Editorial Board

Publication date: 15 February 2018
Source:Journal of Neuroscience Methods, Volume 296





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Detecting Structural and Inflammatory Response after In Vivo Stretch Injury in the Rat Median Nerve via Second Harmonic Generation

Publication date: Available online 14 February 2018
Source:Journal of Neuroscience Methods
Author(s): Matthew J. Gluck, Surabhi Vijayaraghavan, Elaine B. Sinclair, Asad Ashraf, Michael R. Hausman, Paul J. Cagle
BackgroundSecond Harmonic Generation (SHG) microscopy is a promising method for visualizing the collagenous structure of peripheral nerves. Assessing collagen continuity and damage after a stretch injury provides inferential insight into the level of axonal damage present.New MethodsThis study utilizes SHG microscopy after a calibrated in vivo stretch injury of rat median nerves to evaluate collagen continuity at several time points throughout the recovery process. Endoneurial collagen was qualitatively assessed in nerves that were subjected to low strain (LS) and high strain (HS) injuries using SHG microscopy, conventional histology, and immunohistochemistry.ResultsFollowing an in vivo stretch injury, both LS and HS damaged nerves exhibit signs of structural collagen damage in comparison with sham control nerves (SC). Furthermore, LS nerves exhibit signs of full regeneration while HS nerves exhibited signs of only partial regeneration with lasting damage and intra-neural scar formation.Comparison with Existing MethodsSHG observations of structural changes and inflammatory response due to stretch injury were validated upon comparison with conventional histological methodsConclusionsWe propose that SHG microscopy can be utilized to visualize significant structural artifacts in sectioned median nerves following in vivo stretch injury. Based on the findings in this study, we believe that the in vivo application of SHG microscopy should be further investigated as a means for real-time, intra-operative, quantitative assessment of nerve damage.



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Table of contents

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Masthead

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Open Access: Is There a Predator at the Door?

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Novel In Vitro Cancer Models for Optimizing Anti-EGFR Therapies

Preclinical models, which are able to recapitulate the biology and pathology of the original individual cancer, are needed to better investigate mechanisms of response and resistance to anticancer therapies. In this respect, novel in vitro models for metastatic colorectal cancer could be of high value. Clin Cancer Res; 24(4); 727–9. ©2017 AACR.

See related article by Luraghi et al., p. 807

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Olaratumab Exerts Antitumor Activity in Preclinical Models of Pediatric Bone and Soft Tissue Tumors through Inhibition of Platelet-Derived Growth Factor Receptor {alpha}

Purpose: Platelet-derived growth factor receptor α (PDGFRα) is implicated in several adult and pediatric malignancies, where activated signaling in tumor cells and/or cells within the microenvironment drive tumorigenesis and disease progression. Olaratumab (LY3012207/IMC-3G3) is a human mAb that exclusively binds to PDGFRα and recently received accelerated FDA approval and conditional EMA approval for treatment of advanced adult sarcoma patients in combination with doxorubicin. In this study, we investigated olaratumab in preclinical models of pediatric bone and soft tissue tumors.

Experimental Design: PDGFRα expression was evaluated by qPCR and Western blot analysis. Olaratumab was investigated in in vitro cell proliferation and invasion assays using pediatric osteosarcoma and rhabdoid tumor cell lines. In vivo activity of olaratumab was assessed in preclinical mouse models of pediatric osteosarcoma and malignant rhabdoid tumor.

Results: In vitro olaratumab treatment of osteosarcoma and rhabdoid tumor cell lines reduced proliferation and inhibited invasion driven by individual platelet-derived growth factors (PDGFs) or serum. Furthermore, olaratumab delayed primary tumor growth in mouse models of pediatric osteosarcoma and malignant rhabdoid tumor, and this activity was enhanced by combination with either doxorubicin or cisplatin.

Conclusions: Overall, these data indicate that olaratumab, alone and in combination with standard of care, blocks the growth of some preclinical PDGFRα-expressing pediatric bone and soft tissue tumor models. Clin Cancer Res; 24(4); 847–57. ©2017 AACR.

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Whole-Exome Sequencing of Cell-Free DNA Reveals Temporo-spatial Heterogeneity and Identifies Treatment-Resistant Clones in Neuroblastoma

Purpose: Neuroblastoma displays important clinical and genetic heterogeneity, with emergence of new mutations at tumor progression.

Experimental Design: To study clonal evolution during treatment and follow-up, an innovative method based on circulating cell-free DNA (cfDNA) analysis by whole-exome sequencing (WES) paired with target sequencing was realized in sequential liquid biopsy samples of 19 neuroblastoma patients.

