Functional analyses of mutations in receptor tyrosine kinase genes in non-small cell lung cancer: double-edged sword of DDR2

Purpose: This study investigated whether mutations of receptor tyrosine kinase (RTK) genes detected using next-generation sequencing (NGS) are suitable therapeutic targets. Experimental design: Fifty surgically resected NSCLC samples were target-resequenced using NGS. We then investigated the functions of the identified RTK gene mutations, including their oncogenic potential, in vitro. Results: Mutations in RTK genes were found in 20 samples (EGFR, 15; ERBB4, 1; ALK, 1; DDR2, 2; FGFR1, 1), mutations in MAPK pathway genes were found in 9 samples (KRAS, 7; NRAS, 1; BRAF, 2), and mutations in PI3K pathway genes were found in 3 samples (PIK3CA, 1; PTEN, 3). Among the mutations in RTKs, the functions of 4 mutations were unclear (ERBB4 D245G; DDR2 H246R and E655K; FGFR1 A263V). These mutations did not exhibit any transformational activities. Neither the phosphorylation nor the protein expressions of RTKs were changed by the DDR2 H246R, ERBB4 D245G, and FGFR1 A263V mutations, although the expression level of the DDR2 protein harboring the E655K mutation was particularly low. Collagen stimulation decreased cellular proliferation through p38 activation in the DDR2 wild-type-overexpressed cell lines, whereas the growth suppressive effect was weakened in DDR2 E655K-overexpressed cell lines. Furthermore, the DDR2 E655K protein strongly bound to ubiquitin ligase E3 (Cbl-b), and the mutant protein expression was increased after treatment with a proteasome inhibitor. Conclusion: Our experimental findings suggest that RTK mutations are not always suitable as therapeutic targets. The DDR2 E655K mutation can play a role in cancer progression by reducing the growth inhibitory effect of collagen.

from Cancer via ola Kala on Inoreader http://ift.tt/1Sqoo9r
via IFTTT

A Matter of Life or Death: Pediatric Oncologists Issue Guidance for Allocating Scarce Chemotherapy Drugs

from Cancer via ola Kala on Inoreader http://ift.tt/1SqomhV
via IFTTT

An Ethical Framework for Allocating Scarce Life-Saving Chemotherapy and Supportive Care Drugs for Childhood Cancer

Shortages of life-saving chemotherapy and supportive care agents for children with cancer are frequent. These shortages directly affect patients' lives, compromise both standard of care therapies and clinical research, and create substantial ethical challenges. Efforts to prevent drug shortages have yet to gain traction, and existing prioritization frameworks lack concrete guidance clinicians need when faced with difficult prioritization decisions among equally deserving children with cancer. The ethical framework proposed in this Commentary is based upon multidisciplinary expert opinion, further strengthened by an independent panel of peer consultants. The two-step allocation process includes strategies to mitigate existing shortages by minimizing waste and addresses actual prioritization across and within diseases according to a modified utilitarian model that maximizes total benefit while respecting limited constraints on differential treatment of individuals. The framework provides reasoning for explicit decision-making in the face of an actual drug shortage. Moreover, it minimizes bias that might occur when individual clinicians or institutions are forced to make bedside rationing and prioritization decisions and addresses the challenge that individual clinicians face when confronted with bedside decisions regarding allocation. Whenever possible, allocation decisions should be supported by evidence-based recommendations. "Curability," prognosis, and the incremental importance of a particular drug to a given patient's outcome are the critical factors to consider when deciding how to allocate scarce life-saving cancer drugs.

from Cancer via ola Kala on Inoreader http://ift.tt/1PopqlA
via IFTTT

Robotic Stereotactic Body Radiation Therapy in Patients With Recurrent or Metastatic Abdominopelvic Tumors: A Single Institute Experience

Background:

The aim of this study was to evaluate the efficacy and toxicity of robotic CyberKnife (Accuray Incorporated, Sunnyvale, California)-based stereotactic body radiation therapy (SBRT) in patients with recurrent or metastatic abdominopelvic tumors.

Methods and Materials:

A total of 69 patients treated between May 2008 and January 2011 were evaluated retrospectively. Indication for SBRT was persistent disease in 3 (4%) patients, local recurrence in 29 (42%) patients, regional recurrence in 13 (19%) patients, and oligometastatic disease in 24 (35%) patients. Forty-two (61%) patients were previously irradiated to the same region and 27 (39%) patients were treated for the first time. The median age was 59 years (range, 24-86 years). There were 31 (45%) male and 38 (55%) female patients. The median total dose was 30 Gy (range, 15-60 Gy) delivered with a median 3 fractions (range, 2-5 fractions). The tumor response to treatment was assessed by computed tomography, magnetic resonance imaging, or positron emission tomography.

Results:

At the 12-month (range, 2-44 months) median follow-up, local control was 65% and median overall survival (OS) was 20 months. A larger gross tumor volume (≥ 67 cm³) was significantly correlated with worse 1-year OS (81% vs 48%, P = .03). The patients with local recurrence occurring <11 months had a significantly shorter 1-year local control rate than patients with ≥11 months (31% vs 91%, P < .001). Grade 3-4 acute and late toxicities were seen in 7% and 15% of patients, respectively. The patients with previous radiotherapy history had significantly higher rate of acute toxicity (19% vs 0%, P = .019). Late toxicity was significantly higher in pelvic tumors than in abdominal tumors (3% vs 28%, P = .004).

Conclusion:

The SBRT seems to be feasible and resulted in good treatment outcomes in patients with recurrent or metastatic abdominopelvic tumors.

from Cancer via ola Kala on Inoreader http://ift.tt/1ZZHKD8
via IFTTT

Comparison of Ray Tracing and Monte Carlo Calculation Algorithms for Thoracic Spine Lesions Treated With CyberKnife-Based Stereotactic Body Radiation Therapy

Stereotactic body radiation therapy (SBRT) is an emerging technology for the treatment of spinal metastases, although the dosimetric impact of the calculation method on spinal dose distribution is unknown. This study attempts to determine whether CyberKnife (CK)-based SBRT using a Ray Tracing (RyTc) algorithm is comparable dosimetrically to that of Monte Carlo (MC) for thoracic spinal lesions. Our institutional CK-based SBRT database for thoracic spinal lesions was queried and a cohort was generated. Patients were planned using RyTc and MC algorithms using the same beam angles and monitor units. Dose–volume histograms of the planning target volume (PTV), spinal cord, esophagus, and skin were generated, and dosimetric parameters were compared. There were 37 patients in the cohort. The average percentage volume of PTV covered by the prescribed dose with RyTc and MC algorithms was 91.1% and 80.4%, respectively (P < .001). The difference in average maximum spinal cord dose between RyTc and MC plans was significant (1126 vs 1084 cGy, P = .004), with the MC dose ranging from 18.7% below to 13.8% above the corresponding RyTc dose. A small reduction in maximum skin dose was also noted (P = .017), although no difference was seen in maximum esophageal dose (P = .15). Only PTVs smaller than 27 cm³ were found to correlate with large (>10%) changes in dose to 90% of the volume (P = .014), while no correlates with the average percentage volume of PTV covered by the prescribed dose were demonstrated. For thoracic spinal CK-based SBRT, RyTc computation may overestimate the MC calculated average percentage volume of PTV covered by the prescribed dose and have unpredictable effects on doses to organs at risk, particularly the spinal cord. In this setting, use of RyTc optimization should be limited and always verified with MC.

from Cancer via ola Kala on Inoreader http://ift.tt/1JNLOEv
via IFTTT

Treatment of Large Brain Metastases With Stereotactic Radiosurgery

Introduction:

We report our series of patients with large brain metastases, >3 cm in diameter, who received stereotactic radiosurgery (SRS) as a component of their treatment, focusing on survival and intracranial recurrence rates.

Materials and Methods:

The brain tumor database was queried for patients treated with SRS for large brain metastases. Local recurrence (LR) and distant brain recurrence (DBR) rates were calculated using cumulative incidence analysis, and overall survival (OS) was calculated using Kaplan-Meier analysis. Patients were classified into 1 of the 4 groups based on treatment strategy: SRS alone, surgery plus SRS, SRS plus whole-brain radiation therapy (WBRT), and salvage SRS from more remote WBRT and/or surgery.

Results:

A total of 153 patients with 164 lesions were evaluated. The SRS alone was the treatment approach in 62 lesions, surgery followed by SRS to the resection bed (S + SRS) in 33, SRS + WBRT in 19, and salvage SRS in 50. There was no statistically significant difference in OS between the 4 treatment groups (P = .06). Median survival was highest in patients receiving surgery + SRS (12.2 months) followed by SRS + WBRT (6.9 months), SRS alone (6.6 months), and salvage SRS (6.1 months). There was also no significant difference for LR rates between the groups at 12 months. No significant variables on univariate analysis were noted for LR. The 12-month DBR rates were highest in the S + SRS group (52%), followed by salvage SRS (31%), SRS alone (28%), and SRS + WBRT (13%; P = .03).

Conclusion:

There were no significant predictors for local control. Keeping in mind that patient numbers in the SRS + WBRT group are small, the addition of WBRT to SRS did not appear to significantly improve survival or local control, supporting the delayed use of WBRT for some patients to prevent potential side effects provided regular imaging surveillance and salvage therapy are utilized. Prospective studies are needed to optimize SRS treatment regimens for patients with large brain metastases.

from Cancer via ola Kala on Inoreader http://ift.tt/1ZZHILk
via IFTTT

High-Dose Robotic Stereotactic Body Radiotherapy in the Treatment of Patients With Prostate Cancer: Preliminary Results in 26 Patients

Background:

Stereotactic body radiotherapy (SBRT) can emulate high dose rate brachytherapy (HDR-BRT) dose fractionation. We report our preliminary results using SBRT in monotherapy or pre-external-beam radiotherapy (EBRT) boost in patients with localized prostate cancer (LpC). The primary end point was the evaluation of both acute and late toxicities; secondary end point was the observation of prostate-specific antigen (PSA) nadir.

Patients and Methods:

Patients with LpC having prostate volume ≤90 cm³ were enrolled in the present study. Patients were treated with SBRT alone or in combined modality (SBRT + EBRT). SBRT was performed using a CyberKnife System (Accuray Incorporated, Sunnyvale, California) and fiducial tracking system.

Results:

From February 2008 to July 2013, 21 patients for monotherapy (38 Gy/4 fractions) and 5 for combined modality (9.5 Gy/2 fractions plus 46 Gy/23 fractions EBRT) were enrolled. Androgen deprivation therapy (ADT) was administered in 16 of the 26 patients. The median pretreatment PSA was 9.4 (range, 4.5-14.3) ng/mL. All patients completed the planned therapy. Acute Grade 1 toxicity was observed in 18 patients, genitourinary (GU) in 12 / 26 patients, and gastrointestinal (GI) in 6 / 26 patients. Acute Grade 2 GU toxicity was reported in 1 / 26 patients, and Grade 2 GI toxicity was observed in 2 / 26 patients. The median PSA nadir was 0.15 (range, 0.02 = 1.4) ng/mL. Late toxicities were observed in 5 / 26 patients: Grade 1 GU (3 of 26), Grade 2 GU (1 of 26), and Grade 1 GI (1 of 26). Median follow-up was 21.5 (range, 8-65) months.

