Effects of calcium chloride coadministered with neostigmine on neuromuscular blockade recovery: A double-blind randomised study.

BACKGROUND: Ionised calcium plays an important role in neuromuscular transmission, but its effects on the reversal of nondepolarising neuromuscular blockade have not been fully evaluated. OBJECTIVE: We examined whether calcium chloride coadministered with neostigmine could enhance the rate of neuromuscular recovery. DESIGN: Prospective randomised double-blind trial. SETTING: A tertiary teaching hospital. PATIENTS: In total, 53 patients undergoing elective surgery under general anaesthesia with neuromuscular monitoring by acceleromyography using a TOF-Watch SX monitor. INTERVENTIONS: Patients were randomly allocated to receive either 5 mg kg-1 of calcium chloride (calcium group, n = 26) or the same volume of normal saline (control group, n = 27) coadministered with 25 [mu]g kg-1 of neostigmine and 15 [mu]g kg-1 of atropine at the end of surgery. MAIN OUTCOME MEASURES: The primary end point was the neuromuscular recovery time [time from neostigmine administration to recovery of the TOF ratio (TOFr) to 0.9]. Secondary end points included the TOFr at 5, 10 and 20 min after neostigmine administration and the incidence of postoperative residual curarisation (PORC), defined as a TOFr less than 0.9 at each time point. RESULTS: The neuromuscular recovery time was significantly faster in the calcium group than in the control group (median [Q1 to Q3]; 5.0 [3.0 to 7.0] vs. 6.7 [5.7 to 10.0] min, respectively; P = 0.007). At 5 min after neostigmine administration, the TOFr was higher [87 (74 to 100) vs. 68 (51 to 81)%, respectively; P = 0.002] and the incidence of PORC was lower (50.0 vs. 81.5%, respectively; P = 0.016) in the calcium group than in the control group. There were no differences between the two groups with respect to the TOFr or incidence of PORC at 10 and 20 min after neostigmine administration. CONCLUSION: Calcium chloride coadministered with neostigmine enhanced neuromuscular recovery in the early period of nondepolarising neuromuscular blockade reversal. (C) 2017 European Society of Anaesthesiology

http://ift.tt/2q3a9Og

Intraoperative magnesium sulphate decreases agitation and pain in patients undergoing functional endoscopic surgery: A randomised double-blind study.

BACKGROUND: Postoperative agitation is harmful for the patient as it may be associated with removal of catheters, nasal packs, oxygen masks and self-injury, and pose a danger to operating theatre staff. OBJECTIVE: The current study investigated the potential role of magnesium sulphate in treatment of postoperative agitation following functional endoscopic sinus surgery. DESIGN: A randomised, double-blinded, placebo-controlled trial. SETTING: ENT operating room, Menofia University Hospitals, Egypt. PATIENTS: A total of 312 adult patients (171 men and 141 women) were enrolled in the study. Eighteen patients (10 men and eight women) were excluded; data from 294 patients were analysed. Inclusion criteria were age between 20 and 60 years, American Society of Anesthesiologists' physical status 1 or 2 scheduled for functional endoscopic sinus surgery. Exclusion criteria were hypertension, cardiac ischaemia, cerebrovascular insufficiency, neuromuscular diseases, pregnancy, prolonged treatment with calcium-channel blockers, diabetic neuropathy or a known allergy to magnesium compounds. INTERVENTIONS: Patients were allocated randomly to either the magnesium group (a magnesium infusion of 30 mg kg-1 in the first hour followed by 9 mg kg-1 h-1 until the end of the surgical procedure) or the control group (0.9% saline at the same volume and rate). Hypotensive anaesthesia was induced by nitroglycerine 5 to 20 [mu]g kg-1 min-1. In the postanaesthetic care unit (PACU), patients were assessed for agitation and pain using the Richmond agitation-sedation scale and numerical rating scale, respectively. PRIMARY OUTCOME: The incidence and severity of agitation measured 5 min after admission to the PACU. RESULTS: Magnesium reduced postoperative agitation at time 0 (P = 0.009) and 5, 10, 15 and 30 min after PACU admission (P

http://ift.tt/2rnOzYF

Comparison of laryngeal mask airway insertion methods, including the external larynx lift with pre-inflated cuff, on postoperative pharyngolaryngeal complications: A randomised clinical trial.

BACKGROUND: Postoperative pharyngolaryngeal complications are commonly reported following laryngeal mask airway (LMA) insertion. After induction of anaesthesia, the airway structures fall backwards under the influence of gravity, and this may contribute to difficulty in placement of a LMA. External airway alignment by lifting the larynx during insertion of an airway may avoid collision of the airway with laryngeal structures. OBJECTIVE(S): To compare pharyngolaryngeal complications after either conventional airway insertion with or without cuff semi-inflation and a method, including an external larynx lift. DESIGN: Randomised controlled double blind clinical trial. SETTING: Ambulatory surgical operating rooms of a university hospital. PATIENTS: American Society of Anaesthesiologists class 1 to 3 patients undergoing ambulatory surgery scheduled to receive general anaesthesia for which a LMA was not contraindicated. INTERVENTIONS: Patients were randomised into three groups for LMA placement: G1, deflated airway; G2, pre-inflated cuff; G3, pre-inflated cuff with external lifting of the larynx. Assessment of pharyngolaryngeal complications (blinded assessor) was made at the time of LMA removal and again at 1, 2 and 24 h. MAIN OUTCOME MEASURES: A pharyngolaryngeal complication, defined as a composite of one or more of sore throat, dysphonia or dysphagia at any time point, or blood on the airway at removal. RESULTS: Of the 450 consecutive patients, 441 were studied. There were no differences in insertion times or number of insertion attempts among the groups. There was no difference in pharyngolaryngeal complications among the groups: G1, 57%; G2, 55%; G3, 52%, (P = 0.77). Blood on the airway was observed less frequently in G3 (9%) compared with G1 and G2 combined (17%): difference -8% (95% confidence interval of the difference -0.8 to -16%, P = 0.01). CONCLUSION: The external larynx lift technique was associated with a lower incidence of blood on the airway at removal, suggesting that the method may decrease trauma to the tissues of the upper airway during insertion. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT01749033. (C) 2017 European Society of Anaesthesiology

http://ift.tt/2q2IhKe

Perioperative factors related to the severity of vocal cord paralysis after thoracic cardiovascular surgery: A retrospective review.

BACKGROUND: Vocal cord paralysis (VCP) is a rare complication of thoracic cardiovascular surgery. In severe cases, life-threatening airway obstruction may occur. OBJECTIVE: To evaluate the incidence and severity of VCP among patients who underwent thoracic cardiovascular surgery and to identify possible risk factors. DESIGN: Single-centre retrospective review of adult patients. SETTING: Osaka University Hospital, Suita, Japan, from January 2013 to August 2015. PATIENTS: We included 688 patients in the final analysis. Preoperative, intraoperative and postoperative data were collected from medical records. Patients with preoperative VCP or tracheostomy prior to extubation were excluded. The VCP severity in relation to functional recovery was graded using the following categories: absent; mild, remission at 6 months; moderate, partial or persistent VCP at 6 months; or severe, airway obstruction after extubation requiring reintubation. An otolaryngologist diagnosed all VCP cases. MAIN OUTCOME MEASURES: The incidence and severity of VCP after extubation. RESULTS: The incidence (number) of VCP was 4.7% (32), with those of mild, moderate and severe VCP being 1.7% (12), 1.5% (10) and 1.5% (10), respectively. The ICU stay was significantly longer in patients with severe VCP than in patients without VCP [12.5 days (interquartile range 5.5 to 25.5) vs. 3 days (interquartile range 2 to 5), P = 0.0002]. In our multivariable analysis, type 2 diabetes mellitus [odds ratio (OR) 1.853, P = 0.009], intubation period (OR per 24 h 1.136, P = 0.014), ascending aortic arch surgery with brachiocephalic artery reconstruction (OR 8.708, P

http://ift.tt/2rnKWSG

Effects of dexamethasone on early cognitive decline after cardiac surgery: A randomised controlled trial.

BACKGROUND: Postoperative cognitive decline (POCD), a very common complication after cardiac surgery, is characterised by impairment of both memory function and intellectual ability as well as being associated with increased use of healthcare resources. The investigators focused on the role of the inflammatory response to a surgical procedure as a potential factor involved in the pathogenesis of POCD. OBJECTIVE: The use of prophylactic dexamethasone to attenuate the inflammatory response was hypothesised to reduce the risk of POCD. DESIGN: Randomised controlled study. SETTING: Single university teaching hospital, from March 2015 to January 2016. PATIENTS: A total of 169 patients scheduled for elective cardiac surgery were enrolled, and 161 patients were included in the analyses. INTERVENTION: Patients were randomised to receive a single intravenous bolus of 0.1 mg kg-1 dexamethasone (n = 85) or placebo (n = 84) 10 h before the surgery. MAIN OUTCOME MEASURES: The primary outcome measure in both groups was the incidence of POCD on the 6th day after surgery. The investigators also evaluated the effect of dexamethasone on the incidence of systemic inflammatory response syndrome, postoperative C-reactive protein levels and postoperative serum S100[beta] protein levels. RESULTS: Compared to the placebo group, the dexamethasone group showed statistically significant reductions in the incidence of POCD (relative risk, 0.43; 95% confidence interval, 0.21 to 0.89; P = 0.02), the incidence of systemic inflammatory response syndrome (30.0 versus 58.0%, P

http://ift.tt/2q2DNmQ

Anaesthesiology research in the European Union and the European Free Trade Association: An overview from 2001 to 2015.

