns and role of SCAI during physiological and pathophysiological processes is still poorly understood. Earlier we demonstrated that SCAI is regulating the epithelial-mesenchymal transition of proximal tubular epithelial cells, it is downregulated during renal fibrosis and it is overexpressed in Wilms' tumors. Here we bring further evidence for the involvement of SCAI during cell plasticity and we examine the prognostic value and expression patterns of SCAI in various tumors. SCAI prevented the activation of the SMA promoter induced by angiotensin II. SCAI expression decreased in a model of endothelial-mesenchymal transition and increased during iPS reprogramming of fibroblasts. During renal fibrosis SCAI expression declined, as evidenced in a rat model of renal transplant rejection and in TGF-β1 overexpressing transgenic mice. High expression of SCAI correlated with better survival in patients with breast and lung cancers. Intriguingly, in the case of other cancers (gastric, prostate, colorectal) high SCAI expression correlated with poor survival of patients. Finally, we bring evidence for SCAI overexpression in colorectal cancer patients, irrespective of stage or metastatic status of the disease, suggesting a diverse role of SCAI in various diseases and cancer.

http://ift.tt/2x5WZDo

Sparing all salivary glands with IMRT for head and neck cancer: Longitudinal study of patient-reported xerostomia and head-and-neck quality of life

While parotid-sparing intensity modulated radiotherapy (IMRT) has demonstrated superiority to conventional RT in terms of observer-rated xerostomia, patient-reported outcome measures (PROMs) have only marginally improved. We investigated how sparing all salivary glands affects PROMs.

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Antitumor activity of the dual PI3K/MTOR inhibitor, PF-04691502, in combination with radiation in head and neck cancer

Head and neck squamous cell carcinoma (HNSCC) remains a clinical challenge where new treatments are required to supplement the current-standard-of care of concurrent chemoradiation. The PI3K/AKT/MTOR pathway has been identified from several next generation DNA sequencing studies to be commonly altered and activated in HNSCC.

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Development of a virtual spacer to support the decision for the placement of an implantable rectum spacer for prostate cancer radiotherapy: Comparison of dose, toxicity and cost-effectiveness

Previous studies have shown that the implantable rectum spacer (IRS) is not beneficial for all patients. A virtual IRS (V-IRS) was constructed to help identify the patients for whom it is cost-effective to implant an IRS, and its viability as a tool to tailor the decision of an IRS implantation to be beneficial for the specified patient was assessed. Please watch animation:(https://www.youtube.com/watch?v=tDlagSXMKqw)

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Inhibitory growth evaluation and apoptosis induction in MCF-7 cancer cells by new 5-aryl-2-butylthio-1,3,4-oxadiazole derivatives

Abstract

Background

Cancer has become one of the global health issues and it is the life-threatening disease characterized by unrestrained growth of cells. Despite various advances being adopted by chemotherapeutic management, the use of the current anticancer drugs such as Doxorubicin, Asparginase, Methotrexate, Vincristine remains limited due to high toxicity, side effects and developing drug resistance. Apoptosis is a crucial cellular process and improper regulation of apoptotic signaling pathways may lead to cancer formation. Subsequently, the synthesis of effective chemotherapeutic agents that can induce apoptosis in tumor cell has emerged as a significant approach in cancer drug discovery.

Methods

The goal of this work is to develop a potential antitumor agent exerting significant inhibitory effects on cancer cell and low cytotoxicity, for which we focused on the structural features of 1,3,4-oxadiazoles as it a privileged scaffold in modern medicinal chemistry and have the ability to inhibit growth factors, enzymes and kinases potentially involved in the attainment of cellular immortality and carcinogenesis.

Result

In vitro MTT screening assay showed the compound 5-aminophenyl-2-butylthio-1,3,4-oxadiazole (5e) showing the highest inhibitory effect against MCF-7 cancer cell with IC₅₀ value 10.05 ± 1.08 µM while it is much safer and less toxic on normal cell line (HEK-293). The dose-dependent treatment of MCF-7 cells with 5e resulted in inhibition of cell migration in the wound healing assay. The flow-cytometry analysis showed the cells arrested in G0/G1 phase of the cell cycle. Compound 5e induced apoptosis of MCF-7 cells was characterized using DAPI staining and Annexin V-PE/7-AAD dual binding assay. Reduction of NBT by compound 5e showed a reduced generation of ROS. Western blotting studies showed high activation of apoptotic protein Caspase3 and decrease in expression of anti-apoptotic protein BCL-2.

Conclusion

Based on the results of in vitro studies, it could be concluded that compound 5e showed a significant inhibitory growth effect on MCF-7 cells and have the potential to be developed as lead molecule and further structural modifications may result in promising new anticancer agents.

Graphical abstract

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Treatment selection in oropharyngeal cancer: a surveillance, epidemiology, and end results (SEER) patterns of care analysis

Abstract

Purpose

Treatment for oropharyngeal cancer (OPC) has changed over the past two decades under multiple influences. We provide a population-based description of the application of radiotherapy, surgery, and chemotherapy to OPC in 1997, 2004, and 2009.

Methods

The National Cancer Institute's Patterns of Care study for OPC included multiple variables not available in the public-use dataset. We identified factors correlating with selection of primary surgery versus radiotherapy with or without chemotherapy (RTC) and analyzed predictors of all-cause mortality. We estimated the frequency of human papillomavirus (HPV) testing.

Results

RTC was more common in 2009 than in 1997, and was more commonly applied to Stage IV cases. However, RTC was not an independent risk factor for mortality compared with surgery. HPV status was known in 14% of patients in 2009.

Conclusions

RTC is the most common treatment for OPC, but it may not provide the best outcomes. HPV testing was uncommon in 2009.

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Table of Content Volume 56, Number 10, October 2017

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Continuing chronic beta-blockade in the acute phase of severe sepsis and septic shock is associated with decreased mortality rates up to 90 days

Abstract

Background. There is growing evidence that beta-blockade may reduce mortality in selected patients with sepsis. However, it is unclear if a pre-existing, chronic oral beta-blocker therapy should be continued or discontinued during the acute phase of severe sepsis and septic shock.Methods. The present secondary analysis of a prospective observational single centre trial compared patient and treatment characteristics, length of stay and mortality rates between adult patients with severe sepsis or septic shock, in whom chronic beta-blocker therapy was continued or discontinued, respectively. The acute phase was defined as the period ranging from two days before to three days after disease onset. Multivariable Cox regression analysis was performed to compare survival outcomes in patients with pre-existing chronic beta-blockade.Results. A total of 296 patients with severe sepsis or septic shock and pre-existing, chronic oral beta-blocker therapy were included. Chronic beta-blocker medication was discontinued during the acute phase of sepsis in 129 patients and continued in 167 patients. Continuation of beta-blocker therapy was significantly associated with decreased hospital (P=0.03), 28-day (P=0.04) and 90-day mortality rates (40.7% vs 52.7%; P=0.046) in contrast to beta-blocker cessation. The differences in survival functions were validated by a Log-rank test (P=0.01). Multivariable analysis identified the continuation of chronic beta-blocker therapy as an independent predictor of improved survival rates (HR = 0.67, 95%-CI (0.48, 0.95), P=0.03).Conclusions. Continuing pre-existing chronic beta-blockade might be associated with decreased mortality rates up to 90 days in septic patients.

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Epidemiology of sepsis and septic shock in critical care units: comparison between sepsis-2 and sepsis-3 populations using a national critical care database

Abstract

Background: New sepsis and septic shock definitions could change the epidemiology of sepsis because of differences in criteria. We therefore compared the sepsis populations identified by the old and new definitions.Methods: We used a high-quality, national, intensive care unit (ICU) database of 654 918 consecutive admissions to 189 adult ICUs in England, from January 2011 to December 2015. Primary outcome was acute hospital mortality. We compared old (Sepsis-2) and new (Sepsis-3) incidence, outcomes, trends in outcomes, and predictive validity of sepsis and septic shock populations.Results: From among 197 724 Sepsis-2 severe sepsis and 197 142 Sepsis-3 sepsis cases, we identified 153 257 Sepsis-2 septic shock and 39 262 Sepsis-3 septic shock cases. The extrapolated population incidence of Sepsis-3 sepsis and Sepsis-3 septic shock was 101.8 and 19.3 per 100 000 person-years, respectively, in 2015. Sepsis-2 severe sepsis and Sepsis-3 sepsis had similar incidence, similar mortality and showed significant risk-adjusted improvements in mortality over time. Sepsis-3 septic shock had a much higher Acute Physiology And Chronic Health Evaluation II (APACHE II) score, greater mortality and no risk-adjusted trends in mortality improvement compared with Sepsis-2 septic shock. ICU admissions identified either as Sepsis-3 sepsis or septic shock and as Sepsis-2 severe sepsis or septic shock had significantly greater risk-adjusted odds of death compared with non-sepsis admissions (P<0.001). The predictive validity was greatest for Sepsis-3 septic shock.Conclusions: In an ICU database, compared with Sepsis-2, Sepsis-3 identifies a similar sepsis population with 92% overlap and much smaller septic shock population with improved predictive validity.