Conclusions:

Our preliminary results of SBRT "simulating" HDR for LpC confirm a minimal toxicity and an optimal PSA response. The PSA nadirs appear comparable with HDR-BRT.

from Cancer via ola Kala on Inoreader http://ift.tt/1JNLNR9
via IFTTT

The Technique, Resources and Costs of Stereotactic Body Radiotherapy of Prostate Cancer: A Comparison of Dose Regimens and Delivery Systems

Robotic system has been used for stereotactic body radiotherapy (SBRT) of prostate cancer. Arc-based and fixed-gantry systems are used for hypofractionated regimens (10-20 ractions) and the standard regimen (39 fractions); they may also be used to deliver SBRT. Studies are currently underway to compare efficacy and safety of these systems and regimens. Thus, we describe the technique and required resources for the provision of robotic SBRT in relation to the standard regimen and other systems to guide investment decisions. Using administrative data of resource volumes and unit prices, we computed the cost per patient, cost per cure and cost per quality adjusted life year (QALY) of four regimens (5, 12, 20 and 39 fractions) and three delivery systems (robotic, arc-based and fixed-gantry) from a payer's perspective. We performed sensitivity analyses to examine the effects of daily hours of operation and in-room treatment delivery times on cost per patient. In addition, we estimated the budget impact when a robotic system is preferred over an arc-based or fixed-gantry system. Costs of SBRT were $6333/patient (robotic), $4368/patient (arc-based) and $4443/patient (fixed-gantry). When daily hours of operation were varied, the cost of robotic SBRT varied from $9324/patient (2 hours daily) to $5250/patient (10 hours daily). This was comparable to the costs of 39 fraction standard regimen which were $5935/patient (arc-based) and $7992/ patient (fixed-gantry). In settings of moderate to high patient volume, robotic SBRT is cost effective compared to the standard regimen. If SBRT can be delivered with equivalent efficacy and safety, the arc-based system would be the most cost effective system.

from Cancer via ola Kala on Inoreader http://ift.tt/1ZZHIv2
via IFTTT

Quality Assurance of a 50-kV Radiotherapy Unit Using EBT3 GafChromic Film: A Feasibility Study

Purpose:

Radiochromic EBT3 film is gaining acceptance as a valuable dosimetry system for high-energy photon beams. The advantages of these films over other dosimetry systems are low spectral sensitivity and high spatial resolution. The aim of this study was to validate EBT3 film as a dosimeter for machine and treatment quality assurance (QA) of a 50-kV radiotherapy unit.

Methods and Materials:

Absolute and relative doses were acquired using EBT3 GafChromic films and compared to a parallel-plate ionization chamber (IC), the standard IC for low-energy X-rays. EBT3 was also used to evaluate beam profiles and output factors. Two films above each other, mimicking the clinical situation of a dosimeter on top of the skin, were simultaneously irradiated to evaluate EBT3 as in vivo dosimeter. All films were irradiated for 3 minutes, which corresponds with a surface dose of 3.25 ± 0.07 Gy.

Results:

A fifth-order polynomial function was found to be the best fit for the calibration curves. Good agreement between IC and EBT3 was found for absolute (0.92% for green and red color channels) and relative (1.2% and 1.0% for green and red color channels, respectively) dosimetry. Output factors for IC and EBT3 were comparable within 2.04% and 1.02% for the green and red color channels, respectively. Flatness and symmetry at the surface were within 2%. By applying film as in vivo dosimeter, an absorption of 4.70% needs to be taken into account with respect to the surface dose.

Conclusion:

EBT3 GafChromic film is a feasible and valuable QA and dosimetry tool for a 50-kV radiotherapy unit. EBT3 can be used for absolute and relative dosimetry, measurement of output factors and beam profiles. In vivo patient-specific QA can also be performed if one corrects for the dose absorption of the film.

from Cancer via ola Kala on Inoreader http://ift.tt/1JNLPbu
via IFTTT

Regarding the Credibility of Data Showing an Alleged Association of Cancer with Radiation from CT Scans

Computed tomography (CT) scans are of high clinical value as a diagnostic technique, and new applications continue to be identified. However, their application is challenged by emerging concerns regarding carcinogenesis from their radiation. Recent articles made a significant contribution to the above-mentioned concerns by reporting evidence for direct association of the radiation from CT scans with cancer. Such interpretation of the data has already been criticized; there is the possibility of reverse causation due to confounding factors. Nevertheless, such work has had a high impact, with one article being cited more than 300 times from the Web of Science Core Collection within 2 years. However, the data points on cancer relative risk versus CT dose in that article fit straight lines corresponding to the linear no-threshold hypothesis suspiciously well. Here, by applying rigorous statistical analysis, it is shown that the probability of the fit truly being that good or better is only 2%. The results of such studies therefore appear "too good to be true" and the credibility of their conclusions must be questioned.

from Cancer via ola Kala on Inoreader http://ift.tt/1ZZHKmH
via IFTTT

Kinetic Models for Predicting Cervical Cancer Response to Radiation Therapy on Individual Basis Using Tumor Regression Measured In Vivo With Volumetric Imaging

This article describes a macroscopic mathematical modeling approach to capture the interplay between solid tumor evolution and cell damage during radiotherapy. Volume regression profiles of 15 patients with uterine cervical cancer were reconstructed from serial cone-beam computed tomography data sets, acquired for image-guided radiotherapy, and used for model parameter learning by means of a genetic-based optimization. Patients, diagnosed with either squamous cell carcinoma or adenocarcinoma, underwent different treatment modalities (image-guided radiotherapy and image-guided chemo-radiotherapy). The mean volume at the beginning of radiotherapy and the end of radiotherapy was on average 23.7 cm³ (range: 12.7-44.4 cm³) and 8.6 cm³ (range: 3.6-17.1 cm³), respectively. Two different tumor dynamics were taken into account in the model: the viable (active) and the necrotic cancer cells. However, according to the results of a preliminary volume regression analysis, we assumed a short dead cell resolving time and the model was simplified to the active tumor volume. Model learning was performed both on the complete patient cohort (cohort-based model learning) and on each single patient (patient-specific model learning). The fitting results (mean error: ~16% and ~6% for the cohort-based model and patient-specific model, respectively) highlighted the model ability to quantitatively reproduce tumor regression. Volume prediction errors of about 18% on average were obtained using cohort-based model computed on all but 1 patient at a time (leave-one-out technique). Finally, a sensitivity analysis was performed and the data uncertainty effects evaluated by simulating an average volume perturbation of about 1.5 cm³ obtaining an error increase within 0.2%. In conclusion, we showed that simple time-continuous models can represent tumor regression curves both on a patient cohort and patient-specific basis; this discloses the opportunity in the future to exploit such models to predict how changes in the treatment schedule (number of fractions, doses, intervals among fractions) might affect the tumor regression on an individual basis.

from Cancer via ola Kala on Inoreader http://ift.tt/1JNLMfT
via IFTTT

Decision Trees Predicting Tumor Shrinkage for Head and Neck Cancer: Implications for Adaptive Radiotherapy

Objective:

To develop decision trees predicting for tumor volume reduction in patients with head and neck (H&N) cancer using pretreatment clinical and pathological parameters.

Methods:

Forty-eight patients treated with definitive concurrent chemoradiotherapy for squamous cell carcinoma of the nasopharynx, oropharynx, oral cavity, or hypopharynx were retrospectively analyzed. These patients were rescanned at a median dose of 37.8 Gy and replanned to account for anatomical changes. The percentages of gross tumor volume (GTV) change from initial to rescan computed tomography (CT; %GTV) were calculated. Two decision trees were generated to correlate %GTV in primary and nodal volumes with 14 characteristics including age, gender, Karnofsky performance status (KPS), site, human papilloma virus (HPV) status, tumor grade, primary tumor growth pattern (endophytic/exophytic), tumor/nodal/group stages, chemotherapy regimen, and primary, nodal, and total GTV volumes in the initial CT scan. The C4.5 Decision Tree induction algorithm was implemented.

Results:

The median %GTV for primary, nodal, and total GTVs was 26.8%, 43.0%, and 31.2%, respectively. Type of chemotherapy, age, primary tumor growth pattern, site, KPS, and HPV status were the most predictive parameters for primary %GTV decision tree, whereas for nodal %GTV, KPS, site, age, primary tumor growth pattern, initial primary GTV, and total GTV volumes were predictive. Both decision trees had an accuracy of 88%.

Conclusions:

There can be significant changes in primary and nodal tumor volumes during the course of H&N chemoradiotherapy. Considering the proposed decision trees, radiation oncologists can select patients predicted to have high %GTV, who would theoretically gain the most benefit from adaptive radiotherapy, in order to better use limited clinical resources.

from Cancer via ola Kala on Inoreader http://ift.tt/1ZZHIuT
via IFTTT

Investigation of Dose Falloff for Intact Brain Metastases and Surgical Cavities Using Hypofractionated Volumetric Modulated Arc Radiotherapy

Introduction:

Intact brain metastases tend to be small and spherical compared to postsurgery brain cavities, which tend to be large and irregular shaped and, as a result, a challenge with respect to treatment planning. The purpose of the present study is to develop guidelines for normal brain tissue dose and to investigate whether there is a dependence on target type for patients treated with hypofractionated volumetric modulated arc radiotherapy (HF-VMAT).

Methods:

Treatment plans from a total of 100 patients and 136 targets (55 cavity and 81 intact) were retrospectively reviewed. All targets were treated with HF-VMAT with total doses ranging between 20 and 30 gray (Gy) in 5 fractions. All plans met institutional objectives for organ-at-risk constraints and were clinically delivered. Dose falloff was quantified using gradient index (GI) and distance between the 100% and 50% isodose lines (R50). Additionally, the dose to normal brain tissue (brain contour excluding all gross tumor or clinical target volumes) was assessed using volume receiving specific doses (Vx) where x ranged from 5 to 30 Gy. Best-fit curves using power law relationships of the form y = ax^b were generated for GI, R50, and Vx (normal brain tissue) versus target volume.

Results:

There was a statistically significant difference in planning target volume (PTV) for cavities versus intact metastases with mean volumes of 37.8 cm³ and 9.5 cm³, respectively (P < .0001). The GI and R50 were statistically different: 3.4 and 9.8 mm for cavities versus 4.6 and 8.3 mm for intact metastases (P < .0001). The R50 increased with PTV with power law coefficients (a, b) = (6.3, 0.12) and (5.9, 0.15) for cavities and intact, respectively. GI decreased with PTV with coefficients (a, b) = (5.9, –0.18) and (5.7, –0.14) for cavities and intact, respectively. The normal brain tissue Vx also exhibited power law relationships with PTV for x = 20 to 28.8 Gy. In conclusion, target volume is the main predictor of dose falloff. The results of the present study can be used for determining target volume-based thresholds for dose falloff and normal brain tissue dose–volume constraints.

from Cancer via ola Kala on Inoreader http://ift.tt/1JNLLIY
via IFTTT

Ga-68 MAA Perfusion 4D-PET/CT Scanning Allows for Functional Lung Avoidance Using Conformal Radiation Therapy Planning

Background:

Ga-68-macroaggregated albumin (⁶⁸Ga-perfusion) positron emission tomography/computed tomography (PET/CT) is a novel imaging technique for the assessment of functional lung volumes. The purpose of this study was to use this imaging technique for functional adaptation of definitive radiotherapy plans in patients with non-small cell lung cancer (NSCLC).

Methods:

This was a prospective clinical trial of patients with NSCLC who received definitive 3-dimensional (3D) conformal radiotherapy to 60 Gy in 30 fx and underwent pretreatment respiratory-gated (4-dimensional [4D]) perfusion PET/CT. The "perfused" lung volume was defined as all lung parenchyma taking up radiotracer, and the "well-perfused" lung volume was contoured using a visually adapted threshold of 30% maximum standardized uptake value (SUVmax). Alternate 3D conformal plans were subsequently created and optimized to avoid perfused and well-perfused lung volumes. Functional dose volumetrics were compared using mean lung dose (MLD), V5 (volume receiving 5 Gy or more), V10, V20, V30, V40, V50, and V60 parameters.

