Magnetic resonance tissue phase mapping demonstrates altered left ventricular diastolic function in children with chronic kidney disease

Abstract

Background

Echocardiographic examinations have revealed functional cardiac abnormalities in children with chronic kidney disease.

Objective

To assess the feasibility of MRI tissue phase mapping in children and to assess regional left ventricular wall movements in children with chronic kidney disease.

Materials and methods

Twenty pediatric patients with chronic kidney disease (before or after renal transplantation) and 12 healthy controls underwent tissue phase mapping (TPM) to quantify regional left ventricular function through myocardial long (Vz) and short-axis (Vr) velocities at all 3 levels of the left ventricle.

Results

Patients and controls (age: 8 years—20 years) were matched for age, height, weight, gender and heart rate. Patients had higher systolic blood pressure. No patient had left ventricular hypertrophy on MRI or diastolic dysfunction on echocardiography. Fifteen patients underwent tissue Doppler echocardiography, with normal z-scores for mitral early diastolic (V_E), late diastolic (V_A) and peak systolic (V_S) velocities. Throughout all left ventricular levels, peak diastolic Vz and Vr (cm/s) were reduced in patients: Vz_base -10.6 ± 1.9 vs. -13.4 ± 2.0 (P < 0.0003), Vz_mid -7.8 ± 1.6 vs. -11 ± 1.5 (P < 0.0001), Vz_apex -3.8 ± 1.6 vs. -5.3 ± 1.6 (P = 0.01), Vr_base -4.2 ± 0.8 vs. -4.9 ± 0.7 (P = 0.01), Vr_mid -4.7 ± 0.7 vs. -5.4 ± 0.7 (P = 0.01), Vr_apex -4.7 ± 1.4 vs. -5.6 ± 1.1 (P = 0.05).

Conclusion

Tissue phase mapping is feasible in children and adolescents. Children with chronic kidney disease show significantly reduced peak diastolic long- and short-axis left ventricular wall velocities, reflecting impaired early diastolic filling. Thus, tissue phase mapping detects chronic kidney disease-related functional myocardial changes before overt left ventricular hypertrophy or echocardiographic diastolic dysfunction occurs.

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Three-dimensional surface and ultrasound imaging for daily IGRT of prostate cancer

Image guided radiotherapy (IGRT) is an essential pre-requisite for delivering high precision radiotherapy. We compared daily variation detected by two non-ionizing imaging modalities (surface imaging and trans...

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Erratum to: Trends in Media Reports of Celebrities’ Breast Cancer Treatment Decisions

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Intravital FRET imaging reveals osteopontin-mediated polymorphonuclear leukocyte activation by tumor cell emboli

Abstract

Myeloid-derived suppressor cells (MDSCs) cause paraneoplastic leukemoid reactions and facilitate tumor cell metastasis. However, the interaction of MDSCs with tumor cells in live tissues has not been adequately visualized. To accomplish this task, we developed an intravital imaging protocol to observe metastasized tumor cells in mouse lungs. For visualization of the activation of MDSCs, bone marrow cells derived from transgenic mice expressing a Förster resonance energy transfer (FRET) biosensor for extracellular signal-regulated kinase (ERK) were implanted into host mice. Under a two-photon excitation microscope, numerous polymorphonuclear cells (PMNs) were found to infiltrate the lungs of tumor-bearing mice in which 4T1 mammary tumor cells were implanted into the footpads. By FRET imaging, we found that ERKs in PMNs were activated around the 4T1 tumor emboli in the lungs. Because antibody array analysis implied the involvement of osteopontin (OPN) in the metastasis of 4T1 cells, we further analyzed the effect of OPN knockdown. The OPN knockdown in 4T1 cells did not affect the cell growth, but markedly suppressed lung metastasis of 4T1 cells and ERK activation in PMNs in the lung. Intravenous injection of recombinant OPN restored the lung metastasis of OPN-deficient 4T1 cells, suggesting that OPN functioned in a paracrine manner. It has been reported that ERK activation of neutrophils causes NETosis and that PMNs promote metastasis of tumor cells by NETosis. In agreement with the previous reports, the NETosis inhibitor DNase I inhibited lung metastasis of 4T1 cells. These observations suggest that OPN promotes metastasis of 4T1 cells by activating PMNs and inducing NETosis.

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Genetic variants at 9p21.3 are associated with risk of esophageal squamous cell carcinoma in a Chinese population

Summary

Genome-wide association studies (GWAS) have linked genetic variants at 9p21.3 to the risk of multiple cancers. However, the roles of genetic variants at 9p21.3 in esophageal squamous cell carcinoma (ESCC) development are largely unknown. Here we evaluated the genetic variants at 9p21.3 reported in cancer GWAS with case-control study including 2,139 ESCC cases and 2,273 controls in a Chinese population, and measured the mRNA expression levels of MTAP, CDKN2A, CDKN2B and CDKN2B-AS1 in paired ESCC tumor and adjacent normal tissues. We found that the G allele of rs7023329 was significantly associated with a decreased risk of ESCC with a per-allele odds ratio (OR) of 0.84 (95% confidence interval (CI), 0.77-0.91; P=2.95×10^-5). The rs7023329-G allele was related to a high expression of MTAP (P=0.020). The rs1679013-C allele was independently associated with an increased risk of ESCC with a per-allele OR of 1.12 (95% CI, 1.01-1.24; P=0.039). We also found that the carriers of the risk allele rs1679013-C had lower expressions of CDKN2B than non-carriers (P=0.035). CDKN2B was also significantly down-regulated in ESCC tumor tissues as compared with adjacent normal tissues (P=3.50×10^-5). Therefore, our findings indicate that genetic variants at 9p21.3 may modulate the expression of MTAP and CDKN2B and contribute to ESCC susceptibility. This may further advance our understanding of 9p21.3 locus in cancer development.

This article is protected by copyright. All rights reserved.