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Frontal alpha-delta EEG does not preclude volitional response during anaesthesia: prospective cohort study of the isolated forearm technique

Abstract

Background: The isolated forearm test (IFT) is the gold standard test of connected consciousness (awareness of the environment) during anaesthesia. The frontal alpha-delta EEG pattern (seen in slow wave sleep) is widely held to indicate anaesthetic-induced unconsciousness. A priori we proposed that one responder with the frontal alpha-delta EEG pattern would falsify this concept.Methods: Frontal EEG was recorded in a subset of patients from three centres participating in an international multicentre study of IFT responsiveness following tracheal intubation. Raw EEG waveforms were analysed for power–frequency spectra, depth-of-anaesthesia indices, permutation entropy, slow wave activity saturation and alpha-delta amplitude-phase coupling.Results: Volitional responses to verbal command occurred in six out of 90 patients. Three responses occurred immediately following intubation in patients (from Sites 1 and 2) exhibiting an alpha-delta dominant (delta power >20 dB, alpha power >10 dB) EEG pattern. The power–frequency spectra obtained during these responses were similar to those of non-responders (P>0.05) at those sites. A further three responses occurred in (Site 3) patients not exhibiting the classic alpha-delta EEG pattern; these responses occurred later relative to intubation, and in patients had been co-administered ketamine and less volatile anaesthetic compared with Site 1 and 2 patients. None of the derived depth-of-anaesthesia indices could robustly discrimate IFT responders and non-responders.Conclusions: Connected consciousness can occur in the presence of the frontal alpha-delta EEG pattern during anaesthesia. Frontal EEG parameters do not readily discriminate volitional responsiveness (a marker of connected consciousness) and unresponsiveness during anaesthesia.Clinical trial registration: NCT02248623

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Prehabilitation

1I052A073J03

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O -(2-[ 18 F]fluoroethyl)- l -tyrosine PET in gliomas: influence of data processing in different centres

Abstract

Background

PET using O-(2-[¹⁸F]fluoroethyl)-l-tyrosine (¹⁸F-FET) is an established method for brain tumour diagnostics, but data processing varies in different centres. This study analyses the influence of methodological differences between two centres for tumour characterization with ¹⁸F-FET PET using the same PET scanner.

Methodological differences between centres A and B in the evaluation of ¹⁸F-FET PET data were identified for (1) framing of PET dynamic data, (2) data reconstruction, (3) cut-off values for tumour delineation to determine tumour-to-brain ratios (TBR) and tumour volume (T_vol) and (4) ROI definition to determine time activity curves (TACs) in the tumour. Based on the ¹⁸F-FET PET data of 40 patients with untreated cerebral gliomas (20 WHO grade II, 10 WHO grade III, 10 WHO grade IV), the effect of different data processing in the two centres on TBR_mean, TBR_max, T_vol, time-to-peak (TTP) and slope of the TAC was compared. Further, the effect on tumour grading was evaluated by ROC analysis.

Results

Significant differences between centres A and B were found especially for TBR_max (2.84 ± 0.99 versus 3.34 ± 1.13; p < 0.001), T_vol (1.14 ± 1.28 versus 1.51 ± 1.44; p < 0.001) and TTP (22.4 ± 8.3 min versus 30.8 ± 6.3 min; p < 0.001) and minor differences for TBR_mean and slope. Tumour grading was not influenced by different data processing.

Conclusions

Variable data processing of ¹⁸F-FET PET in different centres leads to significant differences especially for TBR_max and T_vol. A standardization of data processing and evaluation is needed to make ¹⁸F-FET PET comparable between different centres.

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A human PET study of [ 11 C]HMS011, a potential radioligand for AMPA receptors

Abstract

Background

α-Amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptor is a primary mediator of fast glutamatergic excitatory signaling in the brain and has been implicated in diverse neuropsychiatric diseases. We recently developed a novel positron emission tomography (PET) ligand, 2-(1-(3-([¹¹C]methylamino)phenyl)-2-oxo-5-(pyrimidin-2-yl)-1,2-dihydropyridin-3-yl) benzonitrile ([¹¹C]HMS011). This compound is a radiolabelled derivative of perampanel, an antiepileptic drug acting on AMPA receptors, and was demonstrated to have promising in vivo properties in the rat and monkey brains. In the current study, we performed a human PET study using [¹¹C]HMS011 to evaluate its safety and kinetics.

Four healthy male subjects underwent a 120-min PET scan after injection of [¹¹C]HMS011. Arterial blood sampling and metabolite analysis were performed to obtain parent input functions for three of the subjects using high-performance liquid chromatography. Regional distribution volumes (V _Ts) were calculated based on kinetic models with and without considering radiometabolite in the brain. The binding was also quantified using a reference tissue model with white matter as reference.

Results

Brain uptake of [¹¹C]HMS011 was observed quickly after the injection, followed by a rapid clearance. Three hydrophilic and one lipophilic radiometabolites appeared in the plasma, with notable individual variability. The kinetics in the brain with apparent radioactivity retention suggested that the lipophilic radiometabolite could enter the brain. A dual-input graphical model, an analytical model designed in consideration of a radiometabolite entering the brain, well described the kinetics of [¹¹C]HMS011. A reference tissue model showed small radioligand binding potential (BP*_ND) values in the cortical regions (BP*_ND = 0–0.15). These data suggested specific binding component of [¹¹C]HMS011 in the brain.

Conclusions

Kinetic analyses support some specific binding of [¹¹C]HMS011 in the human cortex. However, this ligand may not be suitable for practical AMPA receptor PET imaging due to the small dynamic range and metabolite in the brain.

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Anaphylactoid Purpura Associated with Streptococcal Cellulitis: A Case Report and Literature Review

A 54-year-old Japanese man noticed painful swelling and redness of his left leg. He was admitted for treatment of cellulitis, which was accompanied with increased anti-streptolysin O and anti-streptokinase titers in his clinical course. After Piperacillin/Tazobactam administration, the skin lesion resolved. However, the patient then developed arthritis, palpable purpura, and intermittent abdominal pain, later found to be secondary to a severe duodenal ulcer. He was diagnosed with cellulitis-associated anaphylactoid purpura and was given prednisolone, which dramatically improved his symptoms. The anaphylactoid purpura was likely caused by Streptococcus-induced cellulitis, which was successfully treated with prednisolone. Association between these diseases is rare.

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Annexin A2 could enhance multidrug resistance by regulating NF-κB signaling pathway in pediatric neuroblastoma

Abstract

Background

Chemotherapy is one of major therapeutic regimens for neuroblastoma (NB) in children. However, recurrence and metastasis associated with poor prognosis caused by acquired multidrug resistance remains a challenge. There is a great need to achieve new insight into the molecular mechanism of drug resistance in NB. The aim of this study is to identify novel drug sensitivity-related biomarkers as well as new therapeutic targets to overcome chemoresistance.

Methods

We proteome-wide quantitatively compared protein expression of two NB cell lines with different drug sensitivities, isolated from the same patient prior to and following chemotherapy. Annexin A2 (ANXA2) emerged as a key factor contributing to drug resistance in NB. Then, we assessed the correlation of ANXA2 expression and clinical characteristics using a tissue microarray. Further, the roles of ANXA2 in chemoresistance for NB and the underlying mechanisms were studied by using short hairpin RNA (shRNA) in vitro and vivo.

Results

First in total, over 6000 proteins were identified, and there were about 460 significantly regulated proteins which were up- or down-regulated by greater than two folds. We screened out ANXA2 which was upregulated by more than 12-fold in the chemoresistant NB cell line, and it might be involved in the drug resistance of NB. Then, using a tissue chip containing 42 clinical NB samples, we found that strong expression of ANXA2 was closely associated with advanced stage, greater number of chemotherapy cycles, tumor metastasis and poor prognosis. Following knockdown of ANXA2 in NB cell line SK-N-BE(2) using shRNA, we demonstrate enhanced drug sensitivity for doxorubicin (2.77-fold) and etoposide (7.87-fold) compared with control. Pro-apoptotic genes such as AIF and cleaved-PARP were upregulated. Inhibiting ANXA2 expression attenuated transcriptional activity of NF-κB via down-regulated nuclear translocation of subunit p50. Finally, simulated chemotherapy in a xenograft NB nude mouse model suggests that ANXA2 knockdown could improve clinical results in vivo.

Conclusion

Our profiling data provided a rich source for further study of the molecular mechanisms of acquired drug resistance in NB. Further study may determine the role of ANXA2 as a prognostic biomarker and a potential therapeutic target for patients with multidrug-resistant NB.