Results:

Fourteen consecutive patients had alternate radiotherapy plans created based on functional lung volumes. When considering the original treatment plan, the dose to perfused and well-perfused functional lung volumes was similar to that of the conventional anatomical lung volumes with an average MLD of 12.15, 12.67, and 12.11 Gy, respectively. Plans optimized for well-perfused lung improved functional V30, V40, V50, and V60 metrics (all P values <.05). The functional MLD of well-perfused lung was improved by a median of 0.86 Gy, P < .01. However, plans optimized for perfused lung only showed significant improvement in the functional V60 dose parameter (median 1.00%, P = .04) but at a detriment of a worse functional V5 (median 3.33%, P = .05).

Conclusions:

This study demonstrates proof of principle that 4D-perfusion PET/CT may enable functional lung avoidance during treatment planning of patients with NSCLC. Radiotherapy plans adapted to well-perfused but not perfused functional lung volumes allow for reduction in dose to functional lung using 3D conformal radiotherapy.

from Cancer via ola Kala on Inoreader http://ift.tt/1JNLLIP
via IFTTT

Stopping Criteria for Log-Domain Diffeomorphic Demons Registration: An Experimental Survey for Radiotherapy Application

A crucial issue in deformable image registration is achieving a robust registration algorithm at a reasonable computational cost. Given the iterative nature of the optimization procedure an algorithm must automatically detect convergence, and stop the iterative process when most appropriate. This paper ranks the performances of three stopping criteria and six stopping value computation strategies for a Log-Domain Demons Deformable registration method simulating both a coarse and a fine registration. The analyzed stopping criteria are: (a) velocity field update magnitude, (b) mean squared error, and (c) harmonic energy. Each stoping condition is formualted so that the user defines a threshold , which quantifies the residual error that is acceptable for the particular problem and calculation strategy. In this work, we did not aim at assigning a value to e, but to give insights in how to evaluate and to set the threshold on a given exit strategy in a very popular registration scheme. Experi-ments on phantom and patient data demonstrate that comparing the optimization metric minimum over the most recent three iterations with the minimum over the fourth to sixth most recent iterations can be an appropriate algorithm stopping strategy. The harmonic energy was found to provide best trade-off between robustness and speed of convergence for the analyzed registration method at coarse registration, but was outperformed by mean squared error when all the original pixel information is used. This suggests the need of developing mathematically sound new convergence criteria in which both image and vector field information could be used to detect the actual convergence, which could be especially useful when considering multi-resolution registrations. Further work should be also dedicated to study same strategies performances in other deformable registration methods and body districts.

from Cancer via ola Kala on Inoreader http://ift.tt/1ZZHK62
via IFTTT

Application of Spatially Fractionated Radiation (GRID) to Helical Tomotherapy using a Novel TOMOGRID Template

Spatially fractionated radiation therapy (GRID) with megavoltage x-ray beam is typically used to treat large and bulky malignant tumors. Currently most of the GRID treatment is performed by using the linear accelerator with either the multileaf collimator or with the commercially available block. A novel method to perform GRID treatments using Helical Tomotherapy (HT) was developed at the Radiation Oncology Department, College of Medicine, the University of Arkansas for Medical Sciences. In this study, we performed a dosimetric comparison of two techniques of GRID therapy: one on linear accelerator with a commercially available GRID block (LINAC-GRID) as planned on the Pinnacle planning station (P-TPS); and helical tomotherapy-based GRID (HT-GRID) technique using a novel virtual TOMOGRID template planned on Tomotherapy treatment planning station (HT-TPS). Three dosimetric parameters: gross target volume (GTV) dose distribution, GTV target dose inhomogeneity, and doses to regions of interest were compared. The comparison results show that HT-GRID dose distributions are comparable to those of LINAC-GRID for GTV coverage. Doses to the majority of organs-at-risk (OAR) are lower in HT-GRID as compared to LINAC-GRID. The maximum dose to the normal tissue is reduced by 120% for HT-GRID as compared to the LINACGRID. This study indicate that HT-GRID can be used to deliver spatially fractionated dose distributions while allowing 3-D optimization of dose to achieve superior sparing of OARs and confinement of high dose to target.

from Cancer via ola Kala on Inoreader http://ift.tt/1JNLLsi
via IFTTT

A Combined Negative and Positive Enrichment Assay for Cancer Cells Isolation and Purification

Cancer cells that detach from solid tumor and circulate in the peripheral blood (CTCs) have been considered as a new "biomarker" for the detection and characterization of cancers. However, isolating and detecting cancer cells from the cancer patient peripheral blood have been technically challenging, owing to the small sub-population of CTCs (a few to hundreds per milliliter). Here we demonstrate a simple and efficient cancer cells isolation and purification method. A biocompatible and surface roughness controllable TiO₂ nanofilm was deposited onto a glass slide to achieve enhanced topographic interactions with nanoscale cellular surface components, again, anti-CD45 (a leukocyte common antigen) and anti-EpCAM (epithelial cell adhesion molecule) were then coated onto the surface of the nanofilm for advance depletion of white blood cells (WBCs) and specific isolation of CTCs, respectively. Comparing to the conventional positive enrichment technology, this method exhibited excellent biocompatibility and equally high capture efficiency. Moreover, the maximum number of background cells (WBCs) was removed, and viable and functional cancer cells were isolated with high purity. Utilizing the horizontally packed TiO₂ nanofilm improved pure CTC-capture through combining cell-capture-agent and cancer cell-preferred nanoscale topography, which represented a new method capable of obtaining biologically functional CTCs for subsequent molecular analysis.

from Cancer via ola Kala on Inoreader http://ift.tt/1ZZHIeo
via IFTTT

Hippocampus-Sparing Whole-Brain Radiotherapy and Simultaneous Integrated Boost for Multiple Brain Metastases From Lung Adenocarcinoma: Early Response and Dosimetric Evaluation

In this study, the volume response and treatment outcome after hippocampus-sparing whole-brain radiotherapy (HS-WBRT) with simultaneous integrated boost (SIB) using tomotherapy were evaluated. Patients with primary lung adenocarcinoma and multiple brain metastases who had a Karnofsky performance status ≥70 and exhibited well-controlled extracranial disease were treated. The prescribed dose was administered in 10 to 14 fractions as 25 to 28 Gy to whole-brain parenchyma, as 40 to 48 Gy to the gross metastatic lesion, and as 30 to 42 Gy to a 5-mm margin to the metastatic lesion. Double-dose gadolinium contrast-enhanced magnetic resonance imaging at 1-mm slice thickness was performed before treatment and at 1, 4, and 7 months post-treatment. The tumor volume reduction ratio was calculated for each follow-up. Between July 2011 and September 2012, 11 patients with 70 lesions were included in this analysis. The median number of lesions per patient was 4 (range, 2-15). The median initial tumor volume was 0.235 cm³ (range, 0.020-10.140 cm³). The treatment plans were evaluated regarding conformation number (CN), target coverage (TC), and homogeneity index (HI). The median follow-up duration was 14 months (range, 3-25 months) and the 1-year intracranial control rate was 67%. The tumor volume reduction was most prominent during the first month with a median reduction rate of 0.717 (range, –0.190 to 1.000). Complete remission was seen in 22 (33%) lesions, and 45 (64%) lesions showed more than 65% reduction in tumor volume. The CN, TC, and HI values were comparable to that of previous studies, and the mean hippocampal dose was 13.65 Gy. No treatment breaks or ≥G3 acute toxicities were observed during or after treatment. The HS-WBRT with SIB in patients with multiple brain metastases was effective and feasible for volume reduction and showed excellent intracranial control.

from Cancer via ola Kala on Inoreader http://ift.tt/1JNLLbL
via IFTTT

Hypoxic Microenvironment Induces EMT and Upgrades Stem-Like Properties of Gastric Cancer Cells

Hypoxia microenvironment, as a major feature of solid tumors, increases tumors progression and metastasis. To research whether hypoxia influences the epithelial–mesenchymal transition (EMT) and cancer stem cells (CSCs) of gastric cancer cells and their cell biological behaviors. Human gastric cancer cell lines BGC823 and SGC7901 were cultivated in different oxygen tensions for proliferation, colony formation, soft agar formation, migration, and invasion analyses. Markers of EMT (E-cadherin, N-cadherin, Vimentin, and Snail) and markers of CSCs (Sox2, Oct4, and Bmi1) were investigated by real-time polymerase chain reaction, Western blotting, and immunofluorescent analysis. Cultivated at hypoxic condition, BGC823 and SGC7901 cells morphology began to change significantly. The cells pretreated under hypoxia grew faster than those cells always cultivated in normoxia. Meanwhile, hypoxia pretreatment dramatically promoted cell proliferation, migration and invasion, and increased capability of colony and soft agar colony formation. Furthermore, under hypoxia, E-cadherin decreased and N-cadherin, Vimentin, Snail, Sox2, Oct4, and Bmi1 increased both on the level of messenger RNA and protein. We drew a conclusion that the hypoxic microenvironment induced EMT, upgraded stem-like properties of gastric cancer cells, promoted invasion and metastasis, and behaved more malignantly.

from Cancer via ola Kala on Inoreader http://ift.tt/1JNLKVn
via IFTTT

4DCT Simulation With Synchronized Contrast Injection in Liver SBRT Patients

Background/Purpose:

Delivering stereotactic body radiotherapy for liver metastases remains a challenge because of respiratory motion and poor visibility without intravenous contrast. The purpose of this article is to describe a novel and simple computed tomography (CT) simulation process of integrating timed intravenous contrast that could overcome the uncertainty of target delineation.

Methods and Results:

The simulation involves two 4-dimensional CT (4DCT) scans. The first scan only encompasses the immediate region of the tumor and surrounding tissue, which reduces the 4DCT scan time so that it can be optimally timed with intravenous contrast injection. The second 4DCT scan covers a larger volume and is used as the primary CT data set for dose calculation, as well as patient setup verification on the treatment unit. The combination of the two 4DCT scans allows us to optimally visualize liver metastases over all phases of the breathing cycle while simultaneously acquiring a long enough 4DCT data set that is suitable for planning and patient setup verification.

Conclusion:

This simulation technique allows for a better target definition when treating liver metastases, without being invasive.

from Cancer via ola Kala on Inoreader http://ift.tt/1JNLJAJ
via IFTTT

Computer-Aided Diagnosis for Distinguishing Pancreatic Mucinous Cystic Neoplasms From Serous Oligocystic Adenomas in Spectral CT Images

Objective:

This preliminary study aims to verify the effectiveness of the additional information provided by spectral computed tomography (CT) with the proposed computer-aided diagnosis (CAD) scheme to differentiate pancreatic serous oligocystic adenomas (SOAs) from mucinous cystic neoplasms of pancreas cystic lesions.

Materials and Methods:

This study was conducted from January 2010 to October 2013. Twenty-three patients (5 men and 18 women; mean age, 43.96 years old) with SOA and 19 patients (3 men and 16 women; mean age, 41.74 years old) with MCN were included in this retrospective study. Two types of features were collected by dual-energy spectral CT imaging as follows: conventional and additional quantitative spectral CT features. Classification results of the CAD scheme were compared using the conventional features and full feature data set. Important features were selected using support vector machine classification method combined with feature-selection technique. The optimal cutoff values of selected features were determined through receiver–operating characteristic curve analyses.

