Novel drug discovery strategies for atherosclerosis that target necrosis and necroptosis.

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Novel drug discovery strategies for atherosclerosis that target necrosis and necroptosis.

Expert Opin Drug Discov. 2018 Mar 29;:1-12

Authors: Coornaert I, Hofmans S, Devisscher L, Augustyns K, Van Der Veken P, De Meyer GRY, Martinet W

Abstract
INTRODUCTION: Formation and enlargement of a necrotic core play a pivotal role in atherogenesis. Since the discovery of necroptosis, which is a regulated form of necrosis, prevention of necrotic cell death has become an attractive therapeutic goal to reduce plaque formation. Areas covered: This review highlights the triggers and consequences of (unregulated) necrosis and necroptosis in atherosclerosis. The authors discuss different pharmacological strategies to inhibit necrotic cell death in advanced atherosclerotic plaques. Expert opinion: Addition of a necrosis or necroptosis inhibitor to standard statin therapy could be a promising strategy for primary prevention of cardiovascular disease. However, a necrosis inhibitor cannot block all necrosis stimuli in atherosclerotic plaques. A necroptosis inhibitor could be more effective, because necroptosis is mediated by specific proteins, termed receptor-interacting serine/threonine-protein kinases (RIPK) and mixed lineage kinase domain-like pseudokinase (MLKL). Currently, only RIPK1 inhibitors have been successfully used in atherosclerotic mouse models to inhibit necroptosis. However, because RIPK1 is involved in both necroptosis and apoptosis, and also RIPK1-independent necroptosis can occur, we feel that targeting RIPK3 and MLKL could be a more attractive therapeutic approach to inhibit necroptosis. Therefore, future challenges will consist of developing RIPK3 and MLKL inhibitors applicable in both preclinical and clinical settings.

PMID: 29598451 [PubMed - as supplied by publisher]

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An Update on the Adjunctive Neurovascular Support of Wide-Neck Aneurysm Embolization and Reconstruction Trial: 1-Year Safety and Angiographic Results.

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An Update on the Adjunctive Neurovascular Support of Wide-Neck Aneurysm Embolization and Reconstruction Trial: 1-Year Safety and Angiographic Results.

AJNR Am J Neuroradiol. 2018 Mar 29;:

Authors: Spiotta AM, Chaudry MI, Turner RD, Turk AS, Derdeyn CP, Mocco J, Tateshima S

Abstract
BACKGROUND AND PURPOSE: The safety and efficacy of the PulseRider for the treatment of wide-neck, bifurcation aneurysms at the basilar and carotid terminus locations were studied in a prospective trial, the Adjunctive Neurovascular Support of Wide-Neck Aneurysm Embolization and Reconstruction (ANSWER) trial, reporting on initial 6-month angiographic and clinical results. This report provides insight into the longer term durability and safety with 12-month data.
MATERIALS AND METHODS: Aneurysms treated with the PulseRider among enrolled sites were prospectively studied. Updated 12-month data on clinical and imaging end points are included.
RESULTS: Thirty-four patients were enrolled (29 women, 5 men) with a mean age of 60.9 years. The mean aneurysm height ranged from 2.4 to 15.9 mm with a mean neck size of 5.2 mm (range, 2.3-11.6 mm). At 1 year, there were no device migrations or symptomatic in-stent stenoses. Raymond-Roy I occlusion was achieved in 53% of cases at the time of treatment and progressed to 61% and 67% at 6 and 12 months, respectively. Adequate occlusion (Raymond-Roy I/II) progressed from 88% at 6 months to 90% at 12 months. No recanalizations were observed. There was 1 delayed ischemic event. Good outcome (mRS 0-2) was achieved in 90% of patients.
CONCLUSIONS: The updated 1-year results from the ANSWER trial demonstrate aneurysm stability and an acceptable safety profile for aneurysms treated at the basilar apex and carotid terminus. Prospective data from a larger set of aneurysms treated at other locations are required to assess how treatment with PulseRider compares with alternatives for treating wide-neck bifurcation aneurysms.

PMID: 29599174 [PubMed - as supplied by publisher]

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Parent Artery Reconstruction for Large or Giant Cerebral Aneurysms Using the Tubridge Flow Diverter: A Multicenter, Randomized, Controlled Clinical Trial (PARAT).

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Parent Artery Reconstruction for Large or Giant Cerebral Aneurysms Using the Tubridge Flow Diverter: A Multicenter, Randomized, Controlled Clinical Trial (PARAT).