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Recommendations for biomarker testing in epithelial ovarian cancer: a National Consensus Statement by the Spanish Society of Pathology and the Spanish Society of Medical Oncology

Abstract

Because of advances in the understanding of histological and molecular characteristics in ovarian cancer, it is now possible to recognize the existence of five subtypes, which in turn has allowed a more refined therapeutic approach and better design of clinical trials. Each of these five subtypes has specific histological features and a particular biomarker expression, as well as mutations in different genes, some of which have prognostic and predictive value. CA125 and HE4 are examples of ovarian cancer biomarkers used in the diagnosis and follow-up of these malignancies. Currently, somatic or germinal mutations on BRCA1 and BRCA2 genes are the most important biomarkers in epithelial ovarian cancer having prognostic and predictive value. This article will review the histological and molecular characteristics of the five subtypes of ovarian cancer, describing the most important biomarkers and mutations that can guide in diagnosis, screening and tailored treatment strategy.

http://ift.tt/2uIBDPu

Recommendations for biomarker testing in epithelial ovarian cancer: a National Consensus Statement by the Spanish Society of Pathology and the Spanish Society of Medical Oncology

Abstract

Because of advances in the understanding of histological and molecular characteristics in ovarian cancer, it is now possible to recognize the existence of five subtypes, which in turn has allowed a more refined therapeutic approach and better design of clinical trials. Each of these five subtypes has specific histological features and a particular biomarker expression, as well as mutations in different genes, some of which have prognostic and predictive value. CA125 and HE4 are examples of ovarian cancer biomarkers used in the diagnosis and follow-up of these malignancies. Currently, somatic or germinal mutations on BRCA1 and BRCA2 genes are the most important biomarkers in epithelial ovarian cancer having prognostic and predictive value. This article will review the histological and molecular characteristics of the five subtypes of ovarian cancer, describing the most important biomarkers and mutations that can guide in diagnosis, screening and tailored treatment strategy.

http://ift.tt/2uIBDPu

Impact of new generation hormone-therapy on cognitive function in elderly patients treated for a metastatic prostate cancer: Cog-Pro trial protocol

Abstract

Background

New generation hormone-therapies (NGHT) targeting the androgen signalling pathway are nowadays proposed to elderly patients with metastatic castration-resistant prostate cancer (CRPCa). The impact of these treatments on cognitive function has never been evaluated whereas cognitive impairment may have an impact on the autonomy and the treatment adherence. The aim of this study is to prospectively assess the incidence of cognitive impairment in elderly men after treatment by NGHT for a metastatic CRPCa.

Methods/design

The Cog-Pro study is a multicentre longitudinal study including CRPCa patients ≥70 years old treated with NGHT (n = 134), control metastatic prostate cancer patients without castration resistance treated with first generation androgen deprivation therapy (n = 55), and healthy participants (n = 33), matched on age and education. Cognitive, geriatric and quality of life assessment and biological tests will be performed at baseline, 3, 6 and 12 months after start of the treatment (inclusion time). The primary endpoint is the proportion of elderly patients receiving a NGHT who will experience a decline in cognitive performances within 3 months after study enrollment. Secondary endpoints concern: autonomy, quality of life, anxiety, depression, cognitive reserve, adherence to hormone-therapy, comparison of the cognitive impact of 2 different NGHT (abiraterone acetate and enzalutamide), impact of co-morbidities and biological assessments.

Discussion

Evaluating, understanding and analyzing the incidence, severity of cognitive impairments and their impact on quality of life, autonomy and adherence in this group of patients with advanced disease is a challenge. This study should help to improve cancer care of elderly patients and secure the use of oral treatments as the risk of non-observance does exist. Our results will provide up-to date information for patients and caregivers on impact of these treatments on cognitive function in order to help the physicians in the choice of the treatment.

Trial registration

NCT02907372, registered: July 26, 2016.

http://ift.tt/2weYEcH

Randomized study comparing full dose monotherapy (S-1 followed by irinotecan) and reduced dose combination therapy (S-1/oxaliplatin followed by S-1/irinotecan) as initial therapy for older patients with metastatic colorectal cancer: NORDIC 9

Abstract

Background

Metastatic colorectal cancer (mCRC) is a disease of older age, but there is a relative lack of knowledge about effects of chemotherapy in older patients as they are under-represented in clinical trials. Little data can guide whether the strategy in older mCRC patients should be a sequential full-dose monotherapy chemotherapy approach or a dose-reduced combination chemotherapy approach. The oral 5FU prodrug S-1 seems to have less side effects than capecitabine and should be an optimal drug for older patients, but few data are available. Improved geriatric assessments are needed to select which older patients should receive therapy.

Methods

The NORDIC 9 trial is a Nordic multicenter randomized phase II study comparing full dose monotherapy (S-1 30 mg/m² twice daily days 1–14 every 3 weeks, followed by second line irinotecan 250–350 mg/m² iv day 1 every 3 weeks or 180–250 mg/m² iv day 1 every 2 weeks) with reduced dose combination therapy (S-1 20 mg/m² days 1–14 + oxaliplatin 100 mg/m² iv day 1 every 3 weeks, followed by second line S-1 20 mg/m² days 1–14 + irinotecan 180 mg/m² day 1 every 3 week) for older patients (≥70 years) with mCRC who are not candidates for full-dose standard combination therapy. Additional bevacizumab (7.5 mg/kg) is optional in first-line. Blood samples and tumor tissue will be collected to investigate predictive markers. Geriatric screening tools (G-8, VES-13, Timed-Up-and-Go and Handgrip strength), Charlson Comorbidty Index and quality of life (EORTC QLQ-C30) will be evaluated as predictors of efficacy and toxicity. The target sample size is 150 patients.

The primary endpoint is progression-free survival and secondary endpoints are time-to-failure of strategy, overall survival, response rate, toxicity, and correlations between biomarkers, pre-treatment characteristics and geriatric assessments.

Discussion

The study will add knowledge on how to treat older mCRC patients who are not candidates for standard combination therapy. Furthermore it may provide understanding of efficacy and tolerability of chemotherapy in older cancer patients and thus offer a better chance for tailored treatment strategies in these patients.

Trial registration

EU Clinical Trial Register, EudraCT no. 2014–000394-39. Registered 05 May 2014.

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RE: “ATTENDANCE AT RELIGIOUS SERVICES, PRAYER, RELIGIOUS COPING, AND RELIGIOUS/SPIRITUAL IDENTITY AS PREDICTORS OF ALL-CAUSE MORTALITY IN THE BLACK WOMEN'S HEALTH STUDY”

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Reproducing Epidemiologic Research and Ensuring Transparency

Abstract

Measures for ensuring that epidemiologic studies are reproducible include making data sets and software available to other researchers so they can verify published findings, conduct alternative analyses of the data, and check for statistical errors or programming errors. Recent developments related to the reproducibility and transparency of epidemiologic studies include the creation of a global platform for sharing data from clinical trials and the anticipated future extension of the global platform to non–clinical trial data. Government agencies and departments such as the US Department of Veterans Affairs Cooperative Studies Program have also enhanced their data repositories and data sharing resources. The Institute of Medicine and the International Committee of Medical Journal Editors released guidance on sharing clinical trial data. The US National Institutes of Health has updated their data-sharing policies. In this issue of the Journal, Shepherd et al. (Am J Epidemiol. 2017;186:387–392) outline a pragmatic approach for reproducible research with sensitive data for studies for which data cannot be shared because of legal or ethical restrictions. Their proposed quasi-reproducible approach facilitates the dissemination of statistical methods and codes to independent researchers. Both reproducibility and quasi-reproducibility can increase transparency for critical evaluation, further dissemination of study methods, and expedite the exchange of ideas among researchers.

http://ift.tt/2uI5Zlm

A Pragmatic Approach for Reproducible Research With Sensitive Data

Abstract

Reproducible research is important for assessing the integrity of findings and disseminating methods, but it requires making original study data sets publicly available. This requirement is difficult to meet in settings with sensitive data, which can mean that resulting studies are not reproducible. For studies in which data cannot be shared, we propose a pragmatic approach to make research quasi-reproducible. On a publicly available website without restriction, researchers should post 1) analysis code used in the published study, 2) simulated data, and 3) results obtained by applying the analysis code used in the published study to the simulated data. Although it is not a perfect solution, such an approach makes analyses transparent for critical evaluation and dissemination and is therefore a significant improvement over current practice.

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Dietary Intake of Antioxidant Vitamins and Carotenoids and Risk of Developing Active Tuberculosis in a Prospective Population-Based Cohort Study

Abstract

Antioxidants may protect against oxidative stress, which is associated with tuberculosis (TB) disease. However, direct evidence for a protective association between dietary antioxidants and TB incidence in humans has been lacking. The relationship between intake of antioxidant vitamins (vitamins A, C, D, and E) and individual carotenoids (α-carotene, β-carotene, β-cryptoxanthin, lycopene, and lutein) and TB incidence was examined in the Singapore Chinese Health Study, a prospective cohort study of 63,257 adults aged 45–74 years enrolled during 1993–1998. Baseline intake of these antioxidants was estimated using a validated semiquantitative food frequency questionnaire including questions on use of dietary supplements. After an average of 16.9 years of follow-up, 1,186 incident active TB cases were identified among cohort participants. Compared with the lowest quartile, reduced risk of active TB was observed for the highest quartile of vitamin A intake (hazard ratio = 0.71, 95% confidence interval: 0.59, 0.85; P-trend < 0.01) and β-carotene intake (hazard ratio = 0.76, 95% confidence interval: 0.63, 0.91; P-trend < 0.01), regardless of smoking status. Lower TB risk was seen for vitamin C intake among current smokers only. Other vitamins and carotenoids were not associated with TB risk. These results suggest that vitamin C may reduce TB risk among current smokers by ameliorating oxidative stress, while vitamin A and β-carotene may have additional antimycobacterial properties.