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Prediction and prioritization of neoantigens: integration of RNA-Seq data with whole-exome sequencing

Abstract

The importance of neoantigens for cancer immunity is now well-acknowledged. However, there are diverse strategies for predicting and prioritizing candidate neoantigens, and thus neoantigen loads reported in the literature vary a great deal. To clarify this issue, we compared the numbers of neoantigen candidates predicted by four currently utilized strategies. Whole-exome sequencing (WES) and RNA-Seq of 4 non-small cell lung cancer patients was performed. We identified 361 somatic missense mutations from which 224 candidate neoantigens were predicted using MHC class I binding affinity prediction software (Strategy I). Of these, 207 exceeded the set threshold of gene expression (fragments per kilobase of transcript per million fragments mapped (FPKM) ≥1) resulting in 124 candidate neoantigens (Strategy II). To verify mutant mRNA expression, sequencing of amplicons from tumor cDNA including each mutation was performed; 204 of the 207 mutations were successfully sequenced, yielding 121 mutant mRNA sequences, resulting in 75 candidate neoantigens (Strategy III). Sequence information was extracted from RNA-Seq to confirm the presence of mutated mRNA. Variant allele frequencies ≥0.04 in RNA-Seq were found for 117 of the 207 mutations and regarded as expressed in the tumor, and finally, 72 candidate neoantigens were predicted (Strategy IV). Without additional amplicon sequencing of cDNA, Strategy IV was comparable to Strategy III. We therefore propose Strategy IV as a practical and appropriate strategy to predict candidate neoantigens fully utilizing currently available information. At any rate, it is of note that different neoantigen loads were deduced from the same tumors depending on the strategies applied.

This article is protected by copyright. All rights reserved.

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A leukemogenic kinase, FIP1L1-PDGFRA, and a SUMO E3 ligase, PIAS1, form a positive crosstalk via their enzymatic activities

Abstract

Fusion tyrosine kinases play a crucial role in the development of hematological malignancies. FIP1L1-PDGFRA is a leukemogenic fusion kinase that causes chronic eosinophilic leukemia. As a constitutively active kinase, FIP1L1-PDGFRA stimulates downstream signaling molecules, leading to cellular proliferation and the generation of an anti-apoptotic state. Contribution of the N-terminal FIP1L1 portion is necessary for FIP1L1-PDGFRA to exert its full transforming activity, but the underlying mechanisms have not been fully characterized. We identified PIAS1 as a FIP1L1-PDGFRA-association molecule by yeast two-hybrid screening. Our analyses indicate that the FIP1L1 portion of FIP1L1-PDGFRA is required for efficient associatiation with PIAS1. As a consequence of the association, FIP1L1-PDGFRA phosphorylates PIAS1. Moreover, the kinase activity of FIP1L1-PDGFRA stabilizes PIAS1. Therefore, PIAS1 is one of the downstream targets of FIP1L1-PDGFRA. Moreover, we found that PIAS1, as a SUMO E3 ligase, sumoylates and stabilizes FIP1L1-PDGFRA. In addition, suppression of PIAS1 activity by a knockdown experiment resulted in destabilization of FIP1L1-PDGFRA. Therefore, FIP1L1-PDGFRA and PIAS1 form a positive crosstalk via their enzymatic activities. Suppression of sumoylation by ginkgolic acid, a small molecule compound inhibiting a SUMO E1-activating enzyme, also destabilizes FIP1L1-PDGFRA, and while the tyrosine kinase inhibitor imatinib suppresses FIP1L1-PDGFRA-dependent cell growth, ginkgolic acid or siRNA of PIAS1 has a synergistic effect with imatinib. In conclusion, our results suggest that sumoylation by PIAS1 is a potential target in the treatment of FIP1L1-PDGFRA-positive chronic eosinophilic leukemia.

This article is protected by copyright. All rights reserved.

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Bilateral sternal infusion of ropivacaine and length of stay in ICU after cardiac surgery with increased respiratory risk: A randomised controlled trial.

BACKGROUND: The continuous bilateral infusion of a local anaesthetic solution around the sternotomy wound (bilateral sternal) is an innovative technique for reducing pain after sternotomy. OBJECTIVE: To assess the effects of the technique on the need for intensive care in cardiac patients at increased risk of respiratory complications. DESIGN: Randomised, observer-blind controlled trial. SETTING: Single centre, French University Hospital. PATIENTS: In total, 120 adults scheduled for open-heart surgery, with one of the following conditions: age more than 75 years, BMI >30 kg m-2, chronic obstructive pulmonary disease, active smoking habit. INTERVENTION: Either a bilateral sternal infusion of 0.2% ropivacaine (3 ml h-1 through each catheter; 'intervention' group), or standardised care only ('control' group). Analgesia was provided with paracetamol and self-administered intravenous morphine. MAIN OUTCOME MEASURES: The length of time to readiness for discharge from ICU, blindly assessed by a committee of experts. RESULTS: No effect was found between groups for the primary outcome (P = 0.680, intention to treat); the median values were 42.4 and 37.7 h, respectively for the control and intervention groups (P = 0.873). Similar nonsignificant trends were noted for other postoperative delays. Significant effects favouring the intervention were noted for dynamic pain, patient satisfaction, occurrence of nausea and vomiting, occurrence of delirium or mental confusion and occurrence of pulmonary complications. In 12 patients, although no symptoms actually occurred, the total ropivacaine plasma level exceeded the lowest value for which neurological symptoms have been observed in healthy volunteers. CONCLUSION: Because of a small size effect, and despite significant analgesic effects, this strategy failed to reduce the time spent in ICU. TRIAL REGISTRATION: EudraCT (N[degrees]: 2012-005225-69); ClinicalTrials.gov (NCT01828788). (C) 2016 European Society of Anaesthesiology

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Low kidney uptake of GLP-1R-targeting, beta cell-specific PET tracer, 18 F-labeled [Nle 14 ,Lys 40 ]exendin-4 analog, shows promise for clinical imaging

Abstract

Background

Several radiometal-labeled, exendin-based tracers that target glucagon-like peptide-1 receptors (GLP-1R) have been intensively explored for β cell imaging. The main obstacle has been the high uptake of tracer in the kidneys. This study aimed to develop a novel GLP1-R-specific tracer, with fluorine-18 attached to exendin-4, to label β cells for clinical imaging with PET (positron emission tomography). We hypothesized that this tracer would undergo reduced kidney uptake. ¹⁸F-labeled [Nle¹⁴,Lys⁴⁰]exendin-4 analog ([¹⁸F]exendin-4) was produced via Cu-catalyzed click chemistry. The biodistribution of [¹⁸F]exendin-4 was assessed with ex vivo organ γ-counting and in vivo PET imaging. We also tested the in vivo stability of the radiotracer. The localization of ¹⁸F radioactivity in rat and human pancreatic tissue sections was investigated with autoradiography. Receptor specificity was assessed with unlabeled exendin-3. Islet labeling was confirmed with immunohistochemistry. The doses of radiation in humans were estimated based on biodistribution results in rats.