Results: WES of the primary tumor and cfDNA at diagnosis showed overlap of single-nucleotide variants (SNV) and copy number alterations, with 41% and 93% of all detected alterations common to the primary neuroblastoma and cfDNA. CfDNA WES at a second time point indicated a mean of 22 new SNVs for patients with progressive disease. Relapse-specific alterations included genes of the MAPK pathway and targeted the protein kinase A signaling pathway. Deep coverage target sequencing of intermediate time points during treatment and follow-up identified distinct subclones. For 17 seemingly relapse-specific SNVs detected by cfDNA WES at relapse but not tumor or cfDNA WES at diagnosis, deep coverage target sequencing detected these alterations in minor subclones, with relapse-emerging SNVs targeting genes of neuritogenesis and cell cycle. Furthermore a persisting, resistant clone with concomitant disappearance of other clones was identified by a mutation in the ubiquitin protein ligase HERC2.

Conclusions: Modelization of mutated allele fractions in cfDNA indicated distinct patterns of clonal evolution, with either a minor, treatment-resistant clone expanding to a major clone at relapse, or minor clones collaborating toward tumor progression. Identification of treatment-resistant clones will enable development of more efficient treatment strategies. Clin Cancer Res; 24(4); 939–49. ©2017 AACR.

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Sequential, Multiple Assignment, Randomized Trial Designs in Immuno-oncology Research

Clinical trials investigating immune checkpoint inhibitors have led to the approval of anti–CTLA-4 (cytotoxic T-lymphocyte antigen-4), anti–PD-1 (programmed death-1), and anti–PD-L1 (PD-ligand 1) drugs by the FDA for numerous tumor types. In the treatment of metastatic melanoma, combinations of checkpoint inhibitors are more effective than single-agent inhibitors, but combination immunotherapy is associated with increased frequency and severity of toxicity. There are questions about the use of combination immunotherapy or single-agent anti–PD-1 as initial therapy and the number of doses of either approach required to sustain a response. In this article, we describe a novel use of sequential, multiple assignment, randomized trial (SMART) design to evaluate immune checkpoint inhibitors to find treatment regimens that adapt within an individual based on intermediate response and lead to the longest overall survival. We provide a hypothetical example SMART design for BRAF wild-type metastatic melanoma as a framework for investigating immunotherapy treatment regimens. We compare implementing a SMART design to implementing multiple traditional randomized clinical trials. We illustrate the benefits of a SMART over traditional trial designs and acknowledge the complexity of a SMART. SMART designs may be an optimal way to find treatment strategies that yield durable response, longer survival, and lower toxicity. Clin Cancer Res; 24(4); 730–6. ©2017 AACR.

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Adaptive Global Innovative Learning Environment for Glioblastoma: GBM AGILE

Glioblastoma (GBM) is a deadly disease with few effective therapies. Although much has been learned about the molecular characteristics of the disease, this knowledge has not been translated into clinical improvements for patients. At the same time, many new therapies are being developed. Many of these therapies have potential biomarkers to identify responders. The result is an enormous amount of testable clinical questions that must be answered efficiently. The GBM Adaptive Global Innovative Learning Environment (GBM AGILE) is a novel, multi-arm, platform trial designed to address these challenges. It is the result of the collective work of over 130 oncologists, statisticians, pathologists, neurosurgeons, imagers, and translational and basic scientists from around the world. GBM AGILE is composed of two stages. The first stage is a Bayesian adaptively randomized screening stage to identify effective therapies based on impact on overall survival compared with a common control. This stage also finds the population in which the therapy shows the most promise based on clinical indication and biomarker status. Highly effective therapies transition in an inferentially seamless manner in the identified population to a second confirmatory stage. The second stage uses fixed randomization to confirm the findings from the first stage to support registration. Therapeutic arms with biomarkers may be added to the trial over time, while others complete testing. The design of GBM AGILE enables rapid clinical testing of new therapies and biomarkers to speed highly effective therapies to clinical practice. Clin Cancer Res; 24(4); 737–43. ©2017 AACR.

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T Cells Expressing Checkpoint Receptor TIGIT Are Enriched in Follicular Lymphoma Tumors and Characterized by Reversible Suppression of T-cell Receptor Signaling

Purpose: T cells infiltrating follicular lymphoma (FL) tumors are considered dysfunctional, yet the optimal target for immune checkpoint blockade is unknown. Characterizing coinhibitory receptor expression patterns and signaling responses in FL T-cell subsets might reveal new therapeutic targets.

Experimental Design: Surface expression of 9 coinhibitory receptors governing T-cell function was characterized in T-cell subsets from FL lymph node tumors and from healthy donor tonsils and peripheral blood samples, using high-dimensional flow cytometry. The results were integrated with T-cell receptor (TCR)-induced signaling and cytokine production. Expression of T-cell immunoglobulin and ITIM domain (TIGIT) ligands was detected by immunohistochemistry.