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Deployment and Alcohol Use in a Military Cohort: Use of Combined Methods to Account for Exposure-Related Covariates and Heterogeneous Response to Exposure

Abstract

Studies have shown that combat-area deployment is associated with increases in alcohol use; however, studying the influence of deployment on alcohol use faces 2 complications. First, the military considers a confluence of factors before determining whether to deploy a service member, creating a nonignorable exposure and unbalanced comparison groups that inevitably complicate inference about the role of deployment itself. Second, regression analysis assumes that a single effect estimate can approximate the population's change in postdeployment alcohol use, which ignores previous studies that have documented that respondents tend to exhibit heterogeneous postdeployment drinking behaviors. Therefore, we used propensity score matching to balance baseline covariates for the 2 comparison groups (deployed and nondeployed), followed by a variable-oriented difference-in-differences approach to account for the confounding and a person-oriented approach using a latent growth mixture model to account for the heterogeneous response to deployment in this prospective cohort study of the US Army National Guard (2009–2014). We observed a nonsignificant increase in estimated monthly drinks in the first year after deployment that regressed to predeployment drinking levels 2 years after deployment. We found a 4-class model that fit these data best, suggesting that common regression analyses likely conceal substantial interindividual heterogeneity in postdeployment alcohol-use behaviors.

http://ift.tt/2uIG4K9

Exposure to Farm Animals and Risk of Lung Cancer in the AGRICAN Cohort

Abstract

Epidemiologic studies have found lower risks of lung cancer in farmers. However, little is known about the types of agricultural activities concerned. In the Agriculture and Cancer cohort, we assessed the relationship between animal farming and lung cancer by investigating the types of animals, tasks, and timing of exposure. Analyses included 170,834 participants from the Agriculture and Cancer (AGRICAN) cohort in France. Incident lung cancers were identified through linkage with cancer registries from enrollment (2005–2007) to 2011. A Cox model, adjusting for pack-years of cigarette smoking, was used to calculate hazard ratios and 95% confidence intervals. Lung cancer risk was inversely related to duration of exposure to cattle (≥40 years: hazard ratio = 0.60, 95% confidence interval: 0.41, 0.89; P for trend < 0.01) and to horse farming (≥20 years: hazard ratio = 0.64, 95% confidence interval: 0.35, 1.17; P for trend = 0.09), especially for adenocarcinomas, but not with poultry or pig farming. More pronounced decreased risks were reported among individuals who had cared for animals, undertaken milking, and who had been exposed to cattle in infancy. Our study provides strong evidence of an inverse association between lung cancer and cattle and horse farming. Further research is warranted to identify the etiologic protective agents and biological mechanisms.

http://ift.tt/2v0WokY

Improving Mental Health Through the Regeneration of Deprived Neighborhoods: A Natural Experiment

Abstract

Neighborhood-level interventions provide an opportunity to better understand the impact of neighborhoods on health. In 2001, the Welsh Government, United Kingdom, funded Communities First, a program of neighborhood regeneration delivered to the 100 most deprived of the 881 electoral wards in Wales. In this study, we examined the association between neighborhood regeneration and mental health. Information on regeneration activities in 35 intervention areas (n = 4,197 subjects) and 75 control areas (n = 6,695 subjects) was linked to data on mental health from a cohort study with assessments made in 2001 (before regeneration) and 2008 (after regeneration). Propensity score matching was used to estimate the change in mental health in intervention neighborhoods versus control neighborhoods. Baseline differences between intervention and control areas were of similar magnitude as produced by paired randomization of neighborhoods. Regeneration was associated with an improvement in the mental health of residents in intervention areas compared with control neighborhoods (β = 1.54, 95% confidence interval: 0.50, 2.59), suggesting a reduction in socioeconomic inequalities in mental health. There was a dose-response relationship between length of residence in regeneration neighborhoods and improvements in mental health (P-trend = 0.05). These results show that targeted regeneration of deprived neighborhoods can improve mental health.

http://ift.tt/2uIBR9s

Imputing the Direct and Indirect Effectiveness of Childhood Pneumococcal Conjugate Vaccine Against Invasive Pneumococcal Disease by Surveying Temporal Changes in Nasopharyngeal Pneumococcal Colonization

Abstract

The limited capability in most low- to middle-income countries to study the benefit of pneumococcal conjugate vaccine (PCV) in protecting against invasive pneumococcal disease (IPD) calls for alternate strategies to assess this. We used a mathematical model to predict the direct and indirect effectiveness of PCV by analyzing serotype-specific colonization prevalence and IPD incidence prior to and following childhood PCV immunization in South Africa. We analyzed IPD incidence from 2005 to 2012 and colonization studies undertaken in human immunodeficiency virus (HIV)-uninfected and HIV-infected child-mother dyads from 2007 to 2009 (pre-PCV era), in 2010 (7-valent PCV era), and in 2012 (13-valent PCV era). We compared the model-predicted changes in IPD incidence with observed changes in IPD incidence, according to HIV status, in children aged 3 months–5 years and in women aged 18–45 years. We observed reductions in vaccine-serotype colonization and IPD due to vaccine serotypes among children and women after PCV introduction. Using the changes in vaccine-serotype colonization data, the model-predicted changes in vaccine-serotype IPD incidence rates were similar to the observed changes in PCV-unvaccinated children and adults, but not among children under age 24 months. Surveillance of colonization prior to and following PCV use can be used to impute the indirect protection afforded by PCV in unvaccinated age groups, including those in high-HIV-prevalence settings.

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Assessing the Potential for Bias From Nonresponse to a Study Follow-up Interview: An Example From the Agricultural Health Study

Abstract

Prospective cohort studies are important tools for identifying causes of disease. However, these studies are susceptible to attrition. When information collected after enrollment is through interview or exam, attrition leads to missing information for nonrespondents. The Agricultural Health Study enrolled 52,394 farmers in 1993–1997 and collected additional information during subsequent interviews. Forty-six percent of enrolled farmers responded to the 2005–2010 interview; 7% of farmers died prior to the interview. We examined whether response was related to attributes measured at enrollment. To characterize potential bias from attrition, we evaluated differences in associations between smoking and incidence of 3 cancer types between the enrolled cohort and the subcohort of 2005–2010 respondents, using cancer registry information. In the subcohort we evaluated the ability of inverse probability weighting (IPW) to reduce bias. Response was related to age, state, race/ethnicity, education, marital status, smoking, and alcohol consumption. When exposure and outcome were associated and case response was differential by exposure, some bias was observed; IPW conditional on exposure and covariates failed to correct estimates. When response was nondifferential, subcohort and full-cohort estimates were similar, making IPW unnecessary. This example provides a demonstration of investigating the influence of attrition in cohort studies using information that has been self-reported after enrollment.

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Total and Cause-Specific Mortality Risk Associated With Low-Level Exposure to Crystalline Silica: A 44-Year Cohort Study From China

Abstract

The association between low-level crystalline silica (silica) exposure and mortality risk is not well understood. We investigated a cohort of 44,807 Chinese workers who had worked in metal mines or pottery factories for at least 1 year from January 1, 1960, to December 31, 1974, and were followed through 2003. Low-level silica exposure was defined as having a lifetime highest annual mean silica exposure at or under a permissible exposure limit (PEL). We considered 3 widely used PELs, including 0.05 mg/m³, 0.10 mg/m³, and 0.35 mg/m³. Cumulative silica exposure was estimated by linking a job exposure matrix with each participant's work history. For the 0.10-mg/m³ exposure level, Cox proportional hazards models showed significantly increased risk of mortality from all diseases (for each 1-ln mg/m³-years increase in logged cumulative silica exposure, hazard ratio (HR) = 1.05, 95% confidence interval (CI): 1.03, 1.07), malignant neoplasms (HR = 1.06, 95% CI: 1.03, 1.09), lung cancer (HR = 1.08, 95% CI: 1.02, 1.14), ischemic heart disease (HR = 1.09, 95% CI: 1.02, 1.16), pulmonary heart disease (HR = 1.08, 95% CI: 1.00, 1.16), and respiratory disease (HR = 1.20, 95% CI: 1.14, 1.26). The 0.05-mg/m³ and 0.35-mg/m³ exposure levels yielded similar associations. Long-term exposure to low levels (PELs ≤0.05 mg/m³, ≤0.10 mg/m³, or ≤0.35 mg/m³) of silica is associated with increased total and certain cause-specific mortality risk. Control of ambient silica levels and use of personal protective equipment should be emphasized in practice.