Results

[¹⁸F]exendin-4 was synthesized with high yield and high specific activity. Results showed specific, sustained [¹⁸F]exendin-4 uptake in pancreatic islets. In contrast to previous studies that tested radiometal-labeled exendin-based tracers, we observed rapid renal clearance of [¹⁸F]exendin-4.

Conclusions

[¹⁸F]exendin-4 showed promise as a tracer for clinical imaging of pancreatic β cells, due to its high specific uptake in native β cells and its concomitant low kidney radioactivity uptake.

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Low kidney uptake of GLP-1R-targeting, beta cell-specific PET tracer, 18 F-labeled [Nle 14 ,Lys 40 ]exendin-4 analog, shows promise for clinical imaging

Abstract

Background

Several radiometal-labeled, exendin-based tracers that target glucagon-like peptide-1 receptors (GLP-1R) have been intensively explored for β cell imaging. The main obstacle has been the high uptake of tracer in the kidneys. This study aimed to develop a novel GLP1-R-specific tracer, with fluorine-18 attached to exendin-4, to label β cells for clinical imaging with PET (positron emission tomography). We hypothesized that this tracer would undergo reduced kidney uptake. ¹⁸F-labeled [Nle¹⁴,Lys⁴⁰]exendin-4 analog ([¹⁸F]exendin-4) was produced via Cu-catalyzed click chemistry. The biodistribution of [¹⁸F]exendin-4 was assessed with ex vivo organ γ-counting and in vivo PET imaging. We also tested the in vivo stability of the radiotracer. The localization of ¹⁸F radioactivity in rat and human pancreatic tissue sections was investigated with autoradiography. Receptor specificity was assessed with unlabeled exendin-3. Islet labeling was confirmed with immunohistochemistry. The doses of radiation in humans were estimated based on biodistribution results in rats.

Results

[¹⁸F]exendin-4 was synthesized with high yield and high specific activity. Results showed specific, sustained [¹⁸F]exendin-4 uptake in pancreatic islets. In contrast to previous studies that tested radiometal-labeled exendin-based tracers, we observed rapid renal clearance of [¹⁸F]exendin-4.

Conclusions

[¹⁸F]exendin-4 showed promise as a tracer for clinical imaging of pancreatic β cells, due to its high specific uptake in native β cells and its concomitant low kidney radioactivity uptake.

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Long-term consequences of acute kidney injury in the perioperative setting.

Purpose of review: Recent studies indicate that acute kidney injury (AKI) and chronic kidney disease (CKD) are interconnected syndromes. Although the majority of patients who suffer an episode of AKI will recover laboratory indices suggesting complete or near complete recovery of renal function, a significant portion of post-AKI survivors will develop major kidney events, including development of late-stage CKD, need for renal replacement therapies, and death. Recent findings: Our review highlights epidemiology of adverse post-AKI events, association of AKI with late development of nonrenal adverse outcomes, use of bedside equations that facilitate prognostication of adverse renal outcomes of AKI, and how variability in serum creatinine values in individual patients, even among those with normal baseline renal function may indicate risk for the development of CKD. Use of common laboratory parameters such as serum creatinine and albumin, along with certain clinical and demographic markers, individualize patients at high risk of complications and in need of close postdischarge follow-up. Evidence that 'organ crosstalk' following a major AKI episode may increase the risk of heart failure, stroke, and hypertension, places its survivors in a special patient category deserving active efforts to minimize risk for cardiovascular events. Summary: AKI is a major cause for acute in-hospital mortality and development of both late-stage CKD and cardiovascular events. Perioperative care to prevent AKI must challenge the notion that a single normal point of contact serum creatinine value substantially reduces the likelihood of its occurrence. Copyright (C) 2016 YEAR Wolters Kluwer Health, Inc. All rights reserved.

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How Does a Shared Decision-Making (SDM) Intervention for Oncologists Affect Participation Style and Preference Matching in Patients with Breast and Colon Cancer?

Abstract

The aims of this study are to assess patients' preferred and perceived decision-making roles and preference matching in a sample of German breast and colon cancer patients and to investigate how a shared decision-making (SDM) intervention for oncologists influences patients' preferred and perceived decision-making roles and the attainment of preference matches. This study is a post hoc analysis of a randomised controlled trial (RCT) on the effects of an SDM intervention. The SDM intervention was a 12-h SDM training program for physicians in combination with decision board use. For this study, we analysed a subgroup of 107 breast and colon cancer patients faced with serious treatment decisions who provided data on specific questionnaires with regard to their preferred and perceived decision-making roles (passive, SDM or active). Patients filled in questionnaires immediately following a decision-relevant consultation (t1) with their oncologist. Eleven of these patients' 27 treating oncologists had received the SDM intervention within the RCT. A majority of cancer patients (60%) preferred SDM. A match between preferred and perceived decision-making roles was reached for 72% of patients. The patients treated by SDM-trained physicians perceived greater autonomy in their decision making (p < 0.05) with more patients perceiving SDM or an active role, but their preference matching was not influenced. A SDM intervention for oncologists boosted patient autonomy but did not improve preference matching. This highlights the already well-known reluctance of physicians to engage in explicit role clarification.

Trial Registration: German Clinical Trials Register DRKS00000539; Funding Source: German Cancer Aid.

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How Does a Shared Decision-Making (SDM) Intervention for Oncologists Affect Participation Style and Preference Matching in Patients with Breast and Colon Cancer?

Abstract

The aims of this study are to assess patients' preferred and perceived decision-making roles and preference matching in a sample of German breast and colon cancer patients and to investigate how a shared decision-making (SDM) intervention for oncologists influences patients' preferred and perceived decision-making roles and the attainment of preference matches. This study is a post hoc analysis of a randomised controlled trial (RCT) on the effects of an SDM intervention. The SDM intervention was a 12-h SDM training program for physicians in combination with decision board use. For this study, we analysed a subgroup of 107 breast and colon cancer patients faced with serious treatment decisions who provided data on specific questionnaires with regard to their preferred and perceived decision-making roles (passive, SDM or active). Patients filled in questionnaires immediately following a decision-relevant consultation (t1) with their oncologist. Eleven of these patients' 27 treating oncologists had received the SDM intervention within the RCT. A majority of cancer patients (60%) preferred SDM. A match between preferred and perceived decision-making roles was reached for 72% of patients. The patients treated by SDM-trained physicians perceived greater autonomy in their decision making (p < 0.05) with more patients perceiving SDM or an active role, but their preference matching was not influenced. A SDM intervention for oncologists boosted patient autonomy but did not improve preference matching. This highlights the already well-known reluctance of physicians to engage in explicit role clarification.