AJNR Am J Neuroradiol. 2018 Mar 29;:

Authors: Liu JM, Zhou Y, Li Y, Li T, Leng B, Zhang P, Liang G, Huang Q, Yang PF, Shi H, Zhang J, Wan J, He W, Liang C, Zhu G, Xu Y, Hong B, Yang X, Bai W, Tian Y, Zhang H, Li Z, Li Q, Zhao R, Fang Y, Zhao K, PARAT investigators

Abstract
BACKGROUND AND PURPOSE: Although flow diverters have been reported with favorable clinical and angiographic outcomes in various literatures, randomized trials determining their true effectiveness and safety are still in lack. The Parent Artery Reconstruction for Large or Giant Cerebral Aneurysms Using the Tubridge Flow Diverter (PARAT) trial was designed to evaluate the safety and efficacy of the Tubridge flow diverter in the treatment of large or giant aneurysms in comparison with Enterprise stent-assisted coiling.
MATERIALS AND METHODS: This prospective, multicenter, randomized trial was conducted at 12 hospitals throughout China. Enrolled adults with unruptured large/giant intracranial aneurysms were randomly assigned (1:1) to receive either Enterprise stent-assisted coiling or Tubridge flow diverter implantation. The primary end point was complete occlusion at 6-month follow-up, while secondary end points included technical success, mortality, target vessel-related stroke, aneurysm bleeding, in-stent stenosis, parent artery occlusion, and the frequency of all adverse events.
RESULTS: Among 185 enrolled subjects, 41 withdrew before procedure initiation. Overall, 82 subjects underwent Tubridge implantation, and 62 subjects were primarily treated with stent-assisted coiling. The results of 6-month follow-up imaging included complete occlusion rates of 75.34% versus 24.53% for the Tubridge and stent-assisted coiling groups, respectively, with a calculated common odds ratio of 9.4 (95% confidence interval, 4.14-21.38; P < .001). There was a higher, nonsignificant frequency of complications for Tubridge subjects. Multivariate analysis showed a decreased stroke rate at the primary investigational site, with a marginal P value (P = .051).
CONCLUSIONS: This trial showed an obviously higher rate of large and giant aneurysm obliteration with the Tubridge FD over Enterprise stent-assisted coiling. However, this higher obliteration rate came at the cost of a nonsignificantly higher rate of complications. Investigational site comparisons suggested that a learning curve for flow-diverter implantation should be recognized and factored into trial designs.

PMID: 29599173 [PubMed - as supplied by publisher]

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Submandibular Gland Transfer: A Potential Imaging Pitfall.

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Submandibular Gland Transfer: A Potential Imaging Pitfall.

AJNR Am J Neuroradiol. 2018 Mar 29;:

Authors: Wu X, Yom SS, Ha PK, Heaton CM, Glastonbury CM

Abstract
BACKGROUND AND PURPOSE: The Seikaly and Jha submandibular gland transfer surgery is performed to facilitate gland shielding during radiation therapy for head and neck tumors to circumvent radiation-induced xerostomia. It results in an asymmetric postsurgical appearance of the submandibular and submental spaces. Our purpose was to characterize the morphologic and enhancement characteristics of the transferred submandibular gland and identify potential pitfalls in postoperative radiologic interpretation.
MATERIALS AND METHODS: This retrospective study identified patients with head and neck cancer who had undergone the submandibular gland transfer procedure at our institution. Chart reviews were performed to identify relevant oncologic histories and therapies. CT and MR neck imaging was reviewed to characterize morphologic and enhancement characteristics of the pre- and postoperative submandibular glands, as well as interpretive accuracy.
RESULTS: Eleven patients with oropharyngeal and nasopharyngeal squamous cell carcinomas who underwent submandibular gland transfer were identified. The transferred glands were significantly lengthened in the anteroposterior dimension compared with contralateral glands (P < .001) and displaced anteriorly and inferiorly within the submandibular and submental spaces. Enhancement patterns of the transferred submandibular glands varied, depending on the time of imaging relative to the operation and radiation therapy. Submandibular gland transfer was acknowledged in the postoperative report in 7/11 cases. Errors in interpretation were present in 2/11 reports.
CONCLUSIONS: After the submandibular gland transfer procedure, the submandibular and submental spaces lose their symmetric appearances as the transferred submandibular glands become lengthened and located more anteriorly and inferiorly, with variable enhancement characteristics. Familiarity with the postsurgical appearance of the transferred submandibular glands is key to accurate imaging interpretation.

PMID: 29599172 [PubMed - as supplied by publisher]

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Signal Change of Acute Cortical and Juxtacortical Microinfarction on Follow-Up MRI.

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Signal Change of Acute Cortical and Juxtacortical Microinfarction on Follow-Up MRI.

AJNR Am J Neuroradiol. 2018 Mar 29;:

