Gender as a risk factor for adverse intraoperative and postoperative outcomes of elective pancreatectomy

Background and Objectives

Patient selection remains paramount when developing and adopting quality-based assessment and reimbursement models, and enhanced recovery protocols. Gender is a patient characteristic known before surgery which can inform risk stratification. Our aim was to evaluate the effect of gender on intraoperative blood transfusions, operative time, length of hospital stay, estimated blood loss (EBL) as well as postoperative surgical site infections (SSIs), and mortality.

Methods

Patients undergoing elective pancreatectomy from 2005 to 2013 were identified in the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) and Northwestern institutional databases. Multivariable analyses were conducted to identify the association between gender and these outcomes.

Results

Analyses demonstrated that male gender was independently associated with blood transfusion (OR 1.23), operative time >6 hr (OR 1.76), length of stay greater than 11 days (OR 1.17), and all-type SSIs (OR 1.17), especially superficial SSIs (OR 1.15) and organ space SSIs (OR 1.18). Analysis of the institutional cohort found that male gender was independently associated with increased odds of EBL > 1 L for Whipple procedures (OR 2.85).

Conclusions

Male gender is a significant predictor of increased operative time, length of stay, transfusions, EBL > 1L, as well as postoperative organ space surgical site infections in these patients. J. Surg. Oncol. © 2016 Wiley Periodicals, Inc.

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Quality End-of-Life Cancer Care: An overdue imperative

Publication date: Available online 3 November 2016
Source:Critical Reviews in Oncology/Hematology
Author(s): Guy B. Faguet
This review assesses the current status of end-of-life care based on large-scale, multiyear nationwide surveys of treatment modality, setting, and cost of care during terminal patients' last months of life. It shows that end-of-life care goals often remain suboptimal. Contributing factors include prioritized life preservation, uneven commitment to palliative care, few palliative care specialists, and perverse financial incentives that encourage costly interventions. Although not determinant per se, these factors coupled to doubts about what constitutes end-of-life can lead to overextended disease treatment and a late implementation of palliative care. In order to bridge the existing gap between care received and care expected and achieve quality end-of-life and promote death with dignity, we propose both to view the person rather than the disease as the unit of care and a pragmatic definition of end-of-life. Such a strategy should facilitate selecting an optimal time to transition from disease-targeted treatment to palliative care.



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Cancer treatment induced metabolic syndrome: improving outcome with lifestyle

Publication date: Available online 3 November 2016
Source:Critical Reviews in Oncology/Hematology
Author(s): N.L. Westerink, J. Nuver, Lefrandt, A.H. Vrieling, J.A. Gietema, A.M.E. Walenkamp
Increasing numbers of long-term cancer survivors face important treatment related adverse effects. Cancer treatment induced metabolic syndrome (CTIMetS) is an especially prevalent and harmful condition. The aetiology of CTIMetS likely differs from metabolic syndrome in the general population, but effective treatment and prevention methods are probably similar. In this review, we summarize the potential mechanisms leading to the development of CTIMetS after various types of cancer treatment. Furthermore, we propose a safe and accessible method to treat or prevent CTIMetS through lifestyle change. In particular, we suggest that a lifestyle intervention and optimization of energy balance can prevent or mitigate the development of CTIMetS, which may contribute to optimal survivorship care.



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Video-assisted thoracic surgery lobectomy in patients with reduced pulmonary function: a single-center series

Future Oncology Ahead of Print.


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Deregulated miRNAs in human cervical cancer: functional importance and potential clinical use

Future Oncology Ahead of Print.


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Issue Information

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PHGDH and Cancer Progression

Phosphoglycerate dehydrogenase (PHGDH) is the metabolic enzyme responsible for shunting the glycolytic intermediate 3-phosphoglycerate to the serine synthesis pathway. In breast cancer and several other types of cancer, increased PHGDH expression is associated with patient mortality. Early studies focused on the role of PHGDH in promoting cell proliferation in the small percentage of breast cancers with PHGDH gene amplification. However, recent studies have revealed a critical role for PHGDH and downstream enzymes of the serine synthesis pathway and one carbon metabolism in NADPH production and the maintenance of redox homeostasis, which are required for enrichment of breast cancer stem cells in response to hypoxia or chemotherapy. These results provide a mechanism for PHGDH overexpression in breast cancers in which PHGDH is not amplified and have implications for improving the response of triple-negative breast cancers to cytotoxic chemotherapy. Cancer Res; 76(22); 1–5. ©2016 AACR.

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Eph Receptors in Tumor Immunity

The family of Eph receptor tyrosine kinases and their ephrin ligands regulate a diverse array of physiologic processes, such as axonal guidance, bone remodeling, and immune cell development and trafficking. Eph/ephrin interactions have also been implicated in various pathologic processes, including inflammation, cancer, and tumor angiogenesis. Because Eph receptors play prominent roles in both the immune system and cancer, they likely impact the tumor immune microenvironment, an area in which Eph receptors remain understudied. Here, we provide the first comprehensive review of Eph receptors in the context of tumor immunity. With the recent rise of cancer immunotherapies as promising therapeutic interventions, further elucidation of the roles of Eph receptors in the tumor immune microenvironment will be critical for understanding and developing novel targets against tumor immune evasion. Cancer Res; 76(22); 1–6. ©2016 AACR.

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NNMT inhibition activates PP2A to inhibit STKs

Purpose: To identify potential molecular hubs that regulate oncogenic kinases and target them to improve treatment outcomes for glioblastoma (GBM) patients. Experimental Design: Data mining of The Cancer Genome Atlas (TCGA) datasets identified Nicotinamide-N-methyl transferase (NNMT) as a prognostic marker for GBM, an enzyme linked to the reorganization of the methylome. We tested our hypothesis that NNMT plays a crucial role by modulating protein methylation leading to inactivation of tumor suppressors and activation of oncogenes. Further experiments were performed to understand the underlying biochemical mechanisms using GBM patient samples, established, primary, and isogenic cells. Results: We demonstrate that NNMT outcompetes leucine carboxyl methyl transferase 1 (LCMT1) for methyl transfer from principal methyl donor SAM in biological systems. Inhibiting NNMT increased the availability of methyl groups for LCMT1 to methylate PP2A, resulting in the inhibition of oncogenic serine/threonine kinases (STKs). Further, NNMT inhibition retained the radiosensitizer nicotinamide and enhanced radiation sensitivity. We have provided the biochemical rationale of how NNMT plays a vital role in inhibiting tumor suppressor PP2A while concomitantly activating STKs. Conclusion: We report the intricate novel mechanism in which NNMT inhibits tumor suppressor PP2A by reorganizing the methylome both at epigenome and proteome levels and concomitantly activating pro-survival STKs. In GBM tumors with NNMT expression, activation of PP2A can be accomplished by FDA approved perphenazine (PPZ) which is currently used to treat mood disorders such as schizophrenia, bipolar disorder, etc. This study forms a foundation for further GBM clinical trials using PPZ with standard of care treatment.

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Randomized auto-transplant trial for low-risk myeloma

Purpose: To determine whether a reduction in the intensity of Total Therapy (TT) reduces toxicity and maintains efficacy. Experimental Design: 289 patients with gene expression profiling (GEP70)-defined low-risk multiple myeloma (LRMM) were randomized between a standard arm (TT4-S) and a light arm (TT4-L). TT4-L employed 1 instead of 2 inductions and consolidations. To compensate for potential loss of efficacy of TT4-L, bortezomib and thalidomide were added to fractionated melphalan 50mg/m2/d x 4. Results: Grade {greater than or equal to}3 toxicities and treatment-related mortalities were not reduced in TT4-L. Complete response (CR) rates were virtually identical (p=0.2; TT4-S, 59%: TT4-L, 61% at 2 years), although CR duration was superior with TT4-S (p=0.05; TT4-S, 87%;TT4-L, 81% at 2 years. With a median follow-up of 4.5yr, there was no difference in overall survival (OS) and progression-free survival (PFS). While metaphase cytogenetic abnormalities (CA) tended to be an adverse feature in TT4-S, as with predecessor TT trials, the reverse applied to TT4-L. Employing historical TT3a as training and TT3b as test set, 51 gene probes (GEP51) significantly differentiated the presence and absence of CA (q<0.0001), 7 of which function in DNA replication, recombination, and repair. Applying the GEP51 model to clinical outcomes, OS and PFS were significantly inferior with GEP51/CA in TT4-S; such difference was not observed in TT4-L. Conclusions: We identified a prognostic CA-linked GEP51 signature, the adversity of which could be overcome by potentially synergizing anti-MM effects of melphalan and bortezomib. These exploratory findings require confirmation in a prospective randomized trial.

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High Estrogen Receptor Beta Expression in Breast Cancer

Purpose: Isoform-specific tumor estrogen receptor beta (ERβ) expression may hold prognostic information in breast cancer, especially among endocrine-treated breast cancer patients. The study's purpose was to evaluate ERβ isoform 1 (ERβ1) expression in relation to tumor characteristics, ERβ genotypes, and prognosis in different treatment groups. Experimental Design: A population-based prospective cohort of 1,026 patients diagnosed with primary invasive breast cancer in Lund, Sweden between October 2002 and June 2012 was followed until June 2014 (median five years). Associations between immunohistochemical ERβ1 expression, patient and tumor characteristics, as well as outcome within treatment groups were analyzed. Results: Tumor ERβ1 expression was available for 911 patients (89%), and was not associated with ERβ genotypes. ERβ1 positivity, defined as >75% (ERβ1₇₅+, 72.7%), was positively associated with established favorable tumor characteristics. Overall, ERβ1₇₅+ was associated with lower risk of breast cancer events (HR_adj 0.60: 95% CI 0.41-0.89). The magnitude of the association was larger in patients with ERα negative tumors (HR_adj 0.30: 95% CI 0.12-0.76), compared with ERα positive tumors (HR_adj 0.66: 95% CI 0.42-1.03). Among the 232 chemotherapy-treated patients, ERβ1₇₅+ tumors were associated with lower risk of breast cancer events compared to ERβ1₇₅- tumors (HR_adj 0.31: 95% CI 0.15-0.64). Among the 671 chemonaïve patients, ERβ1₇₅ status was not associated with the outcome. Conclusions: High ERβ1 expression was a favorable prognostic marker in this breast cancer cohort, especially in chemotherapy-treated patients, but not in endocrine-therapy treated patients. These results warrant confirmation, preferably via a biomarker study in a previously conducted randomized trial.

