Journal of Adolescent and Young Adult Oncology , Vol. 0, No. 0.
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Δευτέρα 23 Οκτωβρίου 2017
Recall of Fertility Discussion by Adolescent Female Cancer Patients: A Survey-Based Pilot Study
Quiste del conducto torácico superior: un hallazgo incidental
Source:Acta Otorrinolaringológica Española
Author(s): Regina María Sánchez Jiménez, Francisca Velázquez Marín
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Physiological augmentation of esophageal distension pressure and peristalsis during conditions of increased esophageal emptying resistance
Abstract
Background
Abdominal compression has been implemented as a provocative maneuver in high-resolution impedance manometry (HRIM) to "challenge" normal esophageal physiology with the aim of revealing abnormal motor patterns which may explain symptoms. In this study, we measured the effects of abdominal compression on esophageal functioning utilizing novel pressure-impedance parameters and attempted to identify differences between healthy controls and globus patients.
Methods
Twenty-two healthy volunteers (aged 23-32 years, 41% female) and 22 globus patients (aged 23-72 years, 68% female) were evaluated with HRIM using a 3.2-mm water perfused manometric and impedance catheter. All participants received 10 × 5 mL liquid swallows; healthy controls also received 10 × 5 mL liquid swallows with abdominal compression created using an inflatable cuff. All swallows were analyzed to assess esophageal pressure topography (EPT) and pressure-flow metrics, indicative of distension pressure, flow timing and bolus clearance were derived.
Key Results
The effect of abdominal compression was shown as a greater contractile vigor of the distal esophagus by EPT and higher distension pressure based on pressure-flow metrics. Age and body mass index also increased contractile vigor and distension pressure. Globus patients were similar to controls.
Conclusions and Interferences
Intrabolus pressure and contractile vigor are indicative of the physiological modulation of bolus transport mechanisms. Provocative testing by abdominal compression induces changes in these esophageal bolus dynamics.
Intrabolus pressure and contractile vigor are indicative of the physiological modulation of bolus transport mechanisms. Provocative testing by abdominal compression induces changes in these esophageal bolus dynamics.
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Age-related changes in cyclic phosphatidic acid-induced hyaluronic acid synthesis in human fibroblasts
Abstract
Hyaluronic acid is a major component of the extracellular matrix, which is important for skin hydration. As aging brings skin dehydration, we aimed to clarify the mRNA expression of hyaluronic acid-related proteins in human skin fibroblasts from donors of various ages (range 0.7–69 years). Previously, we reported that cyclic phosphatidic acid (cPA), a unique phospholipid mediator, stimulated the expression of HAS2 and increased hyaluronic acid synthesis in human skin fibroblasts (donor age: 3 days). In this study, we measured the mRNA expression of hyaluronic acid-related proteins: hyaluronan synthase (HAS) 1–3, hyaluronidase-1, -2, and hyaluronic acid-binding protein (versican). In addition, we tested whether cPA could increase hyaluronic acid synthesis in skin fibroblasts derived from donors of various ages. The expression of HAS1, 3, hyaluronidase-1, and -2 did not change with aging. However, the mRNA expression of versican decreased with aging. Although it is thought that the amount of hyaluronic acid in the dermis decreases with aging, the mRNA expression of HAS2 was increased. But the amount of hyaluronic acid secreted by fibroblasts did not increase with aging. This suggests that the activity and/or protein expression of HAS2 decrease with aging. Furthermore, we observed that cPA caused the increase of hyaluronic acid synthesis at any age, and this effect was increased with aging. These results suggest that aging made the fibroblasts more sensitive to cPA treatment. Therefore, cPA represents a suitable candidate for the health maintenance and improvement of the skin by increasing the level of hyaluronic acid in the dermis.
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Long-Term Outcomes After R0 Resection of Synchronous Peritoneal Metastasis from Colorectal Cancer Without Cytoreductive Surgery or Hyperthermic Intraperitoneal Chemotherapy
Abstract
Background
The National Comprehensive Cancer Network (NCCN) guidelines for colon cancer recently added the following footnote regarding the therapeutic strategy for peritoneal metastases: "If R0 resection can be achieved, surgical resection of isolated peritoneal disease may be considered at experienced centers." This study investigated the efficacy of R0 resection of peritoneal metastasis from colorectal cancer without cytoreductive surgery or hyperthermic intraperitoneal chemotherapy (HIPEC).
Methods
This retrospective cohort study was conducted at a single-institution tertiary care cancer center. Among 496 consecutive M1c colorectal cancer patients, R0 resection was achieved for 94 patients (19%). The subjects were 78 consecutive patients with colorectal cancer and simultaneous peritoneal metastasis but no other distant metastases who underwent R0 resection at the National Cancer Center Hospital from 1971 to 2016 (16% of all M1c patients). Overall survival (OS) was investigated, and clinicopathologic variables were analyzed for prognostic significance.
Results
No perioperative mortality was noted. The 3-year OS rate was 45%, and the 5-year OS rate was 28.7%. The median survival time was 33.4 months. Notably, 17 patients survived for more than 5 years, and 9 of these patients did not receive any chemotherapy. Multivariate analysis showed cancer location in the colon and harvesting of 12 or more lymph nodes to be independent factors associated with a better prognosis.
Conclusions
From the perspective of long-term outcomes and no perioperative mortality, R0 resection of peritoneal metastasis from colorectal cancer, without complete peritonectomy or HIPEC, appeared to be an acceptable therapeutic option for some patients with peritoneal metastasis.
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Acute Effects of Dynamic Stretching on Muscle Flexibility and Performance: An Analysis of the Current Literature
Abstract
Stretching has long been used in many physical activities to increase range of motion (ROM) around a joint. Stretching also has other acute effects on the neuromuscular system. For instance, significant reductions in maximal voluntary strength, muscle power or evoked contractile properties have been recorded immediately after a single bout of static stretching, raising interest in other stretching modalities. Thus, the effects of dynamic stretching on subsequent muscular performance have been questioned. This review aimed to investigate performance and physiological alterations following dynamic stretching. There is a substantial amount of evidence pointing out the positive effects on ROM and subsequent performance (force, power, sprint and jump). The larger ROM would be mainly attributable to reduced stiffness of the muscle–tendon unit, while the improved muscular performance to temperature and potentiation-related mechanisms caused by the voluntary contraction associated with dynamic stretching. Therefore, if the goal of a warm-up is to increase joint ROM and to enhance muscle force and/or power, dynamic stretching seems to be a suitable alternative to static stretching. Nevertheless, numerous studies reporting no alteration or even performance impairment have highlighted possible mitigating factors (such as stretch duration, amplitude or velocity). Accordingly, ballistic stretching, a form of dynamic stretching with greater velocities, would be less beneficial than controlled dynamic stretching. Notwithstanding, the literature shows that inconsistent description of stretch procedures has been an important deterrent to reaching a clear consensus. In this review, we highlight the need for future studies reporting homogeneous, clearly described stretching protocols, and propose a clarified stretching terminology and methodology.
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Correction to: Influence of tumor extent on central lymph node metastasis in solitary papillary thyroid microcarcinomas: a retrospective study of 1092 patients
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Surgical Resection Does Not Improve Survival in Multifocal Intrahepatic Cholangiocarcinoma: A Comparison of Surgical Resection with Intra-Arterial Therapies
Abstract
Background
Multifocal intrahepatic cholangiocarcinoma (ICC) has traditionally been treated with surgical resection when amenable. Intra-arterial therapy (IAT) for multifocal ICC has not been directly compared with surgical resection.
Methods
A single-center, retrospective review of consecutive patients treated for multifocal ICC was conducted. Patients with distant metastases or treatment with systemic chemotherapy alone were excluded. Patients were divided into two groups: surgical resection versus IAT; IAT included transarterial chemoembolization (TACE), transarterial radioembolization (TARE), and hepatic arterial infusion (HAI) pump therapy. Subjects were also analyzed by surgical resection, TACE, and HAI pump therapy.
Results
Overall, 116 patients with multifocal ICC were studied, 57 in the surgical resection group and 59 in the IAT group (TACE = 41, HAI pump = 16, TARE = 2). The IAT group was characterized by a higher incidence of bilobar disease (88.1% vs. 47.4%, p < 0.001), larger tumors (median 10.6 vs. 7.5 cm, p = 0.004), higher incidence of macrovascular invasion (44.1% vs. 24.6%, p = 0.027), and higher rate of nodal metastases (57.6% vs. 28.6%, p = 0.002). Median overall survival for surgical resection was 20 months versus 16 months for IAT (p = 0.627). Multivariate analysis found that macrovascular invasion [hazard ratio (HR) 2.52, 95% confidence interval (CI) 1.56–4.09] and non-receipt of systemic chemotherapy (HR 3.81, 95% CI 2.23–6.52) were independent poor prognostic risk factors. Surgical resection was not associated with a survival advantage over IAT on multivariate analysis (p = 0.242).
Conclusion
Despite selection bias for use of surgical resection compared with IAT, no survival advantage was conferred in the treatment of multifocal ICC.
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Four-Dimensional Computed Tomography: Clinical Impact for Patients with Primary Hyperparathyroidism
Abstract
Background
In recent years, four-dimensional computed tomography (4DCT) has emerged as a new localization study for primary hyperparathyroidism (pHPT).
Objective
We aimed to assess the added value of 4DCT in our institution in the first 4 years of use.
Methods
A retrospective cohort study was conducted from February 2004 to June 2015. Since 2011, patients over 50 years of age without concordant sestamibi-SPECT (SeS) and ultrasound (US) findings underwent 4DCT. Imaging results, surgical findings, histopathology, and postoperative biochemistry were collected.
Results
A total of 536 parathyroid operations in 510 patients were performed during the study period. The overall cure rate was 99.2% after reoperation in some patients, and the overall sensitivity for SeS was 76.0%, and 74.8% for US. Since 2011, 100 patients without concordant SeS/US findings have undergone 4DCT, with a sensitivity of 72.9%. This is in comparison to the sensitivities for SeS (48.3%) and US (52.3%). 4DCT was more sensitive in patients with persistent/recurrent disease (60.0% compared with SeS 43.8% and US 36.4%) and patients with multigland disease (67.4% compared with SeS 40.9% and US 42.1%). Comparison between outcomes in the pre- versus post-CT era demonstrated no difference in the initial cure rate (95.4 vs. 95.9%, p = 0.85) or the rate of minimally invasive parathyroidectomies (74.5 vs. 79.9%, p = 0.22).
Conclusion
Parathyroid 4DCT can aid surgical planning in cases without concordant SeS/US findings; however, the introduction of 4DCT as a second-line test did not change our overall cure rate or rate of minimally invasive parathyroidectomy. The role of 4DCT as the primary localization study for pHPT merits further investigation.