Results:

Combining conventional features with additional spectral CT features improved the overall accuracy from 88.37% to 93.02%. The selected features of the proposed CAD scheme were tumor size, contour, location, and low-energy CT values (43 keV). Iodine–water basis material pair densities in both arterial phase (AP) and portal venous phase (PP) were important factors for differential diagnosis of SOA and MCN. The optimal cutoff values of long axis, short axis, 40 keV monochromatic CT value in AP, iodine (water) density in AP, 43 keV monochromatic CT value in PP, and iodine (water) density in PP were 3.4 mm, 3.1 mm, 35.7 Hu, 0.32533 mg/mL, 39.4 Hu, and 0.348 mg/mL, respectively.

Conclusion:

The combination of conventional features and additional information provided by dual-energy spectral CT shows a high accuracy in the CAD scheme. The quantitative information of spectral CT may prove useful in the diagnosis and classification of SOAs and MCNs with machine learning algorithms.

from Cancer via ola Kala on Inoreader http://ift.tt/1JNLJkg
via IFTTT

Distinguishing Cancerous Liver Cells Using Surface-Enhanced Raman Spectroscopy

Raman spectroscopy has been widely used in biomedical research and clinical diagnostics. It possesses great potential for the analysis of biochemical processes in cell studies. In this article, the surface-enhanced Raman spectroscopy (SERS) of normal and cancerous liver cells incubated with SERS active substrates (gold nanoparticle) was measured using confocal Raman microspectroscopy technology. The chemical components of the cells were analyzed through statistical methods for the SERS spectrum. Both the relative intensity ratio and principal component analysis (PCA) were used for distinguishing the normal liver cells (QSG-7701) from the hepatoma cells (SMMC-7721). The relative intensity ratio of the Raman spectra peaks such as I₉₃₇/I₁₂₀₉, I₁₂₇₆/I₁₃₀₈, I₁₃₄₂/I₁₃₇₅, and I₁₄₀₂/I₁₄₃₅ was set as the judge boundary, and the sensitivity and the specificity using PCA method were calculated. The results indicated that the surface-enhanced Raman spectrum could provide the chemical information for distinguishing the normal cells from the cancerous liver cells and demonstrated that SERS technology possessed the possible applied potential for the diagnosis of liver cancer.

from Cancer via ola Kala on Inoreader http://ift.tt/1JNLKEK
via IFTTT

Management of Liver Cancer Argon-helium Knife Therapy with Functional Computer Tomography Perfusion Imaging

The objective of this study was to observe the change in blood perfusion of liver cancer following argon-helium knife treatment with functional computer tomography perfusion imaging. Twenty-seven patients with primary liver cancer treated with argon-helium knife and were included in this study. Plain computer tomography (CT) and computer tomography perfusion (CTP) imaging were conducted in all patients before and after treatment. Perfusion parameters including blood flows, blood volume, hepatic artery perfusion fraction, hepatic artery perfusion, and hepatic portal venous perfusion were used for evaluating therapeutic effect. All parameters in liver cancer were significantly decreased after argon-helium knife treatment (p < 0.05 to all). Significant decrease in hepatic artery perfusion was also observed in pericancerous liver tissue, but other parameters kept constant. CT perfusion imaging is able to detect decrease in blood perfusion of liver cancer post-argon-helium knife therapy. Therefore, CTP imaging would play an important role for liver cancer management followed argon-helium knife therapy.

from Cancer via ola Kala on Inoreader http://ift.tt/1UwrjN4
via IFTTT

Guido C. Currarino, MD, Dec. 17, 1920 – Dec. 20, 2015

from Cancer via ola Kala on Inoreader http://ift.tt/20yNqGg
via IFTTT

Brain 18 F-FDG, 18 F-Florbetaben PET/CT, 123 I-FP-CIT SPECT and Cardiac 123 I-MIBG Imaging for Diagnosis of a "Cerebral Type" of Lewy Body Disease

Abstract

A 67-year-old man was referred for fluctuating neuropsychiatric symptoms, featuring depression, delirious episodes, recurrent visual hallucinations and catatonic syndrome associated with cognitive decline. No parkinsonism was found clinically even under neuroleptic treatment. ¹⁸F-FDG PET/CT showed hypometabolism in the posterior associative cortex including the occipital cortex, suggesting Lewy body dementia, but ¹²³I-FP-CIT SPECT was normal and cardiac ¹²³I-MIBG imaging showed no signs of sympathetic denervation. Alzheimer's disease was excluded by a normal ¹⁸F-florbetaben PET/CT. This report suggests a rare case of α-synucleinopathy without brainstem involvement, referred to as "cerebral type" of Lewy body disease.

from Cancer via ola Kala on Inoreader http://ift.tt/1nTXhIQ
via IFTTT

Using the inverse Poisson distribution to calculate multiplicity of infection and viral replication by a high-throughput fluorescent imaging system

from Cancer via ola Kala on Inoreader http://ift.tt/1PKExrC
via IFTTT

Risk factors for severity and mortality in patients with MERS-CoV: Analysis of publicly available data from Saudi Arabia

from Cancer via ola Kala on Inoreader http://ift.tt/1m2Sl2A
via IFTTT

Two-tube multiplex real-time reverse transcription PCR to detect six human coronaviruses

from Cancer via ola Kala on Inoreader http://ift.tt/1PKEz2y
via IFTTT

Assessment for diagnosis of lymph node metastasis in esophageal cancer using endoscopic ultrasound elastography

Abstract

Background

We performed endoscopic ultrasound real-time tissue elastography to more accurately diagnose lymph node metastasis of esophageal cancer. The aim of this study was to evaluate the ability of EUS elastography to distinguish benign from malignant lymph nodes in esophageal cancer patients.

Methods

The present study had two steps. As the first step (study 1), we developed diagnostic criteria for metastatic lymph nodes using elastography and verified the validity of the criteria. Three hundred and twenty-two lymph nodes from 35 patients treated by surgical resection were included in the study. As the second step (study 2), we preoperatively examined the lymph nodes of esophageal cancer patients with EUS elastography and compared its diagnostic performance with that of the conventional B-mode EUS images. A total of 115 lymph nodes from 31 patients were included.

Results

In study 1, lymph nodes were considered malignant if 50 % or more of the node appeared blue, or if the peripheral part of the lesion was blue and the central part was red/yellow/green. The sensitivity and specificity of the elastography were 79.7 and 97.6 % with an accuracy of 93.8 %, which was significantly higher than the values for conventional B-mode imaging. In study 2, the sensitivity and specificity of the EUS elastography were 91.2 and 94.5 % with an accuracy of 93.9 %, which was also significantly higher than the values for conventional B-mode EUS imaging.

Conclusions

The present study demonstrated that EUS elastography is useful for diagnosing lymph node metastasis of esophageal cancer.

from Cancer via ola Kala on Inoreader http://ift.tt/1ZZAYNu
via IFTTT

Exploiting IL-17-producing CD4 + and CD8 + T cells to improve cancer immunotherapy in the clinic

Abstract

Cancer immunotherapy is one the most effective approaches for treating patients with tumors, as it bolsters the generation and persistence of memory T cells. In preclinical work, it has been reported that adoptively transferred CD4⁺ and CD8⁺ lymphocytes that secrete IL-17A (i.e., Th17 and Tc17 cells) regress tumors to a greater extent than IFN-γ⁺Th1 or Tc1 cells in vivo. Herein, we review the mechanisms underlying how infused Th17 and Tc17 cells regress established malignancies in clinically relevant mouse models of cancer. We also discuss how unique signaling cues—such as co-stimulatory molecules (ICOS and 41BB), cytokines (IL-12 and IL-23) or pharmaceutical reagents (Akt inhibitors, etc.)—can be exploited to bolster the therapeutic potential of IL-17⁺ lymphocytes with an emphasis on using this knowledge to improve next-generation clinical trials for patients with cancer.

from Cancer via ola Kala on Inoreader http://ift.tt/1QxQA8u
via IFTTT

XBP1 silencing decreases glioma cell viability and glycolysis possibly by inhibiting HK2 expression

Abstract

Glioma cells rely on glycolysis to obtain energy and sustain their survival under microenvironmental stress in vivo. The mechanisms of regulation of glycolysis in glioma cells are unclear. Signaling pathway mediated by the transcription factor X box-binding protein 1 (XBP1) is one of the most important pathways of unfolded protein response which is comprehensively activated in cancer cells upon the microenvironmental stress. Here we showed that XBP1 was significantly activated in glioma tissues in vivo. XBP1 silencing resulted in decreasing of glioma cell viability and ATP/lactate production under hypoxia, which is possibly mediated by inhibition of Hexokinase II (HK2)'s expression. More importantly, XBP1 silenced glioma cells showed the decrease of tumor formation capacity. Our results revealed that XBP1s activation was involved in glioma glycolysis regulation and might be a potential molecular target for glioma treatment.

from Cancer via ola Kala on Inoreader http://ift.tt/1Pa4UUa
via IFTTT

Intra-arterial administration improves temozolomide delivery and efficacy in a model of intracerebral metastasis, but has unexpected brain toxicity

Abstract

We tested the hypothesis that intra-arterial (IA) infusion of temozolomide into the internal carotid artery would safely improve drug delivery to brain and enhance chemotherapy efficacy in a chemosensitive rat brain tumor model. Quantitative autoradiography after 25 µCi ¹⁴C-temozolomide was given by oral, intravenous, or IA route of administration, or IA with osmotic blood–brain barrier disruption (BBBD) (n = 5–7 per group) showed that both IA and IA/BBBD administration increased drug delivery in tumor by over threefold compared to normal brain (P < 0.02), and also significantly elevated delivery throughout the infused right hemisphere. Temozolomide (20 mg/kg; ~150 mg/m²) increased median survival when given by oral (25.5 days), intravenous (25.5 days), or IA (33 days) route of administration, compared to 17.5 days in untreated controls (n = 8 per group; overall P < 0.0001). Survival time after IA temozolomide was significantly longer than all other groups (P < 0.01 for all comparisons). BBBD temozolomide was toxic in the efficacy study, but there was no evidence of symptomatic neurotoxicity in rats given IA temozolomide. After these promising animal results, a 49 year old male with glioblastoma multiforme who failed all standard therapy received temozolomide 100 mg/m² IA. Upon initiation of the second course of IA infusion the patient had increased heart rate, blood pressure, and rash, and the procedure was terminated without sequelae. Follow up IA infusion of temozolomide diluent in normal rats showed damaged cerebrovasculature as determined by dye leakage. These results demonstrate that IA infusion of temozolomide was toxic, with or without BBBD. We conclude that under the current formulation temozolomide is not safe for IA infusion in patients.

from Cancer via ola Kala on Inoreader http://ift.tt/1PZHCy0
via IFTTT

Survival but not brain metastasis response relates to lung cancer mutation status after radiosurgery

Abstract

We prospectively addressed whether EGFR and KRAS mutations, EML4-ALK, ROS1 and RET rearrangements, or wild-type (WT), affects radiosurgery outcomes and overall survival (OS) in non-small cell lung cancer (NSCLC) patients with brain metastases (BM). Of 326 patients with BM treated in 2012–2014 with Gamma Knife radiosurgery (GKRS), 112 NSCLC patients received GKRS as their initial intracranial treatment. OS, intracranial progression-free survival, and time to intracranial failure were determined. Univariate and multivariate analysis were performed to determine factors affecting OS. Toxicity of treatment was evaluated. Median follow-up was 9 months. Patients with EGFR mutant BM had improved survival compared to WT. Median time to development of BM was higher in EGFR mutant patients, but this difference was not significant (2.2 vs 0.9 months; p = 0.2). Median time to distant brain failure was independent of EGFR mutation status. Karnofsky performance status (KPS), non-squamous histopathology, targeted therapy, systemic disease control, EGFR mutation, and low tumor volume were predictive of increased OS on univariate analysis. KPS (p = 0.001) and non-squamous histopathology (p = 0.03) continued to be significant on multivariate analysis. Patients with EGFR mutant BM underwent salvage treatment more often than those without (p = 0.04). Treatment-related toxicity was no different in patients treated with GKRS combined with targeted therapies versus GKRS alone (5 vs 7 %, p = 0.7). Patients with EGFR mutant BM had improved survival compared to a WT cohort. Intracranial disease control following radiosurgery was similar for all tumor subtypes. Radiosurgery is effective for BM and concurrent treatment with targeted therapy appears to be safe.