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Motolimod plus Cetuximab for Recurrent or Metastatic SCCHN

Purpose: As toll-like receptors (TLRs) are key mediators of immune responses, TLR agonists may be important for augmenting the efficacy of therapies for squamous cell carcinoma of the head and neck (SCCHN). Motolimod (VTX-2337), a selective small-molecule agonist of TLR8, stimulates NK cells, dendritic cells, and monocytes. A Phase 1b clinical trial assessed the safety and anti-tumor activity of motolimod in combination with cetuximab in patients with SCCHN. Correlative biomarkers of immune activity were explored. Experimental Design: Thirteen patients with recurrent or metastatic SCCHN were enrolled in this open-label, dose-escalation study using a standard 3+3 design. Doses of motolimod (2.5, 3.0, 3.5 mg/m2) were given on days 1, 8, and 15, in combination with fixed weekly doses of cetuximab in 28-day cycles. Results: There were no protocol-defined dose-limiting toxicities, drug-related deaths, or evidence of synergistic toxicities between motolimod and cetuximab. Clinical tolerability at the 3.5 mg/m2 dose level was not optimal for repeated dosing and 3.0 mg/m2 was identified as the maximum tolerated dose. Two patients achieved partial responses for an overall response rate of 15%. Five patients had disease stabilization equating to a disease control rate of 54%. Statistically significant increases in plasma cytokines and in the frequency and activation of circulating NK cells were observed. Conclusions: Motolimod can be safely administered in combination with cetuximab with an acceptable toxicity profile. Encouraging anti-tumor activity and robust pharmacodynamic responses were observed. Motolimod is being further investigated in a Phase 2 trial in patients with SCCHN (Clinicaltrials.gov NCT01836029).

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The Think A-Head campaign: an introduction to ImageGently 2.0

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Active reviewers (from October 1, 2015 through September 30, 2016)

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Significance of nucleic acid testing in diagnosis and treatment of post-neurosurgical meningitis caused by multidrug-resistant Acinetobacter baumannii: a case report

Neurosurgery may pose the risk of patients' developing nosocomial meningitis caused by infection with hospital pathogens. Rapid detection of the causative pathogens is essential for selecting the appropriate a...

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Successful endoscopic treatment of stapled J-pouch ileoanal canal anastomotic hemorrhage by argon plasma coagulation: a case report

Continuous lower gastrointestinal hemorrhage is a rare condition, but it often requires proper management. We report a case of a patient with gastrointestinal hemorrhage 18 years after stapled J-pouch ileoanal...

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Interstitial pneumonia in a patient treated with TAS-102 for metastatic colorectal cancer: a case report

TAS-102, a new treatment option for patients with metastatic colorectal cancer that is refractory or intolerant to standard therapies, has been improving survival with acceptable tolerability and adverse event...

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Lipoma of the cheek presenting with recurrent sialadenitis of the right parotid gland: a case report

Lipomas are benign neoplasms arising from adipose tissue. Oral lipomas have been reported in the buccal mucosa, tongue, floor of the mouth and lips; however, the case of a lipoma occurring as an antecedent les...

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Spontaneous cerebrospinal fluid leak of the sphenoid sinus mimicking allergic rhinitis, and managed successfully by a ventriculoperitoneal shunt: a case report

Spontaneous cerebrospinal fluid leaks are rare but may lead to confusion with other diseases in patients without history of trauma. We report a rare case unusual for two reasons. First, our patient was put und...

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Penfluridol anticancer activity is ROS-dependent

It was recently demonstrated the penfluridol inhibited breast tumor growth and metastasis and this was associated with downregulation of α6- and β4-integrins. In this study, we observed the penfluridol induced reactive oxygen species (ROS) and this was the primary mechanism of action. Penfluridol-mediated growth inhibition, induction of apoptosis, and inhibition breast cancer cell migration was attenuated after cotreatment with glutathione (GSH). Penfluridol also downregulated Sp transcription factors Sp1, Sp3 and Sp4 through epigenetic downregulation of cMyc and cMyc-regulated microRNAs (miR-27a and miR-20a/miR-17) and induction of the miR-regulated Sp transcriptional repressors ZBTB10 and ZBTB4. α6- and β4-Integrins as well as α5- and β1-integrin are Sp-regulated genes that are also coregulated by the orphan nuclear receptor NR4A1 and these integrins can be targeted by agents such as penfluridol that suppress Sp1, Sp3 and Sp4 and also by NR4A1 antagonists.

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Lapatinib in HER2-Amplified Upper Gastrointestinal Cancers

HER2/ERBB2 status is used to select patients for HER2-targeted therapy. HER2/ERBB2 amplification/overexpression of upper gastrointestinal (UGI) adenocarcinomas was determined locally or in two central laboratories to select patients for the TRIO-013/LOGiC trial of chemotherapy with or without lapatinib. Patients selected locally had central laboratory confirmation of HER2-amplification for inclusion in the primary efficacy population. HER2 was assessed with PathVysion or IQ PharmDx fluorescence in situ hybridization (FISH) and HercepTest immunohistochemistry assays. Associations with outcomes were retrospectively evaluated. Overall, HER2 status was determined in UGI cancers from 4674 patients in a central laboratory for eligibility (1995 cases) and for confirmation of local HER2 results (333 cases). Of 1995 adenocarcinomas screened centrally, 322 (16.1%) had HER2 amplified disease with 29 (1.5%) showing HER2 genomic heterogeneity. Men and older patients had higher rates of amplification. Of 545 patients accrued to the trial (gastric, 87.3%; GEJ, 8.3% and esophageal cancer, 4.4%) 487 patients (89%) were centrally confirmed as having HER2 amplified disease. Concordance between central and local HER2 testing was 83%. Concordance between PathVysion and IQ PharmDx FISH assays was 99% and FISH in the two central laboratories was 95%. Lapatinib-treated Asian participants and those less than 60 years had significant improvement in progression-free survival (PFS), particularly among those whose cancers had 5.01-10.0 and >10.0-fold amplification of HER2. In conclusion, HER2 is commonly amplified in UGI adenocarcinomas with amplification highly correlated to overexpression, and HER2 amplification levels correlated with PFS. While HER2 genomic heterogeneity occurs, its prevalence is low.

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Mena and taxane resistance

Taxane therapy remains the standard of care for triple-negative breast cancer. However, high frequencies of recurrence and progression in treated patients indicate that metastatic breast cancer cells can acquire resistance to this drug. The actin regulatory protein MENA, particularly its invasive isoform, MENAINV, are established drivers of metastasis. MENAINV expression is significantly correlated with metastasis and poor outcome in human breast cancer patients. We investigated whether MENA isoforms might play a role in driving resistance to chemotherapeutics. We find that both MENA and MENAINV confer resistance to the taxane paclitaxel, but not to the widely used DNA damaging agents doxorubicin or cisplatin. Furthermore, paclitaxel treatment does not attenuate growth of MENAINV-driven metastatic lesions. Mechanistically, MENA isoform expression alters the ratio of dynamic and stable microtubule populations in paclitaxel-treated cells. MENA expression also increases MAPK signaling in response to paclitaxel treatment. Decreasing ERK phosphorylation by co-treatment with MEK inhibitor restored paclitaxel sensitivity by driving microtubule stabilization in MENA isoform-expressing cells. Our results reveal a novel mechanism of taxane resistance in highly metastatic breast cancer cells and identify a combination therapy to overcome such resistance.

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MEK and PI3K/Akt Inhibition In Cancer Cachexia

Involuntary weight loss, a part of the cachexia syndrome, is a debilitating co-morbidity of cancer and currently has no treatment options. Results from a recent clinical trial at our institution showed that biliary tract cancer patients treated with a MEK inhibitor exhibited poor tumor responses, but surprisingly gained weight and increased their skeletal muscle mass. This implied that MEK inhibition might be anti-cachectic. To test this potential effect of MEK inhibition, we utilized the established Colon-26 model of cancer cachexia and the MEK1/2 inhibitor MEK162. Results showed that MEK inhibition effectively prevented muscle wasting. Importantly, MEK162 retained its ability to spare muscle loss even in mice bearing a Colon-26 clone resistant to the MEK inhibitor, demonstrating that the effects of blocking MEK is at least in part independent of the tumor. Because single agent MEK inhibitors have been limited as a front-line targeted therapy due to compensatory activation of other oncogenic signaling pathways, we combined MEK162 with the PI3K/Akt inhibitor buparlisib. Results showed that this combinatorial treatment significantly reduced tumor growth due to a direct activity on Colon-26 tumor cells in vitro and in vivo, while also preserving skeletal muscle mass. Together, our results suggest that as a monotherapy MEK inhibition preserves muscle mass, but when combined with a PI3K/Akt inhibitor exhibits potent anti-tumor activity. Thus, combinatorial therapy might serve as a new approach for the treatment of cancer cachexia.