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Pre-operative Axillary Ultrasound-Guided Needle Sampling in Breast Cancer: Comparing the Sensitivity of Fine Needle Aspiration Cytology and Core Needle Biopsy
Abstract
Background
Pre-operative ultrasound-guided needle sampling (UNS) of abnormal axillary lymph nodes in breast cancer can identify patients with axillary metastases and therefore rationalize patient care and inform decision-making. To obtain tissue diagnosis, UNS can be performed by either fine needle aspiration (FNA) or core needle biopsy (CNB). However, few studies have compared the sensitivity of these techniques and the majority show no difference.
Methods
All node-positive patients (those with micro- and macrometastases but not isolated tumor cells) treated at a tertiary referral center between January 2012 and December 2015 were retrospectively identified from pathology records. The result of the first axillary UNS performed on each patient was compared with postoperative histopathology results. The UNS method used was according to individual radiologist preference.
Results
A total of 215 patients underwent FNA (1 patient had bilateral breast cancer and underwent bilateral FNA), and 92 underwent CNB. Sensitivity of CNB was significantly higher than FNA (83.7 vs. 69.0%, P = 0.008). The false-negative rate in the FNA group was therefore higher than in the CNB group by a factor of 2.5. There was no difference in inadequacy rate between the two techniques. There were no complications in the FNA group, and only one hematoma (which did not require operative intervention) in the CNB group.
Conclusions
CNB is safe and should be the preferred technique for UNS to improve sensitivity.
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Long-Term Outcomes After R0 Resection of Synchronous Peritoneal Metastasis from Colorectal Cancer Without Cytoreductive Surgery or Hyperthermic Intraperitoneal Chemotherapy
Abstract
Background
The National Comprehensive Cancer Network (NCCN) guidelines for colon cancer recently added the following footnote regarding the therapeutic strategy for peritoneal metastases: "If R0 resection can be achieved, surgical resection of isolated peritoneal disease may be considered at experienced centers." This study investigated the efficacy of R0 resection of peritoneal metastasis from colorectal cancer without cytoreductive surgery or hyperthermic intraperitoneal chemotherapy (HIPEC).
Methods
This retrospective cohort study was conducted at a single-institution tertiary care cancer center. Among 496 consecutive M1c colorectal cancer patients, R0 resection was achieved for 94 patients (19%). The subjects were 78 consecutive patients with colorectal cancer and simultaneous peritoneal metastasis but no other distant metastases who underwent R0 resection at the National Cancer Center Hospital from 1971 to 2016 (16% of all M1c patients). Overall survival (OS) was investigated, and clinicopathologic variables were analyzed for prognostic significance.
Results
No perioperative mortality was noted. The 3-year OS rate was 45%, and the 5-year OS rate was 28.7%. The median survival time was 33.4 months. Notably, 17 patients survived for more than 5 years, and 9 of these patients did not receive any chemotherapy. Multivariate analysis showed cancer location in the colon and harvesting of 12 or more lymph nodes to be independent factors associated with a better prognosis.
Conclusions
From the perspective of long-term outcomes and no perioperative mortality, R0 resection of peritoneal metastasis from colorectal cancer, without complete peritonectomy or HIPEC, appeared to be an acceptable therapeutic option for some patients with peritoneal metastasis.
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Stereotactic Body Radiation Therapy for Isolated Local Recurrence After Surgical Resection of Pancreatic Ductal Adenocarcinoma Appears to be Safe and Effective
Abstract
Background
A standardized treatment regimen for unresectable isolated local recurrence (ILR) of pancreatic ductal adenocarcinoma has not been established. This study evaluated the outcomes for patients with ILR who underwent stereotactic body radiation therapy (SBRT).
Methods
The records of patients with ILR who underwent SBRT between 2010 and 2016 were retrospectively reviewed. Symptom palliation and treatment-related toxicity were recorded. Associations between patient or treatment characteristics and overall survival (OS), progression-free survival (PFS), and local progression-free survival (LPFS) were assessed.
Results
The study identified 51 patients who received SBRT for ILR. Of the 51 patients, 26 (51%) had not received radiation therapy before SBRT. The median OS was 36 months after diagnosis. From the first day of SBRT, the median OS, PFS, and LPFS were respectively 16, 7, and 10 months. Patients with a recurrence-free interval of 9 months or longer after surgery had superior OS (P = 0.019). Maintenance chemotherapy after SBRT was associated with superior OS (P < 0.001) and LPFS (P = 0.027). In the multivariable analysis, poorly differentiated tumor grade [hazard ratio (HR) 11.274], positive surgical margins (HR 0.126), and reception of maintenance chemotherapy (HR 0.141) were independently associated with OS. Positive surgical margins (HR 0.255) and maintenance chemotherapy (HR 0.299) were associated with improved LPFS. Of 16 patients, 10 (63%) experienced abdominal pain relief after SBRT. Four patients (8%) experienced grade 3 gastrointestinal toxicity, and one patient experienced grade 4 gastrointestinal toxicity.
Conclusions
Use of SBRT for ILR improved pain for a majority of the patients with acceptable acute and late toxicity. The findings show that SBRT is a feasible treatment for select patients with ILR. For those who receive SBRT, maintenance chemotherapy should be considered.
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Prognostic significance of the preoperative neutrophil-to-lymphocyte ratio for complete resection of thymoma
Abstract
Purpose
The preoperative peripheral neutrophil-to-lymphocyte ratio (NLR) is associated with a poor prognosis for various cancers. We evaluated the prognostic role of the preoperative NLR in patients with thymoma.
Methods
We reviewed the medical records of 254 patients who underwent resection of thymic epithelial tumors at our institution. Patients were excluded if they had received steroid therapy, neoadjuvant therapy, or incomplete resection, or if they had thymic carcinoma or Good's syndrome, recurrence of thymoma, or missing data. The NLR was measured preoperatively, and outcomes of patients with a low (< 1.96) vs those with a high (≥ 1.96) NLR were compared statistically.
Results
Of 159 eligible patients, 59 (37.1%) had a high NLR and 100 (62.9%) had a low NLR. Overall survival (OS), recurrence-free survival (RFS), disease-specific survival (DSS), disease-related survival (DRS), and the cumulative incidence of recurrence (CIR) differed significantly between the groups. Multivariate analyses revealed that a high NLR was independently associated with disease-related survival and a cumulative incidence of recurrence. A high NLR was also associated with a higher risk of recurrence of Masaoka stage I or II thymoma.
Conclusions
An elevated preoperative NLR was associated with poor outcomes after thymoma resection. Thus, the NLR may be a useful biomarker of the postoperative prognosis of thymoma.
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Double fluorescent labelling of a bipolar epithelial cell in vitro: The outer hair cell
Publication date: 1 January 2018
Source:Journal of Neuroscience Methods, Volume 293
Author(s): Csaba Harasztosi, Entcho Klenske, Susanne Badum, Emese Harasztosi, Anthony W. Gummer
BackgroundFluorescence membrane markers are efficient tools for visualizing the dynamics of membrane recycling processes in living cells. The outer hair cell (OHC) − a bipolar epithelial cell in the cochlea − possesses endocytic activity at both its apical and basal poles. The best visual overview of transcytosis in the OHC is achieved when the cell is isolated, so that both the apical and the basal poles are in the same focal plane to allow confocal imaging. Until now, fluorescent markers were applied to the extracellular environment of isolated OHCs without distinguishing the apical and basal poles. The drawback of that configuration is that apicobasal and basoapical vesicle traffic labelled at the opposite poles cannot be visualized independently because the same fluorescent marker has access to both poles.New methodA double-barrel, capillary perfusion system was developed to independently stain either one pole or both the apical and the basal poles of isolated OHCs using different types of fluorescence membrane markers.ResultsProducing laminar fluid flow, the double-barrel perfusor allows investigation of the dynamics of apicobasal and basoapical vesicle traffic independently and/or simultaneously in the same OHC.Comparison with existing methodThis method offers a unique option for investigating bidirectional vesicle traffic in bipolar epithelial cells, which is superior to other already established labelling techniques.ConclusionsThe double-barrel perfusion system, suitable for selectively staining a longitudinal section of the plasma membrane of an isolated bipolar epithelial cell, opens new possibilities for investigating cell labelling and intracellular vesicle traffic.
Graphical abstract
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Functional brain connectivity in resting-state fMRI using phase and magnitude data
Publication date: 1 January 2018
Source:Journal of Neuroscience Methods, Volume 293
Author(s): Zikuan Chen, Arvind Caprihan, Eswar Damaraju, Srinivas Rachakonda, Vince Calhoun
BackgroundThe output of BOLD fMRI consists of a pair of magnitude and phase components. While the magnitude data has been widely accepted for brain function analysis, we can also make use of the phase data (unwrapped) since this is a good representation of the internal magnetic field. In this work, we discuss the use of fMRI phase data for brain function analysis.New methodsThe fMRI phase data taken from 100 subjects are preprocessed using standard SPM approaches. Group independent component analysis (ICA) is applied to the magnitude and phase data separately. We then compare the spatial patterns for both magnitude and phase data using an empirical spatial smoothing procedure. We also evaluate the magnitude and phase functional network connectivity (FC) matrices.ResultsWe observed the positive/negative correlation-balanced functional connectivity in phase data, which is distinct from the positive correlation prevalence in magnitude data. The phase FC (pFC) structure is quite different from the magnitude FC (mFC) in functional clusters (on-diagonal blocks or cliques) and inter-cluster couplings (off-diagonal blocks).Comparison with existingMethods since both the magnitude and phase data of the fMRI signals are generated from the same magnetic source, either can be useful for brain function analysis from different perspective (per different measurements). Herein, we report on making use of resting-state fMRI phase data for brain functional analysis in comparison with magnitude data. This exploration in phase fMRI may provide a new arena for more comprehensive brain function analysis.
Graphical abstract
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Disturbance of verticality perception and postural dysfunction in Parkinson's disease
Objectives
Verticality perception is known to be abnormal in Parkinson's disease (PD), but in which stage respective dysfunctions arise and how they relate to postural disorders remains to be settled. These issues were studied with respect to different dimensions of the subjective visual vertical (SVV) in relation to clinical parameters of postural control.
Materials & Methods
All participants had to orientate a luminous line at random planar orientations to a strictly vertical position using an automated operator system. The SVV was analyzed in 58 PD patients and 28 control subjects with respect to (i) the angle between true and subjective vertical (deviation) and (ii) the variability of this across five measurements (variability). Results were referred to the subjective upright head position (SUH), the disease stage, and clinical gait/balance features assessed by the MDS-UPDRS and the Tinetti test.
Results
Parkinson's disease patients had significantly higher SVV deviation and variability than controls. With respect to disease stage, deviation developed before abnormal variability. SVV variability was associated with poor balance and gait performance, as well as postural instability. Deficits in SUH and SVV deviation were correlated and mostly unidirectional, but did not correspond to the side of motor symptom dominance.
Conclusions
Visual verticality perception in PD is deviated already in early stages, conceivably as a relatively static internal misrepresentation of object orientation. Variability about verticality perception emerges in more advanced stages and is associated with postural and balance abnormalities.