Trial Registration: German Clinical Trials Register DRKS00000539; Funding Source: German Cancer Aid.

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Oncology Research Program

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NCCN News

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Psychological Symptoms Among Patients With BCR-ABL-Negative Myeloproliferative Neoplasms

Background: BCR-ABL–negative myeloproliferative neoplasms (MPNs) represent a heterogeneous group of diseases, including essential thrombocythemia (ET), polycythemia vera (PV), and myelofibrosis (MF). Psychological manifestations among these diseases have not been adequately described. Methods: Cross-sectional surveys measuring distress, anxiety, and depression were collected from patients with BCR-ABL–negative MPNs from May 2015 to October 2015. Participants provided demographic information and completed the Distress Thermometer and Problem List (DT&PL) to assess distress and the Hospital Anxiety and Depression Scale (HADS) to assess distress, anxiety, and depression. They provided information on how their MPN affected their lives. Results: Of the 117 participants, 31.2% had PV, 28.4% had ET, 28.4% had MF, and 11.9% had another type of MPN. Time with MPN varied from less than 1 year (7.5%), 1 to 3 years (19.8%), 3 to 5 years (23.6%), 5 to 10 years (19.8%), and more than 10 years (29.2%). Distress averaged 3.14 (SD, 2.83; DT&PL), with 40.4% meeting NCCN criteria for distress, and averaged 8.97 (SD, 7.44; HADS), with 38.5% meeting HADS criteria for distress. Anxiety averaged 5.54 (SD, 4.37), with 31.3% meeting HADS criteria for anxiety. Depression averaged 3.4 (SD, 3.4), with 12.5% meeting HADS criteria for depression. Distress was higher for PV (3.86), MF (3.12), and "other" MPN (4.33) than it was for ET (1.81; P=.016). Distress was more common in non-white patients (P=.015) and those with either PV or MF but not ET (DT&PL ≥4; P=.038). Patients' comments described coping strategies or symptom burden. Conclusions: Distress and anxiety are highly prevalent with BCR-ABL–negative MPNs and may correspond to disease-related symptom burden. These findings deserve further study.

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An Oncologist's Letter to Santa

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Delivery of Adjuvant Oxaliplatin for Colon Cancer: Insights From Routine Clinical Practice

Background: Adjuvant oxaliplatin is now a standard treatment option for patients with early-stage colon cancer. However, treatment delivery and outcomes achieved in routine practice are not well described. Methods: All cases of colon cancer diagnosed in Ontario from 2002 to 2008 were identified using the Ontario Cancer Registry. Pathology reports were obtained for a 25% random sample to identify stage II and III cases; patients treated with adjuvant oxaliplatin were included in this analysis. Treatment records were reviewed to identify oxaliplatin dose reductions or omissions. Modified Poisson regression was used to evaluate factors associated with dose reduction/omission. Cox proportional hazards model was used to explore factors associated with cancer-specific survival (CSS) and overall survival (OS). Results: The study population included 532 patients; 88% (469/532) had stage III disease. The mean/median number of oxaliplatin cycles delivered was 10/12. A dose reduction/omission of oxaliplatin occurred in 54% of cases (288/532), and the dose was subsequently escalated in 34% of these (97/288). Women were more likely than men to have dose reduction/omission (relative risk, 1.29; 95% CI, 1.10–1.51). Dose reduction/omission was not associated with inferior CSS (hazard ratio [HR], 0.76; 95% CI, 0.51–1.14) or OS (HR, 0.81; 95% CI, 0.59–1.13). Five-year CSS and OS of all cases were 77% (95% CI, 72–81) and 72% (95% CI, 68–76), respectively. On-treatment mortality rates were 1% and 3% within 30 and 90 days of oxaliplatin, respectively. Conclusions: Dose reductions of adjuvant oxaliplatin are common in routine practice but are not associated with inferior survival. Long-term survival achieved in the general population is comparable to the results of clinical trials.

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Palliative Care--The Challenge of Application

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Drug Development Pipeline for Myeloproliferative Neoplasms: Potential Future Impact on Guidelines and Management

The unprecedented success of ruxolitinib in myelofibrosis (MF) has paved the way for the development of other Janus kinase (JAK) inhibitors and other agents representing diverse drug classes and mechanisms of action in myeloproliferative neoplasms (MPNs). In particular, the symptomatic benefits afforded by ruxolitinib have led to the recognition of "clinical improvement" in symptoms and the spleen in international consensus response criteria for MF. Ruxolitinib is also approved for the second-line treatment of polycythemia vera and is being developed for essential thrombocythemia. Appreciation of the universal role of activated JAK/signal transducer and activator of transcription (STAT) signaling in MPNs and improved understanding of the canonical and noncanonical actions of JAK2 have yielded a number of drug targets beyond JAK2 in MPNs, which form the basis for a number of ruxolitinib-based rational combinations that are being explored in MF. Other JAK inhibitors with the potential for significantly less myelosuppression or even improvement of anemia continue to be tested. Finally, agents with very distinct mechanisms of action, such as novel interferon formulations, antifibrotic agents, and telomerase inhibitors, are being pursued in polycythemia vera and MF, respectively. This article reviews the current landscape of clinical drug development in MPNs, focusing on the most promising agents and combinations.

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A Polycythemia Vera JAK2 Mutation Masquerading as a Duodenal Cancer Mutation

Next-generation sequencing (NGS) is increasingly being used in cancer care to identify both somatic tumor driver mutations that can be targeted for therapy, and heritable mutations in the germline associated with increased cancer risk. This report presents a case of a JAK2 V617F mutation falsely identified as a duodenal cancer mutation via NGS. The patient was found to have a history of polycythemia vera, a disorder with a high incidence of JAK2 somatic mutations. Buccal cell DNA showed heterozygosity for the mutation, suggesting that it was potentially germline. However, subsequent resequencing of tumor, adjacent normal tissue, and fingernail DNA confirmed the mutation was somatic, and its presence in tumor and buccal cells resulted from contaminating blood cells. This report highlights important nuances of NGS that can lead to misinterpretation of results with potential clinical implications.