Results: TIGIT was a frequently expressed coinhibitory receptor in FL, expressed by the majority of CD8 T effector memory cells, which commonly coexpressed exhaustion markers such as PD-1 and CD244. CD8 FL T cells demonstrated highly reduced TCR-induced phosphorylation (p) of ERK and reduced production of IFN, while TCR proximal signaling (p-CD3, p-SLP76) was not affected. The TIGIT ligands CD112 and CD155 were expressed by follicular dendritic cells in the tumor microenvironment. Dysfunctional TCR signaling correlated with TIGIT expression in FL CD8 T cells and could be fully restored upon in vitro culture. The costimulatory receptor CD226 was downregulated in TIGIT⁺ compared with TIGIT^– CD8 FL T cells, further skewing the balance toward immunosuppression.

Conclusions: TIGIT blockade is a relevant strategy for improved immunotherapy in FL. A deeper understanding of the interplay between coinhibitory receptors and key T-cell signaling events can further assist in engineering immunotherapeutic regimens to improve clinical outcomes of cancer patients. Clin Cancer Res; 24(4); 870–81. ©2017 AACR.

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A Phase I Clinical Trial of the Poly(ADP-ribose) Polymerase Inhibitor Veliparib and Weekly Topotecan in Patients with Solid Tumors

Purpose: To determine the dose limiting toxicities (DLT), maximum tolerated dose (MTD), and recommended phase II dose (RP2D) of veliparib in combination with weekly topotecan in patients with solid tumors. Correlative studies were included to assess the impact of topotecan and veliparib on poly(ADP-ribose) levels in peripheral blood mononuclear cells, serum pharmacokinetics of both agents, and potential association of germline repair gene mutations with outcome.

Experimental Design: Eligible patients had metastatic nonhematologic malignancies with measurable disease. Using a 3 + 3 design, patients were treated with veliparib orally twice daily on days 1–3, 8–10, and 15–17 and topotecan intravenously on days 2, 9, and 16 every 28 days. Tumor responses were assessed by RECIST.

Results: Of 58 patients enrolled, 51 were evaluable for the primary endpoint. The MTD and RP2D was veliparib 300 mg twice daily on days 1–3, 8–10, and 15–17 along with topotecan 3 mg/m² on days 2, 9, and 16 of a 28-day cycle. DLTs were grade 4 neutropenia lasting >5 days. The median number of cycles was 2 (1–26). The objective response rate was 10%, with 1 complete and 4 partial responses. Twenty-two patients (42%) had stable disease ranging from 4 to 26 cycles. Patients with germline BRCA1, BRCA2, or RAD51D mutations remained on study longer than those without homologous recombination repair (HRR) gene mutations (median 4 vs. 2 cycles).

Conclusions: Weekly topotecan in combination with veliparib has a manageable safety profile and appears to warrant further investigation. Clin Cancer Res; 24(4); 744–52. ©2017 AACR.

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FAM198B Is Associated with Prolonged Survival and Inhibits Metastasis in Lung Adenocarcinoma via Blockage of ERK-Mediated MMP-1 Expression

Purpose: The comprehensive understanding of mechanisms involved in the tumor metastasis is urgently needed for discovering novel metastasis-related genes for developing effective diagnoses and treatments for lung cancer.

Experimental Design: FAM198B was identified from an isogenic lung cancer metastasis cell model by microarray analysis. To investigate the clinical relevance of FAM198B, the FAM198B expression of 95 Taiwan lung adenocarcinoma patients was analyzed by quantitative real-time PCR and correlated to patients' survivals. The impact of FAM198B on cell invasion, metastasis, and tumor growth was examined by in vitro cellular assays and in vivo mouse models. In addition, the N-glycosylation–defective FAM198B mutants generated by site-directed mutagenesis were used to study protein stability and subcellular localization of FAM198B. Finally, the microarray and pathway analyses were used to elucidate the underlying mechanisms of FAM198B-mediated tumor suppression.

Results: We found that the high expression of FAM198B was associated with favorable survival in Taiwan lung adenocarcinoma patients and in a lung cancer public database. Enforced expression of FAM198B inhibited cell invasion, migration, mobility, proliferation, and anchorage-independent growth, and FAM198B silencing exhibited opposite activities in vitro. FAM198B also attenuated tumor growth and metastasis in vivo. We further identified MMP-1 as a critical downstream target of FAM198B. The FAM198B-mediated MMP-1 downregulation was via inhibition of the phosphorylation of ERK. Interestingly deglycosylation nearly eliminated the metastasis suppression activity of FAM198B due to a decrease of protein stability.

