A Rare Case of Multilocular Thymic Cyst with Follicular Lymphoid Hyperplasia: Radiologic and Histopathologic Features

Abstract

Multilocular thymic cysts are rare and acquired lesions induced by an inflammatory arising within the thymus. We report a rare case of multilocular thymic cyst with follicular lymphoid hyperplasia in a 59-year-old female. Chest CT and MRI revealed a large multilocular cystic mass, which contains thick septa and nodules in the thymus. F-18 FDG PET/CT showed almost no FDG uptake of the multilocular cystic mass but moderate FDG uptake of the solid nodules. Extended total thymectomy was performed. Histopathological findings revealed follicular lymphoid hyperplasia of thymic tissue but no neoplastic lesion. Based on these findings, diagnosis of multilocular thymic cyst with follicular lymphoid hyperplasia was made. This is a rare case that preoperatively was difficult to diagnose.

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Indeterminate Findings on Oncologic PET/CT: What Difference Does PET/MRI Make?

Abstract

Background

Positron emission tomography/computed tomography (PET/CT) with 2-deoxy-2-[¹⁸F]fluoro-D-glucose (FDG) has become the standard of care for the initial staging and subsequent treatment response assessment of many different malignancies. Despite this success, PET/CT is often supplemented by MRI to improve assessment of local tumor invasion and to facilitate detection of lesions in organs with high background FDG uptake. Consequently, PET/MRI has the potential to expand the clinical value of PET examinations by increasing reader certainty and reducing the need for subsequent imaging. This study evaluates the ability of FDG-PET/MRI to clarify findings initially deemed indeterminate on clinical FDG-PET/CT studies.

Methods

A total of 190 oncology patients underwent whole-body PET/CT, immediately followed by PET/MRI utilizing the same FDG administration. Each PET/CT was interpreted by our institution's nuclear medicine service as a standard-of-care clinical examination. Review of these PET/CT reports identified 31 patients (16 %) with indeterminate findings. Two readers evaluated all 31 PET/CT studies, followed by the corresponding PET/MRI studies. A consensus was reached for each case, and changes in interpretation directly resulting from PET/MRI review were recorded. Interpretations were then correlated with follow-up imaging, pathology results, and other diagnostic studies.

Results

In 18 of 31 cases with indeterminate findings on PET/CT, PET/MRI resulted in a more definitive interpretation by facilitating the differentiation of infection/inflammation from malignancy (15/18), the accurate localization of FDG-avid lesions (2/18), and the characterization of incidental non-FDG-avid solid organ lesions (1/18). Explanations for improved reader certainty with PET/MRI included the superior soft tissue contrast of MRI and the ability to assess cellular density with diffusion-weighted imaging. The majority (12/18) of such cases had an appropriate standard of reference; in all 12 cases, the definitive PET/MRI interpretation proved correct. These 12 patients underwent six additional diagnostic studies to clarify the initial indeterminate PET/CT findings. In the remaining 13 of 31 cases with indeterminate findings on both PET/CT and PET/MRI, common reasons for uncertainty included the inability to distinguish reactive from malignant lymphadenopathy (4/13) and local recurrence from treatment effect (2/13).

Conclusions

Indeterminate PET/CT findings can result in equivocal reads and additional diagnostic studies. PET/MRI may reduce the rate of indeterminate findings by facilitating better tumor staging, FDG activity localization, and lesion characterization. In our study, PET/MRI resulted in more definitive imaging interpretations with high accuracy. PET/MRI also showed potential in reducing the number of additional diagnostic studies prompted by PET/CT findings. Our results suggest that whole-body PET/MRI provides certain diagnostic advantages over PET/CT, promotes more definitive imaging interpretations, and may improve the overall clinical utility of PET.

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Instrumentation for Time-of-Flight Positron Emission Tomography

Abstract

Positron emission tomography (PET) is a molecular imaging modality that provides information at the molecular level. This system is composed of radiation detectors to detect incoming coincident annihilation gamma photons emitted from the radiopharmaceutical injected into a patient's body and uses these data to reconstruct images. A major trend in PET instrumentation is the development of time-of-flight positron emission tomography (ToF-PET). In ToF-PET, the time information (the instant the radiation is detected) is incorporated for image reconstruction. Therefore, precise and accurate timing recording is crucial in ToF-PET. ToF-PET leads to better localization of the annihilation event and thus results in overall improvement in the signal-to-noise ratio (SNR) of the reconstructed image. Several factors affect the timing performance of ToF-PET. In this article, the background, early research and recent advances in ToF-PET instrumentation are presented. Emphasis is placed on the various types of scintillators, photodetectors and electronic circuitry for use in ToF-PET, and their impact on timing resolution is discussed.

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Tumor volume is a better predictor of post-operative wound complications compared to tumor size in soft tissue sarcomas of the proximal lower extremity

Abstract

Background

Wide local excision with or without radiation therapy (RT) and chemotherapy is widely accepted as appropriate management for soft tissue sarcomas (STS) of the extremity. Although survival and local control rates are comparable to amputation, post-operative wound complications (WC) following limb salvage can result in significant morbidity for the patient. Certain risk factors such as location, pre-operative RT, and age have been shown to increase the risk of WCs. Somewhat surprisingly, size has not consistently been shown to impact WC rates. The goal of this study is to assess whether tumor volume, as opposed to the traditional measurement of the largest dimension in one plane, correlates with the development of post-operative WCs.

Methods

Between 2000 and 2013, 81 patients with STS of the proximal lower extremity, buttock and pelvis were retrospectively identified from our prospective database. We reviewed the impact of patient, tumor, and treatment variables on postoperative WC. Predictors for WC were evaluated using the Fisher exact test for univariate analysis and logistic regression for multivariate analysis. Tumor volume was determined using the medical image merge (MIM) ^® software program (version 6.5.4, MIM Software, Cleveland, OH). Tumor size (diameter) was determined the historical way of measuring the widest dimension on the sagittal, coronal, and axial planes from the MRI scan at midplane.

Results

The overall WC rate within 6 months of tumor resection was 32 %. WC were more likely to occur with larger tumor volumes (p = 0.015), although not with tumor diameters ≥10 cm (p = 0.55). Neither volume of subcutaneous fat (p = 0.34) or depth of the subcutaneous fat layer (p = 0.82) significantly impacted WC rates. Tumor proximity to skin surface also did not significantly impact WC risk (p = 0.73).

Conclusions

Increase in tumor volume led to a higher risk of post-operative WCs. Assessing tumor volume may allow clinicians to better counsel patients on their risk of post-operative WCs. Tumor volume, as opposed to size alone, should be considered in future sarcoma outcome studies.

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Gene Fusion May Drive Rare Childhood Brain Tumor

Researchers have identified a genetic rearrangement that may drive the development of a rare benign brain tumor in children. The rearrangement, which causes parts of two genes to fuse, may spur the growth of tumors through three distinct biological mechanisms simultaneously, the researchers found.

The study focused on angiocentric gliomas, a rare subtype of low-grade pediatric tumors that was first described less than a decade ago. Fewer than 30 cases have been reported in the scientific literature. Based on their findings, the study authors propose that angiocentric gliomas should be classified as a distinct biologic entity and that the presence of the gene fusion should be used to confirm the diagnosis.

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A phase I trial of panobinostat and epirubicin in solid tumors with a dose expansion in patients with sarcoma

This phase I study evaluated combined panobinostat and epirubicin in patients with advanced solid tumors, establishing a MTD, and demonstrating a correlation between neutropenia, PBMC histone acetylation and clinical benefit. In a sarcoma expansion cohort, more than half of patients, having previously failed anthracycline therapy, benefited, suggesting HDAC inhibition reverses resistance.