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Effort-Reward Imbalance at Work and the Prevalence of Unsuccessfully Treated Hypertension Among White-Collar Workers

Abstract

We examined the association between effort-reward imbalance (ERI) exposure at work and unsuccessfully treated hypertension among white-collar workers from a large cohort in Quebec City, Canada. The study used a repeated cross-sectional design involving 3 waves of data collection (2000–2009). The study sample was composed of 474 workers treated for hypertension, accounting for 739 observations. At each observation, ERI was measured using validated scales, and ambulatory blood pressure (BP) was measured every 15 minutes during the working day. Unsuccessfully treated hypertension was defined as daytime ambulatory BP of at least 135/85 mm Hg and was further divided into masked and sustained hypertension. Adjusted prevalence ratios and 95% confidence intervals were estimated. Participants in the highest tertile of ERI exposure had a higher prevalence of unsuccessfully treated hypertension (prevalence ratio = 1.45, 95% confidence interval: 1.16, 1.81) after adjustment for gender, age, education, family history of cardiovascular diseases, body mass index, diabetes, smoking, sedentary behaviors, and alcohol intake. The present study supports the effect of adverse psychosocial work factors from the ERI model on BP control in treated workers. Reducing these frequent exposures at work might lead to substantial benefits on BP control at the population level.

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Agreement Between 35 Published Frailty Scores in the General Population

Abstract

In elderly populations, frailty is associated with higher mortality risk. Although many frailty scores (FS) have been proposed, no single score is considered the gold standard. We aimed to evaluate the agreement between a wide range of FS in the English Longitudinal Study of Ageing (ELSA). Through a literature search, we identified 35 FS that could be calculated in ELSA wave 2 (2004–2005). We examined agreement between each frailty score and the mean of 35 FS, using a modified Bland-Altman model and Cohen's kappa (κ). Missing data were imputed. Data from 5,377 participants (ages ≥60 years) were analyzed (44.7% men, 55.3% women). FS showed widely differing degrees of agreement with the mean of all scores and between each pair of scores. Frailty classification also showed a very wide range of agreement (Cohen's κ = 0.10–0.83). Agreement was highest among "accumulation of deficits"-type FS, while accuracy was highest for multidimensional FS. There is marked heterogeneity in the degree to which various FS estimate frailty and in the identification of particular individuals as frail. Different FS are based on different concepts of frailty, and most pairs cannot be assumed to be interchangeable. Research results based on different FS cannot be compared or pooled.

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Experiences of Discrimination and Incident Type 2 Diabetes Mellitus: The Multi-Ethnic Study of Atherosclerosis (MESA)

Abstract

Experiences of discrimination are associated with increased risk of adverse health outcomes; however, it is unknown whether discrimination is related to incident type 2 diabetes mellitus (diabetes). We investigated the associations of major experiences of discrimination (unfair treatment in 6 situations) and everyday discrimination (frequency of day-to-day experiences of unfair treatment) with incident diabetes among 5,310 participants from the Multi-Ethnic Study of Atherosclerosis, enrolled in 2000–2002. Using Cox proportional hazards models, we estimated hazard ratios and confidence intervals, adjusting for demographic factors, depressive symptoms, stress, smoking, alcohol, physical activity, diet, waist circumference, and body mass index. Over a median follow-up of 9.4 years, 654 diabetes cases were accrued. Major experiences of discrimination were associated with greater risk of incident diabetes when modeled continuously (for each additional experience of discrimination, hazard ratio = 1.09, 95% confidence interval: 1.01, 1.17) or categorically (for ≥2 experiences vs. 0, hazard ratio = 1.34, 95% confidence interval: 1.08, 1.66). Similar patterns were observed when evaluating discrimination attributed to race/ethnicity or to a combination of other sources. Everyday discrimination was not associated with incident diabetes. In conclusion, major experiences of discrimination were associated with increased risk of incident diabetes, independent of obesity or behavioral and psychosocial factors. Future research is needed to explore the mechanisms of the discrimination-diabetes relationship.

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Importance of Survey Design for Studying the Epidemiology of Emerging Tobacco Product Use Among Youth

Abstract

Accurate surveillance is critical for monitoring the epidemiology of emerging tobacco products in the United States, and survey science suggests that survey response format can impact prevalence estimates. We utilized data from the 2014 New Jersey Youth Tobacco Survey (n = 3,909) to compare estimates of the prevalence of 4 behaviors (ever hookah use, current hookah use, ever e-cigarette use, and current e-cigarette use) among New Jersey high school students, as assessed using "check-all-that-apply" questions, with estimates measured by means of "forced-choice" questions. Measurement discrepancies were apparent for all 4 outcomes, with the forced-choice questions yielding prevalence estimates approximately twice those of the check-all-that-apply questions, and agreement was fair to moderate. The sensitivity of the check-all-that-apply questions, treating the forced-choice format as the "gold standard," ranged from 38.1% (current hookah use) to 58.3% (ever e-cigarette use), indicating substantial false-negative rates. These findings highlight the impact of question response format on prevalence estimates of emerging tobacco products among youth and suggest that estimates generated by means of check-all-that-apply questions may be biased downward. Alternative survey designs should be considered to avoid check-all-that-apply response formats, and researchers should use caution when interpreting tobacco use data obtained from check-all-that-apply formats.

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Appendicitis Caused by Primary Varicella Zoster Virus Infection in a Child with DiGeorge Syndrome

Introduction. Chickenpox is caused by varicella zoster virus (VZV). Although predominantly a mild disease, it can cause considerable morbidity and in rare occasions even mortality in healthy children as well as increased morbidity and mortality in immunocompromised patients. The aetiology of appendicitis is largely unknown but is thought to be multifactorial. Appendicitis is a suspected, but not well documented, complication from varicella zoster virus infection. Case Presentation. A five-year-old girl diagnosed with DiGeorge syndrome and a prolonged primary VZV infection was admitted due to abdominal pain, increasing diarrhoea, vomiting, and poor general condition. She developed perforated appendicitis and an intraperitoneal abscess. VZV DNA was detected by PCR in two samples from the appendix and pus from the abdomen, respectively. The child was treated with acyclovir and antibiotics and the abscess was drained twice. She was discharged two weeks after referral with no sequela. Conclusion. Abdominal pain in children with viral infections can be a challenge, and appendicitis has to be considered as a complication to acute viral diseases, especially if the child is immunocompromised.

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Next-generation sequencing (NGS) of cell-free circulating tumor DNA and tumor tissue in patients with advanced urothelial cancer: a pilot assessment of concordance

Abstract

Background: Advances in cancer genome sequencing have led to the development of various next generation sequencing (NGS) platforms. There is paucity of data regarding concordance of different NGS tests performed in the same patient.Methods: Here, we report a pilot analysis of 22 patients with metastatic urinary tract cancer and available NGS data from paired tumor tissue [FoundationOne (F1)] and cell-free circulating tumor DNA (ctDNA) [Guardant360 (G360)].Results: The median time between the diagnosis of stage IV disease and the first genomic test was 23.5 days (0-767), after a median number of 0 (0-3) prior systemic lines of treatment for advanced disease. Most frequent genomic alterations (GA) were found in the genes TP53 (50.0%), TERT promoter (36.3%); ARID1 (29.5%); FGFR2/3 (20.5%), PIK3CA (20.5%) and ERBB2 (18.2%). While we identified GA in both tests, the overall concordance between the two platforms was only 16.4% (0-50%), and 17.1% (0-50%) for those patients (n = 6) with both tests conducted around the same time (median difference= 36 days). On the contrary, in the subgroup of patients (n = 5) with repeated NGS in ctDNA after a median of 1 systemic therapy between the two tests, average concordance was 55.5% (12.1-100.0%). Tumor tissue mutational burden was significantly associated with number of GA in G360 report (p<0.001), number of known GA (p = 0.009) and number of variants of unknown significance (VUS) in F1 report (p<0.001), and with total number of GA (non-VUS and VUS) in F1 report (p<0.001).Conclusions: This study suggests a significant discordance between clinically available NGS panels in advanced urothelial cancer, even when collected around the same time. There is a need for better understanding of these two possibly complementary NGS platforms for better integration into clinical practice.

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More Than a Decade of Misdiagnosis of Alternating Hemiplegia of Childhood with Catastrophic Outcome

Alternating hemiplegia of childhood (AHC) is a distinct clinical disorder characterized by recurrent episodes of hemiplegia, abnormal ocular movement, and progressive developmental delay. It is an extremely rare genetic disorder related to ATP1A3 gene mutations. In this paper, we present a case of AHC in which the diagnosis was missed for many years until severe hypoxic brain insult occurred from prolonged status epilepticus. Not only we are presenting an interesting clinical entity and radiological images, but also we are shedding the light on a rare genetic disease with catastrophic sequelae. The challenges in diagnosis and treatment lead to a poor outcome as seen in our case. Although early recognition and accurate diagnosis and treatment of the disease may not change the outcome, counseling of the family may change their expectation and reduce their frustration. Referral to a center with expertise in genetic disorders and access to genetic laboratories is of paramount importance in the diagnosis of this disease. Due to the rarity of this disease in Saudi Arabia, a genotype-phenotype correlation is not feasible.