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Contents

Publication date: December 2016
Source:Anesthesiology Clinics, Volume 34, Issue 4





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Forthcoming Issues

Publication date: December 2016
Source:Anesthesiology Clinics, Volume 34, Issue 4





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Surgical Critical Care for the Trauma Patient with Cardiac Disease

Publication date: December 2016
Source:Anesthesiology Clinics, Volume 34, Issue 4
Author(s): Michael M. Woll, Linda L. Maerz

Teaser

The elderly population is rapidly increasing in number. Therefore, geriatric trauma is becoming more prevalent. All practitioners caring for geriatric trauma patients should be familiar with the structural and functional changes naturally occurring in the aging heart, as well as common preexisting cardiac diseases in the geriatric population. Identification of the shock state related to cardiac dysfunction and targeted assessment of perfusion and resuscitation are important when managing elderly patients. Finally, management of cardiac dysfunction in the trauma patient includes an appreciation of the inherent effects of trauma on cardiac function.


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Anesthesia for Patients with Peripheral Vascular Disease and Cardiac Dysfunction

Publication date: December 2016
Source:Anesthesiology Clinics, Volume 34, Issue 4
Author(s): Sara E. Neves

Teaser

Patients with vascular disease and cardiac dysfunction present particular challenges to the anesthesiologist. They are hemodynamically brittle, at high risk of morbidity and mortality during surgery, and often carry additional comorbidities that increase their complexity and risk. Those with peripheral vascular disease should be assumed to have coronary artery disease and tend to have other systemic vascular problems. Poor cardiac function further worsens perfusion in an already compromised peripheral vascular system. Care of these patients requires judicious monitoring, an anesthetic that optimizes hemodynamic function, and avoidance of particularly likely complications such as perioperative myocardial ischemia, stroke, and bleeding.


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Copyright

Publication date: December 2016
Source:Anesthesiology Clinics, Volume 34, Issue 4





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Editorial Board

Publication date: November–December 2016
Source:Practical Radiation Oncology, Volume 6, Issue 6





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Table of Contents

Publication date: November–December 2016
Source:Practical Radiation Oncology, Volume 6, Issue 6





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Masthead

Publication date: November–December 2016
Source:Practical Radiation Oncology, Volume 6, Issue 6





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Use of non-invasive imaging to monitor response to aflibercept treatment in murine models of colorectal cancer liver metastases

Abstract

The liver is the most frequent metastatic site in colorectal cancer (CRC), and relevant orthotopic in vivo models are needed to study the efficacy of anticancer drugs in the metastatic setting. A challenge when utilizing such models is monitoring tumor growth during the experiments. In this study, experimental liver metastases were established in nude mice by splenic injection of the CRC cell lines HT29 and HCT116, and the mice were treated with the antiangiogenic drug aflibercept. Tumor growth was monitored using magnetic resonance imaging (MRI) and bioluminescence imaging (BLI). Aflibercept treatment was well tolerated and resulted in increased animal survival in HCT116, but not in HT29, while inhibited tumor growth was observed in both models. Treatment efficacy was monitored with high precision using MRI, while BLI detected small-volume disease with high sensitivity, but was less accurate in end-stage disease. Apparent diffusion coefficient (ADC) values obtained by diffusion weighted MRI (DW-MRI) were highly predictive of treatment response, with increased ADC corresponding well with areas of necrosis observed by histological evaluation of aflibercept-treated xenografts. The results showed that the efficacy of the antiangiogenic drug aflibercept varied between the two models, possibly reflecting unique growth patterns in the liver that may be representative of human disease. Non-invasive imaging, especially MRI and DW-MRI, can be used to effectively monitor tumor growth and treatment response in orthotopic liver metastasis models.

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Protein content and functional characteristics of serum-purified exosomes from patients with colorectal cancer revealed by quantitative proteomics

Abstract

Tumour cells of colorectal cancer (CRC) release exosomes into the circulation. These exosomes can mediate communication between cells and affect various tumour-related processes in their target cells. We present a quantitative proteomics analysis of the exosomes purified from serum of patients with CRC and normal volunteers; data are available via ProteomeXchange with identifier PXD003875. We identified 918 proteins with an overlap of 725 Gene IDs in the Exocarta proteins list. Compared with the serum-purified exosomes (SPEs) of normal volunteers, we found 36 proteins upregulated and 22 proteins downregulated in the SPEs of CRC patients. Bioinformatics analysis revealed that upregulated proteins are involved in processes that modulate the pretumorigenic microenvironment for metastasis. In contrast, differentially expressed proteins (DEPs) that play critical roles in tumour growth and cell survival were principally downregulated. Our study demonstrates that SPEs of CRC patients play a pivotal role in promoting the tumour invasiveness, but have minimal influence on putative alterations in tumour survival or proliferation. According to bioinformatics analysis, we speculate that the protein contents of exosomes might be associated with whether they are involved in premetastatic niche establishment or growth and survival of metastatic tumour cells. This information will be helpful in elucidating the pathophysiological functions of tumour-derived exosomes, and aid in the development of CRC diagnostics and therapeutics. This article is protected by copyright. All rights reserved.

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Antiglioma effects of N6-isopentenyladenosine, an endogenous isoprenoid end product, through the Downregulation of Epidermal Growth Factor Receptor

Abstract

Malignant gliomas are highly dependent on the isoprenoid pathway for the synthesis of lipid moieties critical for cell proliferation. The isoprenoid derivative N6-isopentenyladenosine (iPA) displays pleiotropic biological effects, including a direct anti-tumor activity in several tumor models. The antiglioma effects of iPA was then explored in U87MG cells both in vitro and grafted in mice and the related molecular mechanism confirmed in primary derived patients' glioma cells.

iPA powerfully inhibited tumor cell growth and induced caspase-dependent apoptosis through a mechanism involving a marked accumulation of the pro-apoptotic BIM protein and inhibition of EGFR. Indeed, activating AMPK following conversion into its iPAMP active form, iPA stimulated EGFR phosphorylation and ubiquitination along a proteasome-mediated pathway which was responsible for receptor degradation and its downstream signaling pathways inhibition, including the STAT3, ERK and AKT cascade. The inhibition of AMPK by compound C prevented iPA-mediated phosphorylation of EGFR, known to precede receptor loss. As expected the block of EGFR degradation, by exposure to the proteasome inhibitor MG132, significantly reduced iPA-induced cell death.

Given the importance of receptor degradation in iPA-mediated cytotoxicity, we also documented that the EGFR expression levels in a panel of primary glioma cells confers them a high sensitivity to iPA treatment. In conclusion our study provides the first evidence of iPA antiglioma effect. Indeed, as glioma is driven by aberrant signaling of growth factor receptors, particularly the EGFR, iPA, alone or in association with EGFR targeted therapies, might be a promising therapeutic tool to achieve a potent anti-tumoral effect. This article is protected by copyright. All rights reserved.

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Development of Lu-177-trastuzumab for radioimmunotherapy of HER2 expressing breast cancer and its feasibility assessment in breast cancer patients

Abstract

HER2/neu is over expressed in 20-25% of breast cancers. HER2 breast cancers are aggressive and are associated with poor prognosis. The aim of this study was to develop the clinical grade Lu-177-trastuzumab and its preliminary evaluation for specific tumor targeting in HER2 positive breast cancer patients. Trastuzumab was conjugated to bifunctional chelator, DOTA, and characterized for integrity and the number of molecules conjugated. Radiolabeling of DOTA-conjugated trastuzumab was optimized using Lu-177. Quality control parameters including radiochemical purity, stability, sterility, pyrogenicity and immunoreactivity were assessed. A preliminary pilot study was conducted on breast cancer patients (n=6 HER2 positive and n=4 HER2 negative) to evaluate the ability of Lu-177-trastuzumab for HER2 specific tumor targeting. The conjugates were efficiently labeled with Lu-177 with high radiochemical purity (up to 91%) and specific activity (6-13 µCi/µg). Lu-177-trastuzumab was stable up to 12 hours post labeling. The radioimmunoassay demonstrated good antigen binding ability and specificity for HER2 receptor protein. The patient studies showed the localization of Lu-177-trastuzumab at primary as well as metastatic sites (HER2 positive) in the planar and SPECT/CT images. No tracer uptake was observed in HER2 negative patients that indicated the specificity of Lu-177-trastuzumab. The study demonstrated that in-house developed Lu-177-trastuzumab has specific targeting ability for HER2 expressing lesions and may in future become a palliative treatment option in the form of targeted radionuclide therapy for disseminated HER2 positive breast cancer. This article is protected by copyright. All rights reserved.

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Cancer Risks in Nairobi (2000-2014) by Ethnic Group

Abstract

We investigated the ethnic differences in the risk of several cancers in the population of Nairobi, Kenya, using data from the Nairobi Cancer Registry.

Cancer cases from the Nairobi Cancer Registry were used. The registry records the variable "Tribe" for each case, a categorisation that includes, as well as 22 tribal groups, categories for Kenyans of European and of Asian origin, and non-Kenyan Africans. Tribes included in the final analysis were Kikuyu, Kamba, Kisii, Kalenjin, Luo, Luhya, Somalis, Asians, non-Kenyans, Caucasians, Other tribes and unknown.

The largest group was taken as the reference category for the calculation of odds ratios; this was African Kenyans (for comparisons by race), and Kikuyus (the tribe with the largest numbers of cancer registrations (38% of the total)) for comparisons between the Kenyan tribes. P-values are obtained from the Wald test.

Cancers that were more common among the white population than in black Kenyans were skin cancers and cancers of the bladder, while cancers that are more common in Kenyan Asians include colorectal, lung, breast, ovary, corpus uteri and non-Hodgkin lymphoma. Cancers that were less common among Asians and Caucasians were oesophagus, stomach and cervix cancer.