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On the tumor risk from dental diagnostic X-ray exposure

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Comparison of prognostic and predictive impact of genomic or central grade and immunohistochemical subtypes or IHC4 in HR+/HER2- early breast cancer: WSG-AGO EC-Doc Trial

Central grade and luminal-A-like subtype were significant predictors of outcome if genomic grade as dichotomous factor (GG1/EQ vs. GG3) was included into the multivariate analysis in breast cancer patients treated by EC-Doc or FEC within the EC-Doc trial. Only continuous GGI but not IHC4 was strong prognostic factor beyond all other factorsin HR+/HER2- breast cancer even if central grade was available.

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Breast Cancer Incidence and Mortality: Trends over Forty Years among Women in Shanghai, China

With 40-years of cancer data from the oldest population-based cancer registry in China, this study evaluate secular time trends in breast cancer incidence and mortality in an urban Chinese population. Our results show a tremendous increase in incidence and a slight increase in mortality with significant age, cohort and period effects for breast cancer among women in urban Shanghai.

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Large-Scale Prospective Pharmacogenomics Study of Oxaliplatin-Induced Neuropathy in Colon Cancer Patients enrolled in the JFMC41-1001-C2 (JOIN Trial)

Our large-scale and prospective pharmacogenomics study of Japanese patients receiving protocol treatment of adjuvant mFOLFOX6 could not verify a role for any of the 12 SNP markers reported as being significantly associated with oxaliplatin-induced peripheral sensory neuropathy.

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A phase II trial of abiraterone acetate plus prednisone in patients with triple-negative androgen receptor positive locally advanced or metastatic breast cancer (UCBG 12-1)

Treatment with abirterone acetate, in combination with prednisone, is beneficial for some patients with molecular apocrine tumours.

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A Phase 1 Dose-Escalation Study of Apatorsen (OGX-427), an Antisense Inhibitor Targeting Heat Shock Protein 27 (Hsp27), in Patients with Castration Resistant Prostate Cancer and Other Advanced Cancers

Apatorsen is an antisense inhibitor of heat shock protein 27 (Hsp27), a chaperone protein that regulates cell survival via androgen receptor and other signaling pathways. A Phase 1 study was conducted in patients with CRPC and other cancers known to overexpress Hsp27. Apatorsen had an acceptable safety profile and a MTD was not defined. Clinical activity at doses ≥400 mg was suggested by effects on stable measurable disease, declines in PSA, other tumor markers, and CTCs.

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Role of major resection in pulmonary metastasectomy for colorectal cancer in the Spanish Prospective Multicenter Study (GECMP-CCR)

Patients with pulmonary metastases from colorectal cancer (CRC) may benefit from aggressive surgical therapy. The objective of this study was to determine the role of major anatomic resection for pulmonary metastasectomy to improve survival as compared to limited pulmonary resection. Major anatomic resection with lymphadenectomy for pulmonary metastasectomy can be considered in selected CRC patient with sufficient functional reserve to improve the DSS and DFS. Further prospective randomized studies are needed to confirm the present results.

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Response to Angiotensin Blockade with Irbesartan in a Patient with Metastatic Colorectal Cancer

As part of a personalized oncogenomics initiative whole genome and transcriptome sequencing was used to interrogate a mismatch repair-deficient tumour from a patient suffering from metastatic colorectal cancer resistant to standard chemotherapy and radiation. Analysis of gene expression outliers identified high expression of the activating protein-1 (AP-1) transcriptional complex, indicating potential oncogene addiction. Based on this analysis, the possibility of treatment targeting the renin–angiotensin system upstream of the AP-1 complex was raised and a trial of the angiotensin receptor blocker irbesartan was initiated. The patient's disease exhibited a profound and durable response to this treatment indicating a new potential therapeutic axis for patients with similar genomic indications.

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Reply to the letter to the editor 'Survival in young adults diagnosed with follicular lymphoma by Calvo et al.

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Utility of a molecular pre-screening program in advanced colorectal cancer for enrollment on biomarker-selected clinical trials

Incorporation of multiple enrichment biomarkers into prospective clinical trials is an active area of investigation. This report examines the factors that correlate with successful clinical trial enrollment in a large molecular prescreening program in advanced colorectal cancer.

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Tumor-specific promoter-driven adenoviral therapy for insulinoma

Abstract

Background

Insulinomas are the most common type of neuroendocrine (NE) pancreatic islet tumors. Patients with insulinomas may develop complications associated with hyperinsulinemia. To increase the treatment options for insulinoma patients, we have tested a conditionally replicating adenovirus that has been engineered in such a way that it can specifically express therapeutic genes in NE tumors.

Methods

We used a promoter-specific adenoviral vector delivery system that is regulated by an INSM1 (insulinoma-associated-1) promoter, which is silent in normal adult tissues but active in developing NE cells and tumors. Through a series of modifications, using an insulator (HS4) and neuron-restrictive silencer elements (NRSEs), an oncolytic adenoviral vector was generated that retains tumor specificity and drives the expression of a mutated adenovirus E1A gene (Δ24E1A) and the herpes simplex virus thymidine kinase (HSV-tk) gene. The efficacy of this vector was tested in insulinoma-derived MIN, RIN, βTC-1 and pancreatic (Panc-1) cells using in vitro cell survival and in vivo tumor growth assays.

Results

Using in vitro insulinoma-derived cell lines and an in vivo subcutaneous mouse tumor model we found that the INSM1 promoter-driven viruses were able to replicate specifically in INSM1-positive cells. INSM1-specific HSV-tk expression in combination with ganciclovir treatment resulted in dose-dependent tumor cell killing, leaving INSM1-negative cells unharmed. When we combined the INSM1-promoter driven HSV-tk with Δ24E1A and INSM1p-HSV-tk (K5) viruses, we found that the co-infected insulinoma-derived cells expressed higher levels of HSV-tk and exhibited more efficient tumor suppression than cells infected with INSM1p-HSV-tk virus alone.

Conclusions

INSM1 promoter-driven conditionally replicating adenoviruses may serve as a new tool for the treatment of insulinoma and may provide clinicians with additional options to combat this disease.

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The genetic tumor background is an important determinant for heterogeneous MYCN-amplified neuroblastoma

Abstract

Amplification of MYCN is the signature genetic aberration of 20-25% of neuroblastoma and a stratifying marker associated with aggressive tumor behavior. The detection of heterogeneous MYCN amplification (hetMNA) poses a diagnostic dilemma due to the uncertainty of its relevance to tumor behavior. Here, we aimed to shed light on the genomic background which permits hetMNA in neuroblastoma and tied the occurrence to other stratifying markers and disease outcome. We performed SNP analysis using Affymetrix Cytoscan HD arrays on 63 samples including constitutional DNA, tumor, bone marrow and relapse samples of 26 patients with confirmed hetMNA by MYCN- FISH. Tumors of patients ≤18m were mostly aneuploid with numeric chromosomal aberrations (NCA), presented a prominent MNA subclone and carried none or a few segmental chromosomal aberrations (SCA). In older patients, tumors were mostly di- or tetraploid, contained a lower number of MNA cells and displayed a multitude of SCAs including concomitant 11q deletions. These patients often suffered disease progression, tumor dissemination and relapse. Restricted to aneuploid tumors, we detected chromosomes with uniparental di- or trisomy (UPD/UPT) in almost every sample. UPD11 was exclusive to tumors of younger patients whereas older patients featured UPD14. In this study, the MNA subclone appears to be constraint by the tumor environment and thus less relevant for tumor behavior in aggressive tumors with a high genomic instability and many segmental aberrations. A more benign tumor background and lower tumor stage may favor an outgrowth of the MNA clone but tumors generally responded better to treatment. This article is protected by copyright. All rights reserved.