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HSV-1 Encephalitis: High Index of Clinical Suspicion, Prompt Diagnosis, and Early Therapeutic Intervention Are the Triptych of Success—Report of Two Cases and Comprehensive Review of the Literature

Herpes Simplex Virus (HSV) encephalitis is an acute infectious disease of the Central Nervous System (CNS), usually affecting the limbic structures, the median temporal cortex, and the orbitofrontal regions. Its annual incidence has significantly increased over the last 20 years and the mortality rate is 7%, if early diagnosed and treated, and 70%, if left untreated, while it is associated with high rates of morbidity. It should be noted that even when Cerebrospinal fluid (CSF) analysis seems normal, imaging studies are not specific and HSV Polymerase Chain Reaction (PCR) test is negative; the clinician should be more aggressive, if clinical presentation is indicative for HSV encephalitis, by administrating acyclovir early after patient's admission. The latter may be a vital intervention for the patient, modifying the patient's clinical course. Through the presentation of two cases of HSV-1 encephalitis that we managed in our department over the last 1 year and after systematic and comprehensive research of the relevant literature, we aim at showing the crucial role of medical history and physical examination, along with the high index of clinical suspicion, in order to make promptly the diagnosis and administer timely intravenous acyclovir, limiting the possibility of complications during the disease's course.

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Hyperammonaemic encephalopathy following an uncomplicated surgery

A 59-year-old woman who underwent an uncomplicated exploratory laparotomy, adhesiolysis, small bowel resection and anterolateral thigh flap had a complicated postoperative period characterised by wound dehiscence and poor nutritional intake. 29 days postoperatively, a tremor developed in her upper limbs associated with weakness. Her Glasgow Coma Scale (GCS) fell to 4 and she was transferred to the intensive care unit. The patient was reviewed by multiple specialists and multiple differentials were considered and eliminated. Eventually, investigations revealed hyperammonaemic encephalopathy, being a result of low arginine and potentially small intestinal bacterial overgrowth. Following treatment with sodium benzoate, sodium phenylbutyrate and arginine along with haemodialysis and rifaximin, GCS and hyperammonaemia rapidly improved. She was stepped down to surgical high-dependency unit, continued arginine therapy with total parenteral nutrition and percutaneous endoscopic gastrostomy feeds. She was discharged with regular follow-up from surgeons and biochemistry and continues oral arginine therapy.

http://ift.tt/2uOgTBY

Ventrain: from theory to practice. Bridging until re-tracheostomy

Imminent upper airway obstruction due to life-threatening tracheal stenosis of any cause is challenging. A 77-year-old woman, with a history of temporal tracheostomy for prolonged mechanical ventilation, presented with life-threatening tracheal stenosis to the emergency department. After failed intubation with a 5.0 mm internal diameter endotracheal tube, the patient was ventilated via a tube exchanger using Ventrain. Ventrain is a manual ventilation device that, in addition to oxygen supply during inspiration, initiates expiration by actively removing gas from the lungs by suction. Despite the nearly obstructed airway the patient was adequately ventilated with 'permissive' hypercarbia of 50 mm Hg and Saturation of peripheral Oxygen (SpO₂) 95%–98% until surgical re-tracheostomy was performed. The haemodynamic stability of the patient indicated that the active expiration prevented intrapulmonary pressure build-up by air trapping and subsequent barotrauma and/or haemodynamic deterioration, which may well be observed during traditional jet ventilation especially in case of a completely obstructed airway.

http://ift.tt/2weIrUN

Adrenal myelolipoma(s) as presenting manifestation of subclinical Cushings disease (eutopic ACTH-dependent Cushings syndrome)

Primary adrenal myelolipomas, relatively rare benign tumours of the adrenal cortex are typically unilateral, hormonally inactive and asymptomatic, hence often diagnosed as 'adrenal incidentaloma'. Bilateral adrenal myelolipomas, in particular, may be associated with underlying endocrinopathies associated with elevated circulating adrenocorticotropic hormone (ACTH) concentration. Subclinical cortisol hypersecretion, irrespective of its ACTH dependency, does not manifest typical clinical phenotype of hypercortisolemia, and thus termed subclinical Cushing's syndrome. In this article, hormonal evaluation in a middle-aged woman with diabetes, hypertension and incidentally discovered unilateral adrenal myelolipoma revealed underlying subclinical Cushing's disease. Abdominal CT revealed another tiny focus in the contralateral adrenal gland, probably representing incipient myelolipoma.

http://ift.tt/2uOz5LG

Hepatosplenic schistosomiasis: playing hide-and-seek with an elusive parasite

A 27-year-old man of Eritrean origin presented with persistent left-sided abdominal pain. Initial investigation showed signs of liver fibrosis, portal hypertension and splenomegaly. A diagnosis of hepatosplenic schistosomiasis was suspected on grounds of elevated total IgE, grey area antischistosomiasis antibodies and the high endemic status of his native country. However, repeated microscopy of faecal and urine samples, as well as rectal biopsies, failed to demonstrate schistosomal eggs. Finally, the diagnosis of hepatosplenic schistosomiasis was established through demonstration of a Schistosoma mansoni egg in a liver biopsy taken in an attempt to clarify the cause of the above findings. The patient had recently been treated for uncomplicated malaria. Lowered schistosomiasis worm/egg burden and hence reduced sensitivity of classic microscopy-based schistosomiasis testing was attributed to the antischistosomal activity of the antimalarial chemotherapy.

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Perihippocampal metastasis following hippocampus-avoiding prophylactic cranial irradiation for small cell lung cancer: a case report

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Low concentration of quercetin antagonizes the invasion and angiogenesis of human glioblastoma U251 cells

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Epidemiology in Germany—general development and personal experience

Abstract

Did you ever hear about epidemiology in Germany? Starting from an epidemiological desert the discipline has grown remarkably, especially during the last 10–15 years: research institutes have been established, research funding has improved, multiple curriculae in Epidemiology and Public Health are offered. This increase has been quite steep, and now the epidemiological infrastructure is much better. Several medium-sized and even big population cohorts are ongoing, and the number and quality of publications from German epidemiologists has reached a respectable level. My own career in epidemiology started in the field of environmental health. After German reunification I concentrated for many years on environmental problems in East Germany and observed the health benefits after improvement of the situation. Later, I concentrated on population-based cohorts in newborns (GINI/LISA) and adults (KORA, German National Cohort), and on biobanking. This Essay describes the development in Germany after worldwar 2, illustrated by examples of research results and build-up of epidemiological infractructures worth mentioning.

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Alcohol and head and neck cancer

Abstract

In this article, we reviewed the association between alcohol drinking and head and neck cancer (HNC) and its subsites, using the available literature. Alcohol drinking is an established risk factor for HNC, and this association may be stronger among cancers of the oropharynx and hypopharynx than the oral cavity or larynx. In addition, higher alcohol consumption over a shorter period was more harmful than fewer alcohol consumption over a longer period, and the most frequently consumed alcoholic beverages in a population is likely to be associated with the highest risk of HNC in that population. The risk of HNC after ≥ 20 years of alcohol cessation appear to be similar to the risk among never drinkers. The interaction between genetic polymorphisms related to alcohol metabolism and alcohol drinking on the risk of HNC has been noted, and the prevalence of these genetic polymorphisms in each population should be of concern. Finally, the association between alcohol drinking and the survival of individuals with HNC remains unclear, and mortality due to competing causes should be considered in future research to evaluate this association.

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A Novel PRKAR1A Mutation Identified in a Patient with Isolated Primary Pigmented Nodular Adrenocortical Disease

Primary pigmented nodular adrenocortical disease (PPNAD) is a rare cause of Cushing syndrome, especially the isolated form without Carney complex, associated with germline mutations in PRKAR1A, the protein kinase A regulatory subunit type 1 alpha gene. We report a 31-year-old female who presented with secondary amenorrhea, cushingoid appearance, and hypertension without Carney complex. Biochemical laboratory examinations confirmed the ACTH-independent adrenal Cushing syndrome with negative Liddle test. A small right adrenal adenoma of 0.8 cm was shown on computed tomography while magnetic resonance imaging revealed nodularity of both adrenal glands. The histological report confirmed PPNAD using laparoscopic right adrenalectomy, and subsequent left adrenalectomy was performed 6 months later. She had inherited heterozygosity of a novel germline mutation of the PRKAR1A gene (g.114213T#x3e;G or c.709-5T#x3e;G). This splice site mutation results in exon 8 skipping. Her father carrying the same mutation had no clinical features of either PPNAD or Carney complex. This novel PRKAR1A gene mutation, c.709-5T#x3e;G, is reported here for the first time manifesting as an incomplete clinical expression of the isolated form of PPNAD and being inherited with low penetrance unlike other inherited mutations of the Carney complex which have a penetrance of almost 100%.
Case Rep Oncol 2017;10:769–776