Within the African population, there were marked differences in cancer risk by tribe. Among the tribes of Bantu ethnicity, the Kamba had higher risks of melanoma, Kaposi sarcoma, liver and cervix cancer, and lower risks of oesophagus, stomach, corpus uteri and nervous system cancers. Luo and Luhya had much higher odds of Kaposi sarcoma and Burkitt lymphoma. This article is protected by copyright. All rights reserved.

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Quercetin alters the DNA damage response in human hematopoietic stem and progenitor cells via TopoII- and PI3K- dependent mechanisms synergizing in leukemogenic rearrangements

Abstract

Quercetin (Que) is an abundant flavonoid in the human diet and high-concentration food supplement with reported pro- and anti- carcinogenic activities. Topoisomerase II (TopoII) inhibition and subsequent DNA damage induction by Que was implicated in the Mixed Lineage Leukemia gene (MLL) rearrangements that can induce infant and adult leukemias. This notion raised concerns regarding possible genotoxicities of Que in Hematopoietic Stem and Progenitor Cells (HSPCs). However, molecular targets mediating Que effects on DNA repair relevant to MLL translocations have not been defined.

In this study we describe novel and potentially genotoxic Que activities in suppressing Non-Homologous End Joining and Homologous Recombination pathways downstream of MLL cleavage. Using pharmacological dissection of DNA-PK, ATM and PI3K signaling we defined PI3K inhibition by Que with a concomitant decrease in the abundance of key DNA repair genes to be responsible for DNA repair inhibition. Evidence for the downstream TopoII-independent mutagenic potential of Que was obtained by documenting further increased frequencies of MLL rearrangements in human HSPCs concomitantly treated with Etoposide and Que versus single treatments. Importantly, by engaging a tissue engineered placental barrier, we have established the extent of Que transplacental transfer and hence provided the evidence for Que reaching fetal HSPCs.

Thus, Que exhibits genotoxic effects in human HSPCs via different mechanisms when applied continuously and at high concentrations. In light of the demonstrated Que transfer to the fetal compartment our findings are key to understanding the mechanisms underlying infant leukemia and provide molecular markers for the development of safety values. This article is protected by copyright. All rights reserved.

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D-dimers in malignant melanoma: Association with prognosis and dynamic variation in disease progress

Abstract

Malignant cells elicit a chronic hemostatic activation in disease progress. This procoagulant activity does not only bear a risk for thromboembolism but also facilitates tumor growth and dissemination. An elevated plasma D-dimer level indicates an activated coagulation and fibrinolysis. In the present study, the association of D-dimer levels with clinicopathological parameters and patients outcome in melanoma was investigated analyzing in total 533 melanoma patients retrospectively. Using the cut-off point of 0.6 mg/L D-dimer 145 of the total 533 patients (27.2%) were identified with elevated plasma D-dimer levels. This increased D-dimer level positively correlated with tumor thickness (P=0.0003), lymph node invasion (P=0.0004) and metastatic state (P<.0001). To assess the association of D-dimer levels with progression-free survival (PFS) and overall survival (OS), long-rank test and the Cox proportional hazard model was performed. Univariate analyses revealed that elevated D-dimer levels were significantly associated with decreased PFS (HR:2.89, 95% CI (2.07-7.56), P<.0001) and OS (HR:2.22, 95% CI (1.06-4.57), P=0.035). Moreover, multivariate analyses identified elevated D-dimer levels being associated with poor disease outcome (PFS:HR:2.47, 95% CI (1.23-4.98), P=0.012; OS:HR:2.01, 95% CI (0.09-4.45), P=0.087). Additionally, D-dimer levels were significantly increased in terminal stage patients when comparing plasma levels 0-8 versus 24-48 weeks before death (P=0.0003). In summary, this study presents multiple evidence that elevated D-dimer levels in melanoma patients associate with poor prognosis and therefore plasma levels of D-dimers could reveal a more aggressive phenotype of melanoma and may guide the management of anti-melanoma treatment including the concept of an anti-coagulatory therapy in tumor patients. This article is protected by copyright. All rights reserved.

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A longitudinal investigation of parenting stress in caregivers of children with retinoblastoma

Abstract

Background

Retinoblastoma is typically diagnosed in young children and may present unique parenting challenges. Qualitative research suggests that parents experience distress related to the initial diagnosis and treatment that subsequently resolves. The objectives were to systematically assess parenting stress over time in parents of young children with retinoblastoma and to examine associations between parenting stress and child outcomes.

Procedures

Parents of children with retinoblastoma completed the Parenting Stress Index (PSI) during serial psychological assessments scheduled based on the child's age (6 months to 5 years). Caregivers of 92 patients (85.9% mothers) completed the assessments. Child outcomes included developmental functioning and parent-reported adaptive functioning.

Results

At baseline and age 5, all subscales on the PSI were within normal limits, and most were significantly below normative means (i.e., demonstrating low levels of stress). All domains remained relatively stable over time. Associations between parenting stress and child outcomes were much stronger at age 5 than at baseline. Child-directed parenting stress was a small but significant contributor to declines in child functioning over time.

Conclusions

Parents of children with retinoblastoma report normal levels of parenting stress while their children are young. However, baseline parenting stress appears to contribute to changes in child functioning over time. Future studies should assess illness-related aspects of adjustment to further understand the parenting experience of young children with cancer and/or having a visually impaired child.

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Long-term outcomes of 95 children with moderate aplastic anemia treated with horse antithymocyte globulin and cyclosporine

Abstract

Background

Currently, the standard management of moderate aplastic anemia (MAA) has not been well described, although the superiority of the combination of antithymocyte globulin (ATG) and cyclosporine (CyA) over CyA alone has been demonstrated in terms of hematological responses and failure-free survival (FFS).

Procedure

We adopted this therapeutic strategy and treated 95 children with MAA who were enrolled in two consecutive prospective studies between October 1992 and August 2009.

Results

For these patients, the 6-month response rate was 54.7% (complete response, 13.7%; partial response, 41.1%). There were no statistically significant differences in the overall response rates between the transfusion-dependent (48.8%, n = 41) and transfusion-independent groups (59.3%, n = 54; P = 0.4). Treatment failure was defined as the requirement of salvage treatment, and was observed in 52 patients. The 10-year FFS was 44.0% (95% confidence interval [CI], 32.9%–54.6%). Of the 22 patients who underwent a second immunosuppressive therapy (IST), 12 responded. Forty patients underwent hematopoietic stem cell transplantation as second- or third-line therapy and three died of complications. Consequently, the 10-year overall survival rate was 96.0% (95% CI, 88.0%–98.7%) with a median follow-up period of 103 months (range, 29–221 months).

Conclusions

Although current guidelines recommend only observation for patients with transfusion-independent MAA, the results of our study justify early intervention with ATG and CyA in those patients. A prospective randomized trial is warranted to clarify the risks and benefits of early intervention with IST and observation alone until progression to severe AA in patients with MAA.

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Vincristine and Vinblastine: Is checking bilirubin mandatory in children with Brain Tumors?

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Pediatric 8p11 eosinophilic myeloproliferative syndrome (EMS): A case report and review of the literature

Abstract

The 8p11 eosinophilic myeloproliferative syndrome (EMS) is an aggressive neoplasm driven by translocation of the fibroblast growth factor receptor 1 and often transforms to leukemias and lymphomas that are refractory to treatment. The first case was identified in 1983, and to date over 70 cases have been reported in the literature. Despite those reports, no consensus exists on management of this condition, and inconsistency in treatment regimens is even more pronounced in the pediatric literature. We report a case of a male infant with the 8p11 EMS, review the published pediatric experience with EMS, and discuss treatment strategies for this enigmatic hematological disorder.

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Impact of combined FDG-PET/CT and MRI on the detection of local recurrence and nodal metastases in thyroid cancer

Abstract

Background

Suspected recurrence of thyroid carcinoma is a diagnostic challenge when findings of both a radio iodine whole body scan and ultrasound are negative. PET/CT and MRI have shown to be feasible for detection of recurrent disease. However, the added value of a consensus reading by the radiologist and the nuclear medicine physician, which has been deemed to be helpful in clinical routines, has not been investigated. This study aimed to investigate the impact of combined FDG-PET/ldCT and MRI on detection of locally recurrent TC and nodal metastases in high-risk patients with special focus on the value of the multidisciplinary consensus reading.

Materials and methods

Forty-six patients with suspected locally recurrent thyroid cancer or nodal metastases after thyroidectomy and radio-iodine therapy were retrospectively selected for analysis. Inclusion criteria comprised elevated thyroglobulin blood levels, a negative ultrasound, negative iodine whole body scan, as well as combined FDG-PET/ldCT and MRI examinations.

Neck compartments in FDG-PET/ldCT and MRI examinations were independently analyzed by two blinded observers for local recurrence and nodal metastases of thyroid cancer. Consecutively, the scans were read in consensus. To explore a possible synergistic effect, FDG-PET/ldCT and MRI results were combined. Histopathology or long-term follow-up served as a gold standard.

For method comparison, sensitivity, specificity, positive and negative predictive values, and diagnostic accuracy were calculated.

Results

FDG-PET/ldCT was substantially more sensitive and more specific than MRI in detection of both local recurrence and nodal metastases. Inter-observer agreement was substantial both for local recurrence (κ = 0.71) and nodal metastasis (κ = 0.63) detection in FDG-PET/ldCT. For MRI, inter-observer agreement was substantial for local recurrence (κ = 0.69) and moderate for nodal metastasis (κ = 0.55) detection. In contrast, FDG-PET/ldCT and MRI showed only slight agreement (κ = 0.21). However, both imaging modalities identified different true positive results. Thus, the combination created a synergistic effect. The multidisciplinary consensus reading further increased sensitivity, specificity, and diagnostic accuracy.