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In situ validation of VEGFR-2 and α v ß 3 integrin as targets for breast lesion characterization

Abstract

Vascular endothelial growth factor receptor 2 (VEGFR-2) and α _vß ₃ integrin are the most frequently addressed targets in molecular imaging of tumor angiogenesis. In preclinical studies, molecular imaging of angiogenesis has shown potential to detect and differentiate benign and malignant lesions of the breast. Thus, in this retrospective clinical study employing patient tissues, the diagnostic value of VEGFR-2, α _vß ₃ integrin and vascular area fraction for the diagnosis and differentiation of breast neoplasia was evaluated. To this end, tissue sections of breast cancer (n = 40), pre-invasive ductal carcinoma in situ (DCIS; n = 8), fibroadenoma (n = 40), radial scar (n = 6) and normal breast tissue (n = 40) were used to quantify (1) endothelial VEGFR-2, (2) endothelial α _vß ₃ integrin and (3) total α _vß ₃ integrin expression, as well as (4) the vascular area fraction. Sensitivity and specificity to differentiate benign from malignant lesions were calculated for each marker by receiver operating characteristics (ROC) analyses. Whereas vessel density, as commonly used, did not significantly differ between benign and malignant lesions (AUROC: 0.54), VEGFR-2 and α _vß ₃ integrin levels were gradually up-regulated in carcinoma versus fibroadenoma versus healthy tissue. The highest diagnostic accuracy for differentiating carcinoma from fibroadenoma was found for total α _vß ₃ integrin expression (AUROC: 0.76), followed by VEGFR-2 (AUROC: 0.71) and endothelial α _vß ₃ integrin expression (AUROC: 0.68). In conclusion, total α _vß ₃ integrin expression is the best discriminator between breast cancer, fibroadenoma and normal breast tissue. With respect to vascular targeting and molecular imaging of angiogenesis, endothelial VEGFR-2 appeared to be slightly superior to endothelial α _vß ₃ for differentiating benign from cancerous lesions.

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Tumor vasculogenic mimicry predicts poor prognosis in cancer patients: a meta-analysis

Abstract

Background

Vasculogenic mimicry (VM) is the formation of vascular channels by tumor cells or tumor cell-derived, trans-differentiated cells in highly aggressive, solid tumors. However, the disease features and prognostic value of VM for overall survival of cancer patients remain controversial.

Method

To systematically investigate the roles of VM in cancer progression and its prognostic values, we performed a meta-analysis based on 36 studies (33 eligible articles) including 3609 patients. The pooled hazard ratios (HRs) with 95 % confidence intervals (95 % CIs) were used to assess the relationship between VM and overall survival in cancer patients.

Results

Vasculogenic mimicry was significantly associated with cancer differentiation, lymph node metastasis, distant metastasis, and TNM stage. The prognostic value of VM was significant in overall survival (HR 2.16; 95 % CI 1.98–2.38; P < 0.001). Analyses stratified by confounders, such as cancer type, ethnicity, VM detection methods, sample size, and Newcastle–Ottawa quality score, found similar significant results.

Conclusions

The presence of VM predicts poorer survival outcomes in cancer patients.

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Clinical trials of antiangiogenic therapy for hepatocellular carcinoma

Abstract

Angiogenesis is a promising therapeutic target to inhibit tumor growth. This review summarizes data from clinical trials of antiangiogenic agents in hepatocellular carcinoma. A systematic search of PubMed was performed to identify clinical trials of specific antiangiogenic agents in hepatocellular carcinoma treatment, particularly phase III trials involving treatment guidelines for advanced hepatocellular carcinoma. Sorafenib is the only systemic drug approved for the treatment of advanced hepatocellular carcinoma. Two large-scale, randomized phase III trials using sorafenib involving patients with unresectable HCC showed a significant survival benefit compared with placebo control groups. However, subsequent phase III trials of antiangiogenic agents in hepatocellular carcinoma have failed to improve survival compared with standard treatment protocols using sorafenib. The efficacy of antiangiogenic agents in combination with other drugs, transarterial chemoembolization, and surgical resection is currently being investigated. Future research is expected to optimize antiangiogenic therapies in combination with standard treatment with sorafenib.

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PD-1/PD-L1 blockade in cancer treatment: perspectives and issues

Abstract

Recent studies showed that tumor cells 'edit' host immunity in several ways to evade immune defenses in the tumor microenvironment. This phenomenon is called "cancer immune escape." One of the most important components in this system is an immunosuppressive co-signal (immune checkpoint) mediated by the PD-1 receptor and its ligand, PD-L1. PD-1 is mainly expressed on activated T cells, whereas PD-L1 is expressed on several types of tumor cells. Preclinical studies have shown that inhibition of the interaction between PD-1 and PD-L1 enhances the T-cell response and mediates antitumor activity. Several clinical trials of PD-1/PD-L1 signal-blockade agents have exhibited dramatic antitumor efficacy in patients with certain types of solid or hematological malignancies. In this review, we highlight recent clinical trials using anti-PD-1 or anti-PD-L1 antibodies against several types of malignancies, including a trial conducted in our department, and describe the clinical perspectives and issues regarding the PD-1/PD-L1 blockade in cancer treatment.

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Mesalazine Modified-Release Tablet in the Treatment of Ulcerative Colitis in the Active Phase: A Chinese, Multicenter, Single-Blind, Randomized Controlled Study

Abstract

Introduction

This study compared the efficacy and safety of two mesalazine formulations in the treatment of Chinese patients with mildly to moderately active ulcerative colitis (UC).

Methods

In this multicenter, single-blind, randomized controlled study of 251 patients with active UC conducted from November 2010 to January 2012, subjects were randomized to treatment with mesalazine modified-release tablets (MR group, n = 123) or enteric-coated tablets (EC group, n = 128) at 800 mg three-times daily for 8 weeks. The primary efficacy measure was the decrease in UC Disease Activity Index (UCDAI) at final evaluation. If the 95% confidence interval (CI) lower limit of the difference of the decrease in UCDAI between groups was over −1.0, mesalazine modified-release tablets were considered non-inferior to mesalazine enteric-coated tablets. The change in UCDAI in patients with mild and moderate (UCDAI 3–5 and 6–8 at enrollment, respectively) UC was analyzed. Secondary efficacy measures were remission and efficacy rates. Incidences of adverse drug reactions (ADRs) were calculated.

Results

The decreases in UCDAI at final evaluation were 2.84 and 2.56 in the MR and EC groups, respectively, with a difference of 0.27 between groups (95% CI −0.34, 0.88). The remission rates were 48.33% (58/120) and 55.65% (69/124), and the efficacy rates were 63.33% (76/120) and 66.94% (83/124) in the MR and EC groups, respectively (all P > 0.05). In patients with mild UC, the decreases in UCDAI were 2.16 and 2.05 in the MR and EC groups, respectively, while in patients with moderate UC they were 3.49 and 3.03, respectively (all P > 0.05). The incidences of ADRs in the MR and EC groups were 6.61% (8/121) and 10.24% (13/127), respectively (P > 0.05). No serious ADRs were reported during the study.

Conclusion

Mesalazine modified-release tablets are non-inferior to enteric-coated tablets and are an effective and safe treatment option in Chinese patients with mildly to moderately active UC.

Trial registration

ClinicalTrials.gov identifier: NCT01257386.

Funding

Tillotts Pharma AG.

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Report of a rare case of atypical lymphoplasmacyte-rich meningioma in the tentorium mimicking idiopathic hypertrophic pachymeningitis

Abstract

A lymphoplasmacyte-rich meningioma (LPRM) is an extremely rare variant of meningioma. Here, we report a case of atypical LPRM with increased mitosis in a 55-year-old man. Preoperative magnetic resonance imaging suggested meningioma with brain invasion in the left tentorium cerebelli. Histological examination revealed sclerotic fibrosis and dense lymphoplasmacytic infiltration; based on these findings, the differential diagnosis included LPRM and fibroinflammatory lesions of the dura, such as idiopathic hypertrophic pachymeningitis (IHP), IgG4-related disease (IgG4-RD), and Rosai–Dorfman disease. Epithelial membrane antigen (EMA) immunostaining highlighted sheets of meningothelial cells, which strongly supported the diagnosis of meningioma. Although brain invasion was suspected in radiologic image, no histologic evidence of brain invasion was found. However, the mitoses were observed to be 8/10 high power fields, along with increased Ki-67 labeling index with focal spontaneous necrosis, and the final pathologic diagnosis was atypical LPRM. IgG4-RD was ruled out, because IgG4 counts and the IgG4:IgG ratio of plasma cells did not meet the diagnostic criteria for IgG4-RD. To date, only one case of LPRM with brain invasion has been reported as atypical LPRM. This case is therefore the second case of atypical LPRM with increased mitosis that histologically mimicked IHP.