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Subacute Cerebellar Degeneration due to a Paraneoplastic Phenomenon Associated with Metastatic Merkel Cell Carcinoma: A Case Report

Purpose: The aim of this article is to illustrate the diagnostic challenges and management of paraneoplastic neurological syndromes in Merkel cell carcinoma. Materials and Methods: We describe a previously functionally independent 85-year-old woman who presented with subacute onset of dizziness and gait ataxia in the setting of metastatic Merkel cell carcinoma. Results: Diagnosis was made on biopsy after positron emission tomography imaging revealed increased metabolic activity in 2 left inguinofemoral lymph nodes. Cerebrospinal fluid analysis was positive for anti-Hu on subsequent admission. Her functional status improved with methylprednisolone treatment and radiotherapy. Conclusion: The case highlights the challenge of the evaluation of patients who present with progressive cerebellar signs and the need to consider a paraneoplastic syndrome, especially in the setting of previous malignancy.
Case Rep Oncol 2017;10:764–768

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Concomitant carotid aplasia and basilar artery occlusion in a child with PHACES syndrome

We report a case of an 8-year-old girl with posterior fossa abnormalities, haemangioma, arterial lesions, cardiac abnormalities or coarctation of the aorta and eye abnormalities syndrome with right carotid aplasia and complete basilar occlusion. The patient initially presented at 2.5 weeks of age with a growing right facial haemangioma involving segments 1, 3 and 4. Initial MRI at 2.5 weeks of age revealed an extraconal right orbital haemangioma without posterior fossa abnormalities and MR angiography (MRA) 3 weeks later showed right internal carotid aplasia. A follow-up MRA and cerebral angiography at 8 years of age revealed a complete occlusion of the basilar artery that was not appreciated on previous imaging. Neurological function remains normal, meeting all age-appropriate milestones.

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Massive epidermal vulval cyst: an unusual late complication of female genital mutilation

Vulval epidermal cysts are rare and infrequently described in literature. They present a difficult diagnostic dilemma and surgical challenges. They most commonly occur as a late complication of female genital mutilation (FGM) and manifest as a primary condition. We present a case of a large vulval epidermal inclusion cyst, lined by vulval squamous epithelium, in a woman with a background of FGM who was referred with suspected vulval cancer. We discuss the clinical presentation, MRI findings, surgical treatment and outcome.

http://ift.tt/2uNMbJr

Migration of a Kirschner wire into the lung with shoulder dislocation

Description

A 69-year-old female was presented with right shoulder pain due to chronic anterior shoulder dislocation. She underwent an operation for arthroscopic rotator cuff repair (figure 1). Rotator cuff repair was not possible due to massive rotator cuff tears and the glenohumeral joint was not stable. After reduction, therefore, temporary fixation of the glenohumeral joint was performed with two 3.0 mm Kirschner wires (K-wires) (figure 2). One wire was removed due to superficial infection 17 days after the surgery. As a result, the humeral head was dislocated, and the remaining wire migrated into her lung (figure 3). Chest CT showed pulmonary contusion without evidence of pneumothorax (figure 4). Fourteen days later, the K-wire was removed carefully with fluoroscopic guidance to prevent haemorrhage and pneumothorax. Forty-two months postoperatively, the humeral head remained dislocated with modest relief of joint pain. Chest function is normal without...

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Ureaplasma parvum causing life-threatening disease in a susceptible patient

A 56-year-old man with lymphoma developed orchitis followed by septic arthritis of his right glenohumeral joint. Synovial fluid cultures were negative but PCR amplification test was positive forUreaplasmaparvum. The patient was treated with doxycycline. Two and a half years later, the patient presented with shortness of breath and grade III/IV diastolic murmur on auscultation. Echocardiography revealed severely dilated left heart chambers, severe aortic regurgitation and several mobile masses on the aortic valve cusps suspected to be vegetations. He underwent valve replacement; valve tissue culture was negative but the 16S rRNA gene amplification test was positive for U. parvum.

He was treated again with doxycycline. In an outpatient follow-up 1 year and 3 months later, the patient was doing well. Repeated echocardiography showed normal aortic prosthesis function.

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The use of cardiac MRI in a rare case of primary mural endocarditis

Description

A 47-year-old-man with a history of intravenous drug use and recent diagnosis of T-cell lymphoma returned to the emergency department 1 week after initiation of chemotherapy with complaint of left olecranon swelling. Admission vital signs included body temperature of 36.6°C, blood pressure 108/65, heart rate 76 and respiratory rate 18. Physical examination of the left olecranon revealed that it was warm and indurated. An X-ray of the left olecranon and aspiration of the swelling confirmed bursitis. Both the aspiration culture and blood cultures demonstrated methicillin-resistant Staphylococcus aureus. A transthoracic echocardiogram was subsequently performed revealing a large echodensity in the left ventricular apex (figure 1; see online and ). The patient refused to undergo a transoesophageal echocardiogram due to its invasive approach. Therefore, a cardiac MRI (CMRI) was obtained to evaluate the lesion. The CMRI demonstrated left ventricular ejection fraction 65%, no valvular vegetations and two linear...

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Congenitally corrected transposition of great arteries

Description

A 60-year-old woman initially presented 8 years ago with atypical chest pain and palpitations. Her 12-lead ECG demonstrated complete heart block, following which she underwent dual-chamber pacemaker implantation. She also had transthoracic echocardiogram, which was felt to be technically difficult due to body habitus. She was diagnosed to have mild mitral valve regurgitation, due to mild mitral valve prolapse, and was kept under annual surveillance. There was no other significant medical history. Her last TTE was done a year ago and she had been symptom-free up to her recent clinic visit. Her repeat TTE showed apically displaced Ebstein-like left atrioventricular valve (AV) with tricuspid valve morphology (confirmed by three-dimensional (3D) echo) and heavily trabeculated morphologically right ventricle on the left side of the heart (figures 1, 2, 3 and 4, online  and ). Her systemic ventricle was mild to moderately impaired, and the tricuspid, left AV was moderately regurgitant. There are no obvious shunt and no...

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Fungating groin mass in a woman with a history of follicular lymphoma

Description

A 49-year-old woman with no significant medical history presented to her primary care provider for an evaluation of a new lump in her groin. She was found to have enlarged inguinal lymph nodes on the right side, and underwent extensive work-up, including testing for HIV, hepatitides, Epstein-Barr virus, cytomegalovirus and chest imaging. They were all unremarkable. Given persistence of the lymphadenopathy, the patient underwent a fine needle aspiration of one of the lymph nodes with pathology revealing a diagnosis of low-grade follicular lymphoma. Given the natural history of this slow-growing tumour, she was maintained on an observational protocol but unfortunately lost to follow-up.

Three years later, the patient presented to the emergency department for complaints of generalised malaise as well as an enlarging right groin mass. Physical examination revealed a fungating mass with purulent drainage and an impressively pungent smell in the right inguinal area (figure...

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Spleno-renal artery transposition in a solitary functioning kidney for treatment-resistant hypertension and acute kidney injury

Renal Artery Stenosis (RAS) is an important cause of treatment-resistant hypertension. Uncontrolled hypertension with RAS can cause progressive chronic kidney disease (CKD) leading to end-stage kidney disease. Therapeutic revascularisation can be helpful in appropriate circumstances where pharmaceutical intervention has failed and significant renovascular disease contributes to resistant hypertension. We present an interesting case of a Caucasian male with peripheral vasculopathy, abdominal aortic aneurysm (AAA), single functioning kidney and ostial RAS caused by stent struts from an endovascular AAA stent graft. He had escalating medications requirement, with repeated failed attempts at percutaneous radiological intervention that led to an episode of contrast-induced acute kidney injury (AKI), before undergoing successful surgical revascularisation by a splenic artery transposition graft to the left renal artery that was performed to improve kidney function and the blood pressure. This report highlights the challenges faced with regard to the management of severe hypertension and progressive CKD.

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Bleeding ectopic duodenal varix: use of a new microvascular plug (MVP) device along with transjugular intrahepatic portosystemic shunt (TIPSS)

Ectopic varices (ECV) occur along the gastrointestinal (GI) tract outside the common variceal sites and represent 2%–5% of all GI variceal bleeds with mortality rates up to 40%. Management is challenging because of inaccessibility and increased risk of rebleeding. We report what is to our knowledge the first clinical use of a new microvascular plug (MVP) with transjugular intrahepatic portosystemic shunt (TIPSS) for a bleeding duodenal varix (DV). A 68-year-old man presented with melena. Endoscopy demonstrated a grade II varix in the second part of the duodenum with red wale sign. TIPSS was performed and portogram revealed a single DV. Poststent placement venogram revealed a persistent varix and hence a 5–7 mm MVP was deployed. Subsequent imaging showed cessation of blood through the DV. The patient had no further bleeding. TIPSS with embolisation is an effective treatment for ECV. This MVP offers advantages due to its size and compatibility and can be redeployed in case of suboptimal placement.

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Fever and generalised lymphadenopathy in an HIV-positive patient: a diagnostic challenge

Fever and generalised lymphadenopathy is a common presentation of a variety of diseases and a thorough investigation is often necessary for appropriate diagnosis.