Conclusions: Our results implicate FAM198B as a potential tumor suppressor and to be a prognostic marker in lung adenocarcinoma. Clin Cancer Res; 24(4); 916–26. ©2017 AACR.

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Merkel Cell Carcinoma Patients Presenting Without a Primary Lesion Have Elevated Markers of Immunity, Higher Tumor Mutation Burden, and Improved Survival

Purpose: Patients presenting with nodal Merkel cell carcinoma without an identifiable (unknown) primary lesion (MCC-UP) are nearly twice as likely to survive compared with similarly staged patients with known primary lesions (MCC-KP). The basis of this previously reported finding is unclear.

Experimental Design: Survival analyses and markers of immunity were evaluated in 123 patients with advanced MCC. Whole-exome sequence data were analyzed from 16 tumors.

Results: As in prior studies, patients with nodal MCC-UP had strikingly improved MCC-specific survival as compared with MCC-KP patients (HR, 0.297; P < 0.001). Surprisingly, patients presenting with distant metastatic MCC-UP also had significantly improved survival (HR, 0.296; P = 0.038). None of the 72 patients with MCC-UP were immunosuppressed as compared to 12 of the 51 (24%) patients with MCC-KP (P < 0.001). Merkel polyomavirus oncoprotein antibody median titer was higher in MCC-UP patients (26,229) than MCC-KP patients (3,492; P < 0.001). In addition, the median number of nonsynonymous exome mutations in MCC-UP tumors (688 mutations) was markedly higher than MCC-KP tumors (10 mutations, P = 0.016).

Conclusions: This is the first study to our knowledge to explore potential underlying immune-mediated mechanisms of MCC-UP presentation. In this cohort, MCC-UP patients were never immune suppressed, had higher oncoprotein antibody titers, and higher tumor mutational burdens. In addition, we show that nodal tumors identified in MCC-UP patients did indeed arise from primary skin lesions as they contained abundant UV-signature mutations. These findings suggest that stronger underlying immunity against MCC contributes to primary lesion elimination and improved survival. Clin Cancer Res; 24(4); 963–71. ©2017 AACR.

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Autologous Dendritic Cells Pulsed with Allogeneic Tumor Cell Lysate in Mesothelioma: From Mouse to Human

Purpose: Mesothelioma has been regarded as a nonimmunogenic tumor, which is also shown by the low response rates to treatments targeting the PD-1/PD-L1 axis. Previously, we demonstrated that autologous tumor lysate–pulsed dendritic cell (DC) immunotherapy increased T-cell response toward malignant mesothelioma. However, the use of autologous tumor material hampers implementation in large clinical trials, which might be overcome by using allogeneic tumor cell lines as tumor antigen source. The purpose of this study was to investigate whether allogeneic lysate–pulsed DC immunotherapy is effective in mice and safe in humans.

Experimental Design: First, in two murine mesothelioma models, mice were treated with autologous DCs pulsed with either autologous or allogeneic tumor lysate or injected with PBS (negative control). Survival and tumor-directed T-cell responses of these mice were monitored. Results were taken forward in a first-in-human clinical trial, in which 9 patients were treated with 10, 25, or 50 million DCs per vaccination. DC vaccination consisted of autologous monocyte–derived DCs pulsed with tumor lysate from five mesothelioma cell lines.

Results: In mice, allogeneic lysate–pulsed DC immunotherapy induced tumor-specific T cells and led to an increased survival, to a similar extent as DC immunotherapy with autologous tumor lysate. In the first-in-human clinical trial, no dose-limiting toxicities were established and radiographic responses were observed. Median PFS was 8.8 months [95% confidence interval (CI), 4.1–20.3] and median OS not reached (median follow-up = 22.8 months).

Conclusions: DC immunotherapy with allogeneic tumor lysate is effective in mice and safe and feasible in humans. Clin Cancer Res; 24(4); 766–76. ©2017 AACR.

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Mutations in Homologous Recombination Genes and Outcomes in Ovarian Carcinoma Patients in GOG 218: An NRG Oncology/Gynecologic Oncology Group Study

Purpose: We hypothesized that mutations in homologous recombination repair (HRR) genes beyond BRCA1 and BRCA2 improve outcomes for ovarian carcinoma patients treated with platinum therapy and would impact the relative benefit of adding prolonged bevacizumab.

Experimental Design: We sequenced DNA from blood and/or neoplasm from 1,195 women enrolled in GOG-0218, a randomized phase III trial in advanced ovarian carcinoma of bevacizumab added to carboplatin and paclitaxel. Defects in HRR were defined as damaging mutations in 16 genes. Proportional hazards models were used to estimate relative hazards for progression-free survival (PFS) and overall survival (OS).