Conclusions

FDG-PET/ldCT and MRI are complementary imaging modalities and should be combined to improve detection of local recurrence and nodal metastases of thyroid cancer in high-risk patients. The multidisciplinary consensus reading is a key element in the diagnostic approach.

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Metastatic Bladder Cancer: Second-Line Treatment and Recommendations of the Genitourinary Tumor Division of the Galician Oncologic Society (SOG-GU)

Abstract

Once metastatic bladder cancer has progressed to first-line treatment, the number of therapeutic options is scarce. Among chemotherapeutic agents showing activity in phase II trials, including taxanes, vinflunine (VFL) is the only one shown to increase overall survival in a phase III trial. In addition to its efficacy, VFL is safe in special population groups. Despite this, the prognosis for these patients remains poor, and more effective therapies need to be developed. Agents acting on new therapeutic targets as well as biomarkers to aid matching patients to specific treatments are currently under evaluation. In this regard, immunotherapy is showing promising results. In this article, a critical review of current treatments and future prospects is made, and therapy recommendations are made based on existing scientific evidence.

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Palliative Care of Cancer in the Older Patient

Abstract

The scope of palliative care includes goal setting, symptom management, and care of the care giver. Palliative care is essential for patient-centered care of the older cancer patients. The diversity of this population in terms of life expectancy, treatment tolerance, function, disability, and social support mandates personalized treatment plans. The assessment of physiologic age is currently based on a comprehensive geriatric assessment (CGA). A number of biologic markers of aging including the inflammatory index, the genomic clock, the expression of p16INKa4, and the circulating levels of vitamin D may complement the CGA and fine-tune the determination of physiologic age. Goal setting in older patients may be complicated by communication difficulties related to hearing, cognition, expectation, and culture. Cancer-related pain is a major hindrance to the maintenance of functional independence and fatigue is harbinger of disability and death. The article explores the assessment and the management of the most common and debilitating symptoms in older cancer patients.

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Opioids and Chronic Pain: Where Is the Balance?

Abstract

Chronic opioid therapy (defined as greater than 3 months on opioids) is a common practice for those with non-cancer pain, cancer survivors with treatment-related pain, and individuals with cancer undergoing disease-modifying therapy with a survival that can be for a year or more. Recent studies have found unique long-term toxicities with opioids which reduce the utility of opioid therapy in chronic pain. The risk of addiction, depression, central hypogonadism, sleep-disordered breathing, impaired wound healing, infections, cognitive impairment, falls, non-vertebral fractures, and mortality are increased in populations on long-term opioids. Factors associated with these risks are related to dose, duration of opioid therapy, type of opioid, and formula (long-acting, short-acting). This state-of-the-art review discusses the risks and benefits of chronic opioid therapy and strategies to increase utility and diminish risks to opioid therapy.

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Geographic distribution of incidence of pericardial and paratesticular mesotheliomas in the USA

Abstract

Purpose

Exposure to asbestos is thought to cause the large majority of pleural mesotheliomas in the USA. It is unknown whether asbestos exposure plays a role in the etiology of rarer forms of mesothelioma, e.g., those located in the pericardium or in the tunica vaginalis of the testis. In order to address this question, we sought to determine whether geographic patterns of incidence of these mesotheliomas have paralleled those of pleural mesotheliomas.

Methods

We used age-adjusted incidence data from the nine populations served by the National Cancer Institute's Surveillance, Epidemiology, and End Results program during 1973–2011. Among men ages ≥50 years, we compared the incidence of pericardial and paratesticular mesotheliomas, respectively, with the incidence of pleural mesothelioma across the nine populations.

Results

The rate of pleural mesothelioma was approximately twice as high in the San Francisco–Oakland (SFO) and Seattle–Puget Sound (SPS) areas compared to the other regions. In contrast, rates of paratesticular and pericardial mesotheliomas were not elevated in SFO (n = 3 paratesticular, 1 pericardial) or SPS (n = 4 paratesticular, 1 pericardial) relative to other regions.

Conclusions

The results of this ecologic study do not support a role for asbestos exposure in the etiologies of either pericardial or paratesticular mesotheliomas; however, this study was limited by small numbers and was unable to directly ascertain asbestos exposure.

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Potential Impact of Biologically Derived Hyaluronic Acid on Quality of Life in Patients with Knee Osteoarthritis in the United States

Abstract

Introduction

Knee osteoarthritis is one of the leading causes of disability in the world. Intra-articular hyaluronic acid (IA-HA) is a treatment modality that provides a minimally invasive treatment option for the management of osteoarthritis-related symptoms. This study examined the current and potential economic impact of using a biologically derived, high molecular weight hyaluronic acid preparation (Euflexxa) on the US population for the management of knee osteoarthritis.

Methods

A model was developed to estimate the total number of patients with symptomatic knee osteoarthritis in the US in 2015, distributed by Kellgren–Lawrence (K–L) grade, and the number of people living with total knee arthroplasty (TKA). The potential utility of Euflexxa was applied to this model population to determine the current and potential impact of the treatment as the total number of quality adjusted life years (QALY) saved within the US population.

Results

There are approximately 12 million people currently suffering from symptomatic knee osteoarthritis in the US, and approximately 5 million living with TKA. It was estimated that, with a target treatment group of K–L grades 2–3, there are approximately 4 million patients eligible for treatment with a high molecular weight intra-articular hyaluronic acid injection. With current use, it is estimated that Euflexxa can save 36,730 QALY/year among the US population, and has the potential to save an additional 369,181 QALY/year if used by all eligible patients.

Conclusions

This study demonstrates that more widely used, biologically derived, high molecular weight IA-HAs, such as Euflexxa, have the potential to save a substantial number of QALYs among the US population with symptomatic knee osteoarthritis.

Funding: Ferring Pharmaceuticals Inc.

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Infection with hepatitis viruses, FIB-4 index and risk of hepatocellular carcinoma in southern Italy: a population-based cohort study

Abstract

Background

The incidence of hepatocellular carcinoma (HCC) and its association with hepatitis C (HCV) and hepatitis B virus (HBV) infections, FIB-4 index and liver enzymes was assessed in an area of the province of Naples covered by a population-based cancer registry.

Methods

We conducted a cohort investigation on 4492 individuals previously enrolled in a population-based seroprevalent survey on HCV and HBV infections. The diagnosis of HCC was assessed through a record linkage with the cancer registry. Hepatic metabolic activity was measured through serum alanine transaminase, aspartate aminotransferase, gamma-glutamyl-transferase, and platelet. The FIB-4 index was used as a marker of fibrosis. We computed HCC incidence rates (IR) for 100,000 (10⁵) person-years of observation, and multivariable hazard ratios (HR) with 95 % confidence intervals (CI) to assess risk factors for HCC.

Results

Twenty two cases of HCC were diagnosed during follow-up (IR = 63.3 cases/10⁵). Significantly increased HCC risks were documented in individuals with higher than normal liver enzymes and low platelet count; in the 239 HCV RNA-positives (HR = 61.8, 95 % CI:13.3–286); and in the 95 HBsAg-positives (HR = 75.0) –as compared to uninfected individuals. The highest FIB-4 score was associated with a 17.6-fold increased HCC risk.

Conclusions

An elevated FIB-4 index turned out to be an important predictor of HCC occurrence. Although the standard method to assess hepatic fibrosis in chronic hepatitis remains the histologic staging of liver biopsy specimen, the assessment of FIB-4 in HCV RNA-positive individuals may help in identifying the highest HCC-risk individuals who need anti-HCV treatment most urgently.

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Pharmacokinetic dose adjustment of 5-FU in modified FOLFOX7 plus bevacizumab for metastatic colorectal cancer in Japanese patients: a-JUST phase II clinical trial

Abstract

Purpose

Dose adjustment of 5-fluorouracil (FU) based on pharmacokinetic monitoring has been shown to reduce toxicities and increase efficacy compared with dosing based on body surface area in patients with metastatic colorectal cancer (mCRC). We evaluated the efficacy and safety of pharmacokinetic dose adjustment of FU in a modified FOLFOX7 (mFOLFOX7) plus bevacizumab regimen in Japanese patients with previously untreated mCRC.

Methods

This single-arm, multicenter phase II trial enrolled 48 patients with mCRC. Treatment consisted of 5 mg/kg intravenous bevacizumab followed by mFOLFOX7 (oxaliplatin 85 mg/m² on day 1, infused leucovorin 200 mg/m², followed by a 2400 mg/m² infusion of FU for 46 h starting on day 1), repeated every 2 weeks. FU concentrations were measured by immunoassay between 18 and 36 h after the start of continuous FU infusion, and the FU dose was then adjusted if required in subsequent cycles. The primary endpoint was response rate.

Results

The median initial area under the concentration–time curve for FU was 23 mg h/L. Twenty-nine patients (60%) achieved the target concentration at the first cycle, and all 48 achieved it within the fourth cycle. The overall frequency of grade 3/4 adverse effects was 38%, with no significant difference between patients who did and not require dose adjustments. The overall response rate was 48% (95% confidence intervals = 34–62%). The median progression-free and overall survival rates were 11.3 and 24.1 months, respectively.

Conclusions

Pharmacokinetic dose adjustment of FU in mFOLFOX7 plus bevacizumab can optimize FU concentrations promptly and is safe in Japanese patients with mCRC.

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Erufosine increases RhoB expression in oral squamous carcinoma cells independent of its tumor suppressive mode of action - a short report

Abstract

Purpose

Recently, we found that erufosine (erucylphospho-N,N,N trimethylpropylammonium) can induce up-regulation of RhoB expression in oral squamous carcinoma (OSCC) cells, thereby hinting at a tumor suppressive role. Therefore, we aimed to evaluate the role of RhoB in the tumor suppressive mode of action of erufosine on OSCC cells.