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Differential Radiographic Appearance of BRAF V600E-Mutant Metastatic Colorectal Cancer in Patients Matched by Primary Tumor Location

Background: BRAF-mutant metastatic colorectal cancers (mCRCs) share many clinicopathologic features with right-sided colon tumors, including frequent peritoneal involvement. Because of the poorer outcomes associated with BRAF mutations, early enrollment in clinical trials has been encouraged. However, the use of standard eligibility and assessment criteria, such as measurable disease, has anecdotally impeded patient accrual and restricted appraisal of treatment response. We investigated whether the presence of a BRAF V600E mutation is differentially associated with sites and appearance of metastatic disease in patients matched by primary tumor location. Methods: A total of 40 patients with BRAF-mutant mCRC were matched to 80 patients with BRAF wild-type mCRC by location of primary tumor (right or left colon; rectum), sex, and age. Associations between BRAF mutation status and clinicopathologic characteristics and metastatic sites were analyzed using proportion tests. Survival was summarized with Kaplan-Meier and Cox regression methods. Results: The distribution of primary tumor locations was: 60% right colon, 30% left colon, and 10% rectum. Compared with BRAF wild-type tumors, BRAF-mutant tumors more commonly associated with peritoneal metastases (50% vs 31%; P=.045) and ascites (50% vs 24%; P=.0038). In patients with left colon primaries, BRAF mutations were associated with more frequent ascites (58% vs 12%; P=.0038) and less frequent liver metastases (42% vs 79%; P=.024). Among patients with right colon primaries, no significant difference in sites of disease by BRAF mutation status was observed. Disease was not measurable by RECIST 1.1 in 24% of patients with right-sided primary tumors, irrespective of BRAF mutation status. In the BRAF-mutated cohort, ascites correlated unfavorably with survival (hazard ratio, 2.35; 95% CI, 1.14, 4.83; P=.02). Conclusions: Greater frequency of ascites and peritoneal metastases, which pose challenges for RECIST 1.1 interpretation of therapeutic outcomes, are seen with BRAF-mutant mCRC, even when patients are matched for primary tumor location.

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NCCN Guidelines Insights: Chronic Myeloid Leukemia, Version 1.2017

The NCCN Guidelines for Chronic Myeloid Leukemia (CML) provide recommendations for the management of chronic-phase and advanced-phase CML in adult patients. The median age of disease onset is 67 years. However, because CML occurs in all age groups, clinical care teams should be prepared to address issues relating to fertility and pregnancy with patients who are of reproductive age at the time of diagnosis. CML is relatively rare in children and there are no evidence-based recommendations for the management of CML in pediatric population. These NCCN Guidelines Insights discuss special considerations for the management of CML during pregnancy and for the management of CML in the pediatric population.

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Effective Translation of Research to Practice: Hospital-Based Rehabilitation Program Improves Health-Related Physical Fitness and Quality of Life of Cancer Survivors

Background: Although exercise has been widely established as an efficacious rehabilitative therapy for cancer survivors in rigorously designed research studies, demonstration of translation of this research into clinical oncology practice is needed. The purpose of this study was to evaluate the effectiveness of a real-world cancer rehabilitation program implemented within a healthcare setting. Patients and Methods: This study involved 299 adult cancer survivors enrolled in a hospital-based, supervised, individualized, cancer rehabilitation program. A retrospective review of the 132 participants who completed the follow-up assessment was performed. Sixty-minute sessions consisting of aerobic, resistance, flexibility, and relaxation exercises were performed twice weekly. Questionnaires and fitness assessments were administered at enrollment and after 24 sessions by exercise physiologists. Change in a number of health-related physical fitness and patient-reported outcomes and the influence of baseline characteristics on program outcomes were assessed. Results: There were no baseline differences between those who completed the follow-up assessment and those who withdrew. Statistically and/or clinically meaningful improvements occurred in functional capacity, blood pressure, muscular endurance, flexibility, health-related quality of life, and fatigue, but not in body composition. Age, marital status, radiation treatment status, exercise frequency before diagnosis, smoking status, and alcohol consumption frequency influenced functional capacity and/or quality-of-life changes. Conclusions: Adoption of cancer rehabilitation as a standard part of oncology care may improve cancer survivors' health and well-being.

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Factors Associated With Delays in Chemotherapy Initiation Among Patients With Breast Cancer at a Comprehensive Cancer Center

Background: National guidelines endorse time-dependent quality metrics for breast cancer care. We examined factors associated with delays in chemotherapy initiation at an NCI-Designated Comprehensive Cancer Center. Patients and Methods: We identified 523 patients who received postoperative adjuvant chemotherapy between January 2011 and December 2013 at our center. We defined 28 days from last definitive surgery (LDS) to chemotherapy as the target time frame, and an unacceptable delay in chemotherapy initiation (UCD) as greater than 42 days from LDS. Multivariate regression models were used to identify factors associated with UCD and the impact of Oncotype DX testing in patients with hormone receptor (HR)–positive breast cancer. Results: Median days between LDS and chemotherapy initiation was 34 (interquartile range, 15), with 30% of patients starting within 28 days of LDS and 26.9% having UCD. Tumor characteristics such as subtype and stage affected UCD; patients with HR-positive or HER2-positive tumors were more likely to be delayed compared with those with triple-negative breast cancer. Patients with stage I disease, those undergoing mastectomy with or without immediate reconstruction, and those whose pathology sign-out was greater than 10 days postoperatively were more likely to be delayed. A higher proportion of UCD was found in HR-positive patients (31%) for whom Oncotype DX testing was ordered compared with those in whom it was not ordered (20%). Conclusions: This study provides insight into subpopulations that may be at risk to experience delays in chemotherapy initiation, directing interventions to improve the timeliness of care.