from Cancer via ola Kala on Inoreader http://ift.tt/1PZHE9j
via IFTTT

Braf V600E mutation in melanoma: translational current scenario

Abstract

Melanoma was one of the translational cancer examples in clinic, including target therapy related to specific biomarkers impacting in the outcome of melanoma patients. Melanomagenesis involved a wide variety of mutations during his evolution; many of these mutated proteins have a kinase activity. One of the most cited proteins in melanoma is BRAF (about 50–60 % of melanomas harbors activating BRAF mutations), for these the most common is a substitution of valine to glutamic acid at codon 600 (p.V600E). Therefore, the precise identification of this underlying somatic mutation is essential; knowing the translational implications has opened a wide view of melanoma biology and therapy.

from Cancer via ola Kala on Inoreader http://ift.tt/1TswAqF
via IFTTT

Bevacizumab changes vascular structure and modulates the expression of angiogenic factors in recurrent malignant gliomas

Abstract

Bevacizumab (BV), a monoclonal antibody against vascular endothelial growth factor (VEGF), is currently used in the treatment of malignant glioma. To understand mechanisms of resistance to BV, we investigated morphological changes in tumor vessels and expression of angiogenic factors, such as VEGF, Flt-1, basic fibroblast growth factor (bFGF), and platelet-derived growth factor-BB (PDGF-BB), in four autopsied tumors after BV treatment. Three patients had glioblastomas; the fourth had a secondary glioblastoma that developed from a diffuse astrocytoma. BV was administered because of recurrence following the use of the Stupp regimen in these four patients. We compared the initial surgical specimen with that obtained after death following BV treatment. Immunohistochemical staining of the autopsied tumors showed that Flt-1 expression increased while VEGF expression was significantly reduced. Additionally, other angiogenic factors, particularly bFGF, were enhanced. Interestingly, the proliferation of endothelial cells was reduced, but remarkable proliferation of pericytes was observed. These results suggest that following BV treatment, glioblastomas can grow tumor vessels by expressing various angiogenic factors. These mechanisms might be important for rapid regrowth and blood brain barrier repair after BV treatment. Inhibition of multiple angiogenic factors will be required to control tumor vessels in glioblastoma.

from Cancer via ola Kala on Inoreader http://ift.tt/1PFjYXd
via IFTTT

Analysis of Helicobacter pylori genotypes in clinical gastric wash samples

Abstract

Helicobacter pylori is a key factor in the development of gastric cancer; indeed, clearance of H. pylori helps prevent gastric cancer. However, the relationship between gastric cancer and the abundance and diversity of H. pylori genotypes in the stomach remains unknown. Here, we present, for the first time, a quantitative analysis of H. pylori genotypes in gastric washes. A method was first developed to assess diversity and abundance by pyrosequencing and analysis of single nucleotide polymorphisms in 23S ribosomal RNA (rRNA), a gene associated with clarithromycin resistance. This method was then validated using arbitrarily mixed plasmids carrying 23S rRNA with single nucleotide polymorphisms. Multiple strains were detected in many of 34 clinical samples, with frequency 24.3 ± 24.2 and 26.3 ± 33.8 % for the A2143G and A2144G strains, respectively. Importantly, results obtained from gastric washes were similar to those obtained from biopsy samples. The method provides opportunities to investigate drug resistance in H. pylori and assess potential biomarkers of gastric cancer risk, and should thus be validated in large-scale clinical trials.

from Cancer via ola Kala on Inoreader http://ift.tt/1m2K6Uc
via IFTTT

Evaluation of mRNA expression levels of IL-17A and IL-10 cytokines in cervical cancer

Abstract

In this study, we evaluated mRNA expression levels of interleukin (IL)-10/IL-17A by quantitative real-time PCR and their clinical importance in cervical cancer. The IL-10 mRNA levels were higher in cervical cancer tissues as compared with corresponding normal tissues (p < 0.05). Moreover, IL-17A mRNA was significantly increased in cervical cancer tissues than in normal tissues (p < 0.05). Moreover, the high expression level of IL-10 mRNA was markedly related to International League of Gynecology and Obstetrics (FIGO) stage (p = 0.001), but no significant association was found with other clinical factors including age, tumor size, histological grades, and lymph node metastasis. Moreover, high expression levels of IL-17A were not associated with patients' age, tumor size, FIGO stage, and histological grades while IL-17A expression was strongly linked to lymphatic metastasis (p = 0.001). These findings showed that IL-17A might have a crucial role in cervical cancer metastasis. Taken together, IL-17A expression was strongly linked to lymphatic metastasis, indicating that IL-17A might have a crucial role in cervical cancer metastasis. Moreover, our study suggested the association of IL-10 mRNA expression with clinical stage.

from Cancer via ola Kala on Inoreader http://ift.tt/1QMvdlN
via IFTTT

Erratum to: UBE2S is associated with malignant characteristics of breast cancer cells

from Cancer via ola Kala on Inoreader http://ift.tt/1m2K7Yl
via IFTTT

ΔNp63 regulates cell proliferation, differentiation, adhesion, and migration in the BL2 subtype of basal-like breast cancer

Abstract

Triple-negative breast cancers (TNBC) comprise a heterogeneous subgroup of tumors with a generally poor prognosis. Subclassification of TNBC based on genomic analyses shows that basal-like TNBCs, specifically the basal A or BL2 subtype, are characterized by the expression of ΔNp63, a transcription factor that has been attributed a variety of roles in the regulation of proliferation, differentiation, and cell survival. To investigate the role(s) of p63 in basal-like breast cancers, we used HCC1806 cells that are classified as basal A/BL2. We show that these cells endogenously express p63, mainly as the ΔNp63α isoform. TP63 gene knockout by CRISPR resulted in viable cells that proliferate more slowly and adhere less tightly, with an increased rate of migration. Analysis of adhesion-related gene expression revealed a complex set of alterations in p63-depleted cells, with both increased and decreased adhesion molecules and adhesion substrates compared to parental cells expressing p63. Examination of the phenotype of these cells indicated that endogenous p63 is required to suppress the expression of luminal markers and maintain the basal epithelial phenotype, with increased levels of both CK8 and CK18 and a reduction in N-cadherin levels in cells lacking p63. On the other hand, the level of CK5 was not decreased and ER was not increased, indicating that p63 loss is insufficient to induce full luminal-type differentiation. Taken together, these data demonstrate that p63 exerts multiple pro-oncogenic effects on cell differentiation, proliferation and adhesion in basal-like breast cancers.

from Cancer via ola Kala on Inoreader http://ift.tt/1QMvd5x
via IFTTT

MIIP expression predicts outcomes of surgically resected esophageal squamous cell carcinomas

Abstract

The migration and invasion inhibitory protein (MIIP) was shown to function as a tumor suppressor gene in gliomas by inhibiting tumor cell growth, migration, and invasion. However, its role and clinical significance in esophageal squamous cell carcinoma (ESCC) have not been elucidated. We investigated the correlation of MIIP expression and clinical outcome in a group of surgically resected ESCCs. Tissue microarrays constructed of 253 surgically resected ESCC primary tumors and paired paracancerous normal esophageal epithelia were used for MIIP evaluation by immunohistochemistry. The clinical and prognostic significance of MIIP expression was analyzed statistically. The expression of MIIP expression in cancer tissues was increased significantly in comparison with the paired paracancerous normal epithelia (P < 0.001). And, MIIP expression was associated with ESCC cells' differentiation (P < 0.001). By Kaplan-Meier analysis, patients with low MIIP expression exhibited significantly improved overall survival (OS, P = 0.039) and a tendency of improved disease-free survival (DFS, P = 0.086) than those with high MIIP expression. In addition, MIIP expression could distinguish OS or DFS of patients with tumors in stage T3–4 (P = 0.020, 0.028), N0 (P = 0.008, 0.032), and stage II (P = 0.004, 0.019), as well as at lower thoracic esophagus (P = 0.024, 0.090). Multivariate analysis showed that MIIP expression was an independent prognostic factor in ESCC OS and DFS. In conclusion, MIIP expressed higher in ESCCs than in paracancerous normal esophageal epithelia and was a positive, independent prognostic factor in resected ESCCs.

from Cancer via ola Kala on Inoreader http://ift.tt/1m2K6DF
via IFTTT

Erratum to: FAM98A is a novel substrate of PRMT1 required for tumor cell migration, invasion and colony formation

from Cancer via ola Kala on Inoreader http://ift.tt/1QMvd5s
via IFTTT

Long noncoding RNA NEAT1 promotes laryngeal squamous cell cancer through regulating miR-107/CDK6 pathway

Abstract

Background

Long noncoding RNA nuclear paraspeckle assembly transcript 1 (NEAT1) plays key role in the progression of some human cancers. However, the role of NEAT1 in human laryngeal squamous cell cancer (LSCC) is still unknown. We therefore investigated the expression and function of NEAT1 in LSCC.

Methods

NEAT1 level in LSCC and adjacent non-neoplastic tissues were detected by qRT-PCR. NEAT1 was knockdown in LSCC cells and cell proliferation, apoptosis and cell cycle were examined. The growth of xenografts with NEAT1 knockdown LSCC cells was analyzed.

Results

NEAT1 level was significantly higher in LSCC than in corresponding adjacent non-neoplastic tissues, and patients with neck nodal metastasis or advanced clinical stage had higher NEAT1 expression. Moreover, siRNA mediated NEAT1 knockdown significantly inhibited the proliferation and induced apoptosis and cell cycle arrest at G1 phase in LSCC cells. The growth of LSCC xenografts was significantly suppressed by the injection of NEAT1 siRNA lentivirus. Furthermore, NEAT1 regulated CDK6 expression in LSCC cells which was mediated by miR-107.

Conclusion

NEAT1 plays an oncogenic role in the tumorigenesis of LSCC and may serve as a potential target for therapeutic intervention.

from Cancer via ola Kala on Inoreader http://ift.tt/20cekqT
via IFTTT

MicroRNA-224 sustains Wnt/β-catenin signaling and promotes aggressive phenotype of colorectal cancer

Abstract

Background

Growing evidence suggests that Wnt/β-catenin pathway plays an important role in CRC development, progression and metastasis. Aberrant miR-224 expression has been reported in CRC. However, the mechanism of miR-224 promotes both proliferation and metastatic ability largely remains unclear.

Methods

Real-time PCR was used to quantify miR-224 expression. Luciferase reporter assays were conducted to confirm the activity of Wnt/β-catenin pathway and target gene associations, and immunofluorescence staining assay was performed to observe the nuclear translocation of β-catenin. Bioinformatics analysis combined with in vivo and vitro functional assays showed the potential target genes, GSK3β and SFRP2, of miR-224. Specimens from forty patients with CRC were analyzed for the expression of miR-224 and the relationship with GSK3β/SFRP2 by real-time PCR and western blot.

Results

Bioinformatics and cell luciferase function studies verified the direct regulation of miR-224 on the 3'-UTR of the GSK3β and SFRP2 genes, which leads to the activation of Wnt/β-catenin signaling and the nuclear translocation of β-catenin. In addition, knockdown of miR-224 significantly recovered the expression of GSK3β and SFRP2 and attenuated Wnt/β-catenin-mediated cell metastasis and proliferation. The ectopic upregulation of miR-224 dramatically inhibited the expression of GSK3β/SFRP2 and enhanced CRC proliferation and invasion.