Authors: Miyata M, Kakeda S, Yoneda T, Ide S, Watanabe K, Moriya J, Korogi Y

Abstract
BACKGROUND AND PURPOSE: Although the clinical importance of cortical microinfarcts has become well-recognized recently, the evolution of cortical microinfarcts on MR imaging is not fully understood. The aim of this study was to examine the temporal changes in acute cortical microinfarcts using susceptibility-weighted imaging and conventional MR imaging.
MATERIALS AND METHODS: Patients with acute infarcts located in the cortical and/or juxtacortical region measuring ≤10 mm in axial diameter based on diffusion-weighted imaging who had a follow-up 3T MR imaging were retrospectively included in the study. All lesions did not show hypointensity on initial T2*WI. For cortical and/or juxtacortical microinfarcts detected on initial DWI, 2 neuroradiologists evaluated the follow-up MR imaging (T2WI, FLAIR, T2*WI, and SWI) and assessed lesion signal intensities and locations (cortical microinfarcts or microinfarcts with juxtacortical white matter involvement).
RESULTS: On initial DWI, 2 radiologists observed 180 cortical and/or juxtacortical microinfarcts in 35 MR imaging examinations in 25 patients; on follow-up, the neuroradiologists identified 29 cortical microinfarcts (16%) on T2WI, 9 (5%) on FLAIR, 4 (2%) on T2*, and 97 (54%) on SWI. All cortical microinfarcts detected with any follow-up MR imaging showed hyperintensity on T2WI/FLAIR and/or hypointensity on T2*WI and SWI.
CONCLUSIONS: SWI revealed conversion (paramagnetic susceptibility changes) of acute cortical microinfarcts, suggesting that a substantial number of cortical microinfarcts may contain hemorrhagic components.

PMID: 29599171 [PubMed - as supplied by publisher]

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Blood Flow Mimicking Aneurysmal Wall Enhancement: A Diagnostic Pitfall of Vessel Wall MRI Using the Postcontrast 3D Turbo Spin-Echo MR Imaging Sequence.

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Blood Flow Mimicking Aneurysmal Wall Enhancement: A Diagnostic Pitfall of Vessel Wall MRI Using the Postcontrast 3D Turbo Spin-Echo MR Imaging Sequence.

AJNR Am J Neuroradiol. 2018 Mar 29;:

Authors: Kalsoum E, Chabernaud Negrier A, Tuilier T, Benaïssa A, Blanc R, Gallas S, Lefaucheur JP, Gaston A, Lopes R, Brugières P, Hodel J

Abstract
Our aim was to compare the detectability of aneurysmal wall enhancement in unruptured intracranial aneurysms between conventional and motion-sensitized driven equilibrium-prepared postcontrast 3D T1-weighted TSE sequences (sampling perfection with applicationoptimized contrasts by using different flip angle evolution, SPACE). Twenty-two patients with 30 unruptured intracranial aneurysms were scanned at 3T. Aneurysmal wall enhancement was more significantly detected using conventional compared with motion-sensitized driven equilibrium-prepared SPACE sequences (10/30 versus 2/30, P < .0001). Contrast-to-noise ratio measurements did not differ between conventional and motion-sensitized driven equilibrium-prepared sequences (P = .51). Flowing blood can mimic aneurysmal wall enhancement using conventional SPACE sequences with potential implications for patient care.

PMID: 29599170 [PubMed - as supplied by publisher]

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Aneurysmal Parent Artery-Specific Inflow Conditions for Complete and Incomplete Circle of Willis Configurations.

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Aneurysmal Parent Artery-Specific Inflow Conditions for Complete and Incomplete Circle of Willis Configurations.

AJNR Am J Neuroradiol. 2018 Mar 29;:

Authors: Cornelissen BMW, Schneiders JJ, Sprengers ME, van den Berg R, van Ooij P, Nederveen AJ, van Bavel E, Vandertop WP, Slump CH, Marquering HA, Majoie CBLM

Abstract
BACKGROUND AND PURPOSE: Hemodynamics are thought to play a role in intracranial aneurysm growth and rupture. Computational fluid dynamics is frequently performed to assess intra-aneurysmal hemodynamics, using generalized flow waveforms of healthy volunteers as inflow boundary conditions. The purpose of this study was to assess differences in inflow conditions for different aneurysmal parent artery locations and variations of circle of Willis configurations.
MATERIALS AND METHODS: In a series of 96 patients with 103 aneurysms, velocity measurements were acquired using 2D phase-contrast MR imaging perpendicular to the aneurysmal parent arteries in the circle of Willis. Circle of Willis configurations were inspected for variations using multiple overlapping thin-slab-acquisition MRAs. Flow rates, velocity magnitudes, and pulsatility indices were calculated for each parent artery location in subgroups of complete and incomplete circle of Willis configurations.
RESULTS: Flow rates, velocity magnitudes, and pulsatility indices were significantly different among aneurysmal parent arteries. Incomplete circle of Willis configurations were observed in 24% of the cases. Significantly lower basilar artery flow rates were observed in configurations with hypoplastic P1 segments. Significantly higher A1 flow rates were observed in configurations with a hypoplastic contralateral A1 segment.
CONCLUSIONS: Inflow conditions vary substantially between aneurysmal parent arteries and circle of Willis configurations. We have created a collection of parent artery-specific inflow conditions tailored to the patient-specific circle of Willis configuration that can be used in future computational fluid dynamics studies analyzing intra-aneurysmal hemodynamics.

PMID: 29599169 [PubMed - as supplied by publisher]

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Development and Psychometric Testing of the Transition Service Provider Competency Scale.

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Development and Psychometric Testing of the Transition Service Provider Competency Scale.