BACKGROUND: Publication performance in anaesthesiology hints at research activity and attractiveness for a particular centre or country for anaesthetists. OBJECTIVE: The aim of this retrospective bibliographic study is to compare the publication performance of anaesthesiology departments within the countries of the European Union (EU) and European Free Trade Association (EFTA) combined. Outcome measures were the number of publications, the number of original articles, the average impact factor and the number of publications and average impact factor per million inhabitants. METHODS: Articles from anaesthesiology departments within the EU and EFTA countries published between 1 January 2001 and 31 December 2015 were included. Articles were electronically imported from Medline into a database and linked to anaesthesiology departments according to the authors' affiliations. Publication performance was assessed for 2001 to 2005, 2006 to 2010, 2011 to 2015 and 2001 to 2015. RESULTS: From 2001 to 2015, the absolute number of articles increased from 10 513 to 19 037 (+81%), whereas the number of original research articles decreased from 3786 to 1563 (-58%). Germany had the most publications (8948) with 1967 of these being original articles. Denmark achieved not only the highest average impact factor per million inhabitants (319.9) but also the most articles per anaesthesiologist (1.46), and per million habitants (105.7). Countries which moved up the income scale to a higher income class also increased the number of publications. DISCUSSION: In the EU and EFTA countries, the total number of publications increased from 2001 to 2015, but the number of original research articles fell by more than 50%. CONCLUSION: Between 2001 and 2015, in the EU and EFTA countries, the number of publications increased, whereas the number of original articles decreased. Germany published most, but Denmark had most publications per anaesthesiologist and per capita, and also achieved the highest impact factor per article. (C) 2017 European Society of Anaesthesiology

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Zika Virus: Obstetric and Pediatric Anesthesia Considerations

As of November 2016, the Florida Department of Health (FDH) and the Centers for Disease Control and Prevention have confirmed more than 4000 travel-related Zika virus (ZIKV) infections in the United States with >700 of those in Florida. There have been 139 cases of locally acquired infection, all occurring in Miami, Florida. Within the US territories (eg, Puerto Rico, US Virgin Islands), >30,000 cases of ZIKV infection have been reported. The projected number of individuals at risk for ZIKV infection in the Caribbean and Latin America approximates 5 million. Similar to Dengue and Chikungunya viruses, ZIKV is spread to humans by infected Aedes aegypti mosquitoes, through travel-associated local transmission, via sexual contact, and through blood transfusions. South Florida is an epicenter for ZIKV infection in the United States and the year-round warm climate along with an abundance of mosquito vectors that can harbor the flavivirus raise health care concerns. ZIKV infection is generally mild with clinical manifestations of fever, rash, conjunctivitis, and arthralgia. Of greatest concern, however, is growing evidence for the relationship between ZIKV infection of pregnant women and increased incidence of abnormal pregnancies and congenital abnormalities in the newborn, now medically termed ZIKA Congenital Syndrome. Federal health officials are observing 899 confirmed Zika-positive pregnancies and the FDH is currently monitoring 110 pregnant women with evidence of Zika infection. The University of Miami/Jackson Memorial Hospital is uniquely positioned just north of downtown Miami and within the vicinity of Liberty City, Little Haiti, and Miami Beach, which are currently "hot spots" for Zika virus exposure and transmissions. As the FDH works fervently to prevent a Zika epidemic in the region, health care providers at the University of Miami and Jackson Memorial Hospital prepare for the clinical spectrum of ZIKV effects as well as the safe perioperative care of the parturients and their affected newborns. In an effort to meet anesthetic preparedness for the care of potential Zika-positive patients and perinatal management of babies born with ZIKA Congenital Syndrome, this review highlights the interim guidelines from the Centers for Disease Control and Prevention and also suggest anesthetic implications and recommendations. In addition, this article reviews guidance for the evaluation and anesthetic management of infants with congenital ZIKV infection. To better manage the perioperative care of affected newborns, this article also reviews the comparative anesthetic implications of babies born with related congenital malformations.

http://ift.tt/2rnWDsm

Coming to a Patient Near You: The Zika Virus and Anesthetic Implications

No abstract available

http://ift.tt/2rnFOh8

Subcellular Hypoxia: A Survival Guide

No abstract available

http://ift.tt/2rnHgjH

Subcellular Energetics and Metabolism: Potential Therapeutic Applications

Part I of this review discussed the similarities between embryogenesis, mammalian adaptions to hypoxia (primarily driven by hypoxia-inducible factor-1 [HIF-1]), ischemia-reperfusion injury (and its relationship with reactive oxygen species), hibernation, diving animals, cancer, and sepsis, and it focused on the common characteristics that allow cells and organisms to survive in these states. Part II of this review describes techniques by which researchers gain insight into subcellular energetics and identify potential future tools for clinicians. In particular, P31 nuclear magnetic resonance to measure high-energy phosphates, serum lactate measurements, the use of near-infrared spectroscopy to measure the oxidation state of cytochrome aa3, and the ability of the protoporphyrin IX-triplet state lifetime technique to measure mitochondrial oxygen tension are discussed. In addition, this review discusses novel treatment strategies such as hyperbaric oxygen, preconditioning, exercise training, therapeutic gases, as well as inhibitors of HIF-1, HIF prolyl hydroxylase, and peroxisome proliferator-activated receptors.

http://ift.tt/2rnvWnz

Subcellular Energetics and Metabolism: A Cross-Species Framework

Although it is generally believed that oxidative phosphorylation and adequate oxygenation are essential for life, human development occurs in a profoundly hypoxic environment and "normal" levels of oxygen during embryogenesis are even harmful. The ability of embryos not only to survive but also to thrive in such an environment is made possible by adaptations related to metabolic pathways. Similarly, cancerous cells are able not only to survive but also to grow and spread in environments that would typically be fatal for healthy adult cells. Many biological states, both normal and pathological, share underlying similarities related to metabolism, the electron transport chain, and reactive species. The purpose of Part I of this review is to review the similarities among embryogenesis, mammalian adaptions to hypoxia (primarily driven by hypoxia-inducible factor-1), ischemia-reperfusion injury (and its relationship with reactive oxygen species), hibernation, diving animals, cancer, and sepsis, with a particular focus on the common characteristics that allow cells and organisms to survive in these states.

http://ift.tt/2rnvXrD

Thromboembolic and bleeding complications during oral anticoagulation therapy in cancer patients with atrial fibrillation: a Danish nationwide population-based cohort study

Abstract

Coexisting cancer in patients with atrial fibrillation (AF) has been associated with thromboembolism and bleeding. We used Danish population-based medical databases to conduct a population-based cohort study that included all AF patients who redeemed a prescription for vitamin K antagonists (VKA) or non-VKA oral anticoagulant (NOAC) between July 2004 and December 2013. We characterized these patients according to the presence (N = 11,855) or absence (N = 56,264) of a cancer diagnosis before redemption of their oral anticoagulant prescription, and then examined their 1-year risk of thromboembolic or bleeding complications or death. We next used Cox regression to compare the hazard ratios for complications among VKA- or NOAC-treated AF patients with versus without a cancer diagnosis, after adjusting for sex, age, and CHA₂DS₂ VASc score. One-year risks of thromboembolic complications in AF patients who redeemed a VKA prescription were similar in those with (6.5%) and without (5.8%) cancer [hazard ratio (HR) 1.0 (95% confidence interval (CI): 0.93, 1.1)]. This also was found for bleeding complications (5.4% vs. 4.3%, HR 1.1 [95% CI: 1.0, 1.2]). For AF patients with cancer who redeemed a NOAC prescription, risks were also similar for thromboembolic complications (4.9% of cancer patients vs. 5.1% of noncancer patients, HR 0.80 [95% CI: 0.61, 1.1]), and for bleeding complications (4.4% vs. 3.1%, HR 1.2 [95% CI: 0.92, 1.7]). The absolute risks of thromboembolic or bleeding complications were nearly the same in patients with and without cancer who redeemed prescription for VKAs or NOACs.

Since both atrial fibrillation and cancer are common, any increased risk of complications among patients treated with vitamin K antagonists (VKAs) or non-VKA oral anticoagulants (NOACs) may have major public health implications. This study found that the absolute risks of thromboembolic or bleeding complications were nearly the same in patients with and without cancer who redeemed prescriptions for VKAs or NOACs.

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Thromboembolic and bleeding complications during oral anticoagulation therapy in cancer patients with atrial fibrillation: a Danish nationwide population-based cohort study

Abstract

Coexisting cancer in patients with atrial fibrillation (AF) has been associated with thromboembolism and bleeding. We used Danish population-based medical databases to conduct a population-based cohort study that included all AF patients who redeemed a prescription for vitamin K antagonists (VKA) or non-VKA oral anticoagulant (NOAC) between July 2004 and December 2013. We characterized these patients according to the presence (N = 11,855) or absence (N = 56,264) of a cancer diagnosis before redemption of their oral anticoagulant prescription, and then examined their 1-year risk of thromboembolic or bleeding complications or death. We next used Cox regression to compare the hazard ratios for complications among VKA- or NOAC-treated AF patients with versus without a cancer diagnosis, after adjusting for sex, age, and CHA₂DS₂ VASc score. One-year risks of thromboembolic complications in AF patients who redeemed a VKA prescription were similar in those with (6.5%) and without (5.8%) cancer [hazard ratio (HR) 1.0 (95% confidence interval (CI): 0.93, 1.1)]. This also was found for bleeding complications (5.4% vs. 4.3%, HR 1.1 [95% CI: 1.0, 1.2]). For AF patients with cancer who redeemed a NOAC prescription, risks were also similar for thromboembolic complications (4.9% of cancer patients vs. 5.1% of noncancer patients, HR 0.80 [95% CI: 0.61, 1.1]), and for bleeding complications (4.4% vs. 3.1%, HR 1.2 [95% CI: 0.92, 1.7]). The absolute risks of thromboembolic or bleeding complications were nearly the same in patients with and without cancer who redeemed prescription for VKAs or NOACs.

Since both atrial fibrillation and cancer are common, any increased risk of complications among patients treated with vitamin K antagonists (VKAs) or non-VKA oral anticoagulants (NOACs) may have major public health implications. This study found that the absolute risks of thromboembolic or bleeding complications were nearly the same in patients with and without cancer who redeemed prescriptions for VKAs or NOACs.

http://ift.tt/2qH7GKx

The PAZOREAL noninterventional study to assess effectiveness and safety of pazopanib and everolimus in the changing metastatic renal cell carcinoma treatment landscape

Future Oncology Ahead of Print.


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The PAZOREAL noninterventional study to assess effectiveness and safety of pazopanib and everolimus in the changing metastatic renal cell carcinoma treatment landscape

Future Oncology Ahead of Print.


http://ift.tt/2rAWhMl

Preserved Analgesia With Reduction in Opioids Through the Use of an Acute Pain Protocol in Enhanced Recovery After Surgery for Open Hepatectomy.

Background: Enhanced recovery after surgery (ERAS) pathways are designed to restore baseline physiology, mitigate surgical stressors, and hasten recovery. Paramount to this approach is optimal pain control through multimodal analgesia and limiting reliance on opioid-based medications. Recent studies have fostered growing controversy surrounding the use of epidural analgesia in the ERAS setting, especially for higher-risk procedures. We examine the analgesic end points associated with the use of epidural within the ERAS framework for open hepatectomy. Methods: From November 2013 through March 2016, postoperative analgesic end points including daily morphine equivalent administration and self-reported pain scores were prospectively collected and analyzed for 180 consecutive patients scheduled for open hepatectomy. Patients whose surgeries performed prior to July 2014 were managed using traditional strategy (pre-ERAS, n = 60), and those after July 1 underwent a comprehensive perioperative ERAS pathway (ERAS, n = 120). Results: Patients managed using the ERAS pathway had a significant reduction in morphine equivalent requirements at 24 hours (median, 10.0 vs 116.0 mg; P

http://ift.tt/2qAXKUp

The PAZOREAL noninterventional study to assess effectiveness and safety of pazopanib and everolimus in the changing metastatic renal cell carcinoma treatment landscape

Future Oncology Ahead of Print.