Results: Of 1,195 women with ovarian carcinoma, HRR mutations were identified in 307 (25.7%). Adjusted hazards for progression and death compared with those without mutations were lower for women with non-BRCA HRR mutations [HR = 0.73; 95% confidence interval (CI), 0.57–0.94; P = 0.01 for PFS; HR = 0.67; 95% CI, 0.50–0.90; P = 0.007 for OS] and BRCA1 mutations (HR = 0.80; 95% CI, 0.66–0.97; P = 0.02 for PFS; HR = 0.74; 95% CI, 0.59–0.94; P = 0.01 for OS) and were lowest for BRCA2 mutations (HR = 0.52; 95% CI, 0.40–0.67; P < 0.0001 for PFS; HR = 0.36; 95% CI, 0.25–0.53; P < 0.0001 for OS). A test of interaction showed no difference in the effect of bevacizumab on PFS between cases with and without mutations.

Conclusions: HRR mutations, including non-BRCA genes, significantly prolong PFS and OS in ovarian carcinoma and should be stratified for in clinical trials. The benefit of adding bevacizumab was not significantly modified by mutation status. Clin Cancer Res; 24(4); 777–83. ©2017 AACR.

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Honokiol Radiosensitizes Squamous Cell Carcinoma of the Head and Neck by Downregulation of Survivin

Purpose: Previous studies revealed diverging results regarding the role of survivin in squamous cell carcinoma of the head and neck (SCCHN). This study aimed to evaluate the clinical significance of survivin expression in SCCHN; the function of survivin in DNA-damage repair following ionizing radiation therapy (RT) in SCCHN cells; and the potential of honokiol to enhance RT through downregulation of survivin.

Experimental Design: Expression of survivin in SCCHN patient primary tumor tissues (n = 100) was analyzed and correlated with clinical parameters. SCCHN cell lines were used to evaluate the function of survivin and the effects of honokiol on survivin expression in vitro and in vivo.

Results: Overexpression of survivin was significantly associated with lymph nodes' metastatic status (P = 0.025), worse overall survival (OS), and disease-free survival (DFS) in patients receiving RT (n = 65, OS: P = 0.024, DFS: P = 0.006) and in all patients with SCCHN (n = 100, OS: P = 0.002, DFS: P = 0.003). In SCCHN cells, depletion of survivin led to increased DNA damage and cell death following RT, whereas overexpression of survivin increased clonogenic survival. RT induced nuclear accumulation of survivin and its molecular interaction with -H2AX and DNA-PKCs. Survivin specifically bound to DNA DSB sites induced by I-SceI endonuclease. Honokiol (which downregulates survivin expression) in combination with RT significantly augmented cytotoxicity in SCCHN cells with acquired radioresistance and inhibited growth in SCCHN xenograft tumors.

Conclusions: Survivin is a negative prognostic factor and is involved in DNA-damage repair induced by RT. Targeting survivin using honokiol in combination with RT may provide novel therapeutic opportunities. Clin Cancer Res; 24(4); 858–69. ©2017 AACR.

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A Polymorphism within the Vitamin D Transporter Gene Predicts Outcome in Metastatic Colorectal Cancer Patients Treated with FOLFIRI/Bevacizumab or FOLFIRI/Cetuximab

Purpose: Vitamin D exerts its inhibitory influence on colon cancer growth by inhibiting Wnt signaling and angiogenesis. We hypothesized that SNPs in genes involved in vitamin D transport, metabolism, and signaling are associated with outcome in metastatic colorectal cancer (mCRC) patients treated with first-line FOLFIRI and bevacizumab.

Experimental Design: 522 mCRC patients enrolled in the FIRE-3 (discovery cohort) and TRIBE (validation set) trials treated with FOLFIRI/bevacizumab were included in this study. 278 patients receiving FOLFIRI and cetuximab (FIRE-3) served as a control cohort. Six SNPs in 6 genes (GC, CYP24A1, CYP27B1, VDR, DKK1, CST5) were analyzed.

Results: In the discovery cohort, AA carriers of the GC rs4588 SNP encoding for the vitamin D–binding protein, and treated with FOLFIRI/bevacizumab had a shorter overall survival (OS) than those harboring any C allele (15.9 vs. 25.1 months) in both univariable (P = 0.001) and multivariable analyses (P = 0.047). This association was confirmed in the validation cohort in multivariable analysis (OS 18.1 vs. 26.2 months, HR, 1.83; P = 0.037). Interestingly, AA carriers in the control set exhibited a longer OS (48.0 vs. 25.2 months, HR, 0.50; P = 0.021). This association was further confirmed in a second validation cohort comprising refractory mCRC patients treated with cetuximab ± irinotecan (PFS 8.7 vs. 3.7 months) in univariable (P = 0.033) and multivariable analyses (P = 0.046).