J Behav Health Serv Res. 2018 Mar 29;:

Authors: Sellmaier C, Jivanjee P, Brennan EM, Grover L

PMID: 29600490 [PubMed - as supplied by publisher]

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Oncologic outcomes of surgical treatment for T3 glottic laryngeal squamous cell carcinoma.

Oncologic outcomes of surgical treatment for T3 glottic laryngeal squamous cell carcinoma.

Head Neck. 2018 Mar 30;:

Authors: Zhou J, Zhou L, Tao L, Zhang M, Wu H, Chen X, Li X, Li C, Gong H

Abstract
BACKGROUND: The purpose of this study was to assess the clinical results of patients with T3 glottic laryngeal carcinoma treated with total laryngectomy or partial laryngectomy.
METHODS: We conducted a retrospectively review of 307 patients with T3 glottic laryngeal squamous cell carcinoma (SCC).
RESULTS: The 5-year cancer-specific survival (CSS) rate was 71.5% and the overall survival (OS) rate was 70.6%. For patients who underwent total laryngectomy, the 5-year disease-free survival (DFS) rate was 59.8%, and the CSS rate was 67.9%. For partial laryngectomy, the 5-year DFS rate was 64.8%, and the CSS rate was 78.0%. High lymph node and stage status are predictors of mortality for these patients. No difference was found in DFS and CSS rates between patients with negative margins and those with positive margins after postoperative radiotherapy and chemotherapy.
CONCLUSION: Postoperative radiotherapy and chemotherapy are effective treatments for patients with T3 glottic laryngeal carcinoma, especially with a positive margin. For selected patients with T3 glottic laryngeal carcinoma, partial laryngectomy is a good choice because it can achieve satisfactory oncologic results while preserving laryngeal function.

PMID: 29601122 [PubMed - as supplied by publisher]

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Three-dimensional imaging assessment of anatomic invasion and volumetric considerations for chemo/radiotherapy-based laryngeal preservation in T3 larynx cancer.

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Three-dimensional imaging assessment of anatomic invasion and volumetric considerations for chemo/radiotherapy-based laryngeal preservation in T3 larynx cancer.

Oral Oncol. 2018 Apr;79:1-8

Authors: Kamal M, Ng SP, Eraj SA, Rock CD, Pham B, Messer JA, Garden AS, Morrison WH, Phan J, Frank SJ, El-Naggar AK, Johnson JM, Ginsberg LE, Ferrarotto R, Lewin JS, Hutcheson KA, Cardenas CE, Zafereo ME, Lai SY, Hessel AC, Weber RS, Gunn GB, Fuller CD, Mohamed ASR, Rosenthal DI

Abstract
OBJECTIVES: To investigate the impact of 3-Diminsional (3D) tumor volume (TV) and extent of involvement of primary tumor on treatment outcomes in a large uniform cohort of T3 laryngeal carcinoma patients treated with nonsurgical laryngeal preservation strategies.
MATERIALS AND METHODS: The pretreatment contrast-enhanced computed tomography images of 90 patients with T3 laryngeal carcinoma were reviewed. Primary gross tumor volume (GTVp) was delineated to calculate the 3D TV and define the extent of invasion. Cartilage and soft tissue involvement was coded. The extent of invasion was dichotomized into non/limited invasion versus multiple invasion extension (MIE), and was subsequently correlated with survival outcomes.
RESULTS: The median TV was 6.6 cm3. Sixty-five patients had non/limited invasion, and 25 had MIE. Median follow-up for surviving patients was 52 months. The 5-year local control and overall survival rates for the whole cohort were 88% and 68%, respectively. There was no correlation between TV and survival outcomes. However, patients with non/limited invasion had better 5-year local control (LC) than those with MIE (95% vs 72%, p = .009) but did not have a significantly higher rate of overall survival (OS) (74% vs 67%, p = .327). In multivariate correlates of LC, MIE maintained statistical significance whereas baseline airway status showed a statistically significance trend with poor LC (p = .0087 and 0.06, respectively). Baseline good performance status was an independent predictor of improved OS (p = .03) in multivariate analysis.
CONCLUSION: The extent of primary tumor invasion is an independent prognostic factor of LC of the disease after definitive radiotherapy in T3 larynx cancer.

PMID: 29598944 [PubMed - in process]

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Nonsurgical Treatment for Vocal Fold Leukoplakia: An Analysis of 178 Cases.

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Nonsurgical Treatment for Vocal Fold Leukoplakia: An Analysis of 178 Cases.