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Awareness and Knowledge Levels of 18-Year-Old and Older Individuals Regarding Human Papillomavirus (HPV) and HPV Vaccine in Hatay, Turkey
Abstract
The aim of this study was to evaluate the knowledge and awareness levels of 18-year-old and older women and men on HPV infection, HPV vaccine, and the potential risk factors in Hatay, Turkey. In our study, it was found that overall 27.0 and 23.2% of the participants reported having heard of HPV infection and HPV vaccine. The rate of participants who had heard of HPV infection and HPV vaccine was higher in women than in men (p < 0.000). Thirteen percent of the participants was aware of the fact that HPV triggers cervical cancer, 10.2% penile cancer, and 16.7% genital warts, respectively. The overall vaccination rate of the participants was 2.7%. When the total knowledge score of the participants about HPV infection and HPV vaccine was evaluated according to independent variables, it was found that being a woman, urbanization, and having a high level of education had a positive effect on knowledge score, while never having heard of HPV infection and HPV vaccine had a negative effect on knowledge score (p < 0.000). It was determined in the linear regression model that gender, educational status, residential area, and having heard of HPV infection before influenced knowledge levels. It was determined that the relation between these variables and the total knowledge scores of the participants was statistically significant (p < 0.05). It was also determined that women who had higher educational levels, those who were living in urban areas, and those who had heard HPV infection before had higher knowledge levels. The level of knowledge of the participants about HPV infection and HPV vaccine was found to be very low. Having adequate knowledge about HPV infection and increasing the acceptance of HPV vaccination in public will play an important role in decreasing the rate of mortality and morbidity of the different HPV-associated cancers in women and men.
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HALO-109–301: a Phase III trial of PEGPH20 (with gemcitabine and nab-paclitaxel) in hyaluronic acid-high stage IV pancreatic cancer
Future Oncology, Ahead of Print.
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An updated review of the JAK1/2 inhibitor (ruxolitinib) in the Philadelphia-negative myeloproliferative neoplasms
Future Oncology, Ahead of Print.
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Awareness and Knowledge Levels of 18-Year-Old and Older Individuals Regarding Human Papillomavirus (HPV) and HPV Vaccine in Hatay, Turkey
Abstract
The aim of this study was to evaluate the knowledge and awareness levels of 18-year-old and older women and men on HPV infection, HPV vaccine, and the potential risk factors in Hatay, Turkey. In our study, it was found that overall 27.0 and 23.2% of the participants reported having heard of HPV infection and HPV vaccine. The rate of participants who had heard of HPV infection and HPV vaccine was higher in women than in men (p < 0.000). Thirteen percent of the participants was aware of the fact that HPV triggers cervical cancer, 10.2% penile cancer, and 16.7% genital warts, respectively. The overall vaccination rate of the participants was 2.7%. When the total knowledge score of the participants about HPV infection and HPV vaccine was evaluated according to independent variables, it was found that being a woman, urbanization, and having a high level of education had a positive effect on knowledge score, while never having heard of HPV infection and HPV vaccine had a negative effect on knowledge score (p < 0.000). It was determined in the linear regression model that gender, educational status, residential area, and having heard of HPV infection before influenced knowledge levels. It was determined that the relation between these variables and the total knowledge scores of the participants was statistically significant (p < 0.05). It was also determined that women who had higher educational levels, those who were living in urban areas, and those who had heard HPV infection before had higher knowledge levels. The level of knowledge of the participants about HPV infection and HPV vaccine was found to be very low. Having adequate knowledge about HPV infection and increasing the acceptance of HPV vaccination in public will play an important role in decreasing the rate of mortality and morbidity of the different HPV-associated cancers in women and men.
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Prenatal methamphetamine exposure is associated with corticostriatal white matter changes in neonates
Abstract
Diffusion tensor imaging (DTI) studies have shown that prenatal exposure to methamphetamine is associated with alterations in white matter microstructure, but to date no tractography studies have been performed in neonates. The striato-thalamo-orbitofrontal circuit and its associated limbic-striatal areas, the primary circuit responsible for reinforcement, has been postulated to be dysfunctional in drug addiction. This study investigated potential white matter changes in the striatal-orbitofrontal circuit in neonates with prenatal methamphetamine exposure. Mothers were recruited antenatally and interviewed regarding methamphetamine use during pregnancy, and DTI sequences were acquired in the first postnatal month. Target regions of interest were manually delineated, white matter bundles connecting pairs of targets were determined using probabilistic tractography in AFNI-FATCAT, and fractional anisotropy (FA) and diffusion measures were determined in white matter connections. Regression analysis showed that increasing methamphetamine exposure was associated with reduced FA in several connections between the striatum and midbrain, orbitofrontal cortex, and associated limbic structures, following adjustment for potential confounding variables. Our results are consistent with previous findings in older children and extend them to show that these changes are already evident in neonates. The observed alterations are likely to play a role in the deficits in attention and inhibitory control frequently seen in children with prenatal methamphetamine exposure.
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The evidence base for circulating tumour DNA blood-based biomarkers for the early detection of cancer: a systematic mapping review
Abstract
Background
The presence of circulating cell-free DNA from tumours in blood (ctDNA) is of major importance to those interested in early cancer detection, as well as to those wishing to monitor tumour progression or diagnose the presence of activating mutations to guide treatment. In 2014, the UK Early Cancer Detection Consortium undertook a systematic mapping review of the literature to identify blood-based biomarkers with potential for the development of a non-invasive blood test for cancer screening, and which identified this as a major area of interest. This review builds on the mapping review to expand the ctDNA dataset to examine the best options for the detection of multiple cancer types.
Methods
The original mapping review was based on comprehensive searches of the electronic databases Medline, Embase, CINAHL, the Cochrane library, and Biosis to obtain relevant literature on blood-based biomarkers for cancer detection in humans (PROSPERO no. CRD42014010827). The abstracts for each paper were reviewed to determine whether validation data were reported, and then examined in full. Publications concentrating on monitoring of disease burden or mutations were excluded.
Results
The search identified 94 ctDNA studies meeting the criteria for review. All but 5 studies examined one cancer type, with breast, colorectal and lung cancers representing 60% of studies. The size and design of the studies varied widely. Controls were included in 77% of publications. The largest study included 640 patients, but the median study size was 65 cases and 35 controls, and the bulk of studies (71%) included less than 100 patients. Studies either estimated cfDNA levels non-specifically or tested for cancer-specific mutations or methylation changes (the majority using PCR-based methods).
Conclusion
We have systematically reviewed ctDNA blood biomarkers for the early detection of cancer. Pre-analytical, analytical, and post-analytical considerations were identified which need to be addressed before such biomarkers enter clinical practice. The value of small studies with no comparison between methods, or even the inclusion of controls is highly questionable, and larger validation studies will be required before such methods can be considered for early cancer detection.
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Physiopathology of Migraine: What Have We Learned from Functional Imaging?
Abstract
Purpose of Review
This review aims to provide an overview of the most recent and significant functional neuroimaging studies which have clarified the complex mechanisms underlying migraine pathophysiology.
Recent Findings
The recent data allow us to overcome the concept of a migraine generator suggesting that functional networks abnormalities may lead to changes in different brain area activities and consequent reduced migraine thresholds susceptibility, likely associated with higher migraine severity and burden.
Summary
Although functional magnetic resonance imaging studies have allowed recognition of several migraine mechanisms, its pathophysiology is not completely understood and is still a matter of research. Nevertheless, in recent years, functional magnetic resonance imaging studies have allowed us to implement our knowledge of migraine pathophysiology. The pivotal role of both the brainstem and the hippocampus in the first phase of a migraine attack, the involvement of limbic pathway in the constitution of a migrainous pain network, the disrupted functional connectivity in cognitive brain networks, as well as the abnormal function of the visual network in patients with migraine with aura are the main milestones in migraine imaging achieved through functional imaging advances. We believe that further studies based on combined functional and structural techniques and the investigation of the different phases of migraine cycle may represent an efficient methodological approach for comprehensively looking into the migrainous brain secrets.
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Comment on “Serum human epididymis protein 4 is associated with the treatment response of concurrent chemo-radiotherapy and prognosis in patients with locally advanced non-small cell lung cancer” by Lan WG et al.
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Schlaf bei psychischen Erkrankungen
Zusammenfassung
Schlaf und psychische Erkrankungen sind wechselseitig miteinander verbunden: So sind Störungen des Schlafs ein sehr häufiges Symptom psychischer Erkrankungen und möglicherweise auch ein unabhängiger Risikofaktor dafür. Es gibt eine Reihe von Hinweisen, dass Schlafstörungen den Therapieerfolg sowohl kurz- als auch langfristig beeinflussen. Auch können sich bestimmte Veränderungen des Schlafs negativ auf kognitive Hirnleistungen auswirken, wie z. B. auf die Gedächtniskonsolidierung oder auf die Emotionsregulierung. Der Behandlung von Schlafstörungen bei psychischen Erkrankungen kommt somit eine herausragende Bedeutung zu. Im vorliegenden Artikel werden abschließend die Effekte der kognitiven Verhaltenstherapie und von Psychopharmaka auf Schlaf und psychische Symptome dargestellt.
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Comment on “Serum human epididymis protein 4 is associated with the treatment response of concurrent chemo-radiotherapy and prognosis in patients with locally advanced non-small cell lung cancer” by Lan WG et al.
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Subtotal Parathyroidectomy and Relocation of the Parathyroid Remnant for Renal Hyperparathyroidism: modification of a traditional operation
Abstract
Background
We describe a modification of the conventional subtotal parathyroidectomy operation where the parathyroid gland(s) remnant is repositioned with intact vascular supply to a plane superficial to the infrahyoid strap muscles and immediately under the skin incision. This technique called Subtotal Parathyroidectomy and Remnant Relocation (SPARE) retains all the metabolic advantages of the conventional operation with the added advantage of easier identification of a recurrent hyperplastic remnant if re-exploration becomes necessary.
Methods
In the SPARE technique, four parathyroid glands were identified and the quality of each gland and the length of each vascular pedicle to the parathyroid glands were assessed. The optimal parathyroid gland was relocated to a plane superficial to the strap muscles. The remainder of the glands were removed.
Results
In total, 30 patients with hyperparathyroidism secondary to renal failure (HSRF) underwent parathyroidectomy with the SPARE technique. The mean age was 53.1±12.5 years and median follow-up was 17.1 months (range 1-78.9 months). There were no recurrent laryngeal nerve (RLN) injuries or hematomas. The pre- and post-operative value for corrected calcium and PTH were 158.4±109.4 pmol/L and 11.4±12.1 pmol/L, respectively (p < 0.05). Three recurrences were noted (10.0%), with a mean time to recurrence of 15.3±6.6 months. One patient had excision of the remnant parathyroid glands performed under local anaesthetic (29 min); one had re-exploration performed under general anaesthetic (81 min), and one was managed medically.