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Nipple Aspirate Fluid Hormone Concentrations and Breast Cancer Risk

Abstract

Prior reports identify higher serum concentrations of estrogens and androgens as risk factors for breast cancer, but steroids in nipple aspirate fluid (NAF) may be more related to risk. Incident breast cancer cases and mammography controls were recruited. Sex steroids were measured in NAF from the unaffected breasts of cases and one breast of controls. Menopausal status and menstrual cycle phase were determined. NAF steroids were purified by HPLC and quantified by immunoassays. Conditional logistic regression models were used to examine associations between NAF hormones and case-control status. NAF samples from 160 cases and 157 controls were evaluable for hormones. Except for progesterone and dehydroepiandrosterone (DHEA), the NAF and serum concentrations were not significantly correlated. NAF estradiol and estrone were not different between cases and controls. Higher NAF (but not serum) DHEA concentrations were associated with cases, particularly among estrogen receptor (ER)-positive cases (NAF odds ratio (OR) = 1.18, 95 % confidence interval (CI) 1.02, 1.36). NAF DHEA was highly correlated with NAF estradiol and estrone but not with androstenedione or testosterone. Higher progesterone concentrations in both NAF and serum were associated with a lower risk of ER-negative cancer (NAF OR = 0.69, 95 % CI 0.51, 0.92). However, this finding may be explained by case-control imbalance in the number of luteal phase subjects (2 cases and 19 controls). The significantly higher concentration of DHEA in NAF of cases and its correlation with NAF estradiol indicates a potentially important role of this steroid in breast cancer risk; however, the negative association of progesterone with risk is tentative.

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TERT Promoter Mutations in Thyroid Cancer

Abstract

Two mutations (C228T and C250T) in the promoter region of the telomerase reverse transcriptase (TERT) have recently been described in different types of cancer including follicular cell-derived thyroid cancer (TC). In this paper, we reviewed the rates of these mutations in different types and subtypes of TC, their association with a number of clinical and histopathological features and outcome of TC, and their potential diagnostic and prognostic roles in TC. The overall rate of these mutations in TC is about 14 % with least prevalence in the well-differentiated subtypes of papillary thyroid cancer (10–13 %). Their rates increase significantly with increasing aggressiveness of TC reaching about 40 % in the undifferentiated and anaplastic thyroid cancers. There is also clear association with increasing age of patients at the time of diagnosis of TC. The evidence is compelling but with some conflicting results for associations between TERT promoter mutations and tumor size, extrathyroidal invasion, distant metastases, high tumor TNM stage, BRAF ^V600E mutation, recurrence, and mortality. A couple of studies reported a potential diagnostic role for TERT promoter mutations in thyroid nodules with indeterminate cytology of fine needle aspiration biopsy. These studies showed 100 % specificity but very low sensitivity of 7–10 %. The sensitivity increases significantly when TERT promoter mutation testing is combined with other gene mutations, particularly BRAF ^V600E and RAS mutations. Although TERT promoter mutations seem to play significant roles in the pathogenesis of TC, the mechanisms by which they contribute to carcinogenesis remain elusive and future work is needed to fully assess the roles, interactions, and impact of these mutations on the pathogenesis, diagnosis, prognosis, and therapeutics of TC.

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A person-centered intervention targeting the psychosocial needs of gynecological cancer survivors: a randomized clinical trial

Abstract

Purpose

We investigated the effect of a person-centered intervention consisting of two to four nurse-led conversations using guided self-determination tailored to gynecologic cancer (GSD-GYN-C) on gynecological cancer survivors' quality of life (QOL), impact of cancer, distress, anxiety, depression, self-esteem, and self-reported ability to monitor and respond to symptoms of recurrence.

Methods

We randomly assigned 165 gynecological cancer survivors to usual care (UC) plus GSD-GYN-C or UC alone. Self-reported QOL-cancer survivor (QOL-CS) total score and subscale scores on physical, psychological, social, and spiritual well-being were assessed before randomization and at 3 and 9 months after randomization using t tests. Bonferroni and Pipper corrections were applied for multiple testing adjustments.

Results

At 9 months, the GSD-GYN-C plus UC group scored significantly higher on the QOL-CS total scale (P = 0.02) and on the QOL-CS physical well-being subscale (P = 0.01), compared to women receiving UC alone. After adjusting for baseline scores, only the difference in the physical well-being subscale was statistically significant. No other measured outcomes differed between the intervention and control groups after baseline adjustment.

Conclusion

We observed higher physical well-being 9 months after randomization in the GSD-GYN-C group, as compared to women receiving usual care.

Implications for Cancer Survivors

The results suggest that the person-centered intervention GSD-GYN-C may improve physical well-being in gynecological cancer survivors. However, further testing is needed.

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Adverse event grading following CTCAE v3.0 underestimates hypertensive side effects in patients with glioma treated with Bevacizumab

Abstract

Anti-VEGF therapy with Bevacizumab (BEV) is widely used in cases of relapsed high-grade glioma (HGG). Arterial hypertension is a known side effect of anti-VEGF therapy. 42 Patients with relapsed HGG were treated with BEV 10 mg/kg on days 1 and 15 of 28-day cycles in addition to treatment with 40 mg TMZ daily until disease progression, based on magnetic resonance imaging and/or worsening of clinical status. In a retrospective analysis, hypertensive side effects were evaluated as the primary endpoint, while survival information in addition to toxicity was analyzed as secondary endpoint. Grading which employs the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 detected hypertensive events with a significantly higher sensitivity than CTCAE version 3.0. The rate of severe hypertensive events observed as CTCAE ≥ °3 were 9.5 % in version 3.0 and 45.2 % in version 4.0. The results presented here indicate that CTCAE version 3.0 may underreport the incidence and grade of BEV-induced hypertension within clinical trials. As hypertension has not only long-term, but also severe short-term side effects, we suggest that arterial hypertension under BEV should be scored according to CTCAE version 4.0 to avoid clinically relevant hypertension-related adverse events in these patients.

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Primary intracranial soft tissue sarcomas in children, adolescents, and young adults: single institution experience and review of the literature

Abstract

There is a paucity of literature reporting the outcome of intracranial sarcomas (IS) in children, adolescents, and young adults (CAYA). A multimodal therapeutic approach is commonly used, with no well-established treatment consensus. We conducted a retrospective review of CAYA with IS, treated at our institution, to determine their clinical findings, treatments, and outcomes. Immunohistochemistry (PDGFRA and EGFR) and DNA sequencing were performed on 5 tumor samples. A literature review of IS was also conducted. We reviewed 13 patients (median age, 7 years) with a primary diagnosis of IS between 1990 and 2015. Diagnoses included unclassified sarcoma (n = 9), chondrosarcoma (n = 2), and rhabdomyosarcoma (n = 2). Five patients underwent upfront gross total resection (GTR) of the tumor. The 5-drug regimen (vincristine, doxorubicin, cyclophosphamide, etoposide, and ifosfamide) was the most common treatment used. Nine patients died due to progression or recurrence (n = 8) or secondary malignancy (n = 1). The median follow-up period of the 4 surviving patients was 1.69 years (range 1.44–5.17 years). The 5-year progression-free survival and overall survival rates were 21 and 44 %, respectively. BRAF, TP53, KRAS, KIT, ERBB2, MET, RET, ATM, and EGFR mutations were detected in 4 of the 5 tissue samples. All 5 samples were immunopositive for PDGFRA, and only 2 were positive for EGFR. IS remain a therapeutic challenge due to high progression and recurrence rates. Collaborative multi-institutional studies are warranted to delineate a treatment consensus and investigate tumor biology to improve the disease outcome.