Biomed Res Int. 2017;2017:6958250

Authors: Chen M, Cheng L, Li CJ, Chen J, Shu YL, Wu HT

Abstract
OBJECTIVE: To assess the effectiveness and identify vocal fold leukoplakia types appropriate for nonsurgical treatment.
METHODS: The vocal fold leukoplakia in 178 patients was divided by gross appearance into three subtypes: flat and smooth, elevated and smooth, and rough. All patients received nonsurgical treatment including smoking and drinking cessation, voice rest, omeprazole, and Chinese medication therapy. The clinical response of three subtypes was assessed after a 6-month follow-up.
RESULTS: Vocal fold leukoplakia subtypes included flat and smooth (n = 66; 37.1%), elevated and smooth (n = 103; 57.9%), and rough (n = 9; 5.0%). The rate of complete response was 80.3%, 66.0%, and 0.0% for the 3 lesion types, respectively (rough versus flat and smooth, P < 0.001; rough versus elevated and smooth, P < 0.001, Fisher's exact test). The incidence of carcinoma in rough leukoplakia was significantly higher than that in smooth leukoplakia (44.4% versus 2.4%, P = 0.002, Fisher's exact test). Clinical type was the only significant factor for clinical response of nonsurgical treatment (P = 0.005, ordinal logistic regression).
CONCLUSIONS: The effectiveness of nonsurgical treatment for smooth vocal fold leukoplakia is better in comparison to rough vocal fold leukoplakia. Smooth leukoplakia could be managed with nonsurgical treatment; more aggressive treatments should be considered for rough leukoplakia.

PMID: 28695129 [PubMed - indexed for MEDLINE]

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Assessing safety and feasibility of 'pure' laparoscopic total gastrectomy for advanced gastric cancer in the West. Review article.

Assessing safety and feasibility of 'pure' laparoscopic total gastrectomy for advanced gastric cancer in the West. Review article.

Int J Surg. 2018 Mar 27;:

Authors: Lianos GD, Hasemaki N, Rausei S

Abstract
BACKGROUND: Gastric cancer is reported to be the fourth most common cancer and the second leading cause of cancer-related death worldwide. Minimally invasive surgical treatment for gastric cancer is a very challenging approach which offers undoubtedly important advantages.
MATERIALS AND METHODS: There is intense debate concerning the minimally invasive surgical approach for advanced gastric cancer especially in the Western population. A careful literature search was conducted in order to clarify the feasibility and safety of pure laparoscopic total gastrectomy in the West.
RESULTS: Herewith we aim to summarize the current scientific evidence assessing the feasibility and short-term outcomes of laparoscopic gastrectomy for advanced gastric cancer in the West. A lack of data from Western institutions regarding minimally invasive surgical approach for gastric cancer is yet a reality. Nevertheless, the laparoscopic procedure appears to provide satisfactory short-term oncologic outcomes and improved postoperative outcomes.
CONCLUSION: It is obvious that future well-conducted trials on long-term results are necessary for Western patients in order safe conclusions to be reached regarding a potential definitive 'place' for laparoscopy in the curative gastric cancer treatment.

PMID: 29602017 [PubMed - as supplied by publisher]

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TransArterial ChemoEmbolization (TACE) with platinum versus anthracyclines for hepatocellular carcinoma: A meta-analysis.

TransArterial ChemoEmbolization (TACE) with platinum versus anthracyclines for hepatocellular carcinoma: A meta-analysis.

Int J Surg. 2018 Mar 27;:

Authors: Zhao M, Xiang P, Jiang H

Abstract
OBJECTIVE: To determine the clinical efficacy of TACE with platinum versus anthracyclines for hepatocellular carcinoma (HCC) patients using a meta-analysis.
METHODS: We conducted a systematic review of the literature in PubMed, Embase, and the Cochrane Library database to discover relevant randomized controlled trials (RCTs) and observational studies. Data on therapeutic response, adverse event and overall survival rate from studies that compared TACE with platinum versus anthracyclines for HCC patients was extracted for pooled estimation. Subgroup analysis was used if further investigation was needed. The Q statistic and the I2 index statistic were used to assess heterogeneity. Publication bias was evaluated using Egger's test.
RESULTS: Four RCTs and seven observational studies containing 1405 patients were included in this meta-analysis. After comparing RCTs and observational studies separately, the pooled estimation results indicated that no significant difference existed between platinum and anthracyclines regarding therapeutic response, adverse event and overall survival rate. Furthermore, Egger's test revealed bias in pooled estimation of survival rate among RCTs.
CONCLUSIONS: Based on current results, we concluded that TACE with platinum revealed similar clinical efficacy compared with anthracyclines. And more relative studies in this field were expected in the future.

PMID: 29602011 [PubMed - as supplied by publisher]

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Healthcare Costs of Depression in Patients Diagnosed with Cancer.

Healthcare Costs of Depression in Patients Diagnosed with Cancer.