Conclusion
We described a novel parathyroidectomy technique for patients with HSRF, which provides the advantages of conventional subtotal parathyroidectomy while mitigating the challenges of thyroid bed re-exploration when recurrences arise.
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In Situ Monitoring of Labile Vanadium in the Mackenzie River Basin (Canada) Using Diffusive Gradients in Thin Films
Abstract
Vanadium has the potential to be released as a by-product of the combustion of fossil fuels such as oil and coal in the aquatic system. Presence of tailing ponds and other mining operations may pose the largest threat to downstream users and to the long-term aquatic health of the Mackenzie River Basin (MRB, Canada). The need for developing a solid baseline for the MRB aquatic ecosystem against which future changes can be measured is urgent. In this study, 36 sets of triplicate diffusive gradients in thin films (DGT) samplers were deployed in MRB during the 2012–2014 ice-free seasons to investigate temporal and spatial changes in the concentration of DGT-labile vanadium (V) as part of a Northwest Territories community-based project. Average DGT-labile V concentration (5.9 ± 0.9 nmol L−1) was comparable with non-contaminated aquatic systems, suggesting no significant impact of human activities on V speciation in MRB in 2012–2014. The V concentrations reported in this study constitutes a baseline that can be used to enhance ongoing monitoring efforts. Although the DGT samplers were deployed in collaboration with northern communities, the absence of temporal changes in DGT-labile V indicated that in situ DGT passive samplers constitute a reliable and robust alternative for community-based monitoring programs. Excitation emission matrix (EEM) fluorescence combined with parallel factor analysis (PARAFAC) validated three humic-like (C1–C3) and one protein-like (C4) fluorescent component. However, no significant relationships were apparent between DGT-labile V and dissolved organic carbon (DOC), the PARAFAC loadings, and composition (p > 0.05). Hierarchical cluster analysis revealed that DGT-labile V concentration was negatively correlated with aromatic and humified DOM (r = − 0.70 to − 0.84, p < 0.05).
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Coal-Based Carbon Membrane Coupled with Electrochemical Oxidation Process for the Enhanced Microalgae Removal from Simulated Ballast Water
Abstract
A treatment system combining the coal-based carbon membrane with electrochemical oxidation process was designed for the enhanced microalgae removal from simulated ballast water. The effects of various parameters including microalgae species, microalgae density, electric field intensity, and electrical conductivity on the separation performance were carried out. Fouling test was further performed for assessing the antifouling ability of the treatment system. The results showed big microalgae species tended to form a thick fouling layer on the carbon membrane, resulting in low permeate flux. High microalgae density gave rise to serious membrane fouling, which decreases the permeate flux. The treatment system showed enhanced permeate flux and fouling resistance by coupling with electrochemical oxidation process. High conductivity favored the electrochemical reactions on the surface of the carbon membrane, which reduces the clogging of the microalgae to the carbon membrane. After cleaning, the treatment system still kept high permeate flux, implying its good regeneration ability.
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Stryphnodendron rotundifolium Mart. As an Adjuvant for the Plant Germination and Development Under Toxic Concentrations of HgCl 2 and AlCl 2
Abstract
Heavy metals, chemical elements considered toxic at certain concentrations, can be considered potential threats to plants, animals, and biological resources of a particular ecosystem. Among them, mercury and aluminum, when involved in bioaccumulation processes, can cause damage to various organ systems of both animals and plants. In vegetables, heavy metals produce reactive oxygen species (ROS), which are involved in the occurrence of malformations and deficits in the growth of roodets and plumule of several species of plants, which justifies the study of natural antioxidant agents that may come to reverse or ameliorate the deleterious effects caused by these compounds. In this sense, this study aims to evaluate the cytoprotective effect of hydroethanolic extract of Stryphnodendron rotundifolium Mart., species popularly known as "barbatimão" against the heavy metals mercury and aluminum in vegetable model, because of its known antioxidant potential. To this end, there was the cytoprotection test in microbial and lettuce seeds (germination) in order to ascertain the potential of the said extract on the protection of roots and stem this. It was observed that the extract showed no allelopathic effect on lettuce seeds at a concentration of 32 μg/mL and in combination with HgCl2 and AlCl3, it enabled a higher growth in the roodets and stem Lactuta sativa L. These results demonstrated that the extract of Stryphnodendron rotundifolium can be an alternative to solve the problem with soil contamination by heavy metals, showing thus its promising potential cytoprotective in plant species.
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Structure Analysis of Pipe Section Reactor for Pipe-Wall Reaction: A Computational Fluid Dynamics Analysis Approach
Abstract
Pipe section reactor (PSR) is a well-controlled laboratory reactor, which is used to simulate the water quality variations in drinking water distribution systems. However, the hydraulics condition within PSR, which is an essential prerequisite of the water quality studies, still remains unclear. Consequently, the objective of this study is to analyze the hydraulic conditions within PSR by means of a computational fluid dynamics (CFD) approach. The influences of configuration parameters on the hydraulic conditions were tested including propeller diameter, inclined angle of the propeller, distance between the top and inner cylinder, distance between the bottom and inner cylinder, outer cylinder length, baffle length, number of the baffles, rotational speed of the propeller, and inner and outer cylinder diameters. According to the CFD analysis, an optimal structure of PSR was suggested. The data presented here could facilitate the PSR application and improve the simulation of water quality in distribution systems.
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Performance of Natural Coagulant Extracted from Plantago ovata Seed for the Treatment of Turbid Water
Abstract
Present study investigates the coagulation ability of Plantago ovata (P. ovata) seed extracts for turbidity removal. The active coagulant agents were successfully extracted from P. ovata seeds using different solvents such as distilled water (PO-DW), tap water (PO-TW), NaCl (PO-NaCl), and ammonium acetate (PO-AA). Experiments were conducted in batch mode for initial turbidity such as 500 NTU (high), 150 NTU (medium), and 50 NTU (low). Results demonstrated that P. ovata extracts are less efficient in low turbidities, while PO-NaCl was found to provide high coagulation activity in all initial turbidity concentrations compared to other extracts. PO-NaCl was able to remove 98.2, 94.9, and 80.2% of turbidity from water having in initial turbidities of 500, 150, and 50 NTU, respectively. Coagulation activity of the extract was the best when the extraction was performed for 50 min at room temperature. Jar test procedure with the coagulation time of 1 min and flocculation time of 30 min was optimized, irrespective of the initial turbidity. The optimum settling time for 500, 150, and 50 NTU water samples were 20, 30, and 90 min, respectively. PO-NaCl was used in different pH turbid solutions and it was found to be working very efficiently in alkaline conditions. The coagulation efficiency of the coagulant stored in refrigerator was higher than that stored at room temperature. Thus, the natural coagulants extracted from P. ovata seeds revealed to be effective for turbidity removal.
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Coping and adjustment in men with prostate cancer: a systematic review of qualitative studies
Abstract
Purpose
Prostate cancer (PCa) is one of the most common forms of cancer amongst males. Men's coping responses are an important determinant of functioning and adjustment to this disease. Previous qualitative research exists in this area, but the current review sought to systematically review and summarise these studies.
Methods
A systematic review was conducted to identify studies concerned with men's coping strategies in their attempts to live with PCa. A search of relevant electronic databases was conducted to identify studies that met inclusion criteria for this review. Methodological quality assessment was also undertaken for each included study.
Results
One hundred twenty-one publications were identified for initial screening, and 18 studies were included in the review. A total of five coping strategy categories or 'meta-themes' were identified across included studies. These categories were labelled 'avoidance, minimisation, and withdrawal', 'directing cognition and attention', 'reframing masculinity and seeking support', 'retain pre-illness identity and lifestyle', and 'symptom/side-effect management'.
Conclusions
A range of coping strategies were reported by men with PCa. Some of these strategies appear to be partially influenced by gender roles and masculinities. Coping meta-themes reported in this review have also been found in other research on men's coping. Strategies relating to flexible interpretation of gender roles/masculinities may be a particularly relevant category of coping responses due to the hypothesised beneficial impact of flexibility on psychological well-being.
Implications for cancer survivors
PCa survivors utilise a range of coping strategies, and the types of strategies used may have implications for men's well-being. The ability to be flexible in both coping responses used, and in the view of oneself as a man may be particularly important skills in meeting the challenges associated with this disease.
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Significance of a frozen section analysis of the ureteral margin in bladder cancer patients treated with radical cystectomy and neoadjuvant chemotherapy
Abstract
Although the clinical utility of a frozen section analysis (FSA) at the time of radical cystectomy (RC) has already been established, its significance and utility in bladder cancer patients receiving neoadjuvant chemotherapy (NAC) have not yet been fully evaluated. We identified 458 patients (937 ureters) who underwent open RC for bladder cancer at our 7 Japanese institutions between 2004 and 2015. Among these patients, 139 (284 ureters) received NAC before RC (NAC group), while 319 (653 ureters) underwent RC alone (non-NAC group). FSA was performed on 356 out of 937 (38.0%) ureters and 179 out of 458 (39.1%) patients. FSA was positive in 30 out of 356 (8.4%) ureters and its sensitivity, specificity, and accuracy were 89.3, 98.5, and 97.8%, respectively. In the NAC group, FSA was performed on 138 out of 284 (48.6%) ureters and 68 out of 139 (48.9%) patients. FSA was positive in 8 out of 138 ureters (5.8%), and its sensitivity, specificity, and accuracy were 77.8, 99.2, and 97.8%, respectively. In the non-NAC group, FSA was performed on 218 out of 653 (33.4%) ureters and 111 out of 319 (34.8%) patients. FSA was positive in 22 out of 218 (10.1%) ureters, and its sensitivity, specificity, and accuracy were 94.7, 98.0, and 97.7%, respectively. No correlation was observed between preoperative clinical factors and FSA positivity in the NAC group; however, in the non-NAC group, the incidence of FSA positivity in the ureters of patients with concomitant CIS in TUR-BT specimens was 8/41 (19.5%), which was significantly higher than that in their counterpart (14/177, 7.9%, p = 0.033). Even in the era of NAC in the management of bladder cancer patients, the performance of FSA does not change and FSA at the time of RC may provide useful diagnostic information.
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Prognostic significance of the preoperative neutrophil-to-lymphocyte ratio for complete resection of thymoma
Abstract
Purpose
The preoperative peripheral neutrophil-to-lymphocyte ratio (NLR) is associated with a poor prognosis for various cancers. We evaluated the prognostic role of the preoperative NLR in patients with thymoma.
Methods
We reviewed the medical records of 254 patients who underwent resection of thymic epithelial tumors at our institution. Patients were excluded if they had received steroid therapy, neoadjuvant therapy, or incomplete resection, or if they had thymic carcinoma or Good's syndrome, recurrence of thymoma, or missing data. The NLR was measured preoperatively, and outcomes of patients with a low (< 1.96) vs those with a high (≥ 1.96) NLR were compared statistically.