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Quantitative imaging of magnesium distribution at single-cell resolution in brain tumors and infiltrating tumor cells with secondary ion mass spectrometry (SIMS)

Abstract

Glioblastoma multiforme (GBM) is one of the deadliest forms of human brain tumors. The infiltrative pattern of growth of these tumors includes the spread of individual and/or clusters of tumor cells at some distance from the main tumor mass in parts of the brain protected by an intact blood–brain-barrier. Pathophysiological studies of GBM could be greatly enhanced by analytical techniques capable of in situ single-cell resolution measurements of infiltrating tumor cells. Magnesium homeostasis is an area of active investigation in high grade gliomas. In the present study, we have used the F98 rat glioma as a model of human GBM and an elemental/isotopic imaging technique of secondary ion mass spectrometry, a CAMECA IMS-3f ion microscope, for studying Mg distribution with single-cell resolution in freeze-dried brain tissue cryosections. Quantitative observations were made on tumor cells in the main tumor mass, contiguous brain tissue, and infiltrating tumor cells in adjacent normal brain. The brain tissue contained a significantly lower total Mg concentration of 4.70 ± 0.93 mmol/kg wet weight (mean ± SD) in comparison to 11.64 ± 1.96 mmol/kg wet weight in tumor cells of the main tumor mass and 10.72 ± 1.76 mmol/kg wet weight in infiltrating tumor cells (p < 0.05). The nucleus of individual tumor cells contained elevated levels of bound Mg. These observations have established that there was enhanced influx and increased binding of Mg in tumor cells. They provide strong support for further investigation of altered Mg homeostasis and activation of Mg-transporting channels in GBMs as possible therapeutic targets.

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Primary Burkitt lymphoma of the fourth ventricle mimicking a medulloblastoma in a child

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Population pharmacokinetics and exposure–response relationship of amatuximab, an anti-mesothelin monoclonal antibody, in patients with malignant pleural mesothelioma and its application in dose selection

Abstract

Purpose

To characterize amatuximab pharmacokinetics (PK) and the relationship of amatuximab exposure with response in patients with unresectable malignant pleural mesothelioma (MPM) receiving amatuximab with pemetrexed and cisplatin.

Methods

A nonlinear mixed effects PK model was built using data from all of the amatuximab studies conducted to date. Patients received amatuximab alone or in combination with chemotherapy. The influence of demographic, laboratory and disease characteristics on PK parameters was assessed. Exposure–response analyses explored relationships between amatuximab exposure and overall survival (OS), progression-free survival (PFS) and safety. Alternative amatuximab dosing regimens were explored with simulations using population PK and parametric survival models.

Results

Amatuximab PK was best described by a two-compartment model with parallel linear and nonlinear elimination pathways. Body weight and an antidrug antibodies reaction with the titer >64 affected volume of distribution and clearance, respectively. Exposure–response analyses demonstrated that the amatuximab exposure (C _min) showed a significant effect on OS (log-rank test, P = 0.0202). For patients with amatuximab C _min above the median (38.2 μg/mL), the median OS was 583 days (90 % CI 418 –NE). For patients with C _min ≤ 38.2 μg/mL, the median OS was 375 days (90 % CI 325–486). The amatuximab exposure showed similar significant effect on PFS. Exposure–response analysis for adverse events did not reveal any relationship.

Conclusions

In patients with MPM, higher amatuximab exposure in combination with chemotherapy was shown to be associated with longer OS, supporting evaluation of more frequent dosing in future trials to achieve higher exposure and subsequently longer OS.

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Population pharmacokinetics of sonidegib (LDE225), an oral inhibitor of hedgehog pathway signaling, in healthy subjects and in patients with advanced solid tumors

Abstract

Purpose

Sonidegib (Odomzo) selectively inhibits smoothened and suppresses the growth of hedgehog pathway-dependent tumors. A population pharmacokinetic (PK) analysis of sonidegib in healthy subjects and patients with advanced solid tumors was conducted to characterize PK, determine variability, and estimate covariate effects.

Methods

PK data from five phase 1 or 2 studies (N = 436) in the dose range from 100 to 3000 mg were analyzed using NONMEM. A two-compartment base model with first-order absorption, lag time, linear elimination, and bioavailability that decreased with dose was updated to describe the PK of sonidegib. Covariate analyses were performed and were incorporated into the population PK full model.

Results

The base and full models were robust with a good fit to the study data. Population-predicted geometric means (inter-individual variability, CV%) of apparent oral clearance, apparent volume of distribution at steady state, accumulation ratio, and elimination half-life were 9.5 L/h (71.4 %), 9163 L (74.9 %), 21 (131 %) and 29.6 days (109 %). Clinically relevant covariate effects were: A high-fat meal increased sonidegib bioavailability fivefold, healthy volunteers had threefold higher clearance, sonidegib bioavailability decreased with increasing dose levels, and PPI coadministration reduced sonidegib bioavailability by 30 %. Sonidegib PK was not significantly impacted by baseline age, weight, total bilirubin, alanine aminotransferase, albumin, creatinine clearance, gender, and ethnicity (Western countries versus Japanese).

Conclusion

No dose adjustment is needed for mild hepatic impairment, mild and moderate renal impairment, age, weight, gender, or ethnicity. This population PK model adequately characterizes sonidegib PK characteristics and can be used for various simulations and applications.

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The novel EZH2 inhibitor, GSK126, suppresses cell migration and angiogenesis via down-regulating VEGF-A

Abstract

Purpose

To explore the effects and mechanisms of GSK126, a novel inhibitor of histone methyltransferase enhancer of zeste homologue 2, on cancer cell migration.

Methods

Gastric cancer cell line MGC803 and human lung adenocarcinoma cell line A549 were treated with GSK126 at three doses. Transwell and wound healing assays were conducted to detect cell migration. Human umbilical vein endothelial cells tube formation assay and chick embryo chorioallantoic membrane assay were performed to assess the effects of GSK126 on angiogenesis in vitro and in vivo, respectively. The mRNA level of VEGF-A was detected by quantitative PCR, and the protein levels of VEGF-A were detected both by western blot analysis and immunohistochemistry. Epi-fluorescent intensity was obtained by in vivo imaging.

Results

GSK126 inhibited cell migration in both MGC803 and A549 in a dose-dependent manner, as revealed by transwell and wound healing assays. The effects of GSK 126 were similar to those of gefitinib at the same doses. Moreover, GSK126 at doses of 20 and 50 µM inhibited angiogenesis both in vitro and in vivo. GSK126 reduced both the mRNA and protein expression of VEGF-A in a dose-dependent manner. Finally, in vivo imaging assay revealed that GSK126 at 200 mg/kg significantly inhibited cancer cell migration.

Conclusions

GSK126 inhibits cell migration and angiogenesis in solid tumor cell lines through down-regulation of VEGF-A expression. Thus, it may be considered as a novel anticancer drug candidate for solid tumor.