Conclusions: GC rs4588 SNP might serve as a predictive marker in mCRC patients treated with FOLFIRI/bevacizumab or FOLFIRI/cetuximab. Whereas AA carriers derive a survival benefit with FOLFIRI/cetuximab, treatment with FOLFIRI/bevacizumab is associated with a worse outcome. Clin Cancer Res; 24(4); 784–93. ©2017 AACR.

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NKG2D-Dependent Antitumor Effects of Chemotherapy and Radiotherapy against Glioblastoma

Purpose: NKG2D is a potent activating immune cell receptor, and glioma cells express the cognate ligands (NKG2DL). These ligands are inducible by cellular stress and temozolomide (TMZ) or irradiation (IR), the standard treatment of glioblastoma, could affect their expression. However, a role of NKG2DL for the efficacy of TMZ and IR has never been addressed.

Experimental Design: We assessed the effect of TMZ and IR on NKG2DL in vitro and in vivo in a variety of murine and human glioblastoma models, including glioma-initiating cells, and a cohort of paired glioblastoma samples from patients before and after therapy. Functional effects were studied with immune cell assays. The relevance of the NKG2D system for the efficacy of TMZ and IR was assessed in vivo in syngeneic orthotopic glioblastoma models with blocking antibodies and NKG2D knockout mice.

Results: TMZ or IR induced NKG2DL in vitro and in vivo in all glioblastoma models, and glioblastoma patient samples had increased levels of NKG2DL after therapy with TMZ and IR. This enhanced the immunogenicity of glioma cells in a NGK2D-dependent manner, was independent from cytotoxic or growth inhibitory effects, attenuated by O⁶-methylguanine-DNA-methyltransferase (MGMT), and required the DNA damage response. The survival benefit afforded by TMZ or IR relied on an intact NKG2D system and was decreased upon inhibition of the NKG2D pathway.

Conclusions: The immune system may influence the activity of convential cancer treatments with particular importance of the NKG2D pathway in glioblastoma. Our data provide a rationale to combine NKG2D-based immunotherapies with TMZ and IR. Clin Cancer Res; 24(4); 882–95. ©2017 AACR.

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Genome-Wide Association Study Identifies a New Locus at 7q21.13 Associated with Hepatitis B Virus-Related Hepatocellular Carcinoma

Purpose: Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. In China, chronic hepatitis B virus (HBV) infection remains the major risk factor for HCC. In this study, we performed a genome-wide association study (GWAS) among Chinese populations to identify novel genetic loci contributing to susceptibility to HBV-related HCC.

Experimental Design: GWAS scan is performed in a collection of 205 HBV-related HCC trios (each trio includes an affected proband and his/her both parents), and 355 chronic HBV carriers with HCC (cases) and 360 chronic HBV carriers without HCC (controls), followed by two rounds of replication studies totally consisting of 3,796 cases and 2,544 controls.

Results: We identified a novel association signal within the CDK14 gene at 7q21.13 (index rs10272859, OR = 1.28, P = 9.46 x 10^–10). Furthermore, we observed that the at-risk rs10272859[G] allele was significantly associated with higher mRNA expression levels of CDK14 in liver tissues. Chromosome conformation capture assays in liver cells confirmed that a physical interaction exists between the promoter region of CDK14 and the risk-associated SNPs in strong linkage disequilibrium with the index rs10272859 at 7q21.13. This index rs10272859 also showed significant association with the survival of HCC patients.

Conclusions: Our findings highlight a novel locus at 7q21.13 conferring both susceptibility and prognosis to HBV-related HCC, and suggest the CDK14 gene to be the functional target of the 7q21.13 locus. Clin Cancer Res; 24(4); 906–15. ©2017 AACR.

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A Molecularly Annotated Model of Patient-Derived Colon Cancer Stem-Like Cells to Assess Genetic and Nongenetic Mechanisms of Resistance to Anti-EGFR Therapy

Purpose: Patient-derived xenografts ("xenopatients") of colorectal cancer metastases have been essential to identify genetic determinants of resistance to the anti-EGFR antibody cetuximab and to explore new therapeutic strategies. From xenopatients, a genetically annotated collection of stem-like cultures ("xenospheres") was generated and characterized for response to targeted therapies.

Experimental Design: Xenospheres underwent exome-sequencing analysis, gene expression profile, and in vitro targeted treatments to assess genetic, biological, and pharmacologic correspondence with xenopatients, and to investigate nongenetic biomarkers of therapeutic resistance. The outcome of EGFR family inhibition was tested in an NRG1-expressing in vivo model.