Methods

Anti-proliferative effects of erufosine were determined in HN-5 and FaDu OSCC-derived cells using a MTT assay. RhoB up-regulation was detected using microarray and qRT-PCR-based expression assays at IC₂₅, IC₅₀ and IC₇₅ concentrations of erufosine. The results obtained were verified by Western blotting. In addition, siRNA-mediated RhoB knockdown was carried out and combined with erufosine treatment, after which cell cycle, colony formation and migration assays were performed to evaluate its combined effects.

Results

We found that after erufosine treatment of HN-5 and FaDu cells for 24, 48 and 72 h the IC₅₀ values ranged from 43 to 37 μM and 27– to 15 μM, respectively. Microarray and qRT-PCR-based expression analyses revealed RhoB up-regulation up to 9-fold and 20-fold, respectively. Using Western blotting, an increase in RhoB protein expression was observed, as well as a decrease in pAkt (Ser⁴⁷³ and Thr³⁰⁸) expression and an increase in PARP cleavage. Combined siRNA-mediated RhoB knockdown and erufosine treatment resulted in slightly reduced RhoB and pAkt levels compared to erufosine treatment alone. Subsequent cell cycle analyses revealed an increased apoptotic induction, but a reduced G2 cell cycle arrest, of the combination. At the functional level, synergistic effects were observed using cell migration and colony formation assays.

Conclusions

Our data show that erufosine can cause up-regulation of RhoB expression in OSCC cells. Combining erufosine treatment with siRNA-mediated RhoB knockdown did, however, not reveal a role of RhoB in its tumor suppressive mode of action.

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Glomerular hyperfiltration in children with cancer: prevalence and a hypothesis

Abstract

Background

Glomerular hyperfiltration has recently been reported in children with malignancies and has been attributed to increased solute from breakdown of tumor tissues.

Objective

To evaluate the prevalence of hyperfiltration in the pediatric oncology population and explore its pathophysiological mechanism.

Materials and methods

Tc-99 m diethylenetriaminepentaacetic acid (DTPA) glomerular filtration rate (GFR) examinations (437 studies) and medical records of 177 patients <21 years of age diagnosed with a malignancy between January 2005 and October 2013 were retrospectively reviewed. Hyperfiltration was defined as a GFR ≥ 160 ml/min/1.73 m².

Results

Seventy-seven (43.5%) patients had hyperfiltration in at least one GFR exam. A significantly higher percentage of patients with central nervous system (CNS) tumors (63.6%) had hyperfiltration when compared to other tumor types (27.3%, P < 0.001). No association was found between hyperfiltration and age, gender, race or bone marrow involvement. There was a significant trend toward decreasing hyperfiltration after the second cycle of chemotherapy (P = 0.006) and a significant increase in subjects with low GFR (<100 ml/min/1.73 m²) with increasing number of cycles of chemotherapy (P = 0.005).

Conclusion

Glomerular hyperfiltration is common in children with malignancies at diagnosis and during initial cycles of chemotherapy. It is particularly prevalent in patients with central nervous tumors, which are frequently smaller in volume. Therefore, the pathophysiological mechanism of hyperfiltration cannot be explained solely on the basis of large tumor volume and subsequent cell breakdown. We hypothesize that host hypermetabolic state plays an important role in pathophysiology of hyperfiltration.

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Hematological and biochemical values in Brazilian four-beat gaited horses

Abstract

Horse selection is still associated with gait type, and this aspect is important for four-beat gaited horses, a large group that is distributed around the globe with more than 140 breeds. However, there is little information about their hematological and biochemical profiles, and such information will contribute to improving their exercise and nutritional evaluation programs. The aim of this study was to determine the hematological and biochemical values of athletic Campolina (CAMP) and Mangalarga Marchador (MM) horses performing two different types of gait. Overall, 100 adult horses (53 males and 47 females) with ages between 5 and 15 years and body weights between 350 and 550 kg were evaluated. The horses were grouped as follows: 25 Campolina marcha batida (CAMP-batida), 25 Campolina marcha picada (CAMP-picada), 25 Mangalarga Marchador marcha batida (MM-batida), and 25 Mangalarga Marchador marcha picada (MM-picada). They were fed fresh elephant grass (Pennisetum purpureum Schum; ~15–20 kg/day) and commercial concentrate (5–7 kg/day) as well as commercial mineral salt and water ad libitum. They were trained three times a week (~40–50 min/day), and ~60% of the sessions involved speeds ranging from 3.0 to 4.0 m/s. The results of hematological and biochemical tests were analyzed with ANOVA and Tukey's test (P ≤ 5%). The results showed no differences in the hematological values that were found between the CAMP and MM horses, even when they were grouped by gait. In contrast, differences in the biochemical values were observed between the groups for triglycerides, cholesterol, non-esterified fatty acids, total plasma protein, urea, creatinine, uric acid, alanine aminotransferase, and creatine kinase (P < 0.05). The highest values were recorded in the following groups: CAMP-batida (triglycerides ~33.77 mg/dL, urea ~35.88 mg/dL, and uric acid ~2.11 mg/dL), CAMP-picada (creatinine ~1.44 mg/dL), and MM-batida (cholesterol ~95.77 mg/dL, non-esterified fatty acid ~0.35 mmol/L, total plasma protein ~10.00 mg/dL, ALT ~11.30 U/L, and CK ~198.80 U/L). In conclusion, despite having different gaits, there were no differences in hematological parameters between Campolina and Mangalarga Marchador horses; however, biochemical values associated with fat and protein metabolism were significantly different between the groups.

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Pharmacological targeting of CXCL12/CXCR4 signaling in prostate cancer bone metastasis

Abstract

Background

The CXCL12/CXCR4 axis transactivates HER2 and promotes intraosseous tumor growth. To further explore the transactivation of HER2 by CXCL12, we investigated the role of small GTP protein G_αi2 in Src and HER2 phosphorylation in lipid raft membrane microdomains and the significance of CXCR4 in prostate cancer bone tumor growth.

Methods

We used a variety of methods such as lipid raft isolation, invasion assays, an in vivo model of intratibial tumor growth, bone histomorphometry, and immunohistochemistry to determine the role of CXCR4 signaling in lipid raft membrane microdomains and effects of targeting of CXCR4 for bone tumor growth.

Results

We determined that (a) CXCL12/CXCR4 transactivation of EGFR and HER2 is confined to lipid raft membrane microdomains, (b) CXCL12 activation of HER2 and Src is mediated by small GTP proteins in lipid rafts, (c) inhibition of the CXCL12/CXCR4 axis through plerixafor abrogates the initial establishment of tumor growth without affecting the growth of established bone tumors, and (d) inhibition of EGFR signaling through gefitinib leads to inhibition of established bone tumor growth.

Conclusions

These data suggest that lipid raft membrane microdomains are key sites for CXCL12/CXCR4 transactivation of HER2 via small GTP binding protein G_αi2 and Src kinase. The initial establishment of prostate cancer is supported by the endosteal niche, and blocking the CXCL12/CXCR4 axis of this niche along with its downstream signaling severely compromises initial establishment of tumors in the bone microenvironment, whereas expanding bone tumors are sensitive only to the members of growth factor receptor inhibition.

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European Code against Cancer 4th Edition: Alcohol drinking and cancer

Publication date: Available online 2 November 2016
Source:Cancer Epidemiology
Author(s): Chiara Scoccianti, Michele Cecchini, Annie S. Anderson, Franco Berrino, Marie-Christine Boutron-Ruault, Carolina Espina, Timothy J. Key, Michael Leitzmann, Teresa Norat, Hilary Powers, Martin Wiseman, Isabelle Romieu
Alcohol consumption is the third leading risk factor for disease and mortality in Europe. As evaluated by the International Agency for Research on Cancer (IARC) Monographs, a causal relationship is established for consumption of alcoholic beverages and cancers of the oral cavity, pharynx, larynx, oesophagus, liver, colorectum and female breast, even at low and moderate alcohol intakes. The higher the amount of alcohol consumed, the higher the risk of developing cancer. In Europe, an estimated 10% (95% CI: 7%–13%) of all cancer cases in men and 3% (95% CI: 1%–5%) of all cancer cases in women are attributable to alcohol consumption. Several biological mechanisms explain the carcinogenicity of alcohol; among them, ethanol and its genotoxic metabolite, acetaldehyde, play a major role. Taking all this evidence into account, a recommendation of the 4th edition of European Code against Cancer is: "If you drink alcohol of any type, limit your intake. Not drinking alcohol is better for cancer prevention."



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Just a Cut

Foreword. In this Journal feature, information about a real patient is presented in stages (boldface type) to an expert clinician, who responds to the information, sharing his or her reasoning with the reader (regular type). The authors' commentary follows. Stage. A 51-year-old surgeon lacerated…

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Molecular and Biochemical Aspects of the PD-1 Checkpoint Pathway

The pathway consisting of the receptor programmed cell death 1 (PD-1; also called CD279) and its ligands, PD-L1 (B7-H1 or CD274) and PD-L2 (B7-DC or CD273), plays a vital role in the maintenance of peripheral tolerance (i.e. mechanisms that maintain the quiescence of autoreactive T cells that have…

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Age-related Disparity: Breast Cancer in the Elderly

Abstract

Aging poses an unique opportunity to study cancer biology and treatment in older adults. Breast cancer is often studied in young women; however, much investigation remains to be done on breast cancer in our expanding elderly population. Diagnostic and management strategies applicable to younger patients cannot be empirically used to manage older breast cancer patients. Lack of evidence-based data continues to be the major impediment toward delivery of personalized cancer care to elderly breast cancer patients. This article reviews the relevant literature on management of curable breast cancer in the elderly, the role of geriatric assessment, complex treatment decision making within the context of patient's expected life expectancy, comorbidities, physical function, socioeconomic status, barriers to health care delivery, goals of treatment, and therapy-related side effects. Continuing efforts for enrolling elderly breast cancer patients in contemporary clinical trials, and thus improving age-appropriate care, are emphasized.