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Tobacco smoking and the risk of gallbladder disease

Abstract

Tobacco smoking has been inconsistently associated with gallbladder disease risk. To clarify the association we conducted a systematic review and meta-analysis of cohort studies published on the subject. We searched the PubMed and Embase databases for studies of smoking and gallbladder disease up to January 9th 2015. Prospective studies were included if they reported relative risk estimates and 95 % confidence intervals of gallbladder disease associated with current, former or ever smoking and by number of cigarettes per day. Summary relative risks were estimated by use of a random effects model. We identified ten prospective studies including 59,530 gallbladder disease cases among 4,213,482 participants that could be included in the meta-analysis. The summary RR was 1.19 (95 % CI 1.12–1.28, I² = 46.9 %, n = 6) for current smokers, 1.10 (95 % CI 1.07–1.13, I² = 0 %, n = 6) for former smokers and 1.15 (95 % CI 1.13–1.18, I² = 0 %, n = 7) for ever smokers. In the dose–response analysis the summary relative risk was 1.11 (95 % CI 1.08–1.14, I² = 33 %, n = 3) per 10 cigarettes per day and although there was indication of nonlinearity there was a dose-dependent positive association with increasing number of cigarettes smoked per day. The current meta-analysis provides evidence of an increased risk of gallbladder disease associated with tobacco smoking.

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Predicting Parkinson disease in the community using a nonmotor risk score

Abstract

At present, there are no validated methods to identify persons who are at increased risk for Parkinson Disease (PD) from the general population. We investigated the clinical usefulness of a recently proposed non-motor risk score for PD (the PREDICT-PD risk score) in the population-based Rotterdam Study. At baseline (1990), we constructed a weighted risk score based on 10 early nonmotor features and risk factors in 6492 persons free of parkinsonism and dementia. We followed these persons for up to 20 years (median 16.1 years) for the onset of PD until 2011. We studied the association between the PREDICT-PD risk score and incident PD using competing risk regression models with adjustment for age and sex. In addition, we assessed whether the PREDICT-PD risk score improved discrimination (C-statistics) and risk classification (net reclassification improvement) of incident PD beyond age and sex. During follow-up, 110 persons were diagnosed with incident PD. The PREDICT-PD risk score was associated with incident PD (hazard ratio [HR] = 1.30; 95 % confidence interval [1.06; 1.59]) and yielded a small, non-significant improvement in overall discrimination (ΔC-statistic = 0.018[−0.005; 0.041]) and risk classification (net reclassification improvement = 0.172[−0.017; 0.360]) of incident PD. In conclusion, the PREDICT-PD risk score only slightly improves long-term prediction of PD in the community.

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Cryoablation in fibro-adipose vascular anomaly (FAVA): a minimally invasive treatment option

Abstract

Background

Fibro-adipose vascular anomaly (FAVA) is a complex vascular malformation that typically presents with persistent pain, discomfort, contracture and other disabling symptoms. There are no minimally invasive treatment options to effectively control these symptoms. Image-guided percutaneous cryoablation, which has been used to control pain in people with cancer, could be used for similar indications in FAVA.

Objective

To assess the role of image-guided percutaneous cryoablation for control of symptoms in FAVA lesions.

Materials and methods

We conducted a retrospective cohort study of 20 children and young adults with FAVA who underwent percutaneous cryoablation at 26 sites, from September 2013 to August 2015. The outcome was based on the brief pain inventory scoring (BPI), concurrent symptoms, clinical response and patient satisfaction.

Results

After cryoablation there was significant improvement in pain, which dropped by 3 points (pain now) to 3.7 points (pain in the last 24 h). Most patients indicated that pain interfered less in their everyday social life. Concurrent symptoms like swelling, physical limitations and skin hyperesthesia also improved. Clinical response was greatest at 2–5 months follow-up after cryoablation, with acceptable patient satisfaction thereafter. Technical response was 100%. There were no major complications.

Conclusion

Image-guided percutaneous cryoablation is a safe and effective option for treatment of symptomatic FAVA lesions.

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The classic metaphyseal lesion and traumatic injury

Abstract

Background

It is widely accepted that the classic metaphyseal lesion (CML) is a traumatic lesion, strongly associated with abuse in infants. Nevertheless, various non-traumatic origins for CMLs continue to be suggested in medical and legal settings. No studies to date systematically describe the association of CMLs with other traumatic injuries.

Objective

The primary objective of this study is to examine the association of CMLs with other traumatic injuries in a large data set of children evaluated for physical abuse.

Materials and methods

This was a retrospectively planned secondary analysis of data from a prospective, observational study of children <120 months of age who underwent evaluation by a child abuse physician. For this secondary analysis, we identified all children ≤12 months of age with an identified CML and determined the number and type of additional injuries identified. Descriptive analysis was used to report frequency of additional traumatic injuries.

Results

Among 2,890 subjects, 119 (4.1%) were identified as having a CML. Of these, 100 (84.0%) had at least one additional (non-CML) fracture. Thirty-three (27.7%) had traumatic brain injury. Nearly half (43.7%) of children had cutaneous injuries. Oropharyngeal injuries were found in 12 (10.1%) children. Abdominal/thoracic injuries were also found in 12 (10.1%) children. In all, 95.8% of children with a CML had at least one additional injury; one in four children had three or more categories of injury.

Conclusion

CMLs identified in young children are strongly associated with traumatic injuries. Identification of a CML in a young child should prompt a thorough evaluation for physical abuse.

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Comparison of two single-breath-held 3-D acquisitions with multi-breath-held 2-D cine steady-state free precession MRI acquisition in children with single ventricles

Abstract

Background

Breath-held two-dimensional balanced steady--state free precession cine acquisition (2-D breath-held SSFP), accelerated with parallel imaging, is the method of choice for evaluating ventricular function due to its superior blood-to-myocardial contrast, edge definition and high intrinsic signal-to-noise ratio throughout the cardiac cycle.

Objective

The purpose of this study is to qualitatively and quantitatively compare the two different single-breath-hold 3-D cine SSFP acquisitions using 1) multidirectional sensitivity encoding (SENSE) acceleration factors (3-D multiple SENSE SSFP), and 2) k-t broad-use linear acceleration speed-up technique (3-D k-t SSFP) with the conventional 2-D breath-held SSFP in non-sedated asymptomatic volunteers and children with single ventricle congenital heart disease.

Materials and methods

Our prospective study was performed on 30 non-sedated subjects (9 healthy volunteers and 21 functional single ventricle patients), ages 12.5 +/- 2.8 years. Two-dimensional breath-held SSFP with SENSE acceleration factor of 2, eight-fold accelerated 3-D k-t SSFP, and 3-D multiple SENSE SSFP with total parallel imaging factor of 4 were performed to evaluate ventricular volumes and mass in the short-axis orientation. Image quality scores (blood myocardial contrast, edge definition and interslice alignment) and volumetric analysis (end systolic volume, end diastolic volume and ejection fraction) were performed on the data sets by experienced users. Paired t-test was performed to compare each of the 3-D k-t SSFP and 3-D multiple SENSE SSFP clinical scores against 2-D breath-held SSFP. Bland-Altman analysis was performed on left ventricle (LV) and single ventricle volumetry. Interobserver and intraobserver variability in volumetric measurements were determined using intraclass coefficients.

Results

The clinical scores were highest for the 2-D breath-held SSFP images. Between the two 3-D sequences, 3-D multiple SENSE SSFP performed better than 3-D k-t SSFP. Bland-Altman analysis for volumes indicated that variability was more between 3-D k-t SSFP and 2-D breath-held SSFP acquisitions than between 3-D multiple SENSE SSFP and 2-D breath-held SSFP acquisitions. In the non-sedated population, interslice alignment scores were better for 3-D k-t SSFP and 3-D multiple SENSE SSFP than 2-D breath-held SSFP. The blood-myocardial contrast and edge definition scores were better for 2-D breath-held SSFP than 3-D k-t SSFP and 3-D multiple SENSE SSFP. Scan duration was shorter for 3-D acquisition sequences compared to the 2-D breath-held stack.

Conclusion

Three-dimensional k-t SSFP and 3-D multiple SENSE for ventricular volumetry release the constraints of multiple breath-holds in children and overcome problems related to interslice misalignment caused by inconsistent amplitude of breathing. Three-dimensional multiple SENSE SSFP performed better in our pediatric population than 3-D k-t SSFP. However, these 3-D sequences produce lower-quality diagnostic images than the gold standard 2-D breath-held SSFP sequence.