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Open Journal of Apoptosis Vol.6,No.2 (April 2017)

Antiepileptic Drug-Induced Apoptosis Was Prevented by L-Type Calcium Channel Activator in Cultured Rat Cortical Cells
Antiepileptic Drug, Valproate, Carbamazepine, L-Type Calcium Channel, Glycogen Synthase Kinase-3, Apoptosis
Paper Information Full Paper: PDF (Size:1127KB)
DOI: 10.4236/ojapo.2017.62002

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Open Journal of Apoptosis Vol.6,No.2 (April 2017)

Antiepileptic Drug-Induced Apoptosis Was Prevented by L-Type Calcium Channel Activator in Cultured Rat Cortical Cells
Antiepileptic Drug, Valproate, Carbamazepine, L-Type Calcium Channel, Glycogen Synthase Kinase-3, Apoptosis
Paper Information Full Paper: PDF (Size:1127KB)
DOI: 10.4236/ojapo.2017.62002

http://ift.tt/2mVKZTt

Water Concentration Analysis of the Surgical Margin—Response

http://ift.tt/2q2eGk6

Water Concentration Analysis of the Surgical Margin—Letter

http://ift.tt/2rmUKMQ

TAM Receptor Tyrosine Kinases in Cancer Drug Resistance

Receptor tyrosine kinases (RTK) are major regulators of key biological processes, including cell growth, survival, and differentiation, and were established early on as proto-oncogenes, with aberrant expression linked to tumor progression in many cancers. Therefore, RTKs have emerged as major targets for selective therapy with small-molecule inhibitors. However, despite improvements in survival rates, it is now apparent that the targeting of RTKs with selective inhibitors is only transiently effective, as the majority of patients eventually become resistant to therapy. As chemoresistance is the leading cause of cancer spread, progression, and mortality, there is an increasing need for understanding the mechanisms by which cancer cells can evade therapy-induced cell death. The TAM (Tyro3, Axl, Mer) subfamily of RTKs in particular feature in a variety of cancer types that have developed resistance to a broad range of therapeutic agents, including both targeted as well as conventional chemotherapeutics. This article reviews the roles of TAMs as tumor drivers and as mediators of chemoresistance, and the potential effectiveness of targeting them as part of therapeutic strategies to delay or combat resistance. Cancer Res; 77(11); 1–4. ©2017 AACR.

http://ift.tt/2q2Bekx

Therapeutic IgE Antibodies: Harnessing a Macrophage-Mediated Immune Surveillance Mechanism against Cancer

IgG monoclonal antibodies have made significant contributions to cancer therapy, but suffer from several limitations that restrict their effectiveness in unleashing host immune system components against tumors. The development of monoclonal antibodies of an alternative class, namely IgE, may offer enhanced immune surveillance and superior effector cell potency against cancer cells. In our recent article, we elaborate our proof-of-concept studies of a mouse/human chimeric IgE antibody (MOv18 IgE), which is specific for the cancer-associated antigen folate receptor alpha. We demonstrate superior antitumor efficacy for IgE compared with an otherwise identical IgG in a syngeneic immunocompetent animal, and we identify TNFα/MCP-1 signaling as an IgE-mediated mechanism of monocyte and macrophage activation and recruitment to tumors. These findings draw parallels with powerful macrophage-activating functions employed by IgE against parasites, rather than allergic IgE mechanisms. The potential clinical application of IgE-derived drugs in clinical oncology is clear if the antitumor activity of MOv18 IgE in these preclinical experiments can be replicated in patients. In particular, different IgE antibodies with specificity for many other antigens already validated as targets for IgG suggest a wide potential for development of a novel class of antibody therapy. Cancer Res; 77(11); 1–5. ©2017 AACR.

http://ift.tt/2rniMac

Water Concentration Analysis of the Surgical Margin—Response

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Water Concentration Analysis of the Surgical Margin—Letter

from Cancer via ola Kala on Inoreader http://ift.tt/2rmUKMQ
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TAM Receptor Tyrosine Kinases in Cancer Drug Resistance

Receptor tyrosine kinases (RTK) are major regulators of key biological processes, including cell growth, survival, and differentiation, and were established early on as proto-oncogenes, with aberrant expression linked to tumor progression in many cancers. Therefore, RTKs have emerged as major targets for selective therapy with small-molecule inhibitors. However, despite improvements in survival rates, it is now apparent that the targeting of RTKs with selective inhibitors is only transiently effective, as the majority of patients eventually become resistant to therapy. As chemoresistance is the leading cause of cancer spread, progression, and mortality, there is an increasing need for understanding the mechanisms by which cancer cells can evade therapy-induced cell death. The TAM (Tyro3, Axl, Mer) subfamily of RTKs in particular feature in a variety of cancer types that have developed resistance to a broad range of therapeutic agents, including both targeted as well as conventional chemotherapeutics. This article reviews the roles of TAMs as tumor drivers and as mediators of chemoresistance, and the potential effectiveness of targeting them as part of therapeutic strategies to delay or combat resistance. Cancer Res; 77(11); 1–4. ©2017 AACR.

from Cancer via ola Kala on Inoreader http://ift.tt/2q2Bekx
via IFTTT

Therapeutic IgE Antibodies: Harnessing a Macrophage-Mediated Immune Surveillance Mechanism against Cancer

IgG monoclonal antibodies have made significant contributions to cancer therapy, but suffer from several limitations that restrict their effectiveness in unleashing host immune system components against tumors. The development of monoclonal antibodies of an alternative class, namely IgE, may offer enhanced immune surveillance and superior effector cell potency against cancer cells. In our recent article, we elaborate our proof-of-concept studies of a mouse/human chimeric IgE antibody (MOv18 IgE), which is specific for the cancer-associated antigen folate receptor alpha. We demonstrate superior antitumor efficacy for IgE compared with an otherwise identical IgG in a syngeneic immunocompetent animal, and we identify TNFα/MCP-1 signaling as an IgE-mediated mechanism of monocyte and macrophage activation and recruitment to tumors. These findings draw parallels with powerful macrophage-activating functions employed by IgE against parasites, rather than allergic IgE mechanisms. The potential clinical application of IgE-derived drugs in clinical oncology is clear if the antitumor activity of MOv18 IgE in these preclinical experiments can be replicated in patients. In particular, different IgE antibodies with specificity for many other antigens already validated as targets for IgG suggest a wide potential for development of a novel class of antibody therapy. Cancer Res; 77(11); 1–5. ©2017 AACR.

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Interpreting findings from Mendelian randomization using the MR-Egger method

Abstract

Mendelian randomization-Egger (MR-Egger) is an analysis method for Mendelian randomization using summarized genetic data. MR-Egger consists of three parts: (1) a test for directional pleiotropy, (2) a test for a causal effect, and (3) an estimate of the causal effect. While conventional analysis methods for Mendelian randomization assume that all genetic variants satisfy the instrumental variable assumptions, the MR-Egger method is able to assess whether genetic variants have pleiotropic effects on the outcome that differ on average from zero (directional pleiotropy), as well as to provide a consistent estimate of the causal effect, under a weaker assumption—the InSIDE (INstrument Strength Independent of Direct Effect) assumption. In this paper, we provide a critical assessment of the MR-Egger method with regard to its implementation and interpretation. While the MR-Egger method is a worthwhile sensitivity analysis for detecting violations of the instrumental variable assumptions, there are several reasons why causal estimates from the MR-Egger method may be biased and have inflated Type 1 error rates in practice, including violations of the InSIDE assumption and the influence of outlying variants. The issues raised in this paper have potentially serious consequences for causal inferences from the MR-Egger approach. We give examples of scenarios in which the estimates from conventional Mendelian randomization methods and MR-Egger differ, and discuss how to interpret findings in such cases.

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Interpreting findings from Mendelian randomization using the MR-Egger method

Abstract

Mendelian randomization-Egger (MR-Egger) is an analysis method for Mendelian randomization using summarized genetic data. MR-Egger consists of three parts: (1) a test for directional pleiotropy, (2) a test for a causal effect, and (3) an estimate of the causal effect. While conventional analysis methods for Mendelian randomization assume that all genetic variants satisfy the instrumental variable assumptions, the MR-Egger method is able to assess whether genetic variants have pleiotropic effects on the outcome that differ on average from zero (directional pleiotropy), as well as to provide a consistent estimate of the causal effect, under a weaker assumption—the InSIDE (INstrument Strength Independent of Direct Effect) assumption. In this paper, we provide a critical assessment of the MR-Egger method with regard to its implementation and interpretation. While the MR-Egger method is a worthwhile sensitivity analysis for detecting violations of the instrumental variable assumptions, there are several reasons why causal estimates from the MR-Egger method may be biased and have inflated Type 1 error rates in practice, including violations of the InSIDE assumption and the influence of outlying variants. The issues raised in this paper have potentially serious consequences for causal inferences from the MR-Egger approach. We give examples of scenarios in which the estimates from conventional Mendelian randomization methods and MR-Egger differ, and discuss how to interpret findings in such cases.

http://ift.tt/2qDjm39

Risk factors for osteonecrosis of the jaw in oral cancer patients after surgery and eventual adjuvant treatment: The potential role of chemotherapy

To identify the risk factors for osteonecrosis of the jaw (ONJ) in oral cancer patients after surgery with and without adjuvant therapy in a nationwide, population-based study.

http://ift.tt/2qGKCM1

Assessment of the novel online delineation workshop dummy run approach using FALCON within a European multicentre trial in cervical cancer (RAIDs)

Online delineation workshops (ODW) permit training of geographically dispersed participants. The purpose is to evaluate the methodology of an ODW using FALCON to harmonize delineation within a European multicentre trial on locally advanced cervical cancer (LACC).

http://ift.tt/2pUAhPe

Risk of hypothyroidism among patients with nasopharyngeal carcinoma treated with radiation therapy: A Population-Based Cohort Study

This study aimed to assess the incidence and risk of hypothyroidism among patients with nasopharyngeal carcinoma (NPC) after radiation therapy (RT).

http://ift.tt/2qGVzgE

Three-dimensional intrafractional internal target motions in accelerated partial breast irradiation using three-dimensional conformal external beam radiotherapy

We evaluated three-dimensional intrafractional target motion, divided into respiratory-induced motion and baseline drift, in accelerated partial breast irradiation (APBI).

http://ift.tt/2pUpqFa

Verifying tumor position during stereotactic body radiation therapy delivery using (limited-arc) cone beam computed tomography imaging

Proof of tumor position during stereotactic body radiotherapy (SBRT) delivery is desirable. We investigated if cone-beam CT (CBCT) scans reconstructed from (collimated) fluoroscopic kV images acquired during irradiation could show the dominant tumor position.

http://ift.tt/2qGKv2U

Cancer Patient Experience in the Teenage Young Adult Population— Key Issues and Trends Over Time: An Analysis of the United Kingdom National Cancer Patient Experience Surveys 2010–2014

Journal of Adolescent and Young Adult Oncology , Vol. 0, No. 0.