We present a 53-year-old male patient admitted with fever, weight loss of 15 kg in 3 months and abdominal discomfort. Examination was only remarkable for axillary and inguinal lymphadenopathy. Blood tests showed normocytic normochromic anaemia, cholestasis and a previously unknown HIV-1 infection with lymphocyte CD4 +count of 239 cells/mm³ and viral load 3.172.370 copies/mL. A body CT scan showed multiple axillary, mediastinal, lumbar, aortic, iliac and pelvic lymphadenopathy as well as hepatosplenomegaly. An excisional biopsy of the left axillary lymphadenopathy was performed and histology ultimately revealed multicentric Castleman's disease associated with Human Herpes Virus-8. After initiation of antiretroviral therapy, rituximab was given and progressive clinical improvement occurred.

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Hydropneumothorax as an iatrogenic complication after nasogastric intubation

Description

A 62-year-old woman with history of frontotemporal dementia was admitted to a Psychiatry ward due to severe insomnia. In the morning, after the admission a nasogastric tube was placed to initiate enteral feeding and medication since she was refusing all oral intake. Later that night, she was found unresponsive, dyspnoeic and with severe hypotension. Physical examination identified clinical signs of respiratory distress and decreased vesicular breath sounds on the right hemithorax. The gasometric evaluation revealed the presence of hypoxaemia and lactic acidosis. A posteroanterior chest radiograph showed a right pleural effusion and a misplaced nasogastric tube (figure 1). A thoracic CT scan revealed the presence of a right hydropneumothorax and also identified a tube inside the trachea and the right main bronchus, which perforated the lung parenchyma and ended in the pleural cavity (figure 2).

Figure 1

Posteroanterior chest radiograph showing...

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Unique case of herniated small bowel infarction within a colonic stomal prolapse

The number of permanent colostomies carried out in the United Kingdom is approximately 6400 per year1. Stomal prolapse is a known complication of colostomy formation. We presented the first case of small bowel herniation into a healthy stomal prolapse with subsequent ischaemia of the herniated bowel in a 102-year-old patient. This rare sequela of a relatively common stomal complication highlights an important consideration when faced with a large prolapse presenting acutely. It also raises an important discussion point for the management of our ever-ageing patient population.

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Total alimentary canal necrosis: infarction from oesophagus to anus

Description

A middle-aged woman presented with a 12-hour history of generalised abdominal pain and septic. Her medical history included chronic alcoholism and a 40 pack-year smoking history. Laboratory tests revealed raised inflammatory markers and a macrocytosis. There were no liver, renal or clotting derangements, and haemoglobin and platelet levels were within normal limits. Blood gas analysis showed acidaemia and raised lactate. A CT scan of the abdomen revealed pneumoperitoneum, extensive portal venous gas and pneumatosis intestinalis throughout the entire imaged gut—from distal oesophagus all the way to anus—suggestive of complete intestinal necrosis (figures 1–3). The mesenteric arteries appeared patent. The patient rapidly deteriorated and died within 3 hours of admission.

Figure 1

Axial CT image of upper abdomen showing extensive portal gas, pneumoperitoneum (long arrow) and intra-abdominal free fluid (short arrow). Gastric wall intramural gas (pneumatosis) is visible.

...

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A case of cardiopulmonary arrest due to spontaneous coronary artery dissection in a pregnant woman

We present the case of a young pregnant woman with cardiopulmonary arrest due to acute coronary syndrome. Emergent coronary angiography (CAG) and intravascular ultrasound (IVUS) showed extensive coronary artery dissection in the left anterior descending artery, which was treated with primary percutaneous coronary intervention. After managing the heart failure and disseminated intravascular coagulation, a dead fetus was delivered via caesarean section 4 days after admission to the hospital. Follow-up CAG and IVUS at 18 months showed persistent dissection in the non-stented site; hence, another stent was implanted. Dual antiplatelet therapy was discontinued 6 months later; however, aspirin and beta-blockers were continued lifelong.

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A Narrative Review of Adherence to Subarachnoid Hemorrhage Guidelines.

Over the past 2 decades, a large number of guidelines for aneurysmal subarachnoid hemorrhage (aSAH) management have been proposed. The primary aim of these "evidence-based" guidelines is to improve the care of aSAH patients by summarizing and making current knowledge readily available to clinicians. However, an investigation into aSAH guidelines, their changes along time and their successful translation into clinical practice is still lacking. We performed a literature search of historical events and subarachnoid hemorrhage guidelines using the Entrez PubMed NIH, Embase, and Cochrane databases for articles published up to November of 2016. Data were summarized for guidelines on aSAH management and cross-sectional studies of their application. A total of 11 guidelines and 10 cross-sectional studies on aSAH management were analyzed. The use of nimodipine for the treatment of SAH is the only recommendation that remained consistent across guidelines over time (r=0.82; P

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Cerebral Oxygen Saturation During Electroconvulsive Therapy: A Secondary Analysis of a Randomized Crossover Trial.

Background: Electroconvulsive therapy (ECT) causes acute changes in cerebral perfusion and oxygenation. Near-infrared spectroscopy is a novel, noninvasive technique to assess cerebral oxygen saturation (cSO2). We hypothesized that cSO2 increases during ECT and more so with atropine premedication and decreases when systemic desaturation (peripheral oxygen saturation 60% at any measured time point, even in those with systemic desaturation. Conclusions: ECT increased cSO2 irrespective of atropine premedication. cSO2 was lower when systemic desaturation occurred. Future studies should explore the effect of cerebral oxygenation changes during ECT on outcome of psychiatric conditions. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved

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Paraplegia in Subarachnoid Hemorrhage Complicated With Coarctation of Aorta: An Unusual Complication.

No abstract available

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The Shikani Optical Stylet as an Alternative to Awake Fiberoptic Intubation in Patients at Risk of Secondary Cervical Spine Injury: A Randomized Controlled Trial.

Background: Conventional intubation of the trachea and consequent prone positioning of anesthetized patients with cervical spine instability may result in secondary neurological injury. Historically, flexible fiberoptics used to be the chief choice for patients presenting with cervical spine instability surgery with difficult airway. Recently, the rigid optical stylets have shown promise in assisting difficult intubations. Purpose: The aim of the present study was to compare the efficacy of Shikani optical stylet (SOS) with the flexible fiberscope for awake intubation in patients with cervical spine instability. Patients and Methods: In total, 60 adult patients diagnosed with cervical instability or at risk of secondary cervical injury, who were planned for awake intubation and/or self-positioning prone, were registered in this study and were randomly categorized into 2 equal groups (30 patients each), a fiberoptic group and an SOS group, followed by assessment of coughing and gagging during intubation, time to successful intubation, number of attempts for successful intubation, and hemodynamic parameters. Results: As regards time to successful intubation, statistically significant differences were detected between the 2 studied groups, with the fiberoptic group having significantly longer intubation time than the Shikani group, whereas no statistically significant differences were recorded between the 2 groups with regard to the first-attempt success, the mean heart rate value, the mean arterial blood pressure, coughing, and occurrence of complications. Conclusion: This study validates the efficacy of both SOS and flexible fiberoptic bronchoscope for awake oral intubation in patients with cervical spine instability. SOS has been found to be more effective in reducing time to intubation. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved

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Insulin-Like Growth Factor (IGF) Pathway Targeting in Cancer: Role of the IGF Axis and Opportunities for Future Combination Studies

Abstract

Despite a strong preclinical rationale for targeting the insulin-like growth factor (IGF) axis in cancer, clinical studies of IGF-1 receptor (IGF-1R)-targeted monotherapies have been largely disappointing, and any potential success has been limited by the lack of validated predictive biomarkers for patient enrichment. A large body of preclinical evidence suggests that the key role of the IGF axis in cancer is in driving treatment resistance, via general proliferative/survival mechanisms, interactions with other mitogenic signaling networks, and class-specific mechanisms such as DNA damage repair. Consequently, combining IGF-targeted agents with standard cytotoxic agents, other targeted agents, endocrine therapies, or immunotherapies represents an attractive therapeutic approach. Anti-IGF-1R monoclonal antibodies (mAbs) do not inhibit IGF ligand 2 (IGF-2) activation of the insulin receptor isoform-A (INSR-A), which may limit their anti-proliferative activity. In addition, due to their lack of specificity, IGF-1R tyrosine kinase inhibitors are associated with hyperglycemia as a result of interference with signaling through the classical metabolic INSR-B isoform; this may preclude their use at clinically effective doses. Conversely, IGF-1/IGF-2 ligand-neutralizing mAbs inhibit proliferative/anti-apoptotic signaling via IGF-1R and INSR-A, without compromising the metabolic function of INSR-B. Therefore, combination regimens that include these agents may be more efficacious and tolerable versus IGF-1R-targeted combinations. Herein, we review the preclinical and clinical experience with IGF-targeted therapies to-date, and discuss the rationale for future combination approaches as a means to overcome treatment resistance.

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