Results: Xenospheres faithfully retained the genetic make-up of their matched xenopatients over in vitro and in vivo passages. Frequent and rare genetic lesions triggering primary resistance to cetuximab through constitutive activation of the RAS signaling pathway were conserved, as well as the vulnerability to their respective targeted treatments. Xenospheres lacking such alterations (RAS^wt) were highly sensitive to cetuximab, but were protected by ligands activating the EGFR family, mostly NRG1. Upon reconstitution of NRG1 expression, xenospheres displayed increased tumorigenic potential in vivo and generated tumors completely resistant to cetuximab, and sensitive only to comprehensive EGFR family inhibition.

Conclusions: Xenospheres are a reliable model to identify both genetic and nongenetic mechanisms of response and resistance to targeted therapies in colorectal cancer. In the absence of RAS pathway mutations, NRG1 and other EGFR ligands can play a major role in conferring primary cetuximab resistance, indicating that comprehensive inhibition of the EGFR family is required to achieve a significant therapeutic response. Clin Cancer Res; 24(4); 807–20. ©2017 AACR.

See related commentary by Napolitano and Ciardiello, p. 727

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Saturation reduces in-vitro leakage of monomers from composites

Publication date: Available online 14 February 2018
Source:Dental Materials
Author(s): Stevan M. Cokic, Radu C. Duca, Jan De Munck, Peter Hoet, Bart Van Meerbeek, Mario Smet, Lode Godderis, Kirsten L. Van Landuyt
ObjectiveAccurate knowledge of the quantity of released monomers from composites is important. To evaluate the elution of monomers, polymerized composites are typically immersed in an extraction solvent. The objective was to determine whether the volume of extraction solvent and the immersion time influences monomer leachability from dental composite materials.MethodsComposite disks of two commercial composites, (Filtek Supreme XTE, 3M ESPE and G-aenial Universal Flo, GC) were prepared. The disks (n=10) were placed in a glass vial with 1ml, 2ml or 3ml of extraction solvent (100% ethanol with deuterated diethylphalate as internal standard). After either 7 or 30 days at 37°C, the supernatant was collected and the amount of released monomers (BisEMA, BisGMA, UDMA, TEGDMA) and bisphenol A was measured with liquid chromatography mass spectroscopy.ResultsFor both tested composites, the highest amount of released monomers was measured after sample incubation in 3ml, while the lowest amount was measured in 1ml of extraction solvent. Furthermore, 30 days did not result in much more monomer release compared to 7 days, and for most monomers, there was no statistically significant difference in release between 7 and 30 days.SignificanceRelease kinetics in in-vitro experiments are also influenced by saturation of the extraction solvent with the leached monomers. This is important as it is unlikely that saturation can be reached in an in-vivo situation, where saliva (or pulpal fluid) is continuously refreshed. Saturation of the extraction solvent can be avoided in-vitro by refreshing the extraction medium after equal time intervals.



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Hyperglycemia and risk of adverse outcomes following microvascular reconstruction of oncologic head and neck defects

Publication date: April 2018
Source:Oral Oncology, Volume 79
Author(s): Anaeze C. Offodile, Hsuan-Yu Chou, Jennifer An-Jou Lin, Charles Yuen Yung Loh, Kai-Ping Chang, Mario A. Aycart, Huang-Kai Kao
IntroductionOur aim is to examine the correlation between perioperative hyperglycemia and post-operative outcomes following microvascular reconstruction of head and neck defects.Patients and methodsRetrospective review of a prospectively collected database of 350 consecutive patients who underwent microvascular reconstruction of malignant head and neck defects over a 2 year period. The relationship between perioperative hyperglycemia (≥ 180 mg/dL) and the incidence of the following complications was evaluated: flap loss, flap-related complications and surgical site infections (SSI). Sub-group analysis based on timing of hyperglycemia was also performed.ResultsWe identified 313 patients (89.4%) in the normoglycemic group and 37 patients (10.6%) in the hyperglycemic group. Baseline demographics, tumor stage, operative variable were comparable. There were no significant differences in flap-related complications and overall mortality. SSI were significantly higher in the hyperglycemic cohort (48% vs. 28%, p = 0.01). On multivariate analysis, hyperglycemia [OR 2.07; 95% CI, 1.87–4.89], perioperative insulin administration [OR 4.805; 95% CI, 2.18–10.60], prolonged operative time [OR 1.003; 95% CI, 1.002–1.025] and higher Charlson co-morbidity indices [II: OR 2.286 & III: OR 2.284] were independent predictors of SSI. On sub-group analysis, only patients with early (POD 1) post-operative hyperglycemia had a significant OR for SSI (OR 1.88; 95% CI, 1.07–3.29).ConclusionOur findings suggest that perioperative hyperglycemia, specifically during the first 24 h post-operatively, is associated with SSI in microvascular head and neck reconstruction. This association highlights the need for strict screening of head and neck patients for hyperglycemia especially in the immediate post-operative period.