Results
Of 159 eligible patients, 59 (37.1%) had a high NLR and 100 (62.9%) had a low NLR. Overall survival (OS), recurrence-free survival (RFS), disease-specific survival (DSS), disease-related survival (DRS), and the cumulative incidence of recurrence (CIR) differed significantly between the groups. Multivariate analyses revealed that a high NLR was independently associated with disease-related survival and a cumulative incidence of recurrence. A high NLR was also associated with a higher risk of recurrence of Masaoka stage I or II thymoma.
Conclusions
An elevated preoperative NLR was associated with poor outcomes after thymoma resection. Thus, the NLR may be a useful biomarker of the postoperative prognosis of thymoma.
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Normative prosthodontic care need: does it impact the daily life of young Saudis with high level of oral diseases? A cross sectional study
Abstract
Background
Assessing the need for prosthodontic care previously included older age groups. There is less information about younger populations who may need this care because of high disease levels. The aim of this study was to assess the normative need for prosthodontic care in a young Saudi population with high oral disease levels, the associated factors and its impact on daily life.
Methods
A cross sectional study included Saudi adults in the Eastern Province in 2016. A questionnaire was used to assess personal background (confounders), risk factors affecting oral diseases (exposures) and the impact of oral problems on daily life. A clinical examination assessed tooth loss, the presence of prosthodontic appliances, the presence of untreated decay and need for periodontal care. Directed acyclic graphs identified the confounders to be included in regression models with separate outcomes: normative need for prosthodontic care (binary logistic model) and impact on 6 daily life aspects (ordinal regression models).
Results
Complete data were available for 574/ 700 = 82% and 46.7% needed prosthodontic care with 2 lost teeth on average among adults of mean age = 33.2 years. The confounders controlled for the need for prosthodontic care included socioeconomic status (SES), dental visits last year and health insurance. The confounders for the impact on daily life included age and SES. In adjusted models, normative need for prosthodontic care was significantly associated with untreated decay (OR = 2.09, 95% C.I. = 1.37, 3.19). The impact on daily life was not significantly associated with prosthodontic care need but with untreated decay, especially sleeplessness (regression coefficient = 0.53, 95% C.I. = 0.02, 1.04) and dropping daily activities (regression coefficient = 0.79, 95% C.I. = 0.13, 1.46). In addition, the need for periodontal care was associated with food avoidance (regression coefficient = 0.73, 95% C.I. = 0.28, 1.18).
Conclusions
In Saudi adults in the Eastern Province, there was a considerable normative need for prosthodontic care due to untreated decay. The impact on daily life was related to the underlying oral diseases rather than the need for prosthodontic care itself.
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Pre-emptive Diclofenac Versus Ketoprofen as a Transdermal Drug Delivery System: How They Face
Abstract
Aim
To compare the analgesic efficacy of Diclofenac vis-a-vis Ketoprofen transdermal patch, in the management of immediate post-operative pain following orthognathic procedures.
Material and Method
A prospective, double-blinded, randomised controlled study was conducted among 50 subjects, between 2012 and 2015. These patients were diagnosed clinically and cephalometrically as skeletal and dental class II malocclusion and underwent bi-jaw surgical procedure. In total, 25 Diclofenac and 25 Ketoprofen transdermal patches, sealed in envelopes and numbered, were administered to subjects. The patches used, contained 100 mg of either Diclofenac or Ketoprofen and administered by a nurse prior to induction. Duration of analgesia, severity of pain using Visual Analog Scale, necessity of rescue analgesia (spontaneous pain > 5 on a 10-cm scale) and any other adverse effect associated with the drug were evaluated.
Results
Mean duration of analgesia was significantly higher in the Ketoprofen group (20 h), compared to Diclofenac group (13 h) (p = 0.001). Rescue analgesia was required in 12% of subjects who received Diclofenac patch, compared to 4% in Ketoprofen group. None of the subjects showed any allergic reactions.
Conclusion
The study was designed to evaluate the efficacy of transdermal patch in reduction of post-operative pain in subjects undergoing bi-jaw surgeries. Subjects in both groups were comfortable and returned to early function. However, Ketoprofen transdermal patch had an edge over the Diclofenac transdermal patch with respect to analgesic efficacy.
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Prospective evaluation of poly-4-hydroxybutyrate mesh in CDC class I/high-risk ventral and incisional hernia repair: 18-month follow-up
Abstract
Background
Long-term resorbable mesh represents a promising technology for complex ventral and incisional hernia repair (VIHR). Preclinical studies indicate that poly-4-hydroxybutyrate (P4HB) resorbable mesh supports strength restoration of the abdominal wall. This study evaluated outcomes of high-risk subjects undergoing VIHR with P4HB mesh.
Methods
This was a prospective, multi-institutional study of subjects undergoing retrorectus or onlay VIHR. Inclusion criteria were CDC Class I, defect 10–350 cm2, ≤ 3 prior repairs, and ≥ 1 high-risk criteria (obesity (BMI: 30–40 kg/m2), active smoker, COPD, diabetes, immunosuppression, coronary artery disease, chronic corticosteroid use, hypoalbuminemia, advanced age, and renal insufficiency). Physical exam and/or quality of life surveys were performed at regular intervals through 18 months (to date) with longer-term, 36-month follow-up ongoing.
Results
One hundred and twenty-one subjects (46M, 75F) with an age of 54.7 ± 12.0 years and BMI of 32.2 ± 4.5 kg/m2 (mean ± SD), underwent VIHR. Comorbidities included the following: obesity (n = 95, 78.5%), hypertension (n = 72, 59.5%), cardiovascular disease (n = 42, 34.7%), diabetes (n = 40, 33.1%), COPD (n = 34, 28.1%), malignancy (n = 30, 24.8%), active smoker (n = 28, 23.1%), immunosuppression (n = 10, 8.3%), chronic corticosteroid use (n = 6, 5.0%), advanced age (n = 6, 5.0%), hypoalbuminemia (n = 3, 2.5%), and renal insufficiency (n = 1, 0.8%). Hernia types included the following: primary ventral (n = 17, 14%), primary incisional (n = 54, 45%), recurrent ventral (n = 15, 12%), and recurrent incisional hernia (n = 35, 29%). Defect and mesh size were 115.7 ± 80.6 and 580.9 ± 216.1 cm2 (mean ± SD), respectively. Repair types included the following: retrorectus (n = 43, 36%), retrorectus with additional myofascial release (n = 45, 37%), onlay (n = 24, 20%), and onlay with additional myofascial release (n = 8, 7%). 95 (79%) subjects completed 18-month follow-up to date. Postoperative wound infection, seroma requiring intervention, and hernia recurrence occurred in 11 (9%), 7 (6%), and 11 (9%) subjects, respectively.
Conclusions
High-risk VIHR with P4HB mesh demonstrated positive outcomes and low incidence of hernia recurrence at 18 months. Longer-term 36-month follow-up is ongoing.
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What happens to biliary colic patients in New York State? 10-year follow-up from emergency department visits
Abstract
Introduction
Biliary colic is a common diagnosis for patients presenting to the emergency department (ED). The purpose of this study is to examine the outcomes of patients coming to the ED with biliary colic.
Methods
The NYS longitudinal SPARCS database was used to identify patients presenting to the ED with biliary colic from 2005 to 2014. Through the use of a unique identifier, patients were followed in NYS across multiple institutions. Patients who were lost to follow-up, with duplicated records, and those that underwent percutaneous cholecystectomy tubes were excluded from the analysis.
Results
Between 2005 and 2014, there were 72,376 patients who presented to an ED with biliary colic. The admission rate was 20.7–26.02%. Overall, most patients who presented to the ED did not undergo surgery (39,567, 54.7%), of which 35,204 (89%) had only one ED visit, while 4,363(11%) returned to the ED (≥ 2 visits). Only 3.23–5.51% of patients underwent cholecystectomy at the time of initial presentation. Most subsequent cholecystectomies were performed electively (27.38–52.51%) (See Table 1 in this article). Average time to surgery among patients with elective cholecystectomy was 178.4 days. From the patients who underwent cholecystectomy, 10.35% had cholecystectomy at their first ED visit, 77.7% had cholecystectomy following the first ED visit, and 12% had multiple ED visits prior to surgery. Among patients who were discharged from the ED, 32% had their surgery at a different hospital than index presentation.
Conclusion
A significant portion of patients (48.6%) who present to the ED with biliary colic will not return or have surgery within 5 years. A third of patients who eventually undergo cholecystectomy will go to another hospital for their surgery.
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Erratum to: Phase 1 study of darolutamide (ODM-201), a new-generation androgen receptor antagonist, in Japanese patients with metastatic castration-resistant prostate cancer
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Surgical Resection Does Not Improve Survival in Multifocal Intrahepatic Cholangiocarcinoma: A Comparison of Surgical Resection with Intra-Arterial Therapies
Abstract
Background
Multifocal intrahepatic cholangiocarcinoma (ICC) has traditionally been treated with surgical resection when amenable. Intra-arterial therapy (IAT) for multifocal ICC has not been directly compared with surgical resection.
Methods
A single-center, retrospective review of consecutive patients treated for multifocal ICC was conducted. Patients with distant metastases or treatment with systemic chemotherapy alone were excluded. Patients were divided into two groups: surgical resection versus IAT; IAT included transarterial chemoembolization (TACE), transarterial radioembolization (TARE), and hepatic arterial infusion (HAI) pump therapy. Subjects were also analyzed by surgical resection, TACE, and HAI pump therapy.
Results
Overall, 116 patients with multifocal ICC were studied, 57 in the surgical resection group and 59 in the IAT group (TACE = 41, HAI pump = 16, TARE = 2). The IAT group was characterized by a higher incidence of bilobar disease (88.1% vs. 47.4%, p < 0.001), larger tumors (median 10.6 vs. 7.5 cm, p = 0.004), higher incidence of macrovascular invasion (44.1% vs. 24.6%, p = 0.027), and higher rate of nodal metastases (57.6% vs. 28.6%, p = 0.002). Median overall survival for surgical resection was 20 months versus 16 months for IAT (p = 0.627). Multivariate analysis found that macrovascular invasion [hazard ratio (HR) 2.52, 95% confidence interval (CI) 1.56–4.09] and non-receipt of systemic chemotherapy (HR 3.81, 95% CI 2.23–6.52) were independent poor prognostic risk factors. Surgical resection was not associated with a survival advantage over IAT on multivariate analysis (p = 0.242).
Conclusion
Despite selection bias for use of surgical resection compared with IAT, no survival advantage was conferred in the treatment of multifocal ICC.
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Pre-operative Axillary Ultrasound-Guided Needle Sampling in Breast Cancer: Comparing the Sensitivity of Fine Needle Aspiration Cytology and Core Needle Biopsy
Abstract
Background
Pre-operative ultrasound-guided needle sampling (UNS) of abnormal axillary lymph nodes in breast cancer can identify patients with axillary metastases and therefore rationalize patient care and inform decision-making. To obtain tissue diagnosis, UNS can be performed by either fine needle aspiration (FNA) or core needle biopsy (CNB). However, few studies have compared the sensitivity of these techniques and the majority show no difference.