Psychooncology. 2018 Mar 30;:

Authors: Mausbach BT, Yeung P, Bos T, Irwin SA

Abstract
OBJECTIVE: Depression is common among patients diagnosed with cancer. Patients with cancer and depression utilize more healthcare services compared to non-depressed cancer patients. The current study seeks to estimate the added cost of depression in cancer patients in the first year after cancer diagnosis.
METHODS: Healthcare charges were obtained for 2,051 depressed and 11,182 non-depressed patients with an ICD-9 diagnosis of cancer in the 2014 calendar year from the University of California San Diego Healthcare System. The annual healthcare charges for cancer patients with and without depression were analyzed using generalized linear models with a log link function and gamma distribution, covarying for age, sex, race/ethnicity, comorbid diseases, and presence of metastatic disease. Total cost data were broken down into several categories including ambulatory care, emergency department visits, and hospital visits.
RESULTS: Depressed cancer patients had total annual healthcare charges that were 113% higher than non-depressed cancer patients (B = 0.76; p < 0.001). The estimated mean charges for depressed patients was $235,337 compared to $110,650 for non-depressed patients. Depressed cancer patients incurred greater charges than non-depressed patients in ambulatory care (B = 0.70; p < 0.001), emergency department charges (B = 0.31; p < 0.001), and hospital charges (B = 0.39; p < 0.001).
CONCLUSIONS: Depressed cancer patients incur significantly higher healthcare charges across multiple cost categories including ambulatory care, emergency department visits, and hospital visits. Future research should investigate if interventions for detecting and treating depression are effective for reducing healthcare use and costs in cancer patients.

PMID: 29601657 [PubMed - as supplied by publisher]

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Predictors of anxiety and depression two years following treatment in uveal melanoma survivors.

Predictors of anxiety and depression two years following treatment in uveal melanoma survivors.

Psychooncology. 2018 Mar 30;:

Authors: Brown SL, Hope-Stone L, Heimann H, Damato B, Salmon P

Abstract
BACKGROUND: We examined the role of post-treatment symptoms and functional problems, and of worry about recurrent disease (WREC), in predicting and probable anxiety and depression cases 24 months after diagnosis in survivors of posterior uveal melanoma (UM). We examined whether WREC mediates links between symptoms, functional problems, and probable anxiety and depression cases.
METHODS: Prospective cohort study of 261 treated UM survivors 6, 12 and 24 months after diagnosis. Hierarchical logistic regression analyses predicting anxiety and depression 24 months after diagnosis identified by Hospital Anxiety and Depression Scale cut-off scores. Symptoms, functional problems and WREC 6 months post-treatment were entered into the analyses as predictors, then the same variables at 12 months. We controlled anxiety or depression at 6 and 12 months and chromosome 3 status, which accurately predicts 10-year survival. Mediation of links between 6-month symptoms and functional problems and 24-month anxiety and depression by 12-month WREC was tested.
RESULTS: Anxiety caseness at 24 months was predicted by 6-month ocular irritation, headache and functional problems, and 12-month WREC. Depression caseness at 24 months was predicted by 6-month headache and functional problems. WREC at 12-months mediated prediction of anxiety caseness by 6-month symptoms and functional problems. Chromosome 3 status predicted neither anxiety nor depression.
CONCLUSIONS: Survivors reporting symptoms, functional problems and WREC should be monitored for anxiety and depression. Appropriate reassurance that symptoms do not signify future disease might help prevent anxiety.

PMID: 29601654 [PubMed - as supplied by publisher]

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Treatment Options for Paediatric Anaplastic Large Cell Lymphoma (ALCL): Current Standard and beyond.

Treatment Options for Paediatric Anaplastic Large Cell Lymphoma (ALCL): Current Standard and beyond.

Cancers (Basel). 2018 Mar 30;10(4):

Authors: Prokoph N, Larose H, Lim MS, Burke GAA, Turner SD

Abstract
Anaplastic Lymphoma Kinase (ALK)-positive Anaplastic Large Cell Lymphoma (ALCL), remains one of the most curable cancers in the paediatric setting; multi-agent chemotherapy cures approximately 65-90% of patients. Over the last two decades, major efforts have focused on improving the survival rate by intensification of combination chemotherapy regimens and employing stem cell transplantation for chemotherapy-resistant patients. More recently, several new and 'renewed' agents have offered the opportunity for a change in the paradigm for the management of both chemo-sensitive and chemo-resistant forms of ALCL. The development of ALK inhibitors following the identification of the EML4-ALK fusion gene in Non-Small Cell Lung Cancer (NSCLC) has opened new possibilities for ALK-positive ALCL. The uniform expression of CD30 on the cell surface of ALCL has given the opportunity for anti-CD30 antibody therapy. The re-evaluation of vinblastine, which has shown remarkable activity as a single agent even in the face of relapsed disease, has led to the consideration of a revised approach to frontline therapy. The advent of immune therapies such as checkpoint inhibition has provided another option for the treatment of ALCL. In fact, the number of potential new agents now presents a real challenge to the clinical community that must prioritise those thought to offer the most promise for the future. In this review, we will focus on the current status of paediatric ALCL therapy, explore how new and 'renewed' agents are re-shaping the therapeutic landscape for ALCL, and identify the strategies being employed in the next generation of clinical trials.

PMID: 29601554 [PubMed]

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Antifungal Treatment and Outcome in Very-Low-Birth-Weight-Infants - A Population-Based Observational Study of the German Neonatal Network.

Antifungal Treatment and Outcome in Very-Low-Birth-Weight-Infants - A Population-Based Observational Study of the German Neonatal Network.