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Myeloproliferative Neoplasms, Version 2.2017, NCCN Clinical Practice Guidelines in Oncology

Myelofibrosis (MF), polycythemia vera (PV), and essential thrombocythemia (ET) are a group of heterogeneous disorders of the hematopoietic system collectively known as Philadelphia chromosome–negative myeloproliferative neoplasms (MPNs). The diagnosis and the management of patients with MPNs have evolved since the identification of mutations that activate the JAK pathway (JAK2, CALR, and MPL mutations) and the development of targeted therapies has resulted in significant improvements in disease-related symptoms and quality of life. This manuscript discusses the recommendations outlined in the NCCN Guidelines for the diagnostic workup of MPN (MF, PV, and ET), risk stratification, treatment, and supportive care strategies for the management of MF.

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Neoadjuvant Therapy for Rectal Cancer Affects Lymph Node Yield and Status Without Clear Implications on Outcome: The Case for Eliminating a Metric and Using Preoperative Staging to Guide Therapy

Background: Nodal status has long been considered pivotal to oncologic care, staging, and management. This has resulted in the establishment of rudimentary metrics regarding adequate lymph node yield in colon and rectal cancers for accurate cancer staging. In the era of neoadjuvant treatment, the implications of lymph node yield and status on patient outcomes remains unclear. Patient and Methods: This study included 1,680 patients with locally advanced rectal cancer from the NCCN prospective oncology database stratified into 3 groups based on preoperative therapy received: no neoadjuvant therapy, neoadjuvant chemoradiation, and neoadjuvant chemotherapy. Clinicopathologic characteristics and survival were compared between the groups, with univariate and multivariate analyses undertaken. Results: The clinicopathologic characteristics demonstrated statistically significant differences and heterogeneity among the 3 groups. The neoadjuvant chemoradiation group demonstrated the statistically lowest median lymph node yield (n=15) compared with 17 and 18 for no-neoadjuvant and neoadjuvant chemotherapy, respectively (P<.0001). Neoadjuvant treatment did impact survival, with chemoradiation demonstrating increased median overall survival of 42.7 compared with 37.3 and 26.6 months for neoadjuvant chemotherapy and no-neoadjuvant therapy, respectively (P<.0001). Patients with a yield of fewer than 12 lymph nodes had improved median overall survival of 43.3 months compared with 36.6 months in patients with 12 or more lymph nodes (P=.009). Multivariate analysis demonstrated that neither node yield nor status were predictors for overall survival. Discussion: This analysis reiterates that nodal yield in rectal cancer is multifactorial, with neoadjuvant therapy being a significant factor. Node yield and status were not significant predictors of overall survival. A nodal metric may not be clinically relevant in the era of neoadjuvant therapy, and guidelines for perioperative therapy may need reconsideration.

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Experience of Myeloproliferative Neoplasms Guidelines in the United Kingdom: Perspective and International Context

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The Hearing Journal

Zika and Hearing Loss: The Race for a Cure Continues By Gordon Glantz Hearing loss was recently found to be a side effect of the Zika virus in surviving infants. Researchers are still trying to identify risk factors and develop a vaccine, but what role do audiologists play in the fight against Zika? Read More. Mental Health Status and Perceived Tinnitus Severity By Steven L. Benton, AuD Dr. Benton investigates the impact of coexisting mental health conditions on perceived tinnitus severity, as well as the likely impact of mental disorders on tinnitus management strategies and outcomes. Read More. Synergy Between ENT Surgeons, Audiologists By Purushothaman Ganesan, MASLP; Jason Schmiedge, MSc; & Simham Swapna, MBBS, DNB The shift of the assessment and treatment of hearing disorders from a medical to biopsychosocial model calls for closer collaboration between ENT surgeons and audiologists in rehabilitation efforts. Read More. Inadvertent Central Auditory Impairment in Young Children By Raymond H. Hull, PhD Lack of understanding of children's central nervous system places them at risk of being assessed as having a central auditory processing deficit, impaired hearing, or delayed language development when that might not be the case. Read More.

LATEST COLUMNS Editorial: Goodbye Google Glass, Hello Smart Earphones By Fan-Gang Zeng, PhD This year, we saw the departure of Google Glass, the device once thought to be the future of wearable technology. Now all signs point to the rise of smart earphones, the next tech frontier, in the coming year. Read More. Journal Club: Expansion of Pediatric Cochlear Implant Indications By René H. Gifford, PhD Expanding the criteria for cochlear implants in children to include infants younger than 12 months could help children with hearing impairment catch up with their peers in learning and psychosocial development later in life. Read More. Clinical Consultation: Symptom: Facial Paralysis By Hamid R. Djalilian, MD An 83-year-old patient with a history of chronic otitis media and recent onset complete facial paralysis presents with pressure and pain in the left ear. His CT scan showed fluid in the middle ear and mastoid. What's the diagnosis? Read More. Golden Rules: Revisiting Age-Related Hearing Loss Screening - Part 1 By Barbara E. Weinstein, PhD This is the first installment of a two-part article on preventive services like behavioral counseling and screening for older adults regarding age-related hearing loss. Read More. Hearing Matters: Ultra-High Frequency Sudden Sensorineural Hearing Loss By Dennis Colucci, AuD, MA Ultra-high frequency testing may provide a better understanding of patient complaints in the absence of hearing loss, like in the case of sudden sensorineural hearing loss,using standard audiometric measurements. Read More.