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Cancer Patient Experience in the Teenage Young Adult Population— Key Issues and Trends Over Time: An Analysis of the United Kingdom National Cancer Patient Experience Surveys 2010–2014

Journal of Adolescent and Young Adult Oncology , Vol. 0, No. 0.


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Epithelial Mesenchymal Transition (EMT) in Metastatic Breast Cancer in Omani Women

Abstract

Breast cancer (BC) in Oman affects younger women and has a more aggressive course. Clinical and biological variables like age, pregnancy, tumor size, type, grade, receptor expression and proliferation predict disease aggression but there is no direct predictor of metastasis except lymphovascular invasion. Epithelial-mesenchymal transition (EMT) is characterized by epithelial cells losing epithelial and acquiring mesenchymal morpho-immunophenotypic characteristics. In tumors, EMT-like transitions may signify a metastatic phenotype and have features in common with cancer stem cells (CSC) which show resistance to chemotherapy. This study aimed to identify EMT and CSC phenotypes in metastatic and non-metastatic breast cancer in Omani women and their association with conventional clinico-pathological predictors of BC. In a retrospective study of ninety-six Omani women with breast cancer, the association of age, pregnancy/lactation, tumor size, type, grade, ductal carcinoma insitu (DCIS), lymphovascular invasion, hormone/ HER2 receptor expression and Ki67 proliferation index (Ki67 PI) was tested with EMT/ CSC phenotype and metastasis. Young age ≤ 40 years, lymphovascular invasion and EMT had a strong association with metastasis; CSC approached significance. Vimentin expression in tumor cells, fibronectin and MMP-11 in stroma were reliable markers of EMT; dual EMT and CSC phenotype (Vim+/ CD44+/ CD 24−/low) had a strong association with apocrine variant, basal-like tumors and triple negative cancers. EMT had a strong association with Ki67 proliferation index (PI) and CSC with HER2-like tumors and distant metastasis. These select markers may be useful in metastasis-prediction in pre-treatment biopsies.

http://ift.tt/2qCMhnB

Epithelial Mesenchymal Transition (EMT) in Metastatic Breast Cancer in Omani Women

Abstract

Breast cancer (BC) in Oman affects younger women and has a more aggressive course. Clinical and biological variables like age, pregnancy, tumor size, type, grade, receptor expression and proliferation predict disease aggression but there is no direct predictor of metastasis except lymphovascular invasion. Epithelial-mesenchymal transition (EMT) is characterized by epithelial cells losing epithelial and acquiring mesenchymal morpho-immunophenotypic characteristics. In tumors, EMT-like transitions may signify a metastatic phenotype and have features in common with cancer stem cells (CSC) which show resistance to chemotherapy. This study aimed to identify EMT and CSC phenotypes in metastatic and non-metastatic breast cancer in Omani women and their association with conventional clinico-pathological predictors of BC. In a retrospective study of ninety-six Omani women with breast cancer, the association of age, pregnancy/lactation, tumor size, type, grade, ductal carcinoma insitu (DCIS), lymphovascular invasion, hormone/ HER2 receptor expression and Ki67 proliferation index (Ki67 PI) was tested with EMT/ CSC phenotype and metastasis. Young age ≤ 40 years, lymphovascular invasion and EMT had a strong association with metastasis; CSC approached significance. Vimentin expression in tumor cells, fibronectin and MMP-11 in stroma were reliable markers of EMT; dual EMT and CSC phenotype (Vim+/ CD44+/ CD 24−/low) had a strong association with apocrine variant, basal-like tumors and triple negative cancers. EMT had a strong association with Ki67 proliferation index (PI) and CSC with HER2-like tumors and distant metastasis. These select markers may be useful in metastasis-prediction in pre-treatment biopsies.

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Advances in systemic therapy for metastatic breast cancer: future perspectives

Abstract

Breast cancer (BC) is the most common cancer in women worldwide. One in eight women will develop the disease in her lifetime. Notwithstanding the incredible progress made in this field, BC still represents the second most common cause of cancer-related death in women. Targeted drugs have revolutionised breast cancer treatment and improved the prognosis as well as the life expectancy of millions of women. However, the phenomenon of primary and secondary pharmacological resistance is becoming increasingly evident, limiting the efficacy of these agents and calling for a better in-depth knowledge and understanding of the biology as well as the biochemical crosstalk underlying the disease. The advent of laboratory technologies in the clinical setting such as the routine use of next generation sequencing has allowed identification of new genetic alterations as well as providing a precise picture of the molecular landscapes of each tumour. Consequently, new specific therapeutic approaches are becoming available to minimise or delay the occurrence of resistance. In this review, we analyse the latest research and news from the clinical development side for each BC subtype.

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Advances in systemic therapy for metastatic breast cancer: future perspectives

Abstract

Breast cancer (BC) is the most common cancer in women worldwide. One in eight women will develop the disease in her lifetime. Notwithstanding the incredible progress made in this field, BC still represents the second most common cause of cancer-related death in women. Targeted drugs have revolutionised breast cancer treatment and improved the prognosis as well as the life expectancy of millions of women. However, the phenomenon of primary and secondary pharmacological resistance is becoming increasingly evident, limiting the efficacy of these agents and calling for a better in-depth knowledge and understanding of the biology as well as the biochemical crosstalk underlying the disease. The advent of laboratory technologies in the clinical setting such as the routine use of next generation sequencing has allowed identification of new genetic alterations as well as providing a precise picture of the molecular landscapes of each tumour. Consequently, new specific therapeutic approaches are becoming available to minimise or delay the occurrence of resistance. In this review, we analyse the latest research and news from the clinical development side for each BC subtype.

http://ift.tt/2qBr5P9

NAFLD as a Sexual Dimorphic Disease: Role of Gender and Reproductive Status in the Development and Progression of Nonalcoholic Fatty Liver Disease and Inherent Cardiovascular Risk

Abstract

Nonalcoholic fatty liver disease (NAFLD) spans steatosis through nonalcoholic steatohepatis, cirrhosis, and hepatocellular carcinoma (HCC) associated with striking systemic features and excess cardiovascular and liver-related mortality. The pathogenesis of NAFLD is complex and multifactorial. Endocrine derangements are closely linked with dysmetabolic traits. For example, in animal and human studies, female sex is protected from dysmetabolism thanks to young individuals' ability to partition fatty acids towards ketone body production rather than very low density lipoprotein (VLDL)-triacylglycerol, and to sex-specific browning of white adipose tissue. Ovarian senescence facilitates both the development of massive hepatic steatosis and the fibrotic progression of liver disease in an experimental overfed zebrafish model. Consistently, estrogen deficiency, by potentiating hepatic inflammatory changes, hastens the progression of disease in a dietary model of nonalcoholic steatohepatitis (NASH) developing in ovariectomized mice fed a high-fat diet. In humans, NAFLD more often affects men; and premenopausal women are equally protected from developing NAFLD as they are from cardiovascular disease. It would be expected that early menarche, definitely associated with estrogen activation, would produce protection against the risk of NAFLD. Nevertheless, it has been suggested that early menarche may confer an increased risk of NAFLD in adulthood, excess adiposity being the primary culprit of this association. Fertile age may be associated with more severe hepatocyte injury and inflammation, but also with a decreased risk of liver fibrosis compared to men and postmenopausal status. Later in life, ovarian senescence is strongly associated with severe steatosis and fibrosing NASH, which may occur in postmenopausal women. Estrogen deficiency is deemed to be responsible for these findings via the development of postmenopausal metabolic syndrome. Estrogen supplementation may at least theoretically protect from NAFLD development and progression, as suggested by some studies exploring the effect of hormonal replacement therapy on postmenopausal women, but the variable impact of different sex hormones in NAFLD (i.e., the pro-inflammatory effect of progesterone) should be carefully considered.

http://ift.tt/2qEMxRc

NAFLD as a Sexual Dimorphic Disease: Role of Gender and Reproductive Status in the Development and Progression of Nonalcoholic Fatty Liver Disease and Inherent Cardiovascular Risk

Abstract

Nonalcoholic fatty liver disease (NAFLD) spans steatosis through nonalcoholic steatohepatis, cirrhosis, and hepatocellular carcinoma (HCC) associated with striking systemic features and excess cardiovascular and liver-related mortality. The pathogenesis of NAFLD is complex and multifactorial. Endocrine derangements are closely linked with dysmetabolic traits. For example, in animal and human studies, female sex is protected from dysmetabolism thanks to young individuals' ability to partition fatty acids towards ketone body production rather than very low density lipoprotein (VLDL)-triacylglycerol, and to sex-specific browning of white adipose tissue. Ovarian senescence facilitates both the development of massive hepatic steatosis and the fibrotic progression of liver disease in an experimental overfed zebrafish model. Consistently, estrogen deficiency, by potentiating hepatic inflammatory changes, hastens the progression of disease in a dietary model of nonalcoholic steatohepatitis (NASH) developing in ovariectomized mice fed a high-fat diet. In humans, NAFLD more often affects men; and premenopausal women are equally protected from developing NAFLD as they are from cardiovascular disease. It would be expected that early menarche, definitely associated with estrogen activation, would produce protection against the risk of NAFLD. Nevertheless, it has been suggested that early menarche may confer an increased risk of NAFLD in adulthood, excess adiposity being the primary culprit of this association. Fertile age may be associated with more severe hepatocyte injury and inflammation, but also with a decreased risk of liver fibrosis compared to men and postmenopausal status. Later in life, ovarian senescence is strongly associated with severe steatosis and fibrosing NASH, which may occur in postmenopausal women. Estrogen deficiency is deemed to be responsible for these findings via the development of postmenopausal metabolic syndrome. Estrogen supplementation may at least theoretically protect from NAFLD development and progression, as suggested by some studies exploring the effect of hormonal replacement therapy on postmenopausal women, but the variable impact of different sex hormones in NAFLD (i.e., the pro-inflammatory effect of progesterone) should be carefully considered.

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Notch ligand Delta-like 1 as a novel molecular target in childhood neuroblastoma

Abstract

Background

Neuroblastoma is the most common extracranial solid malignancy in childhood, responsible for 15% of all pediatric cancer deaths. It is an heterogeneous disease that does not always respond to classical therapy; so the identification of new and specific molecular targets to improve existing therapy is needed. We have previously demonstrated the involvement of the Notch pathway in the onset and progression of neuroblastoma. In this study we further investigated the role of Notch signaling and identified Delta-like 1 (DLL1) as a novel molecular target in neuroblastoma cells with a high degree of MYCN amplification, which is a major oncogenic driver in neuroblastoma. The possibility to act on DLL1 expression levels by using microRNAs (miRNAs) was assessed.