Conclusion

Our research showed mechanistic links between miR-224 and Wnt/β-catenin in the pathogenesis of CRC through modulation of GSK3β and SFRP2.

from Cancer via ola Kala on Inoreader http://ift.tt/1NGmM4X
via IFTTT

Targeted Therapies for the Treatment of Brain Metastases in Solid Tumors

Abstract

Brain metastases are a major cause of morbidity and mortality in cancer patients. While the mainstay treatment comprises surgery and radiation therapy, the role of systemic agents remains controversial. In general, it has been presumed that poor blood–brain barrier (BBB) penetration and inherently more resistant metastatic brain disease preclude a favorable systemic treatment approach. However, a better understanding of tumor biology and the subsequent development of targeted drugs have reawakened interest in systemic therapy. Despite still limited brain distribution, a variety of targeted drugs have demonstrated activity in brain metastases in early clinical trials. Nevertheless, disease progression commonly occurs, and it remains to be elucidated whether limited CNS drug distribution or the acquisition of resistant metastatic clones must be held responsible for this prognosis. Moreover, micrometastatic brain disease beyond an intact BBB—and ultimately prevention of brain metastasis formation—may generally remain inaccessible for first-generation targeted agents with poor CNS penetration. To overcome limited brain distribution and possibly emerging acquired resistance, highly potent next-generation targeted drugs with enhanced CNS distribution have been developed. In view of this emerging but yet undefined role of targeted therapies in the treatment of brain metastases from solid tumors, this review aims to summarize the current knowledge from clinical trials and discusses clinically relevant obstacles to overcome.

from Cancer via ola Kala on Inoreader http://ift.tt/1PYMrYm
via IFTTT

The P21-activated kinase expression pattern is different in non-small cell lung cancer and affects lung cancer cell sensitivity to epidermal growth factor receptor tyrosine kinase inhibitors

Abstract

Exploring methods for increasing epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) sensitivity has become a major focus in non-small cell lung cancer (NSCLC). Major downstream effectors of the Rho family small guanosine triphosphatases, P21-activated kinases (PAKs) activate the main signaling pathways downstream of EGFR and thus promote tumor cell proliferation. In this study, we explored the expression pattern of phosphorylated PAKs in NSCLC and their potential value as drug targets for treating cancer. The expression and prognostic significance of phosphorylated group I and II PAKs were evaluated in 182 patients with NSCLC. Immunohistochemical analysis revealed low group I PAK expression in normal lung tissues and increased expressed in the cytoplasm, particularly in lung squamous cell carcinoma. Abnormal group I PAK expression was associated with lymph node metastases and high tumor-node-metastases (TNM) stage in NSCLC patients and correlated with poor prognosis. We used group I PAK inhibitor (IPA3) to specifically decrease group I PAK activity in human lung cancer cell lines. Decreased group I PAK activity inhibited cell proliferation and combined IPA3 and EGFR-TKI (gefitinib) treatment inhibited cell proliferation in an obvious manner. Together, our results revealed the PAK expression pattern in NSCLC, and a role for group I PAK in cell proliferation, which provides evidence that decreased PAK activity may have a potential application as a molecular targeted therapy in advanced NSCLC.

from Cancer via ola Kala on Inoreader http://ift.tt/1OUEHJr
via IFTTT

Phase II study of oral vitamin B 12 supplementation as an alternative to intramuscular injection for patients with non-small cell lung cancer undergoing pemetrexed therapy

Abstract

Purpose

A vitamin B12 supplement is required in pemetrexed single agent therapy. Intramuscular administration is the method of choice; however, oral administration is simpler and easier and may be sufficiently effective. We conducted a Phase II study to evaluate the safety of oral administration of vitamin B12 in patients with advanced non-small cell lung cancer who received pemetrexed single agent therapy.

Methods

Folic acid and vitamin B12 were given orally for ˃1 week before pemetrexed administration. The primary end-point was onset of a grade ≥3 neutropenia ratio (50 % of threshold expression ratios; an expectation expression ratio of 21 %; α, 0.05; β, 0.1). Blood concentration of folic acid and homocysteine which are markers of vitamin B12 deficiency were also examined (UMIN000003180).

Results

A total of 25 cases were registered from February 2010 to July 2014. The ratio of grade ≥3 neutropenia was 36 % (95 % CI 22–52 %). Grade ≥3 non-hematologic toxicity and hematologic toxicity were seen in 20 % (5 cases) and 44 % (11 cases) of patients, respectively. In addition, the homocysteine blood concentration just before the first cycle dosage of pemetrexed was significantly elevated relative to the 2–3 cycle.

Conclusion

This study failed to meet its primary endpoint. We could not demonstrate the safety and efficacy of the 1-week vitamin B12 oral administration protocol as compared with intramuscular administration.

from Cancer via ola Kala on Inoreader http://ift.tt/1Pmlul9
via IFTTT

Technetium Tc 99m sulfur colloid phenotypic probe for the pharmacokinetics and pharmacodynamics of PEGylated liposomal doxorubicin in women with ovarian cancer

Abstract

Purpose

Significant variability in the pharmacokinetics and pharmacodynamics of PEGylated liposomal doxorubicin (PLD) exists. PLD undergoes clearance via the mononuclear phagocyte system (MPS). Technetium Tc 99m sulfur colloid (TSC) is approved for imaging MPS cells. We investigated TSC as a phenotypic probe of PLD pharmacokinetics and pharmacodynamics in women with epithelial ovarian cancer.

Methods

TSC 10 mCi IVP was administered and followed by dynamic planar and SPECT/CT imaging and blood pharmacokinetics sampling. PLD 30–40 mg/m² IV was administered with or without carboplatin, followed by plasma pharmacokinetics sampling.

Results

There was a linear relationship between TSC clearance and encapsulated doxorubicin clearance (R ² = 0.61, p = 0.02), particularly in patients receiving PLD alone (R ² = 0.81, p = 0.04). There was a positive relationship (ρ = 0.81, p = 0.01) between maximum grade palmar-plantar erythrodysesthesia toxicity developed and estimated encapsulated doxorubicin concentration in hands.

Conclusions

TSC is a phenotypic probe for PLD pharmacokinetics and pharmacodynamics and may be used to individualize PLD therapy in ovarian cancer and for other nanoparticles in development.

from Cancer via ola Kala on Inoreader http://ift.tt/1QwqPFI
via IFTTT

Phase I trial of panobinostat and fractionated stereotactic re-irradiation therapy for recurrent high grade gliomas

Abstract

Panobinostat is an oral HDAC inhibitor with radiosensitizing activity. We investigated the safety, tolerability and preliminary efficacy of panobinostat combined with fractionated stereotactic re-irradiation therapy (FSRT) for recurrent high grade gliomas. Patients with recurrent high grade gliomas were enrolled in a 3 + 3 dose escalation study to determine dose limiting toxicities (DLTs), maximum tolerated dose (MTD), safety, tolerability, and preliminary efficacy. FSRT was prescribed to 30–35 Gy delivered in 10 fractions. Panobinostat was administrated concurrently with radiotherapy. Of 12 evaluable patients, 8 had recurrent GBM, and 4 had recurrent anaplastic astrocytoma. There were three grade 3 or higher toxicities in each the 10 and 30 mg cohorts. In the 30 mg cohort, there was one DLT; grade 4 neutropenia. One patient developed late grade 3 radionecrosis. The median follow up was 18.8 months. The PFS6 was 67, 33, and 83 % for 10, 20, and 30 mg cohorts, respectively. The median OS was 7.8, 6.1 and 16.1 months for the 10, 20 and 30 mg cohorts, respectively. Panobinostat administrated with FSRT is well tolerated at 30 mg. A phase II trial is warranted to assess the efficacy of panobinostat plus FSRT for recurrent glioma.

from Cancer via ola Kala on Inoreader http://ift.tt/1WRX2ts
via IFTTT

A Case of Signet Ring Cell Carcinoma of the Gallbladder Which Was Treated by Aggressive Surgery and Intensive Adjuvant Chemotherapy

from Cancer via ola Kala on Inoreader http://ift.tt/1TrH1KU
via IFTTT

Isolated Portal Venous Hepatocellular Carcinoma

from Cancer via ola Kala on Inoreader http://ift.tt/1TrGZ5O
via IFTTT

A Rare Case of a Gastrointestinal Stromal Tumor (GIST) Presenting as a Perforated Meckel’s Diverticulum

from Cancer via ola Kala on Inoreader http://ift.tt/1SO6JKs
via IFTTT

Dietary Patterns in the Frail Elderly

Abstract

Frail older adults have an increased vulnerability to health and environmental stressors and are at a greater risk of functional decline, disability, loss of independence and mortality. Inadequate caloric, protein and micronutrient intakes have been positively associated with an increased risk of frailty, however this traditional single nutrient approach does not account for potential interactions and synergies of nutrients within the total diet. Using dietary patterns as a means of exploring the impact of overall food consumption offers an alternative approach to investigating associations between nutrition and frailty. The purpose of this paper is to review the existing body of knowledge about the frailty syndrome in relationship with various dietary patterns in aged populations and identify areas for further research.

from Cancer via ola Kala on Inoreader http://ift.tt/1SfVTgB
via IFTTT

Associations Between Food Restriction and Pressure-to-Eat Parenting Practices and Dietary Intake in Children: a Selective Review of the Recent Literature

Abstract

The identification of modifiable determinants child dietary intake has become a public health priority. Food-related parenting practices, including pressure-to-eat and food restriction, have been identified as potentially significant determinants of dietary intake in children. This is a review of the literature to date that has explored the relationship between food restriction and pressure-to-eat and child dietary intake. In general, findings from laboratory-based studies and longitudinal studies suggest that children exposed to high levels of food restriction and pressure-to-eat are more likely to consume sugar-sweetened beverages, palatable snack foods, and calorie-dense food items than children exposed to lower levels. Results from the body of cross-sectional studies examining this relationship are decidedly less conclusive, yielding inconsistent and sometimes contradictory results. Overall, the concept of food-related parenting practices as a potentially modifiable factor with the potential to positively impact child dietary intake patterns continues to be worth pursuing through additional future research.

from Cancer via ola Kala on Inoreader http://ift.tt/1P1N17S
via IFTTT

Current Systemic Treatment Options for Tenosynovial Giant Cell Tumor/Pigmented Villonodular Synovitis: Targeting the CSF1/CSF1R Axis