Pediatr Infect Dis J. 2018 Mar 29;:

Authors: Fortmann I, Hartz A, Paul P, Pulzer F, Müller A, Böttger R, Proquitté H, Dawczynski K, Simon A, Rupp J, Herting E, Göpel W, Härtel C, German Neonatal Network

Abstract
INTRODUCTION: The diagnostic proof of fungal infection in preterm infants is difficult. Antifungal treatment (AFT) is often initiated empirically when infants with suspected infection do not improve despite broad spectrum antibiotic therapy. It was the aim of our study to determine the rate of exposure to empirical AFT in a large cohort of very low birth weight infants (VLBWI) of the German Neonatal Network (GNN) and to address associated risks and outcomes.
METHODS: The epidemiological database consisted of n= 13.343 VLBWI born in 54 GNN centers between 2009 and 2015. AFT was defined as number of neonates who got any dose of at least one of the following antifungal drugs: Fluconazole, Amphotericin B, Voriconazole and Caspofungin (denominator: number of infants enrolled in GNN) for treatment (not prophylaxis) of (suspected) fungal infection. Univariate and logistic regression analyses were used to identify risk factors for exposure to AFT as well as associated short-term morbidities and long-term outcomes at 5 year-follow-up.
RESULTS: In our cohort, 724/13.343 (5.4%) VLBWI were exposed to empiric antifungal treatment, and had a mean gestational age of 25.7 (± 2.1) weeks. 44/13.343 (0.3%) had proven bloodstream infection with Candida spp. The main risk factors for exposure to AFT were gestational age, postnatal steroid treatment, need for abdominal surgery and use of carbapenems. Notably, antifungal treatment was associated with adverse outcomes such as bronchopulmonary dysplasia (BPD; adjusted OR 1.9, 95% CI 1.6-2.3, p < 0.001) and Retinopathy of prematurity requiring intervention (ROP; adjusted OR 1.69, 95% CI 1.3-2.3, p <0.001) but not mortality. In the subgroup of infants available for 5-year-follow-up (n= 895), exposure to antifungal treatment was associated with a risk for cerebral palsy (CP; adjusted OR 2.79, 95% CI 1.11-7.04, p = 0.04) and IQ < 85 (adjusted OR 2.07, 95% CI 1.01-4.28, p = 0.049).
CONCLUSION: A significant proportion of VLBWI is exposed to AFT, specifically those born < 26 weeks. Exposed infants were found to have a higher risk for adverse outcomes which may reflect their significant vulnerability in general. Given the observational design of our study, it remains unclear whether potential side effects of empirical or target antifungal treatment itself contribute to adverse outcome. Future studies need to include risk-based strategies and stewardship programs to restrict the use of antifungal management in VLBWI.

PMID: 29601449 [PubMed - as supplied by publisher]

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Intratibial Injection Causes Direct Pulmonary Seeding of Osteosarcoma Cells and Is Not a Spontaneous Model of Metastasis: A Mouse Osteosarcoma Model.

Intratibial Injection Causes Direct Pulmonary Seeding of Osteosarcoma Cells and Is Not a Spontaneous Model of Metastasis: A Mouse Osteosarcoma Model.

Clin Orthop Relat Res. 2018 Mar 28;:

Authors: Maloney C, Edelman MC, Kallis MP, Soffer SZ, Symons M, Steinberg BM

Abstract
BACKGROUND: Although metastasis is the major cause of mortality in patients with osteosarcoma, little is known about how micrometastases progress to gross metastatic disease. Clinically relevant animal models are necessary to facilitate development of new therapies to target indolent pulmonary metastases. Intratibial injection of human and murine osteosarcoma cell lines have been described as orthotopic models that develop spontaneous pulmonary metastasis over time. However, there is variability in reported injection techniques and metastatic efficiency.
QUESTIONS/PURPOSES: We aimed to characterize a widely used murine model of metastatic osteosarcoma, determine whether it is appropriate to study spontaneous pulmonary metastasis by establishing a reliable volume for intratibial injection, determine the incidence of primary tumor and metastatic formation, determine the kinetics of pulmonary metastatic seeding and outgrowth, and the contribution of the primary tumor to subsequent development of metastasis.
METHODS: The metastatic mouse osteosarcoma cell line K7M2 was injected into the tibia of mice. The maximum volume that could be injected without leakage was determined using Evan's blue dye (n = 8 mice). Primary tumor formation and metastatic efficiency were determined by measuring the incidence of primary tumor and metastatic formation 4 weeks after intratibial injection (n = 30). The kinetics of metastatic development were determined by performing serial euthanasia at 1, 2, 3, and 4 weeks after injection (n = 24; five to six mice per group). Number of metastatic foci/histologic lung section and metastatic burden/lung section (average surface area of metastatic lesions divided by the total surface area of the lung) was calculated in a blinded fashion. To test the contribution of the primary tumor to subsequent metastases, amputations were performed 30 minutes, 4 hours, or 24 hours after injection (n = 21; five to six mice per group). Mice were euthanized after 4 weeks and metastatic burden calculated as described previously, comparing mice that had undergone amputation with control, nonamputated mice. Differences between groups were calculated using Kruskal-Wallis and one-way analysis of variance.
RESULTS: The maximum volume of cell suspension that could be injected without leakage was 10 μL. Intratibial injection of tumor cells led to intramedullary tumor formation in 93% of mice by 4 weeks and resulted in detectable pulmonary metastases in 100% of these mice as early as 1 week post-injection. Metastatic burden increased over time (0.88% ± 0.58, week 1; 6.6% ± 5.3, week 2; 16.1% ± 12.5, week 3; and 40.3% ± 14.83, week 4) with a mean difference from week 1 to week 4 of -39.38 (p < 0.001; 95% confidence interval [CI], -57.39 to -21.37), showing pulmonary metastatic growth over time. In contrast, the mean number of metastatic foci did not increase from week 1 to week 4 (36.4 ± 33.6 versus 49.3 ± 26.3, p = 0.18). Amputation of the injected limb at 30 minutes, 4 hours, and 24 hours after injection did not affect pulmonary metastatic burden at 4 weeks, with amputation as early as 30 minutes post-injection resulting in a metastatic burden equivalent to tumor-bearing controls (48.9% ± 6.1% versus 40.9% ± 15.3%, mean difference 7.96, p = 0.819; 95% CI, -33.9 to 18.0).
CONCLUSIONS: There is immediate seeding of the metastatic site after intratibial injection of the K7M2 osteosarcoma cell line, independent of a primary tumor. This is therefore not a model of spontaneous metastasis.
CLINICAL RELEVANCE: This model should not be used to study the early components of the metastatic cascade, but rather used as an experimental model of metastasis. Improved understanding of this commonly used model will allow for proper interpretation of existing data and inform the design of future studies exploring the biology of metastasis in osteosarcoma.