Methods

DLL1 mRNA and protein expression levels were measured in three different neuroblastoma cell lines using quantitative real-time PCR and Western Blot analysis, respectively. Activation of the Notch pathway as a result of increased levels of DLL1 was analyzed by Immunofluorescence and Western Blot methods. In silico tools revealed the possibility to act on DLL1 expression levels with miRNAs, in particular with the miRNA-34 family. Neuroblastoma cells were transfected with miRNA-34 family members, and the effect of miRNAs transfection on DLL1 mRNA expression levels, on cell differentiation, proliferation and apoptosis was measured.

Results

In this study, the DLL1 ligand was identified as the Notch pathway component highly expressed in neuroblastoma cells with MYCN amplification. In silico analysis demonstrated that DLL1 is one of the targets of miRNA-34 family members that maps on chromosome regions that are frequently deregulated or deleted in neuroblastoma. We studied the possibility to use miRNAs to target DLL1. Among all miRNA-34 family members, miRNA-34b is able to significantly downregulate DLL1 mRNA expression levels, to arrest cell proliferation and to induce neuronal differentiation in malignant neuroblastoma cells.

Conclusions

Targeted therapies have emerged as new strategies for cancer treatment. This study identified the Notch ligand DLL1 as a novel and attractive molecular target in childhood neuroblastoma and its results could help to devise a targeted therapy using miRNAs.

http://ift.tt/2qCrtNo

Notch ligand Delta-like 1 as a novel molecular target in childhood neuroblastoma

Abstract

Background

Neuroblastoma is the most common extracranial solid malignancy in childhood, responsible for 15% of all pediatric cancer deaths. It is an heterogeneous disease that does not always respond to classical therapy; so the identification of new and specific molecular targets to improve existing therapy is needed. We have previously demonstrated the involvement of the Notch pathway in the onset and progression of neuroblastoma. In this study we further investigated the role of Notch signaling and identified Delta-like 1 (DLL1) as a novel molecular target in neuroblastoma cells with a high degree of MYCN amplification, which is a major oncogenic driver in neuroblastoma. The possibility to act on DLL1 expression levels by using microRNAs (miRNAs) was assessed.

Methods

DLL1 mRNA and protein expression levels were measured in three different neuroblastoma cell lines using quantitative real-time PCR and Western Blot analysis, respectively. Activation of the Notch pathway as a result of increased levels of DLL1 was analyzed by Immunofluorescence and Western Blot methods. In silico tools revealed the possibility to act on DLL1 expression levels with miRNAs, in particular with the miRNA-34 family. Neuroblastoma cells were transfected with miRNA-34 family members, and the effect of miRNAs transfection on DLL1 mRNA expression levels, on cell differentiation, proliferation and apoptosis was measured.

Results

In this study, the DLL1 ligand was identified as the Notch pathway component highly expressed in neuroblastoma cells with MYCN amplification. In silico analysis demonstrated that DLL1 is one of the targets of miRNA-34 family members that maps on chromosome regions that are frequently deregulated or deleted in neuroblastoma. We studied the possibility to use miRNAs to target DLL1. Among all miRNA-34 family members, miRNA-34b is able to significantly downregulate DLL1 mRNA expression levels, to arrest cell proliferation and to induce neuronal differentiation in malignant neuroblastoma cells.

Conclusions

Targeted therapies have emerged as new strategies for cancer treatment. This study identified the Notch ligand DLL1 as a novel and attractive molecular target in childhood neuroblastoma and its results could help to devise a targeted therapy using miRNAs.

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Mentor Spotlight: Monica L. Baskin, PhD

Dr. Tiffany Carson, a K01 awardee, recognizes her mentor Dr. Monica Baskin for the guidance and encouragement that she has provided throughout her career.

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A prospective study of XELIRI plus bevacizumab as a first-line therapy in Japanese patients with unresectable or recurrent colorectal cancer (KSCC1101)

Abstract

Background

This study was designed to evaluate the efficacy and toxicity of XELIRI plus bevacizumab for the treatment of Japanese patients with unresectable or recurrent colorectal cancer (CRC).

Methods

This was a multicenter, single-arm, open-label prospective study. The major inclusion criteria were previously untreated unresectable or recurrent CRC, presence of measurable lesions, ≥20 years of age, Eastern Cooperative Oncology Group performance status 0 or 1, and adequate organ function. Patients received bevacizumab (7.5 mg/kg on day 1) and XELIRI (irinotecan 200 mg/m² on day 1 plus capecitabine 800 mg/m² b.i.d. on days 1–14) every 3 weeks. The primary endpoint was the objective tumor response rate.

Results

A total of 36 patients were enrolled in this study from July 2011 to September 2012. One patient did not fulfill the eligibility criteria and one patient withdrew their consent before the start of the treatment protocol. The confirmed objective response rate was 58.8% (95% CI 35.1–70.2%). The median progression-free survival was 9.6 months (95% CI 5.1–11.1 months) and the median overall survival was 23.1 months (95% CI 11.3–36.7 months). The grade ≥3 adverse events that were frequently encountered in this study were neutropenia (31.4%), leukopenia (22.9%), diarrhea (22.9%), anemia (20.0%), anorexia (20.0%) and febrile neutropenia (17.2%). The frequency of grade 3/4 adverse events, such as neutropenia and leukopenia, was much higher in patients with a UGT1A1 polymorphism.

Conclusions

A first-line therapy comprising XELIRI plus bevacizumab yielded a promising response rate. However, careful attention should be given to adverse clinical events in Japanese patients receiving treatment with unresectable or recurrent CRC.

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Mentor Spotlight: Monica L. Baskin, PhD

Dr. Tiffany Carson, a K01 awardee, recognizes her mentor Dr. Monica Baskin for the guidance and encouragement that she has provided throughout her career.

http://ift.tt/2r11Si7

A prospective study of XELIRI plus bevacizumab as a first-line therapy in Japanese patients with unresectable or recurrent colorectal cancer (KSCC1101)

Abstract

Background

This study was designed to evaluate the efficacy and toxicity of XELIRI plus bevacizumab for the treatment of Japanese patients with unresectable or recurrent colorectal cancer (CRC).

Methods

This was a multicenter, single-arm, open-label prospective study. The major inclusion criteria were previously untreated unresectable or recurrent CRC, presence of measurable lesions, ≥20 years of age, Eastern Cooperative Oncology Group performance status 0 or 1, and adequate organ function. Patients received bevacizumab (7.5 mg/kg on day 1) and XELIRI (irinotecan 200 mg/m² on day 1 plus capecitabine 800 mg/m² b.i.d. on days 1–14) every 3 weeks. The primary endpoint was the objective tumor response rate.

Results

A total of 36 patients were enrolled in this study from July 2011 to September 2012. One patient did not fulfill the eligibility criteria and one patient withdrew their consent before the start of the treatment protocol. The confirmed objective response rate was 58.8% (95% CI 35.1–70.2%). The median progression-free survival was 9.6 months (95% CI 5.1–11.1 months) and the median overall survival was 23.1 months (95% CI 11.3–36.7 months). The grade ≥3 adverse events that were frequently encountered in this study were neutropenia (31.4%), leukopenia (22.9%), diarrhea (22.9%), anemia (20.0%), anorexia (20.0%) and febrile neutropenia (17.2%). The frequency of grade 3/4 adverse events, such as neutropenia and leukopenia, was much higher in patients with a UGT1A1 polymorphism.

Conclusions

A first-line therapy comprising XELIRI plus bevacizumab yielded a promising response rate. However, careful attention should be given to adverse clinical events in Japanese patients receiving treatment with unresectable or recurrent CRC.

http://ift.tt/2r17ysd

FDA Grants Brigatinib Accelerated Approval for Metastatic Non-Small Cell Lung Cancer

On April 28, the FDA granted accelerated approval to the targeted therapy brigatinib (Alunbrig™) for patients with metastatic non-small cell lung cancer (NSCLC) and alterations in the ALK gene whose cancer has progressed during their initial therapy.

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FDA Grants Brigatinib Accelerated Approval for Metastatic Non-Small Cell Lung Cancer

On April 28, the FDA granted accelerated approval to the targeted therapy brigatinib (Alunbrig™) for patients with metastatic non-small cell lung cancer (NSCLC) and alterations in the ALK gene whose cancer has progressed during their initial therapy.

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Glioblastoma multiforme (GBM) in the elderly: initial treatment strategy and overall survival

Abstract

The EORTC trial which solidified the role of external beam radiotherapy (EBRT) plus temozolomide (TMZ) in the management of GBM excluded patients over age 70. Randomized studies of elderly patients showed that hypofractionated EBRT (HFRT) alone or TMZ alone was at least equivalent to conventionally fractionated EBRT (CFRT) alone. We sought to investigate the practice patterns and survival in elderly patients with GBM. We identified patients age 65–90 in the National Cancer Data Base (NCDB) with histologically confirmed GBM from 1998 to 2012 and known chemotherapy and radiotherapy status. We analyzed factors predicting treatment with EBRT alone vs. EBRT plus concurrent single-agent chemotherapy (CRT) using multivariable logistic regression. Similarly, within the EBRT alone cohort we compared CFRT (54–65 Gy at 1.7–2.1 Gy/fraction) to HFRT (34–60 Gy at 2.5-5 Gy/fraction). Multivariable Cox proportional hazards model (MVA) with propensity score adjustment was used to compare survival. A total of 38,862 patients were included. Initial treatments for 1998 versus 2012 were: EBRT alone = 50 versus 10%; CRT = 6 versus 50%; chemo alone = 1.6% (70% single-agent) versus 3.2% (94% single-agent). Among EBRT alone patients, use of HFRT (compared to CFRT) increased from 13 to 41%. Numerous factors predictive for utilization of CRT over EBRT alone and for HFRT over CFRT were identified. Median survival and 1-year overall survival were higher in the CRT versus EBRT alone group at 8.6 months vs. 5.1 months and 36.0 versus 15.7% (p < 0.0005 by log-rank, multivariable HR 0.65 [95% CI = 0.61–0.68, p < 0.0005], multivariable HR with propensity adjustment 0.66 [95% CI = 0.63–0.70, p < 0.0005]). For elderly GBM patients in the United States, CRT is the most common initial treatment and appears to offer a survival advantage over EBRT alone. Adoption of hypofractionation has increased over time but continues to be low.

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CIP2A mediates fibronectin-induced bladder cancer cell proliferation by stabilizing β-catenin

Fibronectin (FN) is associated with tumorigenesis and progression in bladder cancer, however, the underlying mechanisms causing this remain largely unknown. Furthermore, cancerous inhibitor of protein phosphat...

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Increased complications of chronic erythrocytapheresis compared with manual exchange transfusions in children and adolescents with sickle cell disease

Abstract

Background

Children and adolescents with sickle cell disease (SCD) are at high risk of strokes and are frequently treated with red blood cell (RBC) transfusions. The goal is to suppress hemoglobin (Hb) S while minimizing transfusion-induced iron overload. RBCs may be given via simple transfusion, manual exchange transfusion (MET), or erythrocytapheresis (aRBCX). Chronic transfusion practices vary among institutions.