Opinion statement

Adequate surgical resection remains the treatment of choice for tenosyovial giant cell tumor (TGCT). However, diffuse type TGCT (D-TGCT) is more difficult to resect and has a higher rate of recurrence (up to 50 %), which is often multiple. D-TGCT is rarely lethal and only rare cases of metastases have been described. Nevertheless, patients might have a significant decline in their quality of life due to multiple operations, which may sometimes result in a partial loss of function of the affected joint and may also be associated with perioperative morbidity and secondary arthrosis. As of today, no systemic treatment is approved for this rare disease. The aims of systemic therapy in the context of a non-lethal tumor are to reduce surgical morbidity and to preserve function and patient quality of life. Because TGCT is associated with characteristic cytogenetic abnormalities resulting in the overexpression of CSF1, systemic therapies targeting the CSF1/CSF1R axis (imatinib, nilotinib, emactuzumab, and PLX3397) have been tested in patients with locally advanced or relapsed D-TGCT. The more recent and more specific CSF1R inhibitors have shown a very interesting clinical activity with acceptable toxicity in early phase trials. These results will need to be confirmed in larger, ideally randomized, trials. But the high rate of clinical and functional improvement seen in some patients with advanced D-TGCT, often after multiple operations, suggests that these inhibitors will likely have a role in the management of patients with an inoperable disease; the definition of "inoperable TGCT" still requires refinement to reach a consensus. Another point that will need to be addressed is that of "the optimal duration of therapy" for these patients. Indeed, we and others have observed often prolonged clinical benefit and symptomatic relief even after treatment was stopped, with both monoclonal antibodies and tyrosine kinase inhibitors. Responses were observed very early on with emactuzumab and PLX3397, and patients experienced significant symptom improvement within a few weeks of starting therapy (2–4 weeks). Another possible application of CSF1R inhibitors could be used either as a preoperative or postoperative therapy for patients with operable TGCT. However, we currently lack sufficient follow-up to adequately address these questions which will each require specific trial designs. Overall, the striking clinical activity of CSF1R specific inhibitors in TGCT has created great enthusiasm among clinicians, and further development of these agents is clearly medically needed. Nevertheless, further investigations are necessary to validate those treatments and assess how to best incorporate them among other treatment modalities into the overall therapeutic strategy for a given patient.

from Cancer via ola Kala on Inoreader http://ift.tt/1m0xZac
via IFTTT

Health-Related Quality of Life After Spine Surgery for Primary Bone Tumour

Opinion Statement

Treatment of primary bone tumours (PBT) of the spine is complex, often involving numerous surgical and oncology disciplines. Surgical en bloc resection with oncologically appropriate margins is the modality of choice when treating malignant PBT. En bloc resection with wide or marginal margins appears to offer better local and systemic control of the disease. This type of surgical resection can also be considered when treating benign aggressive tumours such as aneurysmal bone cyst, giant cell tumour and osteoblastoma. Although these surgeries respect oncologic principles, significant morbidity and mortality are associated. Adverse event collection is highly variable in the literature and mostly from retrospective studies. Wound complication, neurologic deficit and significant blood loss are encountered with surgical resection of PBT of the mobile spine and especially, the sacrum. The adverse event profile of these surgeries is high even in experienced quaternary referral centres. Therefore, primary spinal tumour resection is best performed in experienced centre with adequate multidisciplinary support. Furthermore, prospective and systematic adverse event data collection should be developed to ensure accurate data. The impact of such extensive and potentially impairment producing procedures on health-related quality of life (HRQOL) is another critically valuable piece of information in the era of shared treatment decision making. At the present time, there is paucity of published data regarding HRQOL following these surgeries. Nonetheless, in theory, it seems that health-related quality of life after surgery for PBT is acceptable given the curative intent of the treatment. However, a decision-making process should be tailored to each patient and his or her expectations. Comprehensive discussions should be held preoperatively with the patient, family and other related allied health professionals if the informed consent and decision-making process is to be optimal.

from Cancer via ola Kala on Inoreader http://ift.tt/1m0xYDp
via IFTTT

Management of Hyperleukocytosis

Opinion statement

Hyperleukocytosis has a high morbidity index. The involvement of the respiratory or central nervous system and the metabolic derangements accompanying tumor lysis are responsible for early mortality. Standard care for acute hyperleukocytosis must include cytoreduction, proper supportive care, and prevention of tumor lysis. Hydration, alkalization, allopurinol, or urate oxidase should be started immediately. In patients with low platelet count of less than 20,000/mm³, platelet transfusions should be given to prevent cerebral hemorrhage, as platelets do not add substantially to blood viscosity. Packed red blood cells must be given with caution as they can significantly increase blood viscosity. If the patient is hemodynamically stable, packed red transfusions should be planned when the hemoglobin level is less than 7–8 g/dl, avoiding post-transfusional levels above 10 g/dl. Coagulation abnormalities should be corrected. Leukapheresis has been advocated to correct metabolic abnormalities and to decrease viscosity by reducing the peripheral white blood count. However, leukapheresis may fail to decrease the leukocyte count substantially or may achieve only a transient tumor bulk reduction. The procedure is generally well tolerated but can involve problems such as the need for anticoagulation or difficulty of access, and limited availability in many institutions.

Specific antileukemic therapy must be initiated as soon as life-threatening complications have been corrected as it remains the first-line treatment of hyperleukocytosis.

from Cancer via ola Kala on Inoreader http://ift.tt/1m0xYD9
via IFTTT

The Role of Surgery in Metastatic Gastrointestinal Stromal Tumors

Opinion statement

Gastrointestinal stromal tumors (GISTs) are the most common sarcomas and mesenchymal neoplasms of the gastrointestinal tract. Macroscopically complete (R0/R1) resection is the standard treatment for localized resectable GIST with adjuvant imatinib therapy recommended for patients with intermediate or high-risk disease. In patients with advanced unresectable or metastatic GIST, imatinib has significantly improved outcomes. However, while most patients achieve partial response (PR) or stable disease (SD) on imatinib (with maximal response typically seen by 6 months on treatment), approximately half will develop secondary resistance by 2 years. Available data suggest that cytoreductive surgery may be considered in patients with metastatic GIST who respond to imatinib, particularly if a R0/R1 resection is achieved. The benefit of surgery in patients with focal tumor progression on imatinib is unclear, but may be considered. Patients with multifocal progression undergoing surgery generally have poor outcomes. Thus, surgery should be considered in patients with metastatic GIST whose disease responds to imatinib with a goal of performing R0/R1 resection. Optimal timing of surgery is unclear but should be considered between 6 months and 2 years after starting imatinib. Although surgery in patients with metastatic GIST treated with sunitinib is feasible, incomplete resections are common, complication rates are high, and survival benefit is unclear. Therefore, a careful multidisciplinary consultation is required to determine optimal treatment options on a case-by-case basis. Finally, patients with metastatic GIST should resume tyrosine kinase inhibitor treatment postoperatively.

from Cancer via ola Kala on Inoreader http://ift.tt/20aXDfi
via IFTTT

Current Systemic Treatment Options for Tenosynovial Giant Cell Tumor/Pigmented Villonodular Synovitis: Targeting the CSF1/CSF1R Axis

Opinion statement

Adequate surgical resection remains the treatment of choice for tenosyovial giant cell tumor (TGCT). However, diffuse type TGCT (D-TGCT) is more difficult to resect and has a higher rate of recurrence (up to 50 %), which is often multiple. D-TGCT is rarely lethal and only rare cases of metastases have been described. Nevertheless, patients might have a significant decline in their quality of life due to multiple operations, which may sometimes result in a partial loss of function of the affected joint and may also be associated with perioperative morbidity and secondary arthrosis. As of today, no systemic treatment is approved for this rare disease. The aims of systemic therapy in the context of a non-lethal tumor are to reduce surgical morbidity and to preserve function and patient quality of life. Because TGCT is associated with characteristic cytogenetic abnormalities resulting in the overexpression of CSF1, systemic therapies targeting the CSF1/CSF1R axis (imatinib, nilotinib, emactuzumab, and PLX3397) have been tested in patients with locally advanced or relapsed D-TGCT. The more recent and more specific CSF1R inhibitors have shown a very interesting clinical activity with acceptable toxicity in early phase trials. These results will need to be confirmed in larger, ideally randomized, trials. But the high rate of clinical and functional improvement seen in some patients with advanced D-TGCT, often after multiple operations, suggests that these inhibitors will likely have a role in the management of patients with an inoperable disease; the definition of "inoperable TGCT" still requires refinement to reach a consensus. Another point that will need to be addressed is that of "the optimal duration of therapy" for these patients. Indeed, we and others have observed often prolonged clinical benefit and symptomatic relief even after treatment was stopped, with both monoclonal antibodies and tyrosine kinase inhibitors. Responses were observed very early on with emactuzumab and PLX3397, and patients experienced significant symptom improvement within a few weeks of starting therapy (2–4 weeks). Another possible application of CSF1R inhibitors could be used either as a preoperative or postoperative therapy for patients with operable TGCT. However, we currently lack sufficient follow-up to adequately address these questions which will each require specific trial designs. Overall, the striking clinical activity of CSF1R specific inhibitors in TGCT has created great enthusiasm among clinicians, and further development of these agents is clearly medically needed. Nevertheless, further investigations are necessary to validate those treatments and assess how to best incorporate them among other treatment modalities into the overall therapeutic strategy for a given patient.

from Cancer via ola Kala on Inoreader http://ift.tt/1m0xZac
via IFTTT

Health-Related Quality of Life After Spine Surgery for Primary Bone Tumour

Opinion Statement

Treatment of primary bone tumours (PBT) of the spine is complex, often involving numerous surgical and oncology disciplines. Surgical en bloc resection with oncologically appropriate margins is the modality of choice when treating malignant PBT. En bloc resection with wide or marginal margins appears to offer better local and systemic control of the disease. This type of surgical resection can also be considered when treating benign aggressive tumours such as aneurysmal bone cyst, giant cell tumour and osteoblastoma. Although these surgeries respect oncologic principles, significant morbidity and mortality are associated. Adverse event collection is highly variable in the literature and mostly from retrospective studies. Wound complication, neurologic deficit and significant blood loss are encountered with surgical resection of PBT of the mobile spine and especially, the sacrum. The adverse event profile of these surgeries is high even in experienced quaternary referral centres. Therefore, primary spinal tumour resection is best performed in experienced centre with adequate multidisciplinary support. Furthermore, prospective and systematic adverse event data collection should be developed to ensure accurate data. The impact of such extensive and potentially impairment producing procedures on health-related quality of life (HRQOL) is another critically valuable piece of information in the era of shared treatment decision making. At the present time, there is paucity of published data regarding HRQOL following these surgeries. Nonetheless, in theory, it seems that health-related quality of life after surgery for PBT is acceptable given the curative intent of the treatment. However, a decision-making process should be tailored to each patient and his or her expectations. Comprehensive discussions should be held preoperatively with the patient, family and other related allied health professionals if the informed consent and decision-making process is to be optimal.

from Cancer via ola Kala on Inoreader http://ift.tt/1m0xYDp
via IFTTT

Management of Hyperleukocytosis

Opinion statement

Hyperleukocytosis has a high morbidity index. The involvement of the respiratory or central nervous system and the metabolic derangements accompanying tumor lysis are responsible for early mortality. Standard care for acute hyperleukocytosis must include cytoreduction, proper supportive care, and prevention of tumor lysis. Hydration, alkalization, allopurinol, or urate oxidase should be started immediately. In patients with low platelet count of less than 20,000/mm³, platelet transfusions should be given to prevent cerebral hemorrhage, as platelets do not add substantially to blood viscosity. Packed red blood cells must be given with caution as they can significantly increase blood viscosity. If the patient is hemodynamically stable, packed red transfusions should be planned when the hemoglobin level is less than 7–8 g/dl, avoiding post-transfusional levels above 10 g/dl. Coagulation abnormalities should be corrected. Leukapheresis has been advocated to correct metabolic abnormalities and to decrease viscosity by reducing the peripheral white blood count. However, leukapheresis may fail to decrease the leukocyte count substantially or may achieve only a transient tumor bulk reduction. The procedure is generally well tolerated but can involve problems such as the need for anticoagulation or difficulty of access, and limited availability in many institutions.