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com

Photochemistry and Photobiology © The American Society of Photobiology Accepted Articles (Accepted, unedited articles published online and citable. The final edited and typeset version of record will appear in future.) THESE ACCEPTED ARTICLES ARE NOW AVAILABLE ON WILEY ONLINE LIBRARY Research Articles The Anthocyanins, Oenin and Callistephin, Protect RPE Cells Against Oxidative Stress Sally M. Yacout and Elizabeth R. Gaillard Accepted manuscript online: 9 DEC 2016 07:36AM EST | DOI: 10.1111/php.12683 Chemiluminescence of Cigarette Smoke: Salient Features of the Phenomenon Galina F. Fedorova, Valery A. Menshov, Aleksei V. Trofimov, Yury B. Tsaplev, Rostislav F. Vasil'ev and Olga I. Yablonskaya Accepted manuscript online: 9 DEC 2016 07:36AM EST | DOI: 10.1111/php.12689 Special Issue Invited Reviews Crosstalk Among UV-Induced Inflammatory Mediators, DNA Damage and Epigenetic Regulators Facilitates Suppression of the Immune System Ram Prasad and Santosh K. Katiyar Accepted manuscript online: 9 DEC 2016 07:34AM EST | DOI: 10.1111/php.12687 Insight in DNA Repair of UV-induced Pyrimidine Dimers by Chromatographic Methods Thierry Douki, Anne von Koschembahr and Jean Cadet Accepted manuscript online: 9 DEC 2016 07:33AM EST | DOI: 10.1111/php.12685 Damaging Effects of Ultraviolet Radiation on the Cornea Naomi C. Delic, J. Guy Lyons, Nick Di Girolamo and Gary M. Halliday Accepted manuscript online: 9 DEC 2016 07:27AM EST | DOI: 10.1111/php.12686 Research Articles Sub-cellular Targeting as a Determinant of the Efficacy of Photodynamic Therapy David Kessel Accepted manuscript online: 9 DEC 2016 07:26AM EST | DOI: 10.1111/php.12692 Special Issue Research Articles RNA Polymerase-I Dependent Transcription-coupled Nucleotide Excision Repair of UV Induced DNA Lesions at Transcription Termination Sites, in Saccharomyces cerevisiae François Peyresaubes, Carlos Zeledon, Laetitia Guintini, Romain Charton, Alexia Muguet and Antonio Conconi Accepted manuscript online: 9 DEC 2016 07:24AM EST | DOI: 10.1111/php.12690 Special Issue Invited Reviews Autophagy in UV Damage Response Ashley Sample and Yu-Ying He Accepted manuscript online: 9 DEC 2016 07:22AM EST | DOI: 10.1111/php.12691 Special Issue Research Articles An Ethenoadenine FAD Analog Accelerates UV Dimer Repair by DNA Photolyase Madhavan Narayanan, Vijay R. Singh, Goutham Kodali, Kimberly Jacoby, Katarina Moravcevic and Robert J. Stanley Accepted manuscript online: 9 DEC 2016 07:07AM EST | DOI: 10.1111/php.12684 Research Articles Bimodal Targeting Using Sulfonated, Mannosylated PEI for Combined Gene Delivery and Photodynamic Therapy Upendra Chitgupi, Yi Li, Mingfu Chen, Shuai Shao, Marie Beitelshees, Myles Joshua Tan, Sriram Neelamegham, Blaine A. Pfeifer, Charles Jones and Jonathan F. Lovell Accepted manuscript online: 9 DEC 2016 07:00AM EST | DOI: 10.1111/php.12688 Special Issue Invited Reviews Insights into Light-driven DNA Repair by Photolyases: Challenges and Opportunities for Electronic Structure Theory Shirin Faraji and Andreas Dreuw Accepted manuscript online: 7 DEC 2016 07:43AM EST | DOI: 10.1111/php.12679 Special Issue Invited Review Fluorescent Protein-photoprotein Fusions and Their Applications in Calcium Imaging Adil Bakayan, Beatriz Domingo, Cecilia F. Vaquero, Nadine Peyriéras and Juan Llopis Accepted manuscript online: 7 DEC 2016 07:38AM EST | DOI: 10.1111/php.12682 Conformational and Intermolecular Interaction Dynamics of Photolyase/Cryptochrome Proteins Monitored by the Time-resolved Diffusion Technique Masato Kondoh and Masahide Terazima Accepted manuscript online: 7 DEC 2016 07:37AM EST | DOI: 10.1111/php.12681 Light Regulation of Alternative Pre-mRNA Splicing in Plants Hangxiao Zhang, Chentao Lin and Lianfeng Gu Accepted manuscript online: 7 DEC 2016 07:35AM EST | DOI: 10.1111/php.12680

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com

Journal of Indian Academy of Oral Medicine and Radiology (J Indian Acad Oral Med Radiol)

Alexandros Sfakianakis

GUEST EDITORIAL

Me and my future as an Oral Medicine, Diagnosis, and Radiology specialist [pg. 227]
Latika Bachani, Ashok Lingappa
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ORIGINAL ARTICLES

Control of odontogenic pain by diclofenac and meloxicam mucoadhesive patches: A randomized, double-blinded, placebo-controlled, preliminary study [pg. 229]
Pratik R Pipalia, Rajeshwari G Annegeri, Thimmasetty Juturu, Rajneeta Mehta
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A retrospective radiographic analysis of osseous changes in oral malignancy [pg. 236]
Palak H Shah, Rashmi Venkatesh, Chandramani B More, Vaishnavee Vassandacoumara
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Retrospective panoramic radiographic analysis for idiopathic osteosclerosis in Indians [pg. 242]
Srikanth H Srivathsa
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Effectiveness of transcutaneous electrical nerve stimulation on saliva production in post-radiated oral cancer patients [pg. 246]
Sakshi Ojha, Thimmarasa V Bhovi, Prashant P Jaju, Manas Gupta, Neha Singh, Kriti Shrivastava
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Reliability of panoramic radiography in assessing gonial angle compared to lateral cephalogram in adult patients with Class I malocclusion [pg. 252]
Girish Katti, Chandrika Katti, Karuna , Syed Shahbaz, Munnawwarulla Khan, Sreenivas Rao Ghali
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Association of oral lichen planus with hepatitis C virus, surface antigen of hepatitis B virus, and diabetes: A clinical and biochemical study [pg. 256]
Pavani Donempudi, Harsha Bhayya, Venkateswarlu Meduri, Geetha Paramkusam, Avinash M L Tejasvi
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Oral manifestations of stress-related disorders in the general population of Ludhiana [pg. 262]
Damanpreet Kaur, Ashima B Behl, Parminder P S Isher
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Hepatitis B awareness and attitudes among dental professionals in Central India[pg. 270]
Aparajita D Shitoot, Mukta Motwani, Durga P Chamele, Abhinay P Shitoot, Jay Chamele, Akash Ghosh
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REVIEW ARTICLE

Risk factors, quality of life, and oral implications of osteoporosis in postmenopausal women [pg. 274]
Ravleen Nagi, Yashoda Devi Bhoomareddy Kantraj, Rakesh Nagaraju, Sujatha S Reddy
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CASE REPORTS