PMID: 29601385 [PubMed - as supplied by publisher]

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Tumor lysate-based vaccines: on the road to immunotherapy for gallbladder cancer.

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Tumor lysate-based vaccines: on the road to immunotherapy for gallbladder cancer.

Cancer Immunol Immunother. 2018 Mar 29;:

Authors: Rojas-Sepúlveda D, Tittarelli A, Gleisner MA, Ávalos I, Pereda C, Gallegos I, González FE, López MN, Butte JM, Roa JC, Fluxá P, Salazar-Onfray F

Abstract
Immunotherapy based on checkpoint blockers has proven survival benefits in patients with melanoma and other malignancies. Nevertheless, a significant proportion of treated patients remains refractory, suggesting that in combination with active immunizations, such as cancer vaccines, they could be helpful to improve response rates. During the last decade, we have used dendritic cell (DC) based vaccines where DCs loaded with an allogeneic heat-conditioned melanoma cell lysate were tested in a series of clinical trials. In these studies, 60% of stage IV melanoma DC-treated patients showed immunological responses correlating with improved survival. Further studies showed that an essential part of the clinical efficacy was associated with the use of conditioned lysates. Gallbladder cancer (GBC) is a high-incidence malignancy in South America. Here, we evaluated the feasibility of producing effective DCs using heat-conditioned cell lysates derived from gallbladder cancer cell lines (GBCCL). By characterizing nine different GBCCLs and several fresh tumor tissues, we found that they expressed some tumor-associated antigens such as CEA, MUC-1, CA19-9, Erb2, Survivin, and several carcinoembryonic antigens. Moreover, heat-shock treatment of GBCCLs induced calreticulin translocation and release of HMGB1 and ATP, both known to act as danger signals. Monocytes stimulated with combinations of conditioned lysates exhibited a potent increase of DC-maturation markers. Furthermore, conditioned lysate-matured DCs were capable of strongly inducing CD4+ and CD8+ T cell activation, in both allogeneic and autologous cell co-cultures. Finally, in vitro stimulated CD8+ T cells recognize HLA-matched GBCCLs. In summary, GBC cell lysate-loaded DCs may be considered for future immunotherapy approaches.

PMID: 29600445 [PubMed - as supplied by publisher]

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Target Therapy for Esophageal Adenocarcinoma.

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Target Therapy for Esophageal Adenocarcinoma.

Methods Mol Biol. 2018;1756:51-65

Authors: Lam KO, Kwong DLW

Abstract
Adenocarcinoma of the esophagus is a deadly disease and median survival of patients with metastatic disease is around 1 year only. There is an unmet need to personalize treatment by identifying molecular targets and respective target therapy in esophageal adenocarcinoma. There has been success in targeting the human epidermal growth factor receptor 2 (HER2) and vasoendothelial growth factor (VEGF) pathway while more failures were encountered in the clinical studies targeting epidermal growth factor (EGFR), mammalian target of rapamycin (mTOR), and mesenchymal-epithelial transition (MET). Studies using immune-checkpoint inhibitors have shown early success, and we await mature data for clinical application. In the chapter, the target therapy and novel treatment strategy will be reviewed. In the future, it is hoped that advances in translational research in targeted therapy against esophageal adenocarcinoma will bring about new progress in clinical practice.

PMID: 29600359 [PubMed - in process]

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