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Determination of loss of consciousness: a comparison of clinical assessment, bispectral index and electroencephalogram: An observational study

BACKGROUND: Computer-processed algorithms of encephalographic signals are widely used to assess the depth of anaesthesia. However, data indicate that the bispectral index (BIS), a processed electroencephalography monitoring system, may not be reliable for assessing the depth of anaesthesia. OBJECTIVE: The aim of this study was to evaluate the ability of the BIS monitoring system to assess changes in the level of unconsciousness, specifically during the transition from consciousness to unconsciousness, in patients undergoing total intravenous anaesthesia with propofol. We compared BIS with the electroencephalogram (EEG), and clinical loss of consciousness (LOC) defined as loss of verbal commands and eyelash reflex. DESIGN: This was an observational cohort study. SETTING: University Hospital Linköping, University Hospital Örebro, Finspång Hospital and Kalmar Hospital, Sweden from October 2011 to April 2013. PATIENTS: A total of 35 ASA I patients aged 18 to 49 years were recruited. INTERVENTIONS: The patients underwent total intravenous anaesthesia with propofol and remifentanil for elective day-case surgery. Changes in clinical levels of consciousness were assessed by BIS and compared with assessment of stage 3 neurophysiological activity using the EEG. The plasma concentrations of propofol were measured at clinical LOC and 20 and 30 min after LOC. MAIN OUTCOME MEASURES: The primary outcome was measurement of BIS, EEG and clinical LOC. RESULTS: The median BIS value at clinical LOC was 38 (IQR 30 to 43), and the BIS values varied greatly between patients. There was no correlation between BIS values and EEG stages at clinical LOC (r = −0.1, P = 0.064). Propofol concentration reached a steady state within 20 min. CONCLUSION: There was no statistically significant correlation between BIS and EEG at clinical LOC. BIS monitoring may not be a reliable method for determining LOC. CLINICAL TRIALS REGISTRY: This trial was not registered because registration was not mandatory at the time of the trial.

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A severe complication after ultrasound-guided thoracic paravertebral block for breast cancer surgery: total spinal anaesthesia: A case report

No abstract available

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Postoperative nausea and vomiting: is everything now solved or still more questions than answers?

No abstract available

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Determination of the appropriate sizes of oropharyngeal airways in adults: correlation with external facial measurements: A randomised crossover study

BACKGROUND: Two external facial measurements have been recommended as reference criteria for estimating appropriate oropharyngeal airway sizes: the distances between the maxillary incisors to the angle of the mandible, and that from the corner of the mouth to the angle of the mandible. OBJECTIVE: To compare the two guidelines and to determine the optimal external facial measurements for the selection of an appropriately sized airway in adults. DESIGN: Randomised crossover study. SETTING: Operating theatres in a university hospital. PATIENTS: A total of 113 patients requiring tracheal intubation for general anaesthesia. INTERVENTIONS: Two oropharyngeal airway sizes were selected on the basis of two external facial measurements (tip of the upper central maxillary incisors to the angle of the mandible and corner of the mouth to the angle of the mandible). After assessing manual and pressure-controlled ventilation without an airway, the adequacy of ventilation with each oropharyngeal airway was assessed in a similar manner. Before changing the oropharyngeal airway, the view at the distal end of each airway was evaluated using endoscopy via a fibreoptic bronchoscope. MAIN OUTCOME MEASURES: Ventilation parameters and the endoscopic views at the distal ends of the airways were assessed. RESULTS: In the maxillary incisors to the angle of the mandible group, there was clear manual ventilation through the oropharyngeal airway in all patients, whereas partially obstructed ventilation was observed in 6% of patients in the corner of the mouth to the angle of the mandible group. In the maxillary incisors to the angle of the mandible group, mechanical ventilation through the oropharyngeal airway was adequate in all patients but in the corner of the mouth to the angle of the mandible group, inadequate ventilation was observed in 7% patients. In the maxillary incisors to the angle of the mandible group, the endoscopy did not identify any patient with complete obstruction of the airway by the tongue but in the corner of the mouth to the angle of the mandible group, 40% of patients had complete obstruction by the tongue. In the maxillary incisors to the angle of the mandible group, the tip of the airway passed beyond the tip of the epiglottis in 22% of patients, in contrast, none of the airways in the corner of the mouth to the angle of the mandible group passed beyond the tip of the epiglottis. CONCLUSION: With regard to adequate ventilation in conjunction with an acceptable endoscopic view, an oropharyngeal airway whose size is based upon the distance from the maxillary incisors to the angle of the mandible is more advantageous than if based upon the distance from the corner of the mouth to the angle of the mandible. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT01945411. The clinical trial was registered before patient enrolment.

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Recommended practice for out-of-hospital emergency anaesthesia in adults: Statement from the Out-of-Hospital Emergency Anaesthesia Working Group of the Emergency Medicine Research Group of the German Society of Anaesthesiology and Intensive Care

No abstract available

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Risk prediction instruments to guide perioperative care in elderly patients with advanced disease: A basic necessity

No abstract available

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Impact of a prophylactic combination of dexamethasone–ondansetron on postoperative nausea and vomiting in obese adult patients undergoing laparoscopic sleeve gastrectomy during closed-loop propofol–remifentanil anaesthesia: A randomised double-blind placebo-controlled study

BACKGROUND: In obese patients, the incidence of postoperative nausea and vomiting (PONV) following sleeve gastrectomy under titration of total intravenous anaesthesia (TIVA) and the relevance of risk factors to indicate prophylaxis is unknown. OBJECTIVES: The hypothesis was that after automated TIVA, prophylaxis reduces PONV following laparoscopic sleeve gastrectomy. Our objective was to determine the incidence of PONV and evaluate the efficacy of dexamethasone and ondansetron as prophylaxis when automated intravenous anaesthesia is employed. DESIGN: A randomised, placebo-controlled, single-centre, double-blinded study. SETTING: Secondary care centre in New Caledonia from June 2013 to January 2014. PATIENTS: A total of 122 patients were randomised and 117 (92 women) were included in the analysis (58 in the prophylaxis group and 59 in the placebo group). Eligibility criteria included at least two of the known risk factors for PONV: female sex, nonsmoking status, prior history of PONV or motion sickness and expected postoperative opioid analgesia. Exclusion criteria included disorders limiting the use of the bispectral index. INTERVENTIONS: All patients received propofol and remifentanil controlled by the same automated system during induction and maintenance of general anaesthesia. The controller modifies the calculated effect-site concentrations according to bispectral index values. Patients received either intravenous dexamethasone 4 mg after tracheal intubation and ondansetron 4 mg during skin closure, or placebo. MAIN OUTCOME MEASURES: The primary endpoint was the cumulative incidences of 24-h PONV and severe PONV (vomiting or nausea with a score of ≥4 on an 11-point verbal rating scale). Data are presented as percentage (95% confidence interval). RESULTS: PONV in the first 24 h occurred in 45 (34 to 60)% of patients who received prophylaxis and 54 (41 to 67)% in the placebo group (P = 0.35). The numbers of patients who suffered severe PONV [19 (10 to 32)% in the prophylaxis group vs. 20 (11 to 33)%, P = 1, in the placebo group] and who required rescue antiemetic drugs [55 (41 to 68) vs. 63 (49 to 75)%, P = 0.46] were similar between the groups. CONCLUSION: The combination of dexamethasone and ondansetron was not effective in preventing PONV or severe PONV in obese patients undergoing laparoscopic sleeve gastrectomy after TIVA. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT01876290.

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Effects of hyperventilation on cerebral oxygen saturation estimated using near-infrared spectroscopy: A randomised comparison between propofol and sevoflurane anaesthesia

BACKGROUND: Near-infrared spectroscopy estimates cerebral regional tissue oxygen saturation (rSO2), which may decrease under hyperventilation. Propofol and sevoflurane act differently on cerebral blood vessels. Consequently, cerebral blood flow during hyperventilation with propofol and sevoflurane anaesthesia may differ. OBJECTIVES: The first aim of this study was to compare the changes in rSO2 between propofol and sevoflurane anaesthesia during hyperventilation. The second aim was to assess changes in rSO2 with ventilation changes. DESIGN: A randomised, open-label study. SETTING: University of Yamanashi Hospital, Yamanashi, Japan from January 2014 to September 2014. PARTICIPANTS: Fifty American Society of Anesthesiologists physical status 1 or 2 adult patients who were scheduled for elective abdominal surgery were assigned randomly to receive either propofol or sevoflurane anaesthesia. Exclusion criterion was a known history of cerebral disease such as cerebral infarction, cerebral haemorrhage, transient ischaemic attack and subarachnoid haemorrhage. INTERVENTIONS: After induction of anaesthesia but before the start of surgery, rSO2, arterial carbon dioxide partial pressure (PaCO2) and arterial oxygen saturation were measured. Measurements were repeated at 5-min intervals during 15 min of hyperventilation with a PaCO2 around 30 mmHg (4 kPa), and again after ventilation was normalised. MAIN OUTCOME MEASURES: The primary outcome was the difference of changes in rSO2 between propofol anaesthesia and sevoflurane anaesthesia during and after hyperventilation. The second outcome was change in rSO2 after the initiation of hyperventilation and after the normalisation of ventilation. RESULTS: Changes of rSO2 during hyperventilation were −10 ± 7% (left) and −11 ± 8% (right) in the propofol group, and −10 ± 8% (left) and −9 ± 7% (right) in the sevoflurane group. After normalisation of PaCO2, rSO2 returned to baseline values. Arterial oxygen saturation remained stable throughout the measurement period. The rSO2 values were similar in the propofol and the sevoflurane groups at each time point. CONCLUSION: The effects of hyperventilation on estimated rSO2 were similar with propofol and sevoflurane anaesthesia. Changes in rSO2 correlated well with ventilation changes. TRIAL REGISTRATION: Japan Primary Registries Network (JPRN); UMIN-CTR ID; UMIN000010640