Methods
All node-positive patients (those with micro- and macrometastases but not isolated tumor cells) treated at a tertiary referral center between January 2012 and December 2015 were retrospectively identified from pathology records. The result of the first axillary UNS performed on each patient was compared with postoperative histopathology results. The UNS method used was according to individual radiologist preference.
Results
A total of 215 patients underwent FNA (1 patient had bilateral breast cancer and underwent bilateral FNA), and 92 underwent CNB. Sensitivity of CNB was significantly higher than FNA (83.7 vs. 69.0%, P = 0.008). The false-negative rate in the FNA group was therefore higher than in the CNB group by a factor of 2.5. There was no difference in inadequacy rate between the two techniques. There were no complications in the FNA group, and only one hematoma (which did not require operative intervention) in the CNB group.
Conclusions
CNB is safe and should be the preferred technique for UNS to improve sensitivity.
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Stereotactic Body Radiation Therapy for Isolated Local Recurrence After Surgical Resection of Pancreatic Ductal Adenocarcinoma Appears to be Safe and Effective
Abstract
Background
A standardized treatment regimen for unresectable isolated local recurrence (ILR) of pancreatic ductal adenocarcinoma has not been established. This study evaluated the outcomes for patients with ILR who underwent stereotactic body radiation therapy (SBRT).
Methods
The records of patients with ILR who underwent SBRT between 2010 and 2016 were retrospectively reviewed. Symptom palliation and treatment-related toxicity were recorded. Associations between patient or treatment characteristics and overall survival (OS), progression-free survival (PFS), and local progression-free survival (LPFS) were assessed.
Results
The study identified 51 patients who received SBRT for ILR. Of the 51 patients, 26 (51%) had not received radiation therapy before SBRT. The median OS was 36 months after diagnosis. From the first day of SBRT, the median OS, PFS, and LPFS were respectively 16, 7, and 10 months. Patients with a recurrence-free interval of 9 months or longer after surgery had superior OS (P = 0.019). Maintenance chemotherapy after SBRT was associated with superior OS (P < 0.001) and LPFS (P = 0.027). In the multivariable analysis, poorly differentiated tumor grade [hazard ratio (HR) 11.274], positive surgical margins (HR 0.126), and reception of maintenance chemotherapy (HR 0.141) were independently associated with OS. Positive surgical margins (HR 0.255) and maintenance chemotherapy (HR 0.299) were associated with improved LPFS. Of 16 patients, 10 (63%) experienced abdominal pain relief after SBRT. Four patients (8%) experienced grade 3 gastrointestinal toxicity, and one patient experienced grade 4 gastrointestinal toxicity.
Conclusions
Use of SBRT for ILR improved pain for a majority of the patients with acceptable acute and late toxicity. The findings show that SBRT is a feasible treatment for select patients with ILR. For those who receive SBRT, maintenance chemotherapy should be considered.
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Four-Dimensional Computed Tomography: Clinical Impact for Patients with Primary Hyperparathyroidism
Abstract
Background
In recent years, four-dimensional computed tomography (4DCT) has emerged as a new localization study for primary hyperparathyroidism (pHPT).
Objective
We aimed to assess the added value of 4DCT in our institution in the first 4 years of use.
Methods
A retrospective cohort study was conducted from February 2004 to June 2015. Since 2011, patients over 50 years of age without concordant sestamibi-SPECT (SeS) and ultrasound (US) findings underwent 4DCT. Imaging results, surgical findings, histopathology, and postoperative biochemistry were collected.
Results
A total of 536 parathyroid operations in 510 patients were performed during the study period. The overall cure rate was 99.2% after reoperation in some patients, and the overall sensitivity for SeS was 76.0%, and 74.8% for US. Since 2011, 100 patients without concordant SeS/US findings have undergone 4DCT, with a sensitivity of 72.9%. This is in comparison to the sensitivities for SeS (48.3%) and US (52.3%). 4DCT was more sensitive in patients with persistent/recurrent disease (60.0% compared with SeS 43.8% and US 36.4%) and patients with multigland disease (67.4% compared with SeS 40.9% and US 42.1%). Comparison between outcomes in the pre- versus post-CT era demonstrated no difference in the initial cure rate (95.4 vs. 95.9%, p = 0.85) or the rate of minimally invasive parathyroidectomies (74.5 vs. 79.9%, p = 0.22).
Conclusion
Parathyroid 4DCT can aid surgical planning in cases without concordant SeS/US findings; however, the introduction of 4DCT as a second-line test did not change our overall cure rate or rate of minimally invasive parathyroidectomy. The role of 4DCT as the primary localization study for pHPT merits further investigation.
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Isolation and characterization of three new anti-proliferative Sesquiterpenes from Polygonum barbatum and their mechanism via apoptotic pathway
Abstract
Background
The emergence of chemoresistant cancers and toxicity related to existing chemotherapeutic agents, demand the search for new pharmacophore with enhanced anti-cancer activity and least toxicity. For this purpose, three new sesquiterpenes were isolated from ethyl acetate fraction of the aerial parts of the plant Polygonum barbatum and evaluated for their anti-cancer potential.
Methods
The structural elucidation and characterization of the isolated compounds 1–3 were performed using various spectroscopic techniques such as mass, UV, IR, and extensive 1D/2D–NMR spectroscopy. Furthermore, the compounds 1–3 were subjected to screening of anti-cancer activity against different cell lines followed by brief analysis of apoptotic and anti-angiogenic potentials of the potent hit against non-small cell lung carcinoma cell line.
Results
All the compounds 1–3 were subjected to anti-proliferative potential against non-small cell lung carcinoma (NCI-H460), breast cancer (MCF-7), cervical cancer (HeLa) and normal mouse fibroblast (NIH-3 T3) cell lines. Among these, compound 3 was found to be more cytotoxic against NCI-H460 and MCF-7 cells (IC50 = 17.86 ± 0.72 and 11.86 ± 0.46 μM respectively). When compared with the standard drug cisplatin compound 3 was found to have more potent activity against NCI-H460 (IC50 = 19 ± 1.24 μM) as compared to MCF-7 cell lines (IC50 = 9.62 ± 0.5 μM). Compound 3 induced apoptosis in NCI-H460 cells in a dose dependent manner. It significantly downregulated, the expression of anti-apoptotic (BCL-2 L1 and p53) and increased the expression of pro-apoptotic (BAK and BAX) genes. Besides apoptosis, it also significantly reduced the cell migration and downregulated the angiogenic genes (i.e. VEGF and COX-2), thereby, inhibiting angiogenesis in NCI-H460 cells.
Conclusion
Compound 3 possesses potent anti-proliferative potential as well as induced apoptosis and inhibited the cell migration of the cancerous cells by altering the gene expression, responsible for it.
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Whether intermediate-risk stage 1A, grade 1/2, endometrioid endometrial cancer patients with lesions larger than 2 cm warrant lymph node dissection?
Abstract
Background
Our research aimed to investigate whether lymphadenectomy was required in patients with intermediate-risk endometrioid endometrial cancer (EEC).
Methods
Between 1989 and 2015, 1009 patients with intermediate-risk EEC: grade 1 or 2 tumor, <50% myometrial invasion, and a tumor diameter ≥ 2 cm and 818 low-risk patients with grade 1 or 2 tumor, <50% myometrial invasion, and a tumor diameter < 2 cm were enrolled in this study. The rate and risk factors of node metastasis were evaluated and compared between the two risk groups. Survival data were analyzed in patients with intermediate-risk EEC with or without lymphadenectomy.
Results
In all, 624 of 1009 (61.8%) patients with intermediate-risk EEC underwent pelvic ± para-aortic lymphadenectomy with a nodal metastasis rate of 1.9% (12/624), whereas 394 of 818 (48.2%) patients with low-risk EEC underwent pelvic ± para-aortic lymphadenectomy with a nodal metastasis rate of 0.3% (1/394) (p = 0.021). Notably, intermediate-risk EEC patients with a microcystic, elongated and fragmented (MELF) pattern of invasion, lymphatic vascular space invasion (LVSI), diffuse lesions, or lesions located in the cornua were more likely to have node metastasis. The 5-year overall cancer-related survival and the recurrence-free survival rates of the 742 intermediate-risk EEC patients who were followed for more than 3 years were 99.4% and 94.7%, respectively. In intermediate-risk group, 6 patients (6/443, 1.4%) with lymphadenectomy and 9 patients (9/299, 3.0%) without lymphadenectomy recurred, with a mean recurrence time of 38.3 and 18.7 months respectively. The five-year overall and recurrence-free survival rates of intermediate-risk patients with and without lymphadenectomy were similar (100% vs 98.9%, p = 0.351; 95.2% vs 93.3%, p = 0.464).
Conclusion
Patients with intermediate-risk EEC have low nodal metastasis rate and a favorable outcome whether lymphadenectomy is performed or not. Omission of lymphadenectomy may be a reasonable option in the surgical management of patients with intermediate-risk EEC.
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18 F- FDG PET/CT helps differentiate autoimmune pancreatitis from pancreatic cancer
Abstract
Background
18F-FDG PET/CT could satisfactorily show pancreatic and extra-pancreatic lesions in AIP, which can be mistaken for pancreatic cancer (PC). This study aimed to identify 18F-FDG PET/CT findings that might differentiate AIP from PC.
Methods
FDG-PET/CT findings of 26 AIP and 40 PC patients were reviewed. Pancreatic and extra-pancreatic lesions related findings, including maximum standardized uptake values (SUVmax) and patterns of FDG uptake, were identified and compared.
Results
All 26 patients with AIP had increased pancreatic FDG uptake. Focal abnormal pancreatic FDG activities were found in 38/40 (95.00%) PC patients, while longitudinal were found in 18/26 (69.23%) AIP patients. SUVmax was significantly different between AIP and PC, both in early and delayed PET/CT scans (p < 0.05). AUCs were 0.700 (early SUVmax), 0.687 (delayed SUVmax), 0.683 (early lesions/liver SUVmax), and 0.715 (delayed lesion/liver SUVmax). Bile duct related abnormalities were found in 12/26 (46.15%) AIP and 10/40 (25.00%) PC patients, respectively. Incidentally, salivary and prostate gland SUVmax in AIP patients were higher compared with those of PC patients (p < 0.05). In males,an inverted "V" shaped high FDG uptake in the prostate was more frequent in AIP than PC patients (56.00%, 14/25 vs. 5.71%, 2/35). Increased FDG activity in extra-pancreatic bile duct was present in 4/26 of AIP patients, while was observed in none of the PC patients. Only in AIP patients, both diffuse pancreatic FDG accumulation and increased inverted "V" shaped FDG uptake in the prostate could be found simultaneously.
Conclusions
18F-FDG PET/CT findings might help differentiate AIP from PC.