Specific antileukemic therapy must be initiated as soon as life-threatening complications have been corrected as it remains the first-line treatment of hyperleukocytosis.

from Cancer via ola Kala on Inoreader http://ift.tt/1m0xYD9
via IFTTT

The Role of Surgery in Metastatic Gastrointestinal Stromal Tumors

Opinion statement

Gastrointestinal stromal tumors (GISTs) are the most common sarcomas and mesenchymal neoplasms of the gastrointestinal tract. Macroscopically complete (R0/R1) resection is the standard treatment for localized resectable GIST with adjuvant imatinib therapy recommended for patients with intermediate or high-risk disease. In patients with advanced unresectable or metastatic GIST, imatinib has significantly improved outcomes. However, while most patients achieve partial response (PR) or stable disease (SD) on imatinib (with maximal response typically seen by 6 months on treatment), approximately half will develop secondary resistance by 2 years. Available data suggest that cytoreductive surgery may be considered in patients with metastatic GIST who respond to imatinib, particularly if a R0/R1 resection is achieved. The benefit of surgery in patients with focal tumor progression on imatinib is unclear, but may be considered. Patients with multifocal progression undergoing surgery generally have poor outcomes. Thus, surgery should be considered in patients with metastatic GIST whose disease responds to imatinib with a goal of performing R0/R1 resection. Optimal timing of surgery is unclear but should be considered between 6 months and 2 years after starting imatinib. Although surgery in patients with metastatic GIST treated with sunitinib is feasible, incomplete resections are common, complication rates are high, and survival benefit is unclear. Therefore, a careful multidisciplinary consultation is required to determine optimal treatment options on a case-by-case basis. Finally, patients with metastatic GIST should resume tyrosine kinase inhibitor treatment postoperatively.

from Cancer via ola Kala on Inoreader http://ift.tt/20aXDfi
via IFTTT

Comparison of Cisplatin/Etoposide versus Carboplatin/Etoposide concurrent chemoradiotherapy for limited-stage small cell lung cancer (LS-SCLC) in the elderly population (age >65) using national SEER-Medicare data

Publication date: Available online 28 January 2016
Source:Practical Radiation Oncology
Author(s): Ellen Kim, Tithi Biswas, Paul Bakaki, Afshin Dowlati, Neelesh Sharma, Mitchell Machtay
PurposeStandard therapy for limited stage small cell lung cancer (SCLC) (AJCC stages I-III) is concurrent chemoradiation (CRT) with cisplatin/etoposide (EP) but carboplatin/etoposide (EC) is often used in clinical practice. Though a growing proportion of this disease is diagnosed in older patients, there are limited studies of older patients comparing cisplatin to carboplatin. This study compared survival outcomes of elderly patients with limited stage SCLC treated with concurrent EC or EP and radiation.Methods and MaterialsLimited stage SCLC diagnosed at ages 66–80 during 1992–2007 were selected from the (Surveillance Epidemiology and End Results) SEER-Medicare database to compare EP with EC. Concurrent CRT was defined as starting radiation and cisplatin or carboplatin within 14 days. Study endpoints were overall survival (OS, time from diagnosis until death) and cause specific survival (CSS, time from diagnosis until death from lung cancer).ResultsFinal analysis included 565 cases: 219 EP (39%) and 346 EC (61%), with median age 72 and gender ratio 1.0. A majority of the cases were stage III (85%). Median and 5-year OS were 13.8 months [95% confidence interval 11.4-15.0 months] and 10.2% [95% CI 6.2-15.3%] for EP, versus 13.7 months [95% CI 12.0-15.6 months] and 10.9% [95% CI 7.6-14.8%] for EC (p-value 0.51). CSS were also similar (p-value 0.91). OS and CSS were not statistically different in single- or multi-variable survival analysis.ConclusionsEC and EP had similar survival outcomes, suggesting EC could be used with (or instead of) EP as the standard of care, at least in the elderly population.



from Cancer via ola Kala on Inoreader http://ift.tt/1JLt4pi
via IFTTT

Radiotherapy Quality-of-Care Indicators for Locally Advanced Cervical Cancer: A Consensus Guideline

Publication date: Available online 28 January 2016
Source:Practical Radiation Oncology
Author(s): J. Croke, A. Fyles, L. Barbera, D. D'Souza, R. Pearcey, T. Stuckless, B. Bass, M. Brundage, M. Milosevic
PurposeRadiotherapy plays an important curative role for patients with locally advanced cervical cancer (LACC). There are no standards to define best practice. The purpose of this study was to develop a suite of radiotherapy key quality of care indicators (KQIs) for the curative management of LACC based on expert consensus.MethodsA modified Delphi method was used after identifying candidate KQIs. Round 1 involved surveying all Canadian GYN radiation oncologists. The current and anticipated future (5 years) importance and current achievability of each KQI was ranked. Round 2 consisted of a facilitated face-to-face meeting with a smaller expert panel to discuss, revise and develop consensus on the KQIs.ResultsThe literature review identified 83 candidate KQIs. Survey response was 71%. Round 2 yielded a final suite of 40 KQIs in the following categories: Pre-treatment assessment, External beam radiotherapy, Brachytherapy, Follow-up and Expertise/Workload. A prominent theme was the importance of having KQIs to measure the current state, evolution and future uptake of MR-guided brachytherapy.ConclusionsTo our knowledge this is the first study establishing radiotherapy KQIs in LACC based on expert consensus. These KQIs should be used to guide programmatic direction and resource allocation to assure consistent and optimal patient care.



from Cancer via ola Kala on Inoreader http://ift.tt/1nT5pct
via IFTTT

Comparison of hypoxia-activated prodrug evofosfamide (TH-302) and ifosfamide in preclinical non-small cell lung cancer models.

Comparison of hypoxia-activated prodrug evofosfamide (TH-302) and ifosfamide in preclinical non-small cell lung cancer models.

Cancer Biol Ther. 2016 Jan 28;:0

Authors: Sun JD, Ahluwalia D, Liu Q, Ferraro DJ, Wang Y, Jung D, Matteucci MD, Hart CP

Abstract
Evofosfamide (TH-302) is a hypoxia-activated prodrug of the cytotoxin bromo-isophosphoramide. In hypoxic conditions Br-IPM is released and alkylates DNA. Ifosfamide is a chloro-isophosphoramide prodrug activated by hepatic Cytochrome P450 enzymes. Both compounds are used for the treatment of cancer. Ifosfamide has been approved by the FDA while evofosfamide is currently in the late stage of clinical development. The purpose of this study is to compare efficacy and safety profile of evofosfamide and ifosfamide in preclinical non-small cell lung cancer H460 xenograft models. Immunocompetent CD-1 mice and H460 tumor-bearing immunocompromised nude mice were used to investigate the safety profile. The efficacy of evofosfamide or ifosfamide, alone, and in combination with docetaxel or sunitinib was compared in ectopic and intrapleural othortopic H460 xenograft models in animals exposed to ambient air or different oxygen concentration breathing conditions. At an equal body weight loss level, evofosfamide showed greater efficacy in both ectopic and orthotopic H460 xenograft models. Evofosfamide, but not ifosfamide, exhibited controlled oxygen concentration breathing condition-dependent antitumor activity. However, at an equal body weight loss level, ifosfamide yielded severe hematologic toxicity when compared to evofosfamide, both in monotherapy and in combination with docetaxel. At an equal hematoxicity level, evofosfamide showed superior antitumor activity. These results indicate that evofosfamide shows superior or comparable efficacy and a favorable safety profile when compared to ifosfamide in preclinical human lung carcinoma models. This finding is consistent with multiple clinical trials of evofosfamide as a single agent, or in combination therapy, which demonstrated both anti-tumor activity and safety profile without severe myelosuppression.

PMID: 26818215 [PubMed - as supplied by publisher]

from Cancer via ola Kala on Inoreader http://ift.tt/1P1tRix
via IFTTT

Comparison of hypoxia-activated prodrug evofosfamide (TH-302) and ifosfamide in preclinical non-small cell lung cancer models.

Comparison of hypoxia-activated prodrug evofosfamide (TH-302) and ifosfamide in preclinical non-small cell lung cancer models.

Cancer Biol Ther. 2016 Jan 28;:0

Authors: Sun JD, Ahluwalia D, Liu Q, Ferraro DJ, Wang Y, Jung D, Matteucci MD, Hart CP

Abstract
Evofosfamide (TH-302) is a hypoxia-activated prodrug of the cytotoxin bromo-isophosphoramide. In hypoxic conditions Br-IPM is released and alkylates DNA. Ifosfamide is a chloro-isophosphoramide prodrug activated by hepatic Cytochrome P450 enzymes. Both compounds are used for the treatment of cancer. Ifosfamide has been approved by the FDA while evofosfamide is currently in the late stage of clinical development. The purpose of this study is to compare efficacy and safety profile of evofosfamide and ifosfamide in preclinical non-small cell lung cancer H460 xenograft models. Immunocompetent CD-1 mice and H460 tumor-bearing immunocompromised nude mice were used to investigate the safety profile. The efficacy of evofosfamide or ifosfamide, alone, and in combination with docetaxel or sunitinib was compared in ectopic and intrapleural othortopic H460 xenograft models in animals exposed to ambient air or different oxygen concentration breathing conditions. At an equal body weight loss level, evofosfamide showed greater efficacy in both ectopic and orthotopic H460 xenograft models. Evofosfamide, but not ifosfamide, exhibited controlled oxygen concentration breathing condition-dependent antitumor activity. However, at an equal body weight loss level, ifosfamide yielded severe hematologic toxicity when compared to evofosfamide, both in monotherapy and in combination with docetaxel. At an equal hematoxicity level, evofosfamide showed superior antitumor activity. These results indicate that evofosfamide shows superior or comparable efficacy and a favorable safety profile when compared to ifosfamide in preclinical human lung carcinoma models. This finding is consistent with multiple clinical trials of evofosfamide as a single agent, or in combination therapy, which demonstrated both anti-tumor activity and safety profile without severe myelosuppression.

PMID: 26818215 [PubMed - as supplied by publisher]

from Cancer via ola Kala on Inoreader http://ift.tt/1P1tRix
via IFTTT

Use of two gene panels for prostate cancer diagnosis and patient risk stratification

Abstract

Currently, no ideal prostate cancer (PCa) diagnostic or prognostic test is available due to the lack of biomarkers with high sensitivity and specificity. There is an unmet medical need to develop combinations of multiple biomarkers which may have higher accuracy in detection of PCa and stratification of aggressive and indolent cancer patients. The aim of this study was to test two biomarker gene panels in distinguishing PCa from benign prostate and high-risk, aggressive PCa from low-risk, indolent PCa, respectively. We identified a five-gene panel that can be used to distinguish PCa from benign prostate. The messenger RNA (mRNA) expression signature of the five genes was determined in 144 PCa and benign prostate specimens from prostatectomy. We showed that the five-gene panel distinguished PCa from benign prostate with sensitivity of 96.59 %, specificity of 92.86 %, and area under the curve (AUC) of 0.992 (p < 0.0001). The five-gene panel was further validated in a 137 specimen cohort and showed sensitivity of 84.62 %, specificity of 91.84 %, and AUC of 0.942 (p < 0.0001). To define subtypes of PCa for treatment guidance, we examined mRNA expression signature of an eight-gene panel in 87 PCa specimens from prostatectomy. The signature of the eight-gene panel was able to distinguish aggressive PCa (Gleason score >6) from indolent PCa (Gleason score ≤6) with sensitivity of 90.28 %, specificity of 80.00 %, and AUC of 0.967 (p < 0.0001). This panel was further validated in a 158 specimen cohort and showed significant difference between aggressive PCa and indolent PCa with sensitivity of 92.57 %, specificity of 70.00 %, and AUC of 0.962 (p < 0.0001). Our findings in assessing multiple biomarkers in combination may provide new tools to detect PCa and distinguish aggressive and indolent PCa for precision and personalized treatment. The two biomarker panels may be used in clinical settings for accurate PCa diagnosis and patient risk stratification for biomarker-guided treatment.

from Cancer via ola Kala on Inoreader http://ift.tt/20wOMBr
via IFTTT