Dual cusped protostylid: Case report and clinical significance [pg. 281]
Preeti Bhattacharya, Rupam Sinha
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A rare case report of fracture of the articular eminence diagnosed for the first time using cone-beam volumetric imaging [pg. 285]
Tatu Joy Elenjickal, Shashi Kiran Mohan Ram
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Osteophytes in temporomandibular joint, a spectrum of appearance in cone-beam computed tomography: Report of four cases [pg. 289]
Jayachandran Sadaksharam, Priyanka Khobre
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Retiform hemangioendothelioma: A rare case report [pg. 292]
Mysore K Sunil, Ashwarya Trivedi, Aarti Trakroo, Saloni Arora
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Intraoral capillary haemangioma: A rare case report [pg. 296]
Sushma Parimi, Jitender Reddy Kubbi, Swapna Tipirisety, Venkata Karthik Kalepu
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Portwine stain with nodular thickening and intraoral hemangioma [pg. 300]
Ankita Bohra, Sumit Bhateja, Geetika Arora
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Extensive Type III unicystic ameloblastoma: A case report with conservative management [pg. 305]
Astha Chaudhry, Manjunath Muniraju, Sridevi Koduri, Renu Tanwar
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An odontogenic tumor mimicking a dentigerous cyst in a 13-year-old female: A rare clinical presentation [pg. 310]
Leelavathy Jegadeesan, Winnifred Christy Ambrose, Srivel Vigneshwari Ammamuthu, Sabarinath Thirukonda Ragunath
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Stafne cyst: Report of two unusual cases with review [pg. 314]
Manoharan G V Murali Gopika, Vidhya Kalanjiam
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Case report of gingivitis artefacta (Self-injurious behavior) [pg. 317]
Altaf H Chalkoo, Gowhar Y Peerzada, Nusrat N Makroo
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Osteosarcoma: A rare case report and review of literature [pg. 320]
Mallika Kishore, Sunil R Panat, Abhijeet Alok, Kratika Singhal
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Clear cell carcinoma of hard palate: A rare case report [pg. 324]
Lekshmy Jayasree, Padmashree Srinivasamurthy, Rema Jayalekshmi, Suraksha Bhat
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Pleomorphic adenoma of the palate: A case report and review of a rare entity [pg. 329]
Kamala Rawson, Basavaraj N Kallalli, Kalpana Gokul, Ankur Singh
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Temporomandibular joint ankylosis [pg. 334]
Ashwinirani Suragimath, Girish Suragimath, Shashikiran Nandhihalli Devendrappa
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Zoster and its lurking shadow [pg. 337]
Hina Handa, Balaji Gandhi Babu Dara, Giridhar S Naidu, Ashwini Deshpande
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Pigmentation of oral cavity: A clinical enigma; A rare case report [pg. 342]
Shams Ul Nisa, Tajinder K Saggu, R Sangeetha, Namrata Harchandani
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Teos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com

Huddles and Debriefings

Publication date: Available online 12 December 2016
Source:Anesthesiology Clinics
Author(s): Emily McQuaid-Hanson, May C.M. Pian-Smith

Teaser

Interprofessional teams work together on the labor and delivery unit, where clinical care is often unscheduled, rapidly evolving, and fast paced. Effective communication is key for coordinated delivery of optimal care and for fostering a culture of community and safety in the workplace. The preoperative huddle allows for information sharing, cross-checking, and preparation before the start of surgery. Postoperative debriefings allow the operative team to engage in ongoing process improvement. Debriefings after adverse events allow for shared understanding, mutual healing, and help mitigating the harm to potential "second victims."


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Update in the Management of Patients with Preeclampsia

Publication date: Available online 12 December 2016
Source:Anesthesiology Clinics
Author(s): Nerlyne K. Dhariwal, Grant C. Lynde

Teaser

Hypertensive disorders of pregnancy complicate approximately 10% of all deliveries in the United States and are a leading cause of maternal and fetal morbidity and mortality. Preeclampsia is defined as hypertension in association with proteinuria, thrombocytopenia, impaired liver function, renal insufficiency, pulmonary edema, or new-onset cerebral or visual disturbances. The greatest risk factor for the development of preeclampsia is a history of preeclampsia. There currently is no effective means for the prevention of preeclampsia. Approximately 39% of patients diagnosed with preeclampsia have hypertension and approximately 20% have proteinuria 3 months postpartum. Preeclampsia increases the risk of patients developing hypertension later in life.


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General Anesthesia During the Third Trimester

Publication date: Available online 12 December 2016
Source:Anesthesiology Clinics
Author(s): Annemaria De Tina, Arvind Palanisamy

Teaser

Rodent studies on the effect of general anesthesia during the third trimester on neurocognitive outcomes are mixed, but primate studies suggest that a clinically relevant exposure to anesthetic agents during the third trimester can trigger neuronal and glial cell death. Human studies are conflicting and the evidence is weak. This is an up-to-date review of the literature on the neurodevelopmental effects of anesthetic agents administered during the third trimester. Early brain development and critical periods of neurodevelopment as it relates to neurotoxicity are highlighted. Rodent, nonhuman primate, and population studies are discussed and placed in the context of clinical practice.


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Awareness and Aortocaval Obstruction in Obstetric Anesthesia

Publication date: Available online 12 December 2016
Source:Anesthesiology Clinics
Author(s): Nathaniel Hsu, Robert Gaiser

Teaser

Awareness during general anesthesia for cesarean delivery continues to be a major problem. The key to preventing awareness is strict attention to anesthetic technique. The prevalence and implications of aortocaval compression have been firmly established. Compression of the vena cava is a real occurrence when assuming the supine position. Relief of this compression most likely does not occur until the patient is turned 30°, which is not feasible for performing cesarean delivery. Although it is still wise to tilt the patient, the benefit of this tilt may not be as great as once thought.


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Optimal Pain Management After Cesarean Delivery

Publication date: Available online 12 December 2016
Source:Anesthesiology Clinics
Author(s): Caitlin Dooley Sutton, Brendan Carvalho

Teaser

Cesarean delivery rates are increasing worldwide, and effective postoperative pain management is a key priority of women undergoing cesarean delivery. Inadequate pain management in the acute postoperative period is associated with persistent pain, greater opioid use, delayed functional recovery, and increased postpartum depression. In addition to pain relief, optimal management of patients after cesarean delivery should address the goals of unrestricted maternal mobility, minimal maternal and neonatal side effects, rapid recovery to baseline functionality, and early discharge home. Multimodal analgesia should include neuraxial morphine in conjunction with nonopioid adjuncts, with additional oral or intravenous opioids reserved for severe breakthrough pain.


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