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Diagnosis of vertebral fractures in children: is a simplified algorithm-based qualitative technique reliable?

Abstract

Background

Identification of osteoporotic vertebral fractures allows treatment opportunity reducing future risk. There is no agreed standardised method for diagnosing paediatric vertebral fractures.

Objective

To evaluate the precision of a modified adult algorithm-based qualitative (ABQ) technique, applicable to children with primary or secondary osteoporosis.

Materials and methods

Three radiologists independently assessed lateral spine radiographs of 50 children with suspected reduction in bone mineral density using a modified ABQ scoring system and following simplification to include only clinically relevant parameters, a simplified ABQ score. A final consensus of all observers using simplified ABQ was performed as a reference standard for fracture characterisation. Kappa was calculated for interobserver agreement of the components of both scoring systems and intraobserver agreement of simplified ABQ based on a second read of 29 randomly selected images.

Results

Interobserver Kappa for modified ABQ scoring for fracture detection, severity and shape ranged from 0.34 to 0.49 Kappa for abnormal endplate and position assessment was 0.27 to 0.38. Inter- and intraobserver Kappa for simplified ABQ scoring for fracture detection and grade ranged from 0.37 to 0.46 and 0.45 to 0.56, respectively. Inter- and intraobserver Kappa for affected endplate ranged from 0.31 to 0.41 and 0.45 to 0.51, respectively. Subjectively, observers' felt simplified ABQ was easier and less time-consuming.

Conclusion

Observer reliability of modified and simplified ABQ was similar, with slight to moderate agreement for fracture detection and grade/severity. Due to subjective preference for simplified ABQ, we suggest its use as a semi-objective measure of diagnosing paediatric vertebral fractures.

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Patellofemoral instability in children: T2 relaxation times of the patellar cartilage in patients with and without patellofemoral instability and correlation with morphological grading of cartilage damage

Abstract

Background

Patellofemoral instability is one of the most common causes of cartilage damage in teenagers.

Objective

To quantitatively evaluate the patellar cartilage in patients with patellofemoral instability using T2 relaxation time maps (T2 maps), compare the values to those in patients without patellofemoral instability and correlate them with morphological grades in patients with patellofemoral instability.

Materials and methods

Fifty-three patients with patellofemoral instability (mean age: 15.9 ± 2.4 years) and 53 age- and gender-matched patients without patellofemoral instability were included. Knee MR with axial T2 map was performed. Mean T2 relaxation times were obtained at the medial, central and lateral zones of the patellar cartilage and compared between the two groups. In the patellofemoral instability group, morphological grading of the patellar cartilage (0-4) was performed and correlated with T2 relaxation times.

Results

Mean T2 relaxation times were significantly longer in the group with patellofemoral instability as compared to those of the control group across the patellar cartilage (Student's t-test, P<0.05) with the longest time at the central area. Positive correlation was seen between mean T2 relaxation time and morphological grading (Pearson correlation coefficiency, P<0.001). T2 increased with severity of morphological grading from 0 to 3 (mixed model, P<0.001), but no statistical difference was seen between grades 3 and 4.

Conclusion

In patellofemoral instability, patellar cartilage damage occurs across the entire cartilage with the highest T2 values at the apex. T2 relaxation times directly reflect the severity in low-grade cartilage damage, which implies an important role for T2 maps in differentiating between normal and low-grade cartilage damage.

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Prognostic value of ERBB4 expression in patients with triple negative breast cancer

Abstract

Background

Triple-negative breast cancer (TNBC) is known for aggressive biologic features and poor prognosis. Epidermal growth factor receptor (EGFR) overexpression in TNBC indicates poor prognosis. However, there is no previous study of the relationship between expression of the entire human epidermal growth factor receptor (HER) family genes and patient prognosis in TNBC. Accordingly, we investigated the expression profiles of HER family genes in patients with TNBC to determine the prognostic value and clinical implications of HER family expression.

Methods

We used the nCounter expression assay (NanoString®) to measure the expression of EGFR, erb-B2 receptor tyrosine kinase 2 (ERBB2), ERBB3, ERBB4, and estrogen receptor 1 (ESR1) genes using mRNA extracted from paraffin-embedded tumor tissues from 203 patients diagnosed with TNBC. Our data were validated using a separate cohort of 84 TNBC patients.

Results

A total of 203 TNBC patients who received adjuvant chemotherapy after curative surgery from 2000 to 2004 formed the training set. The 84 TNBC patients in the validation consort were selected from breast cancer patients who received curative surgery since 2005 to 2010. Analysis of the expression profiles of the HER family genes in TNBC tissue specimens revealed that increased expression of ERBB4 was associated with poor prognosis according to survival analysis (5-year distant relapse free survival [5Y DRFS], low vs. high expression [cut-off: median]: 90.1 % vs. 80.2 %; p = 0.022). This trend was also observed in the validation set of TNBC patients (5Y DRFS, low vs. high: 69.4 % vs. 44.7 %; p = 0.053). In a multivariate Cox regression model, ERBB4 expression was identified as a indicator of long-term prognosis in patients with TNBC.

Conclusions

The expression profile of ERBB4, a member of the HER family, might serve as a prognostic marker in patients with TNBC.

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Transketolase-like 1 ectopic expression is associated with DNA hypomethylation and induces the Warburg effect in melanoma cells

Abstract

Background

The metabolism of cancer cells is often reprogrammed by dysregulation of metabolic enzymes. Transketolase-like 1 (TKTL1) is a homodimeric transketolase linking the pentose-phosphate pathway with the glycolytic pathway. It is generally silenced at a transcriptional level in somatic tissues. However, in human cancers its expression is associated with the acquisition of a glycolytic phenotype (the Warburg effect) by cancer cells that contributes to the progression of malignant tumors. In melanoma, defective promoter methylation results in the expression of genes and their products that can affect the tumor cell's phenotype including the modification of immune and functional characteristics. The present study evaluates the role of TKTL1 as a mediator of disease progression in melanoma associated with a defective methylation phenotype.

Methods

The expression of TKTL1 in metastatic melanoma tumors and cell lines was analysed by qRT-PCR and immunohistochemistry. The promoter methylation status of TKTL1 in melanoma cells was evaluated by quantitative methylation specific PCR. Using qRT-PCR, the effect of a DNA demethylating agent 5-aza-2'-deoxycytidine (5aza) on the expression of TKTL1 was examined. Biochemical and molecular analyses such as glucose consumption, lactate production, invasion, proliferation and cell cycle progression together with ectopic expression and siRNA mediated knockdown were used to investigate the role of TKTL1 in melanoma cells.

Results

Expression of TKTL1 was highly restricted in normal adult tissues and was overexpressed in a subset of metastatic melanoma tumors and derived cell lines. The TKTL1 promoter was activated by hypomethylation and treatment with 5aza induced TKTL1 expression in melanoma cells. Augmented expression of TKTL1 in melanoma cells was associated with a glycolytic phenotype. Loss and gain of function studies revealed that TKTL1 contributed to enhanced invasion of melanoma cells.

Conclusions

Our data provide evidence for an important role of TKTL1 in aerobic glycolysis and tumor promotion in melanoma that may result from defective promoter methylation. This epigenetic change may enable the natural selection of tumor cells with a metabolic phenotype and thereby provide a potential therapeutic target for a subset of melanoma tumors with elevated TKTL1 expression.

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Impact on clinical practice of the implementation of guidelines for the toxicity management of targeted therapies in kidney cancer. The protect-2 study

Abstract

Background

The impact of such recommendations after their implementation of guidelines has not usually been evaluated. Herein, we assessed the impact and compliance with the Spanish Oncology Genitourinary Group (SOGUG) Guidelines for toxicity management of targeted therapies in metastatic renal cell carcinoma (mRCC) in daily clinical practice.