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Rhabdomyolysis and acute kidney injury: creatine kinase as a prognostic marker and validation of the McMahon Score in a 10-year cohort: A retrospective observational evaluation

BACKGROUND: High-volume fluid resuscitation and the administration of sodium bicarbonate and diuretics have a theoretical renoprotective role in patients at high risk of acute kidney injury (AKI) following rhabdomyolysis. Abnormally elevated creatine kinase has previously been used as a biological marker for the identification of patients at high risk of AKI following rhabdomyolysis. OBJECTIVE: To assess the sensitivity and specificity of plasma creatine kinase (admission and peak values) for the prediction of AKI requiring renal replacement therapy (RRT) or of death in patients with confirmed rhabdomyolysis. To compare the diagnostic performance of creatine kinase with the McMahon score. DESIGN: Retrospective observational study. Data collection included McMahon and Acute Physiology and Chronic Health Evaluation II (APACHE II) scores; daily creatine kinase; daily creatinine and electrolytes; ICU length of stay and mortality. SETTING: Neurosciences and Trauma Critical Care Unit (Cambridge, UK). PATIENTS: In total, 232 adults with confirmed rhabdomyolysis (creatine kinase > 1000 Ul−1) admitted to Neurosciences and Trauma Critical Care Unit between 2002 and 2012. MAIN OUTCOME MEASURES: AKI, RRT and mortality. RESULTS: Forty-five (19%) patients developed AKI and 29 (12.5%) patients required RRT. Mortality was significantly higher in patients who developed AKI (62 vs. 18%, P 

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C-MAC videolaryngoscope compared with direct laryngoscopy for rapid sequence intubation in an emergency department: A randomised clinical trial

BACKGROUND: Airway management in the emergency room can be challenging when patients suffer from life-threatening conditions. Mental stress, ignorance of the patient's medical history, potential cervical injury or immobilisation and the presence of vomit and/or blood may also contribute to a difficult airway. Videolaryngoscopes have been introduced into clinical practice to visualise the airway and ultimately increase the success rate of airway management. OBJECTIVE: The aim of this study was to test the hypothesis that the C-MAC videolaryngoscope improves first-attempt intubation success rate compared with direct laryngoscopy in patients undergoing emergency rapid sequence intubation in the emergency room setting. DESIGN: A randomised clinical trial. SETTING: Emergency Department of the University Hospital, Zurich, Switzerland. PATIENTS: With approval of the local ethics committee, we prospectively enrolled 150 patients between 18 and 99 years of age requiring emergency rapid sequence intubation in the emergency room of the University Hospital Zurich. Patients were randomised (1 : 1) to undergo tracheal intubation using the C-MAC videolaryngoscope or by direct laryngoscopy. INTERVENTIONS: Owing to ethical considerations, patients who had sustained maxillo-facial trauma, immobilised cervical spine, known difficult airway or ongoing cardiopulmonary resuscitation were excluded from our study. All intubations were performed by one of three very experienced anaesthesia consultants. MAIN OUTCOME MEASURES: First-attempt success rate served as our primary outcome parameter. Secondary outcome parameters were time to intubation; total number of intubation attempts; Cormack and Lehane score; inadvertent oesophageal intubation; ease of intubation; complications including violations of the teeth, injury/bleeding of the larynx/pharynx and aspiration/regurgitation of gastric contents; necessity of using further alternative airway devices for successful intubation; maximum decrease of oxygen saturation and technical problems with the device. RESULTS: A total of 150 patients were enrolled, but three patients had to be excluded from the analysis, resulting in 74 patients in the C-MAC videolaryngoscopy group and 73 patients in the direct laryngoscopy group. Tracheal intubation was achieved successfully at the first attempt in 73 of 74 patients in the C-MAC group and all patients in the direct laryngoscopy group (P = 1.0). Time to intubation was similar (32 ± 11 vs. 31 ± 9 s, P = 0.51) in both groups. Visualisation of the vocal cords, represented as the Cormack and Lehane score, was significantly better using the C-MAC videolaryngoscope (P 

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Implementation of patient blood management remains extremely variable in Europe and Canada: the NATA benchmark project: An observational study

BACKGROUND: Preoperative anaemia is associated with increased postoperative morbidity and mortality. Patient blood management (PBM) is advocated to improve patient outcomes. OBJECTIVES: NATA, the 'Network for the advancement of patient blood management, haemostasis and thrombosis', initiated a benchmark project with the aim of providing the basis for educational strategies to implement optimal PBM in participating centres. DESIGN: Prospective, observational study with online data collection in 11 secondary and tertiary care institutions interested in developing PBM. SETTING: Ten European centres (Austria, Spain, England, Denmark, Belgium, Netherlands, Romania, Greece, France, and Germany) and one Canadian centre participated between January 2010 and June 2011. PATIENTS: A total of 2470 patients undergoing total hip (THR) or knee replacement, or coronary artery bypass grafting (CABG), were registered in the study. Data from 2431 records were included in the final analysis. MAIN OUTCOME MEASURES: Primary outcome measures were the incidence and volume of red blood cells (RBC) transfused. Logistic regression analysis identified variables independently associated with RBC transfusions. RESULTS: The incidence of transfusion was significantly different between centres for THR (range 7 to 95%), total knee replacement (range 3 to 100%) and CABG (range 20 to 95%). The volume of RBC transfused was significantly different between centres for THR and CABG. The incidence of preoperative anaemia ranged between 3 and 40% and its treatment between 0 and 40%, the latter not being related to the former. Patient characteristics, evolution of haemoglobin concentrations and blood losses were also different between centres. Variables independently associated with RBC transfusion were preoperative haemoglobin concentration, lost volume of RBC and female sex. CONCLUSION: Implementation of PBM remains extremely variable across centres. The relative importance of factors explaining RBC transfusion differs across institutions, some being patient related whereas others are related to the healthcare process. The results reported confidentially to each centre will allow them to implement tailored measures to improve their PBM strategies.

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Enhanced Recovery for Major Abdominopelvic Surgery

No abstract available

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Increased expression of interleukin-23 associated with progression of colorectal cancer

Background and Objectives

The prognostic significance of interleukin-23 in colorectal cancer remains unclear. We designed this study to investigate the association between colorectal cancer and interleukin-23 (IL-23) or interleukin-23 receptor (IL-23R) expression and the resulting clinical features and survival.

Methods

Immunohistochemical staining was performed for IL-23 and IL-23R in colorectal cancer samples. H-score was calculated to compare the expression of IL-23 and IL-23R. The median of H-score was used as the cut-off value to separate patients into high or low expression groups. The differences in clinicopathological features were evaluated. Cox regression hazard ratios were used for survival analysis.

Results

A total of 129 colorectal cancer patients were enrolled. H-score for the late TNM stage patients was higher than that for the early TNM stage patients (P = 0.002). Patients with high IL-23 expression were associated with advanced pathological T category (P < 0.001) and late TNM stage (P = 0.003). High IL-23 expression was associated with poor 5-year disease-free survival and overall survival in patients (P = 0.048 and P = 0.028, respectively). Multivariate adjustment demonstrated a significant association between high IL-23 expression and overall survival (hazard ratio = 1.865, P = 0.041).

Conclusions

Elevated IL-23 expression was associated with poor outcome and can be used as a prognostic biomarker for colorectal cancer. J. Surg. Oncol. © 2016 Wiley Periodicals, Inc.

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Borderline operability in hepatectomy patients is associated with higher rates of failure to rescue after severe complications

Background/Objective

To understand the influence of age and comorbidities, this study analyzed the incidence and risk factors for post-hepatectomy morbidity/mortality in patients with "borderline" (BL) operability, defined by the preoperative factors: age ≥75 years, dependent function, lung disease, ascites/varices, myocardial infarction, stroke, steroids, weight loss >10%, and/or sepsis.

Methods

All elective hepatectomies were identified in the 2005–2013 ACS-NSQIP database. Predictors of 30-day morbidity/mortality in BL patients were analyzed.

Results

A 3,574/15,920 (22.4%) patients met BL criteria. Despite non-BL and BL patients undergoing similar magnitude hepatectomies (P > 0.4), BL patients had higher severe complication (SC, 23.3% vs. 15.3%) and mortality rates (3.7% vs. 1.2%, P < 0.001). BL patients with any SC experienced a 14.1% mortality rate (vs. 7.3%, non-BL, P < 0.001). Independent risk factors for SC in BL patients included American Society of Anesthesiologists (ASA) score >3 (odds ratio, OR – 1.29), smoking (OR – 1.41), albumin <3.5 g/dl (OR – 1.36), bilirubin >1 (OR – 2.21), operative time >240 min (OR – 1.58), additional colorectal procedure (OR – 1.78), and concurrent procedure (OR – 1.73, all P < 0.05). Independent predictors of mortality included disseminated cancer (OR – 0.44), albumin <3.5 g/dl (OR – 1.94), thrombocytopenia (OR – 1.95), and extended/right hepatectomy (OR – 2.81, all P < 0.01).

Conclusions

Hepatectomy patients meeting BL criteria have an overall post-hepatectomy mortality rate that is triple that of non-BL patients. With less clinical reserve, BL patients who suffer SC are at greater risk of post-hepatectomy death. J. Surg. Oncol. © 2016 Wiley Periodicals, Inc.

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