Methods

This single-institution, retrospective cohort study compares Hb S control and therapy complication rates between MET and aRBCX in a cohort of children and adolescents with SCD and stroke during a 5-year period from 2008 through 2012. Duration and mode of transfusion therapy, achievement of Hb S suppression goal, iron burden by ferritin levels, and catheter complications were evaluated.

Results

Thirty-seven children were included in analysis. The prevalence of catheter complications was 75% in aRBCX recipients compared with 0% in MET recipients (P < 0.001). There was no significant difference between modalities in achieving Hb S suppression or ferritin goals, but those receiving aRBCX had a greater likelihood of discontinuing chelation therapy. Among aRBCX recipients, adherence to >90% of transfusion appointments was associated with achieving Hb S suppression goals.

Conclusion

aRBCX may have increased complication risks compared with MET for chronic transfusion therapy in SCD. Risks and benefits of aRBCX and MET should be considered when selecting a chronic transfusion modality. Transfusion therapy modalities should be compared in prospective studies for stroke prevention in children with SCD.

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Implementing the psychosocial standards in pediatric cancer: Current staffing and services available

Abstract

Background

Fifteen evidence-based Standards for Psychosocial Care for Children with Cancer and Their Families (Standards) were published in 2015. The Standards cover a broad range of topics and circumstances and require qualified multidisciplinary staff to be implemented. This paper presents data on the availability of psychosocial staff and existing practices at pediatric oncology programs in the United States, providing data that can be used to advocate for expanded services and prepare for implementation of the Standards.

Procedure

Up to three healthcare professionals from 144 programs (72% response rate) participated in an online survey conducted June–December 2016. There were 99 pediatric oncologists with clinical leadership responsibility (Medical Director/Clinical Director), 132 psychosocial leaders in pediatric oncology (Director of Psychosocial Services/Manager/most senior staff member), and 58 administrators in pediatric oncology (Administrative Director/Business Administrator/Director of Operations). The primary outcomes were number and type of psychosocial staff, psychosocial practices, and identified challenges in the delivery of psychosocial care.

Results

Over 90% of programs have social workers and child life specialists who provide care to children with cancer and their families. Fewer programs have psychologists (60%), neuropsychologists (31%), or psychiatrists (19%). Challenges in psychosocial care are primarily based on pragmatic issues related to funding and reimbursement.

Conclusion

Most participating pediatric oncology programs appear to have at least the basic level of staffing necessary to implement of some of the Standards. However, the lack of a more comprehensive multidisciplinary team is a likely barrier in the implementation of the full set of Standards.

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Increased complications of chronic erythrocytapheresis compared with manual exchange transfusions in children and adolescents with sickle cell disease

Abstract

Background

Children and adolescents with sickle cell disease (SCD) are at high risk of strokes and are frequently treated with red blood cell (RBC) transfusions. The goal is to suppress hemoglobin (Hb) S while minimizing transfusion-induced iron overload. RBCs may be given via simple transfusion, manual exchange transfusion (MET), or erythrocytapheresis (aRBCX). Chronic transfusion practices vary among institutions.

Methods

This single-institution, retrospective cohort study compares Hb S control and therapy complication rates between MET and aRBCX in a cohort of children and adolescents with SCD and stroke during a 5-year period from 2008 through 2012. Duration and mode of transfusion therapy, achievement of Hb S suppression goal, iron burden by ferritin levels, and catheter complications were evaluated.

Results

Thirty-seven children were included in analysis. The prevalence of catheter complications was 75% in aRBCX recipients compared with 0% in MET recipients (P < 0.001). There was no significant difference between modalities in achieving Hb S suppression or ferritin goals, but those receiving aRBCX had a greater likelihood of discontinuing chelation therapy. Among aRBCX recipients, adherence to >90% of transfusion appointments was associated with achieving Hb S suppression goals.

Conclusion

aRBCX may have increased complication risks compared with MET for chronic transfusion therapy in SCD. Risks and benefits of aRBCX and MET should be considered when selecting a chronic transfusion modality. Transfusion therapy modalities should be compared in prospective studies for stroke prevention in children with SCD.

http://ift.tt/2rAjihO

Implementing the psychosocial standards in pediatric cancer: Current staffing and services available

Abstract

Background

Fifteen evidence-based Standards for Psychosocial Care for Children with Cancer and Their Families (Standards) were published in 2015. The Standards cover a broad range of topics and circumstances and require qualified multidisciplinary staff to be implemented. This paper presents data on the availability of psychosocial staff and existing practices at pediatric oncology programs in the United States, providing data that can be used to advocate for expanded services and prepare for implementation of the Standards.

Procedure

Up to three healthcare professionals from 144 programs (72% response rate) participated in an online survey conducted June–December 2016. There were 99 pediatric oncologists with clinical leadership responsibility (Medical Director/Clinical Director), 132 psychosocial leaders in pediatric oncology (Director of Psychosocial Services/Manager/most senior staff member), and 58 administrators in pediatric oncology (Administrative Director/Business Administrator/Director of Operations). The primary outcomes were number and type of psychosocial staff, psychosocial practices, and identified challenges in the delivery of psychosocial care.

Results

Over 90% of programs have social workers and child life specialists who provide care to children with cancer and their families. Fewer programs have psychologists (60%), neuropsychologists (31%), or psychiatrists (19%). Challenges in psychosocial care are primarily based on pragmatic issues related to funding and reimbursement.

Conclusion

Most participating pediatric oncology programs appear to have at least the basic level of staffing necessary to implement of some of the Standards. However, the lack of a more comprehensive multidisciplinary team is a likely barrier in the implementation of the full set of Standards.

http://ift.tt/2qBWRvk

Wie lange sollte bis zur Beurteilung des Therapieansprechens nach Radiochemotherapie des Analkarzinoms gewartet werden?

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Comprehensive Registry of Esophageal Cancer in Japan, 2010

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Comprehensive Registry of Esophageal Cancer in Japan, 2010

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Evaluation of HepaRG cells for the assessment of indirect drug-induced hepatotoxicity using INH as a model substance

Abstract

HepaRG cells are widely used as an in vitro model to assess drug-induced hepatotoxicity. However, only few studies exist so far regarding their suitability to detect the effects of drugs requiring a preceding activation via the cytochrome P450 (CYP) system. A prototypic substance is the anti-tuberculosis agent INH, which is metabolized into N-acetylhydrazine, which then triggers hepatotoxicity. Therefore, the aim of the present study was to test if this effect can also be detected in HepaRG cells and if it can be counteracted by the known hepatoprotectant silibinin. For this purpose, differentiated HepaRG cells were treated with increasing concentrations of INH (0.1–100 mM) or 10 mM INH plus escalating concentrations of silibinin (1–100 µM). After 48 h of treatment, cell morphology and parameters indicating cell vitality, oxidative stress, and liver cell function were assessed. High concentrations of INH led to severe histopathological changes, reduced cell vitality and glutathione content, increased LDH and ASAT release into the medium, enhanced lipid peroxidation, and elevated cleaved caspase-3 expression. Additionally, glycogen depletion and reduced biotransformation capacity were seen at high INH concentrations, whereas at low concentrations an induction of biotransformation enzymes was noticed. Silibinin caused clear-cut protective effects, but with few parameters INH toxicity was even aggravated, most probably due to increased metabolization of INH into its toxic metabolite. In conclusion, HepaRG cells are excellently suited to evaluate the effects of substances requiring prior toxification via the CYP system, such as INH. They additionally enable the identification of complex substance interactions.

http://ift.tt/2qBv1iG

Evaluation of HepaRG cells for the assessment of indirect drug-induced hepatotoxicity using INH as a model substance

Abstract

HepaRG cells are widely used as an in vitro model to assess drug-induced hepatotoxicity. However, only few studies exist so far regarding their suitability to detect the effects of drugs requiring a preceding activation via the cytochrome P450 (CYP) system. A prototypic substance is the anti-tuberculosis agent INH, which is metabolized into N-acetylhydrazine, which then triggers hepatotoxicity. Therefore, the aim of the present study was to test if this effect can also be detected in HepaRG cells and if it can be counteracted by the known hepatoprotectant silibinin. For this purpose, differentiated HepaRG cells were treated with increasing concentrations of INH (0.1–100 mM) or 10 mM INH plus escalating concentrations of silibinin (1–100 µM). After 48 h of treatment, cell morphology and parameters indicating cell vitality, oxidative stress, and liver cell function were assessed. High concentrations of INH led to severe histopathological changes, reduced cell vitality and glutathione content, increased LDH and ASAT release into the medium, enhanced lipid peroxidation, and elevated cleaved caspase-3 expression. Additionally, glycogen depletion and reduced biotransformation capacity were seen at high INH concentrations, whereas at low concentrations an induction of biotransformation enzymes was noticed. Silibinin caused clear-cut protective effects, but with few parameters INH toxicity was even aggravated, most probably due to increased metabolization of INH into its toxic metabolite. In conclusion, HepaRG cells are excellently suited to evaluate the effects of substances requiring prior toxification via the CYP system, such as INH. They additionally enable the identification of complex substance interactions.

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Gankyrin as a potential therapeutic target for cancer

Abstract

Gankyrin is an oncoprotein that plays a central role in the development of cancer. Although researchers have increasingly focused on the relationships of gankyrin with carcinogenesis, metastasis and prognosis of different cancers, the molecular mechanisms are still unclear. In recent years, several interacting partners of gankyrin and cell signaling pathways regulated by gankyrin have been elucidated. In addition, accumulating evidence has indicated the contribution of microRNAs to regulating gankyrin expression in tumor cells. In this review, we summarize the major known roles of gankyrin in cancer cells and highlight the potential clinical relevance of targeting gankyrin.

Graphical abstract

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A phase II study of antibody-drug conjugate, TAK-264 (MLN0264) in previously treated patients with advanced or metastatic pancreatic adenocarcinoma expressing guanylyl cyclase C

Summary

Background This phase II open-label, multicenter study evaluated the efficacy, safety, and tolerability of TAK-264 in previously treated patients with advanced or metastatic pancreatic adenocarcinoma expressing guanylyl cyclase C (GCC). Methods Patients with advanced or metastatic pancreatic adenocarcinoma expressing GCC (H-score ≥ 10) received TAK-264 1.8 mg/kg on day 1 of a 21-day cycle as a 30-min intravenous infusion for up to 1 year or until disease progression or unacceptable toxicity. The primary objective was overall response rate (ORR [complete response + partial response (PR)]). Secondary objectives included evaluations of the safety and pharmacokinetic profile of TAK-264 (NCT02202785). Results 43 patients were enrolled and treated with 1.8 mg/kg TAK-264: 11, 15, and 17 patients with low, intermediate, and high GCC expression, respectively. Median number of treatment cycles received was two (range 1–10). The ORR was 3%, including one patient with intermediate GCC expression who achieved a PR. All patients experienced ≥1 adverse events (AE). The majority of patients experienced grade 1/2 AEs affecting the gastrointestinal tract. Fifteen (35%) patients experienced ≥grade 3 drug-related AEs; five (12%) patients had a serious AE. The most common (≥10% of patients) all-grade drug-related AEs were nausea (33%), fatigue (28%), neutropenia (23%), decreased appetite (23%), vomiting (16%), asthenia (16%), and alopecia (14%). Conclusions TAK-264 demonstrated a manageable safety profile; however, the low efficacy of TAK-264 observed in this study did not support further clinical investigation.