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Hepatic artery infusion chemotherapy using mFOLFOX versus transarterial chemoembolization for massive unresectable hepatocellular carcinoma: a prospective non-randomized study
Abstract
Background
Transarterial chemoembolization (TACE) is recommended as the standard care for unresectable hepatocellular carcinoma (HCC) at Barcelona Clinic Liver Cancer (BCLC) stage A–B. However, the efficacy of TACE on large (≥ 10 cm) stage A–B HCC is far from satisfactory, and it is proposed that hepatic artery infusion chemotherapy (HAIC) might be a better first-line treatment of this disease. Hence, we compared the safety and efficacy of HAIC with the modified FOLFOX (mFOLFOX) regimen and those of TACE in patients with massive unresectable HCC.
Methods
A prospective, non-randomized, phase II study was conducted on patients with massive unresectable HCC. The protocol involved HAIC with the mFOLFOX regimen (oxaliplatin, 85 mg/m2 intra-arterial infusion; leucovorin, 400 mg/m2 intra-arterial infusion; and fluorouracil, 400 mg/m2 bolus infusion and 2400 mg/m2 continuous infusion) every 3 weeks and TACE with 50 mg of epirubicin, 50 mg of lobaplatin, 6 mg of mitomycin, and lipiodol and polyvinyl alcohol particles. The tumor responses, time-to-progression (TTP), and safety were assessed.
Results
A total of 79 patients were recruited for this study: 38 in the HAIC group and 41 in the TACE group. The HAIC group exhibited higher partial response and disease control rates than did the TACE group (52.6% vs. 9.8%, P < 0.001; 83.8% vs. 52.5%, P = 0.004). The median TTPs for the HAIC and TACE groups were 5.87 and 3.6 months (hazard radio [HR] = 2.35, 95% confidence interval [CI] = 1.16–4.76, P = 0.015). More patients in the HAIC group than in the TACE group underwent resection (10 vs. 3, P = 0.033). The proportions of grade 3–4 adverse events (AE) and serious adverse events (SAE) were lower in the HAIC group than in the TACE group (grade 3–4 AEs: 13 vs. 27, P = 0.007; SAEs: 6 vs. 15, P = 0.044). More patients in the TACE group than in the HAIC group had the study treatment terminated early due to intolerable treatment-related adverse events or the withdrawal of consent (10 vs. 2, P = 0.026).
Conclusions
HAIC with mFOLFOX yielded significantly better treatment responses and less serious toxicity than did TACE. HAIC might represent a feasible and promising first-line treatment for patients with massive unresectable HCC.
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Erratum to: Phase 1 study of darolutamide (ODM-201), a new-generation androgen receptor antagonist, in Japanese patients with metastatic castration-resistant prostate cancer
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Heart irradiation reduces microvascular density and accumulation of HSPA1 in mice
Abstract
Purpose
Improvement of radiotherapy techniques reduces the exposure of normal tissues to ionizing radiation. However, the risk of radiation-related late effects remains elevated. In the present study, we investigated long-term effects of radiation on heart muscle morphology.
Materials and methods
We established a mouse model to study microvascular density (MVD), deposition of collagen fibers, and changes in accumulation of heat shock 70 kDa protein 1 (HSPA1) in irradiated heart tissue. Hearts of C57BL/6 mice received a single dose of X‑ray radiation in the range 0.2–16 Gy. Analyses were performed 20, 40, and 60 weeks after irradiation.
Results
Reduction in MD was revealed as a long-term effect observed 20–60 weeks after irradiation. Moreover, a significant and dose-dependent increase in accumulation of HSPA1, both cytoplasmic and nuclear, was observed in heart tissues collected 20 weeks after irradiation. We also noticed an increase in collagen deposition in hearts treated with higher doses.
Conclusions
This study shows that some changes induced by radiation in the heart tissue, such as reduction in microvessel density, increase in collagen deposition, and accumulation of HSPA1, are observed as long-term effects which might be associated with late radiation cardiotoxicity.
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Re: “Assessing the Detection of Middle East Respiratory Syndrome Coronavirus IgG in Suspected and Proven Cases of Middle East Respiratory Syndrome Coronavirus Infection” by Alhetheel et al. (Viral Immunol 2017 [Epub ahead of print]; DOI: 10.1089/vim.2017.0091)
Viral Immunology , Vol. 0, No. 0.
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Chemical meningitis related to intra-CSF liposomal cytarabine
CNS Oncology, Ahead of Print.
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Endoscopic surgery of the olfactory cleft
Source:European Annals of Otorhinolaryngology, Head and Neck Diseases
Author(s): R. Jankowski, C. Rumeau, P. Gallet, D.T. Nguyen, A. Russel, B. Toussaint
The olfactory cleft is the specific site of development of many tumours (respiratory epithelial adenomatoid hamartoma, intestinal-type adenocarcinoma, neuroblastoma, inverted papilloma, glomangiopericytoma, etc.) and is also the site of CSF rhinorrhoea via the cribriform plate (cribri-rhinorrhoea). Olfactory cleft surgery must therefore be considered to be a specific type of surgery, complementary to ethmoidal labyrinth surgery and anterior skull base surgery. Olfactory cleft tumours can be resected according to five different surgical procedures: olfactory cleft mucosal resection, partial resection of the olfactory cleft, total resection of the olfactory cleft, unilateral endoscopic anterior skull base resection, and bilateral endoscopic anterior skull base resection. The diagnosis and closure of cribri-rhinorrhoea (i.e. documented CSF rhinorrhoea, demonstrated to arise from the cribriform plate during endoscopic examination of the olfactory cleft under general anaesthesia in a patient with no localizing signs on imaging) completes this range of treatment options.
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HALO-109–301: a Phase III trial of PEGPH20 (with gemcitabine and nab-paclitaxel) in hyaluronic acid-high stage IV pancreatic cancer
Future Oncology, Ahead of Print.
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An updated review of the JAK1/2 inhibitor (ruxolitinib) in the Philadelphia-negative myeloproliferative neoplasms
Future Oncology, Ahead of Print.
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Nitrite administration improves sepsis-induced myocardial and mitochondrial dysfunction by modulating stress signal responses
Abstract
Purpose
A specific therapeutic strategy in sepsis-induced myocardial dysfunction remains to be determined. Nitrite may have cardioprotective effects against sepsis-induced myocardial dysfunction. This study investigated the cardioprotective effects of nitrite on myocardial function, mitochondrial bioenergetics, and its underlying molecular mechanisms in severe septic rats.
Methods
Sepsis was induced in male Wistar rats by cecal ligation and puncture (CLP). After CLP, we administered normal saline (NS group) or nitrite (nitrite group) subcutaneously. We administered nitrite at different doses (0.1–10 mg/kg) to ascertain the most effective dose and examined cardiac function in an isolated heart experiment 8 h after CLP. We investigated mitochondrial bioenergetics and molecular mechanisms underlying the administration of nitrite in vitro.
Results
In isolated heart experiments, the left ventricular developed pressure (96 ± 5 mmHg) at a moderate nitrite dose (1.0 mg/kg) was significantly higher than that in the NS group (75 ± 4 mmHg, P < 0.05). Mitochondrial oxidative phosphorylation in the nitrite group was significantly higher than that in the NS group (P < 0.01). Immunoblotting revealed that nitrite significantly increased the phosphorylation of Akt (P < 0.05) and reduced the nuclear translocation of NF-κB (P < 0.05) compared with the NS group. Nitrite was also shown to improve the rate of survival in severe septic rats (P < 0.001).
Conclusions
Our results showed that a moderate nitrite dose improved septic myocardial dysfunction at organ, cellular, and molecular levels via modulation of stress signal responses, which resulted in an improvement in survival.
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KRAS mutation and Consensus Molecular Subtypes 2 and 3 are independently associated with reduced immune infiltration and reactivity in colorectal cancer
Purpose: KRAS mutation is a common canonical mutation in CRC, found at differing frequencies in all Consensus Molecular Subtypes (CMS). The independent immunobiological impacts of RAS mutation and CMS are unknown. Thus, we explored the immunobiological effects of KRAS mutation across the CMS spectrum. Experimental Design: Transcriptional analysis of immune genes/signatures was performed with RNA-seq using The Cancer Genome Atlas (TCGA) and the KFSYSCC data set. Multivariate analysis included KRAS status, CMS, tumour location, MSI status, and neoantigen load. Protein expression of STAT1, HLA-Class II, and CXCL10 was analysed by digital immunohistochemistry. Results: The Th1-centric co-ordinated immune response cluster (CIRC) was significantly, albeit modestly, reduced in KRAS mutant CRC in both data sets. Cytotoxic T cells, neutrophils and the interferon gamma pathway were suppressed in KRAS mutant samples. The expression of STAT1 and CXCL10, were reduced at the mRNA and protein levels. In multivariate analysis KRAS mutation, CMS2 and CMS3 were independently predictive of reduced CIRC expression. Immune response was heterogeneous across KRAS mutant CRC: CMS2 KRAS mutant samples have the lowest CIRC expression, reduced expression of the interferon gamma pathway, STAT1 and CXCL10 and reduced infiltration of cytotoxic cells and neutrophils relative to CMS1 and CMS4 and to CMS2 KRAS wild type samples in the TCGA. These trends held in the KFSYSCC data set. Conclusions: KRAS mutation is associated with suppressed Th1/cytotoxic immunity in CRC, the extent of the effect being modulated by CMS subtype. These results add a novel immunobiological dimension to the biological heterogeneity of CRC.
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Homologous Recombination DNA Repair Pathway Disruption and Retinoblastoma Protein Loss are Associated with Exceptional Survival in High-Grade Serous Ovarian Cancer
Purpose: Women with epithelial ovarian cancer generally have a poor prognosis, however a subset of patients has an unexpected dramatic and durable response to treatment. We sought to identify clinical, pathological, and molecular determinants of exceptional survival in women with high-grade serous cancer (HGSC), a disease associated with the majority of ovarian cancer deaths. Experimental Design: We evaluated the histories of 2,283 ovarian cancer patients and, after applying stringent clinical, and pathological selection criteria, identified 96 with HGSC that represented significant outliers in terms of treatment response and overall survival. Patient samples were characterized immunohistochemically and by genome sequencing. Results: Different patterns of clinical response were seen: long progression-free survival (Long-PFS), multiple objective responses to chemotherapy (Multiple Responder), and/or greater than 10-year overall survival (Long-Term Survivors). Pathogenic germline and somatic mutations in genes involved in homologous recombination (HR) repair were enriched in all three groups relative to a population-based series. However, 29% of 10-year survivors lacked an identifiable HR pathway alteration, and tumors from these patients had increased Ki-67 staining. CD8+ tumor-infiltrating lymphocytes were more commonly present in Long-Term Survivors. RB1 loss was associated with long progression-free and overall survival. HR-deficiency and RB1 loss were correlated and co-occurrence was significantly associated with prolonged survival. Conclusions: There was diversity in the clinical trajectory of exceptional survivors associated with multiple molecular determinants of exceptional outcome in HGSC patients. Concurrent HR-deficiency and RB1 loss were associated with favorable outcomes, suggesting that co-occurrence of specific mutations might mediate durable responses in such patients.