Methods

Data on 407 mRCC patients who initiated first-line targeted therapy during the year before and the year after publication and implementation of the SOGUG guideline program were available from 34 Spanish Hospitals. Adherence to SOGUG Guidelines was assessed in every cycle.

Results

Adverse event (AE) management was consistent with the Guidelines as a whole for 28.7 % out of 966 post-implementation cycles compared with 23.1 % out of 892 pre-implementation cycles (p = 0.006). Analysis of adherence by AE in non-compliant cycles showed significant changes in appropriate management of hypertension (33 % pre-implementation vs. 44.5 % post-implementation cycles; p < 0.0001), diarrhea (74.0 % vs. 80.5 %; p = 0.011) and dyslipemia (25.0 % vs. 44.6 %; p < 0.001).

Conclusions

Slight but significant improvements in AE management were detected following the implementation of SOGUG recommendations. However, room for improvement in the management of AEs due to targeted agents still remains and could be the focus for further programs in this direction.

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METCAM/MUC18 is a novel tumor and metastasis suppressor for the human ovarian cancer SKOV3 cells

Abstract

Background

Increased expression of METCAM/MUC18, a trans-membrane cell adhesion molecule in the Ig-like gene superfamily, has been associated with the malignant progression of epithelial ovarian carcinomas. To investigate if this is a fortuitous correlation or if METCAM/MUC18 actually plays a role in the progression of the cancer, we tested effects of enforced expression of METCAM/MUC18 on in vitro behaviors, in vivo tumorigenesis, and in vivo malignant progression of human ovarian cancer SK-OV-3 cells, which minimally expressed this protein.

Methods

For in vitro and in vivo tests, we transfected human METCAM/MUC18 cDNA gene into SK-OV-3 cells in a mammalian expression vector pcDNA3.1+ and obtained G418-resistant (G418^R) clones, which expressed various levels of human METCAM/MUC18. To mimic physiological situations, we used pooled METCAM/MUC18-expressing and control (vector) clones for testing effects of human METCAM/MUC18 over-expression on in vitro motility and invasiveness, and on in vivo tumor formation and metastasis in female athymic nude mice. Effects of METCAM/MUC18 on the expression of various downstream key factors related to tumorigenesis were also evaluated by Western blot analyses.

Results

The over-expression of METCAM/MUC18 inhibited in vitro motility and invasiveness of SK-OV-3 cells. SK-OV-3 cells of the control (vector) clone (3D), which did not express human METCAM/MUC18, supported the formation of a solid tumor after SC injection of the cells at dorsal or ventral sites and also formation of solid tumor and ascites after IP injection in the intraperitoneal cavity of nude mice. In contrast, SK-OV-3 cells from the METCAM/MUC18-expressing clone (2D), which expressed a high level of METCAM/MUC18, did not support the formation of a solid tumor at SC sites, or formation of ascites in the intraperitoneal cavity of nude mice. Expression levels of downstream key factors, which may affect tumor proliferation and angiogenesis, were reduced in tumors induced by the METCAM/MUC18-expressing clone (2D).

Conclusions

We conclude that increased human METCAM/MUC18 expression in ovarian cancer SK-OV-3 cells suppressed tumorigenesis and ascites formation in nude mice, suggesting that human METCAM/MUC18 plays a suppressor role in the progression of ovarian cancer, perhaps by reducing proliferation and angiogenesis.

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A novel and accurate predictor of survival for patients with hepatocellular carcinoma after surgical resection: the neutrophil to lymphocyte ratio (NLR) combined with the aspartate aminotransferase/platelet count ratio index (APRI)

Abstract

Background

The occurrence and development of hepatocellular carcinoma (HCC) depends largely on such non-tumor factors as inflammatory condition, immune state, viral infection and liver fibrosis. Various inflammation-based prognostic scores have been associated with survival in patients with HCC, such as the neutrophil/lymphocyte ratio (NLR), the platelet/lymphocyte ratio (PLR) and the prognostic nutritional index (PNI). The aspartate aminotransferase/platelet count ratio index (APRI) is thought to be a biomarker of liver fibrosis and cirrhosis. This study aims to evaluate the ability of these indices to predict survival in HCC patients after curative hepatectomy, and probe the increased prognostic accuracy of APRI combined with established inflammation-based prognostic scores.

Methods

Data were collected retrospectively from 321 patients who underwent curative resection for HCC. Preoperative NLR, PLR, PNI, APRI and clinico-pathological variables were analyzed. Univariate and multivariate analyses were performed to identify the predictive value of the above factors for disease-free survival (DFS) and overall survival (OS).

Results

Univariate analysis showed that NLR, PLR, PNI and APRI were significantly associated with DFS and OS in HCC patients with curative resection. Multivariate analysis showed that NLR and APRI were superior to PLR and PNI, and both were independently correlated with DFS and OS. Preoperative NLR >2 or APRI >1.68 predicted poor prognosis of patients with HCC after hepatectomy. Furthermore, the predictive range of NLR combined with APRI was more sensitive than that of either measure alone.

Conclusions

Preoperative NLR and APRI are independent predictors of DFS and OS in patients with HCC after surgical resection. Higher levels of NLR or APRI predict poorer outcomes in HCC patients. Intriguingly, combining NLR and APRI increases the prognostic accuracy of testing.

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A beneficial tumor microenvironment in oropharyngeal squamous cell carcinoma is characterized by a high T cell and low IL-17 + cell frequency

Abstract

Patients with HPV-positive oropharyngeal squamous cell carcinomas (OPSCCs) have a better prognosis than patients with non-HPV-induced OPSCC. The role of the immune response in this phenomenon is yet unclear. We studied the number of T cells, regulatory T cells (Tregs), T helper 17 (Th17) cells and IL-17⁺ non-T cells (mainly granulocytes) in matched HPV-positive and HPV-negative OPSCC cases (n = 162). Furthermore, the production of IFN-γ and IL-17 by tumor-infiltrating T cells was analyzed. The number of tumor-infiltrating T cells and Tregs was higher in HPV-positive than HPV-negative OPSCC (p < 0.0001). In contrast, HPV-negative OPSCC contained significantly higher numbers of IL-17⁺ non-T cells (p < 0.0001). Although a high number of intra-tumoral T cells showed a trend toward improved survival of all OPSCC patients, their prognostic effect in patients with a low number of intra-tumoral IL-17⁺ non-T cells was significant with regard to disease-specific (p = 0.033) and disease-free survival (p = 0.012). This suggests that a high frequency of IL-17⁺ non-T cells was related to a poor immune response, which was further supported by the observation that a high number of T cells was correlated with improved disease-free survival in the HPV-positive OPSCC (p = 0.008). In addition, we detected a minor Th17 cell population. However, T cells obtained from HPV-positive OPSCC produced significantly more IL-17 than those from HPV-negative tumors (p = 0.006). The improved prognosis of HPV-positive OPSCC is thus correlated with higher numbers of tumor-infiltrating T cells, more active Th17 cells and lower numbers of IL-17⁺ non-T cells.

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Top-down approach to the superior mesenteric artery and the mesopancreas during pancreatoduodenctomy for pancreatic cancer

Complete surgical resection with microscopically tumor-free resection margins (R0) is the most important survival determinant for patients with localized pancreatic cancer. The medial and posterior resection margins are the dominant sites of microscopic tumor involvement, and outline the so-called mesopancreas. In this study, we present a modified surgical approach to the superior mesenteric artery, celiac trunc, and mesopancreas during pancreatoduodenectomy, which enables a comfortable exposure and radical en bloc clearance of the mesopancreas and the tissue adjacent to the superior mesenteric artery. The dissection of the mesopancreas is directed from the ventral aspect of the portal vein downward along the superior mesenteric artery and the celiac trunc, before the transection of the duodenal mesentery is accomplished. The described technique complements the established surgical approaches to pancreatic head tumors, and is indicated in the absence of portal vein infiltration. J. Surg. Oncol. © 2016 Wiley Periodicals, Inc.

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