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Should the FDA Ban Cigarette Filter Ventilation?

Does ventilation of cigarette filters by tiny holes increase risk for adenocarcinoma of the lung? In this issue, Song and colleagues conclude that the answer is "yes," based on their weight-of-evidence review of an array of relevant literature, both peer reviewed and from tobacco industry documents (1). Their affirmative conclusion has regulatory implications under the 2009 Family Smoking Prevention and Tobacco Control Act (TCA) (2) and leads them to propose that "thus, the FDA should consider regulating its use, up to and including a ban…"

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Anxiety and depression in working-age cancer survivors: a register-based study

Abstract

Background

Anxiety and depression can be a long-term strain in cancer survivors. Little is known about the emotional situation of cancer survivors who have to deal with work- and family-related issues. The purpose of this study was to investigate anxiety and depression in working-age cancer survivors and associated factors.

Methods

A register-based sample of 3370 cancer survivors (25 to 55 years at time of diagnosis) diagnosed up to six years prior to the survey was recruited from two German cancer registries. Demographic and medical characteristics as well as self-reported measures were used.

Results

Overall, approximately 40% of the survivors reported moderate to high anxiety scores and approximately 20% reported moderate to high depression scores. Compared to the general population, working-age cancer survivors were more anxious but less depressed (p < .001). Subgroups with regard to time since diagnosis did not differ in anxiety or depression. Anxiety and depression in cancer survivors were associated with various variables. Better social support, family functioning and physical health were associated with lower anxiety and depression.

Conclusions

Overall, we found higher anxiety levels in cancer survivors of working-age than in the general population. A considerable portion of cancer survivors reported moderate to high levels of anxiety and depression. The results indicate the need for psychosocial screening and psycho-oncological support e.g. in survivorship programs for working-age cancer survivors. Assessing the physical health, social support and family background might help to identify survivors at risk for higher emotional distress.

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Hybrid peripheral nerve sheath tumors: report of five cases and detailed review of literature

Abstract

Background

Hybrid peripheral nerve sheath tumors (PNSTs) have been recognized recently and were first included in the 4th edition of World Health Organization (WHO) Classification of Tumors of Soft tissue and Bone, published in 2013. These tumors show combined features of more than one type of conventional benign peripheral nerve sheath tumors. The most common combinations are those of schwannoma/perineurioma followed by combinations of neurofibroma/schwannoma and neurofibroma/perineurioma. A detailed literature review of published cases is presented.

We have discussed the types and etiology, epidemiology and sites of localization, gross and microscopic appearances and immunohistochemical features of hybrid PNSTs and association of these tumors with tumor syndromes.

Case presentation

We have included five cases which were diagnosed in our department as we believe that publication of these new cases is relevant for the improved understanding of these specific tumors. Four of our five patients were males, mean age was 24 years. There was wide variation in the location of these tumors. Mean size of excised tumors was 5.5 cms in the greatest dimensions. Three out of five cases represented hybrid schwannoma/perineurioma histologically. No significant nuclear atypia, mitotic activity or necrosis seen. All five cases were completely excised. All five patients are alive and well at the time of writing with no recurrence.

Conclusion

Hybrid PNSTs are distinct tumors and are usually benign. However, rare case reports have described local recurrence and at least two recent case reports have described malignant transformation in these tumors. Further studies on large number of cases are required to determine the exact pathogenetic basis of these tumors.

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Venous thromboembolism in hospitalized patients receiving chemotherapy for malignancies at Japanese community hospital: prospective observational study

Abstract

Background

Although Asian population was recognized to have a lower risk of venous thromboembolism (VTE), its increasing prevalence and incidence remain unclear in patients with malignancies. We attempted to predict VTE development using activation markers of coagulation and fibrinolysis.

Methods

We enrolled patients with malignancy admitted to Tonan Hospital between April and December 2014 to receive a new-for-them chemotherapy regimen. All patients were examined for VTE by computed tomography and whole-leg compression ultrasonography before chemotherapy and three months later. We also examined plasma levels of thrombin-antithrombin complex (TAT) and plasmin α2-plasmin inhibitor complex (PIC) before chemotherapy. The cut off values of TAT and PIC were set at 2.1 ng/mL and 1.8 μg/mL, respectively.

Results

Of 97 patients, the majority (67%) had distant metastases. The most common malignancies were colorectal (26%), breast (23%), and stomach (19%) cancer. VTE was detected in 29 patients (31%); all were asymptomatic. VTE was newly developed in 12 patients in the three-month observation period, which means the incidence was 49 per 1000 person-years. Non-increased PIC with increased TAT was the only significant risk factor for both VTE prevalence and incidence in multivariate analysis, and the odds ratios were 3.0 (95% confidence interval, 1.1–8.2; P = 0.034) and 9.4 (95% confidence interval, 1.7–51.9; P = 0.011), respectively.

Conclusions

The prevalence and incidence of VTE were high in hospitalized Japanese patients receiving chemotherapy for malignancies. Non-increased PIC with increased levels of TAT may be an independent risk factor for VTE development.

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Cleavage of the urokinase receptor (uPAR) on oral cancer cells: regulation by transforming growth factor – β1 (TGF-β1) and potential effects on migration and invasion

Abstract

Background

Urokinase plasminogen activator (uPA) receptor (uPAR) is up-regulated at the invasive tumour front of human oral squamous cell carcinoma (OSCC), indicating a role for uPAR in tumour progression. We previously observed elevated expression of uPAR at the tumour-stroma interface in a mouse model for OSCC, which was associated with increased proteolytic activity. The tumour microenvironment regulated uPAR expression, as well as its glycosylation and cleavage. Both full-length- and cleaved uPAR (uPAR (II-III)) are involved in highly regulated processes such as cell signalling, proliferation, migration, stem cell mobilization and invasion. The aim of the current study was to analyse tumour associated factors and their effect on uPAR cleavage, and the potential implications for cell proliferation, migration and invasion.

Methods

Mouse uPAR was stably overexpressed in the mouse OSCC cell line AT84. The ratio of full-length versus cleaved uPAR as analysed by Western blotting and its regulation was assessed by addition of different protease inhibitors and transforming growth factor - β1 (TGF-β1). The role of uPAR cleavage in cell proliferation and migration was analysed using real-time cell analysis and invasion was assessed using the myoma invasion model.

Results

We found that when uPAR was overexpressed a proportion of the receptor was cleaved, thus the cells presented both full-length uPAR and uPAR (II-III). Cleavage was mainly performed by serine proteases and urokinase plasminogen activator (uPA) in particular. When the OSCC cells were stimulated with TGF-β1, the production of the uPA inhibitor PAI-1 was increased, resulting in a reduction of uPAR cleavage. By inhibiting cleavage of uPAR, cell migration was reduced, and by inhibiting uPA activity, invasion was reduced. We could also show that medium containing soluble uPAR (suPAR), and cleaved soluble uPAR (suPAR (II-III)), induced migration in OSCC cells with low endogenous levels of uPAR.

Conclusions

These results show that soluble factors in the tumour microenvironment, such as TGF-β1, PAI-1 and uPA, can influence the ratio of full length and uPAR (II-III) and thereby potentially effect cell migration and invasion. Resolving how uPAR cleavage is controlled is therefore vital for understanding how OSCC progresses and potentially provides new targets for therapy.

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Barriers and facilitators to smoking cessation in a cancer context: A qualitative study of patient, family and professional views

Abstract

Background

Continued smoking after cancer adversely affects quality of life and survival, but one fifth of cancer survivors still smoke. Despite its demands, cancer presents an opportunity for positive behaviour change. Smoking often occurs in social groups, therefore interventions which target families and individuals may be more successful. This qualitative study explored patients, family members and health professionals' views and experiences of smoking and smoking cessation after cancer, in order to inform future interventions.

Methods

In-depth qualitative interviews (n = 67) with 29 patients, 14 family members and 24 health professionals. Data were analysed using the 'Framework' method.

Results

Few patients and family members had used National Health Service (NHS) smoking cessation services and more than half still smoked. Most recalled little 'smoking-related' discussion with clinicians but were receptive to talking openly. Clinicians revealed several barriers to discussion. Participants' continued smoking was explained by the stress of diagnosis; desire to maintain personal control; and lack of connection between smoking, cancer and health.

Conclusions

A range of barriers to smoking cessation exist for patients and family members. These are insufficiently assessed and considered by clinicians. Interventions must be more effectively integrated into routine practice.

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Adoptive T cell therapy: An overview of obstacles and opportunities

The therapeutic potential of adoptive cell therapy (ACT) in cancer patients was first acknowledged 3 decades ago, but it was an esoteric approach at the time. In recent years, technological advancements have transformed ACT into a viable therapeutic option that can be curative in some patients. In fact, current ACT response rates are 80% to 90% for hematological malignancies and 30% for metastatic melanoma refractory to multiple lines of therapy. Although these results are encouraging, there is still much to be done to fulfill ACT's potential, specifically with regard to improving clinical efficacy, expanding clinical indications, reducing toxicity, and increasing production and cost-effectiveness. This review addresses the current major obstacles to ACT and presents potential solutions. Cancer 2017;123:2154-62. © 2017 American Cancer Society.

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Issue Information

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Somatic driver mutations in melanoma

Melanoma has one of the highest somatic mutational burdens among solid malignancies. Although the rapid progress in genomic research has contributed immensely to our understanding of the pathogenesis of melanoma, the clinical significance of the vast array of genomic alterations discovered by next-generation sequencing is far from being fully characterized. Most mutations prevalent in melanoma are simply neutral "passengers," which accompany functionally significant "drivers" under transforming conditions. The delineation of driver mutations from passenger mutations is critical to the development of targeted therapies. Novel advances in genomic data analysis have aided in distinguishing true driver mutations involved in tumor progression. Here, the authors review the current literature on important somatic driver mutations in melanoma, along with the implications for treatment. Cancer 2017;123:2104-17. © 2017 American Cancer Society.