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Comprehensive pharmacogenomic profiling of malignant pleural mesothelioma identifies a subgroup sensitive to FGFR inhibition.
Purpose: Despite intense research, treatment options for patients with mesothelioma are limited and offer only modest survival advantage. We screened a large panel of compounds in multiple mesothelioma models, and correlated sensitivity with a range of molecular features to detect biomarkers of drug response. Experimental design: We utilised a high-throughput chemical inhibitor screen in a panel of 889 cancer cell lines, including both immortalised and primary early passage mesothelioma lines, alongside comprehensive molecular characterisation using Illumina whole exome sequencing, copy number analysis and Affymetrix array whole transcriptome profiling. Subsequent validation was done using functional assays such as siRNA silencing and mesothelioma mouse xenograft models. Results: A subgroup of immortalized and primary MPM lines appeared highly sensitive to FGFR inhibition. None of these lines harboured genomic alterations of FGFR family members, but rather BAP1 protein loss was associated with enhanced sensitivity to FGFR inhibition. This was confirmed in a MPM mouse xenograft model and by BAP1 knock-down and overexpression in cell line models. Gene expression analyses revealed an association between BAP1 loss and increased expression of the receptors FGFR1/3 and ligands FGF9/18. These associations were confirmed in a cohort of MPM patient samples. Conclusion: A subgroup of mesotheliomas cell lines harbour sensitivity to FGFR inhibition. BAP1 protein loss enriches for this subgroup, and could serve as a potential biomarker to select patients for FGFR inhibitor treatment. These data identify a clinically relevant MPM subgroup for consideration of FGFR therapeutics in future clinical studies.
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A Phase Ib Study of Immune Biomarker Modulation with Neoadjuvant Cetuximab and TLR8 stimulation in Head and Neck Cancer to Overcome Suppressive Myeloid Signals
Purpose: The response rate of head and neck squamous cell carcinoma (HNSCC) patients to cetuximab therapy is only 15-20%, despite frequent EGFR overexpression. Since immunosuppression is common in HNSCC, we hypothesized that adding a pro-inflammatory TLR8 agonist to cetuximab therapy might result in enhanced T lymphocyte stimulation and anti-EGFR specific priming. Experimental Design: Fourteen patients with previously untreated HNSCC were enrolled in this neoadjuvant trial and treated preoperatively with 3-4 weekly doses of motolimod (2.5 mg/m2) and cetuximab. Correlative tumor and peripheral blood specimens were obtained at baseline and at the time of surgical resection and analyzed for immune biomarker changes. Preclinical in vitro studies were also performed to assess the effect of cetuximab plus motolimod on myeloid cells. Results: TLR8 stimulation skewed monocytes toward an M1 phenotype and reversed MDSC suppression of T cell proliferation in vitro. These data were validated in a prospective phase Ib neoadjuvant trial, in which fewer MDSC and increased M1 monocyte infiltration were found in TIL. Motolimod plus cetuximab also decreased induction of Treg, and reduced markers of suppression, including CTLA-4, CD73 and membrane bound TGF-β. Significantly increased circulating EGFR-specific T cells were observed, concomitant with enhanced CD8+ T cell infiltration into tumors. These T cells manifested increased TCR clonality, upregulation of the costimulatory receptor CD27, and downregulation of inhibitory receptor TIGIT. Conclusions:Enhanced inflammatory stimulation in the tumor microenvironment using a TLR agonist overcomes suppressive myeloid and regulatory cells, enhancing the cellular antitumor immune response by therapeutic mAb in HNSCC.
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Regional Delivery of Chimeric Antigen Receptor-Engineered T Cells Effectively Targets HER2+ Breast Cancer Metastasis to the Brain
Purpose: Metastasis to the brain from breast cancer remains a significant clinical challenge, and may be targeted with CAR-based immunotherapy. CAR design optimization for solid tumors is crucial due to the absence of truly restricted antigen expression and potential safety concerns with "on-target off-tumor" activity. Here, we have optimized HER2-CAR T cells for the treatment of breast to brain metastases, and determined optimal second generation CAR design and route of administration for xenograft mouse models of breast metastatic brain tumors, including multifocal and leptomeningeal disease. Experimental Design: HER2-CAR constructs containing either CD28 or 4-1BB intracellular co-stimulatory signaling domains were compared for functional activity in vitro by measuring cytokine production, T cell proliferation, and tumor killing capacity. We also evaluated HER2-CAR T cells delivered by intravenous, local intratumoral, or regional intraventricular routes of administration using in vivo human xenograft models of breast cancer that have metastasized to the brain. Results: Here, we have shown HER2-CARs containing the 4-1BB co-stimulatory domain confer improved tumor targeting with reduced T cell exhaustion phenotype and enhanced proliferative capacity compared to HER2-CARs containing the CD28 co-stimulatory domain. Local intracranial delivery of HER2-CARs showed potent in vivo anti-tumor activity in an orthotopic xenograft models. Importantly, we demonstrated robust anti-tumor efficacy following regional intraventricular delivery of HER2-CAR T cells for treatment of multifocal brain metastases and leptomeningeal disease. Conclusions: Our study shows the importance of CAR design in defining an optimized CAR T cell, and highlights intraventricular delivery of HER2-CAR T cells for treating multifocal brain metastases.
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Lenalidomide enhances the function of CS1 chimeric antigen receptor redirected T cells against multiple myeloma
Purpose:Multiple myeloma (MM) remains an incurable malignancy of plasma cells despite considerable advances in treatment. The purpose of the study was to develop novel CARs for the treatment of MM and explore combinatorial therapy using CAR T cells and immunomodulatory drugs such as lenalidomide for increasing treatment efficacy. Experimental Design: We redirected central memory T cells to express second-generation CAR specific for CS1 and adoptively transferred them into MM tumor-bearing mice to test their anti-MM activity. CS1 CAR T cells were transduced and expanded in the presence of lenalidomide in vitro. The phenotype and effector function of CS1 CAR T cells treated with and without lenalidomide were compared. Finally, CS1 CAR T cells and lenalidomide were administered to treat MM bearing mice as combinatorial therapy.Results: CS1 CAR T cells exhibited efficient antitumor activity when adoptively transferred into mice. Mechanistic studies indicated that the addition of lenalidomide during CS1 CAR T cell expansion in vitro enhanced the immune functions of CS1 CAR T cells, including cytotoxicity, memory maintenance, Th1 cytokine production, and immune synapse formation. Furthermore, lenalidomide enhanced the anti-tumor activity and persistence of adoptively transferred CS1 CAR T cells in vivo. Conclusions:The study demonstrates that lenalidomide improves the anti-MM properties of CS1-directed CAR T cells and provides a basis for a planned clinical trial using the combination of lenalidomide with engineered T cells against CS1 in relapsed myeloma.
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Meiosis-like Functions in Oncogenesis: A New View of Cancer
Cancer cells have many abnormal characteristics enabling tumors to grow, spread, and avoid immunologic and therapeutic destruction. Central to this is the innate ability of populations of cancer cells to rapidly evolve. One feature of many cancers is that they activate genes that are normally associated with distinct developmental states, including germ cell–specific genes. This has historically led to the proposal that tumors take on embryonal characteristics, the so called embryonal theory of cancer. However, one group of germline genes, not directly associated with embryonic somatic tissue genesis, is the one that encodes the specific factors to drive the unique reductional chromosome segregation of meiosis I, which also results in chromosomal exchanges. Here, we propose that meiosis I–specific modulators of reductional segregation can contribute to oncogenic chromosome dynamics and that the embryonal theory for cancer cell growth/proliferation is overly simplistic, as meiotic factors are not a feature of most embryonic tissue development. We postulate that some meiotic chromosome-regulatory functions contribute to a soma-to-germline model for cancer, in which activation of germline (including meiosis) functions drive oncogenesis, and we extend this to propose that meiotic factors could be powerful sources of targets for therapeutics and biomonitoring in oncology. Cancer Res; 77(21); 1–5. ©2017 AACR.
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miR-6883 family miRNAs target CDK4/6 to induce G1 phase cell cycle arrest in colon cancer cells
CDK4/6 targeting is a promising therapeutic strategy under development for various tumor types. In this study, we used computational methods and TCGA dataset analysis to identify novel miRNAs that target CDK4/6 and exhibit potential for therapeutic development in colorectal cancer (CRC). The 3′UTR of CDK4/6 mRNAs are targeted by a family of miRNAs which includes miR-6883-5p, miR-149*, miR-6785-5p and miR-4728-5p. Ectopic expression of miR-6883-5p or miR-149* downregulated CDK4 and CDK6 levels in human CRC cells. RNA-seq analysis revealed an inverse relationship between the expression of CDK4/6 and miR-149* and intronic miRNA-6883-5p encoding the clock gene PER1 in CRC patient samples. Restoring expression of miR-6883-5p and miR-149* blocked cell growth leading to G0/G1 phase cell cycle arrest and apoptosis in CRC cells. CDK4/6 targeting by miR-6883-5p and miR-149* could only partially explain the observed anti-proliferative effects. Notably, both miRNAs synergized with the frontline CRC chemotherapy drug irinotecan. Further, they re-sensitized mutant p53-expressing cell lines resistant to 5-fluorouracil. Taken together, our results established the foundations of a candidate miRNA-based theranostic strategy to improve CRC management.
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Microglial dysfunction as a key pathologic change in adrenomyeloneuropathy
Abstract
Objective: Mutations in ABCD1 cause the neurodegenerative disease adrenoleukodystrophy, which manifests as the spinal cord axonopathy adrenomyeloneuropathy (AMN) in nearly all males surviving into adulthood. Microglial dysfunction has long been implicated in pathogenesis of brain disease but its role in the spinal cord is unclear.
Methods: We assessed spinal cord microglia in humans and mice with AMN and investigated the role of ABCD1 in microglial activity toward neuronal phagocytosis in cell culture. As mutations in ABCD1 lead to incorporation of very long chain fatty acids into phospholipids, we separately examined the effects of lysophosphatidylcholine (LPC) upon microglia.
Results: Within the spinal cord of humans and mice with AMN, upregulation of several phagocytosis-related markers such as MFGE8 and TREM2 precedes complement activation and synapse loss. Unexpectedly, this occurs in the absence of overt inflammation. LPC C26:0 added to ABCD1-deficient microglia in culture further enhances MFGE8 expression, aggravates phagocytosis and leads to neuronal injury. Furthermore, exposure to a MFGE8 blocking antibody reduces phagocytic activity.
Interpretation: Spinal cord microglia lacking ABCD1 are primed for phagocytosis, affecting neurons within an altered metabolic milieu. Blocking phagocytosis or specific phagocytic receptors may alleviate synapse loss and axonal degeneration. This article is protected by copyright. All rights reserved.
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