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Molecular insights into melanoma brain metastases

Substantial proportions of patients with metastatic melanoma develop brain metastases during the course of their disease, often resulting in significant morbidity and death. Despite recent advances with BRAF/MEK and immune-checkpoint inhibitors in the treatment of patients who have melanoma with extracerebral metastases, patients who have melanoma brain metastases still have poor overall survival, highlighting the need for further therapy options. A deeper understanding of the molecular pathways involved in the development of melanoma brain metastases is required to develop more brain-specific therapies. Here, the authors summarize the currently known preclinical data and describe steps involved in the development of melanoma brain metastases. Only by knowing the molecular background is it possible to design new therapeutic agents that can be used to improve the outcome of patients with melanoma brain metastases. Cancer 2017;123:2163-75. © 2017 American Cancer Society.

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After a treatment breakthrough—progress, plateaus, and raising the bar

Although coverage of the new science of melanoma and its therapy has been extensive in the medical and scientific literature, this special issue of Cancer assembles several important contributions from leaders in the field of melanoma biology and therapy to educate and update readers concerning recent advances and expert thinking, which should be both informative and thought-provoking.

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Gankyrin as a potential therapeutic target for cancer

Abstract

Gankyrin is an oncoprotein that plays a central role in the development of cancer. Although researchers have increasingly focused on the relationships of gankyrin with carcinogenesis, metastasis and prognosis of different cancers, the molecular mechanisms are still unclear. In recent years, several interacting partners of gankyrin and cell signaling pathways regulated by gankyrin have been elucidated. In addition, accumulating evidence has indicated the contribution of microRNAs to regulating gankyrin expression in tumor cells. In this review, we summarize the major known roles of gankyrin in cancer cells and highlight the potential clinical relevance of targeting gankyrin.

Graphical abstract

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A phase II study of antibody-drug conjugate, TAK-264 (MLN0264) in previously treated patients with advanced or metastatic pancreatic adenocarcinoma expressing guanylyl cyclase C

Summary

Background This phase II open-label, multicenter study evaluated the efficacy, safety, and tolerability of TAK-264 in previously treated patients with advanced or metastatic pancreatic adenocarcinoma expressing guanylyl cyclase C (GCC). Methods Patients with advanced or metastatic pancreatic adenocarcinoma expressing GCC (H-score ≥ 10) received TAK-264 1.8 mg/kg on day 1 of a 21-day cycle as a 30-min intravenous infusion for up to 1 year or until disease progression or unacceptable toxicity. The primary objective was overall response rate (ORR [complete response + partial response (PR)]). Secondary objectives included evaluations of the safety and pharmacokinetic profile of TAK-264 (NCT02202785). Results 43 patients were enrolled and treated with 1.8 mg/kg TAK-264: 11, 15, and 17 patients with low, intermediate, and high GCC expression, respectively. Median number of treatment cycles received was two (range 1–10). The ORR was 3%, including one patient with intermediate GCC expression who achieved a PR. All patients experienced ≥1 adverse events (AE). The majority of patients experienced grade 1/2 AEs affecting the gastrointestinal tract. Fifteen (35%) patients experienced ≥grade 3 drug-related AEs; five (12%) patients had a serious AE. The most common (≥10% of patients) all-grade drug-related AEs were nausea (33%), fatigue (28%), neutropenia (23%), decreased appetite (23%), vomiting (16%), asthenia (16%), and alopecia (14%). Conclusions TAK-264 demonstrated a manageable safety profile; however, the low efficacy of TAK-264 observed in this study did not support further clinical investigation.

http://ift.tt/2rzB6cV

Should the FDA Ban Cigarette Filter Ventilation?

Does ventilation of cigarette filters by tiny holes increase risk for adenocarcinoma of the lung? In this issue, Song and colleagues conclude that the answer is "yes," based on their weight-of-evidence review of an array of relevant literature, both peer reviewed and from tobacco industry documents (1). Their affirmative conclusion has regulatory implications under the 2009 Family Smoking Prevention and Tobacco Control Act (TCA) (2) and leads them to propose that "thus, the FDA should consider regulating its use, up to and including a ban…"

http://ift.tt/2qFx4Ag

Anxiety and depression in working-age cancer survivors: a register-based study

Abstract

Background

Anxiety and depression can be a long-term strain in cancer survivors. Little is known about the emotional situation of cancer survivors who have to deal with work- and family-related issues. The purpose of this study was to investigate anxiety and depression in working-age cancer survivors and associated factors.

Methods

A register-based sample of 3370 cancer survivors (25 to 55 years at time of diagnosis) diagnosed up to six years prior to the survey was recruited from two German cancer registries. Demographic and medical characteristics as well as self-reported measures were used.

Results

Overall, approximately 40% of the survivors reported moderate to high anxiety scores and approximately 20% reported moderate to high depression scores. Compared to the general population, working-age cancer survivors were more anxious but less depressed (p < .001). Subgroups with regard to time since diagnosis did not differ in anxiety or depression. Anxiety and depression in cancer survivors were associated with various variables. Better social support, family functioning and physical health were associated with lower anxiety and depression.

Conclusions

Overall, we found higher anxiety levels in cancer survivors of working-age than in the general population. A considerable portion of cancer survivors reported moderate to high levels of anxiety and depression. The results indicate the need for psychosocial screening and psycho-oncological support e.g. in survivorship programs for working-age cancer survivors. Assessing the physical health, social support and family background might help to identify survivors at risk for higher emotional distress.

http://ift.tt/2pTbPxS

Hybrid peripheral nerve sheath tumors: report of five cases and detailed review of literature

Abstract

Background

Hybrid peripheral nerve sheath tumors (PNSTs) have been recognized recently and were first included in the 4th edition of World Health Organization (WHO) Classification of Tumors of Soft tissue and Bone, published in 2013. These tumors show combined features of more than one type of conventional benign peripheral nerve sheath tumors. The most common combinations are those of schwannoma/perineurioma followed by combinations of neurofibroma/schwannoma and neurofibroma/perineurioma. A detailed literature review of published cases is presented.

We have discussed the types and etiology, epidemiology and sites of localization, gross and microscopic appearances and immunohistochemical features of hybrid PNSTs and association of these tumors with tumor syndromes.

Case presentation

We have included five cases which were diagnosed in our department as we believe that publication of these new cases is relevant for the improved understanding of these specific tumors. Four of our five patients were males, mean age was 24 years. There was wide variation in the location of these tumors. Mean size of excised tumors was 5.5 cms in the greatest dimensions. Three out of five cases represented hybrid schwannoma/perineurioma histologically. No significant nuclear atypia, mitotic activity or necrosis seen. All five cases were completely excised. All five patients are alive and well at the time of writing with no recurrence.

Conclusion

Hybrid PNSTs are distinct tumors and are usually benign. However, rare case reports have described local recurrence and at least two recent case reports have described malignant transformation in these tumors. Further studies on large number of cases are required to determine the exact pathogenetic basis of these tumors.

http://ift.tt/2qFhNzo

Venous thromboembolism in hospitalized patients receiving chemotherapy for malignancies at Japanese community hospital: prospective observational study

Abstract

Background

Although Asian population was recognized to have a lower risk of venous thromboembolism (VTE), its increasing prevalence and incidence remain unclear in patients with malignancies. We attempted to predict VTE development using activation markers of coagulation and fibrinolysis.

Methods

We enrolled patients with malignancy admitted to Tonan Hospital between April and December 2014 to receive a new-for-them chemotherapy regimen. All patients were examined for VTE by computed tomography and whole-leg compression ultrasonography before chemotherapy and three months later. We also examined plasma levels of thrombin-antithrombin complex (TAT) and plasmin α2-plasmin inhibitor complex (PIC) before chemotherapy. The cut off values of TAT and PIC were set at 2.1 ng/mL and 1.8 μg/mL, respectively.

Results

Of 97 patients, the majority (67%) had distant metastases. The most common malignancies were colorectal (26%), breast (23%), and stomach (19%) cancer. VTE was detected in 29 patients (31%); all were asymptomatic. VTE was newly developed in 12 patients in the three-month observation period, which means the incidence was 49 per 1000 person-years. Non-increased PIC with increased TAT was the only significant risk factor for both VTE prevalence and incidence in multivariate analysis, and the odds ratios were 3.0 (95% confidence interval, 1.1–8.2; P = 0.034) and 9.4 (95% confidence interval, 1.7–51.9; P = 0.011), respectively.

Conclusions

The prevalence and incidence of VTE were high in hospitalized Japanese patients receiving chemotherapy for malignancies. Non-increased PIC with increased levels of TAT may be an independent risk factor for VTE development.

http://ift.tt/2pTlcNR

Cleavage of the urokinase receptor (uPAR) on oral cancer cells: regulation by transforming growth factor – β1 (TGF-β1) and potential effects on migration and invasion

Abstract

Background

Urokinase plasminogen activator (uPA) receptor (uPAR) is up-regulated at the invasive tumour front of human oral squamous cell carcinoma (OSCC), indicating a role for uPAR in tumour progression. We previously observed elevated expression of uPAR at the tumour-stroma interface in a mouse model for OSCC, which was associated with increased proteolytic activity. The tumour microenvironment regulated uPAR expression, as well as its glycosylation and cleavage. Both full-length- and cleaved uPAR (uPAR (II-III)) are involved in highly regulated processes such as cell signalling, proliferation, migration, stem cell mobilization and invasion. The aim of the current study was to analyse tumour associated factors and their effect on uPAR cleavage, and the potential implications for cell proliferation, migration and invasion.

Methods

Mouse uPAR was stably overexpressed in the mouse OSCC cell line AT84. The ratio of full-length versus cleaved uPAR as analysed by Western blotting and its regulation was assessed by addition of different protease inhibitors and transforming growth factor - β1 (TGF-β1). The role of uPAR cleavage in cell proliferation and migration was analysed using real-time cell analysis and invasion was assessed using the myoma invasion model.

Results

We found that when uPAR was overexpressed a proportion of the receptor was cleaved, thus the cells presented both full-length uPAR and uPAR (II-III). Cleavage was mainly performed by serine proteases and urokinase plasminogen activator (uPA) in particular. When the OSCC cells were stimulated with TGF-β1, the production of the uPA inhibitor PAI-1 was increased, resulting in a reduction of uPAR cleavage. By inhibiting cleavage of uPAR, cell migration was reduced, and by inhibiting uPA activity, invasion was reduced. We could also show that medium containing soluble uPAR (suPAR), and cleaved soluble uPAR (suPAR (II-III)), induced migration in OSCC cells with low endogenous levels of uPAR.

Conclusions

These results show that soluble factors in the tumour microenvironment, such as TGF-β1, PAI-1 and uPA, can influence the ratio of full length and uPAR (II-III) and thereby potentially effect cell migration and invasion. Resolving how uPAR cleavage is controlled is therefore vital for understanding how OSCC progresses and potentially provides new targets for therapy.

http://ift.tt/2qFz0sK