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VEGFR-2 as a novel predictor of survival in gastric cancer: a systematic review and meta-analysis

Publication date: Available online 14 February 2018
Source:Pathology - Research and Practice
Author(s): Teng Li, Jing Yu, Xinyu Luo, Weiguo Ren, Yue Zhang, Bangwei Cao
BackgroundExpression of VEGFRs may affect cancer prognosis. The aim of this work is to evaluate the prognostic significance of VEGFRs of patients with gastric cancer.MethodsThe databases PubMed, Embase, Web of Science, and Cochrane Library as well as ASCO and ESMO were searched systematically for articles reporting the prognostic significance of tissue VEGFRs in gastric cancer. The statistical analyses were carried out using Stata version 12.0.ResultsA total of 8 articles comprising 950 patients were eligible for meta-analysis. The combined HR of studies evaluating total VEGFRs overexpression was 1.42 (95% CI 1.01-2.00, P = 0.044), suggesting that it had prognosis significance in overall survival of gastric cancer. Subgroup analysis showed that it was VEGFR-2 (HR 1.81, 95%CI 1.31–2.49, P < 0.001) but not VEGFR-3 (HR 0.91, 95%CI 0.45–1.82, P = 0.787) overexpression was associated with an increased risk of median overall survival (mOS) and it can be a potentially predictive biomarker for gastric cancer.ConclusionsVEGFR-2 overexpression is a promising negative prognosis predictor for patients with gastric cancer. The prognosis significance of VEGFR-3 still need further study.



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Loss of p27kip1 expression is associated with poor prognosis in patients with taxane-treated breast cancer

Publication date: Available online 14 February 2018
Source:Pathology - Research and Practice
Author(s): Gi Jeong Kim, Dong-Hoon Kim, Kyueng-Whan Min, Young Hwan Kim, Young Ha Oh
PurposeDecreased expression of p27^kip1 and p57^kip2 is considered as a prognostic indicator in patients with breast cancer receiving adjuvant chemotherapy. Previous in vitro studies have reported that reduced expression of p27^kip1 and p57^kip2 is associated with resistance to taxane, which is one of the most effective chemotherapeutic agents. In this study, we investigated the association of low p27^kip1 and p57^kip2 expression with outcomes in patients with breast cancer.MethodsWe investigated 226 cases of breast cancer from Kangbuk SMC between 2000 and 2005. Levels of p27^kip1 and p57^kip2 expression were evaluated using immunohistochemical staining of tumor tissue microarray specimens. The relationships between the expression levels of the markers and patients' outcomes were analyzed using the Kaplan–Meier method and Cox proportional hazard model.ResultsLow p57^kip2 expression was only associated with negative progesterone receptor status (p = 0.034), whereas p27^kip1 expression was associated with poor prognosis of patients receiving adjuvant chemotherapy (p = 0.005). More detailed analysis revealed that low p27^kip1 expression affects the overall survival rate of patients receiving adjuvant chemotherapy including taxane (p = 0.026), but not that of patients receiving chemotherapy without taxane.ConclusionsLow p27^kip1 expression may be useful to predict overall survival in patients with breast cancer who are treated with taxane. Evaluation of p27^kip1 expression may provide further prognostic information beyond traditional prognostic biomarkers and an understanding of the mechanisms that impart resistance against chemotherapy.



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Prognostic significance of epithelial-mesenchymal transition phenotypes in upper urinary tract urothelial carcinoma

Publication date: Available online 14 February 2018
Source:Pathology - Research and Practice
Author(s): Junhun Cho, Sang Yun Ha, Seok-Hyung Kim, Hyun Hwan Sung, Ghee Young Kwon
Epithelial-mesenchymal transition (EMT) is a process which epithelial cells gain mesenchymal phenotype such as motility and invasiveness. We investigated the role of EMT in upper urinary tract urothelial carcinoma (UTUC). The patient cohort included 93 cases of UTUC treated with radical nephroureterectomy. Tissue microarrays were constructed from formalin-fixed paraffin-embedded tissue blocks. Immunohistochemical staining was performed for E-cadherin, vimentin, and smooth muscle actin to evaluate the EMT status. Interpretation criteria were defined for the staining results and EMT phenotypes were assigned as wild type, incomplete type (loss of E-cadherin and negative for vimentin), and complete type (loss of E-cadherin and positive for vimentin). The loss of E-cadherin and vimentin-expression was observed in 76 (81.7%) and 10 (10.8%) cases, respectively, yielding EMT phenotypes comprised of 17 cases (18.3%) of wild type, 66 cases (71.0%) of incomplete type, and 10 cases (10.8%) of complete types. In survival analyses, wild type showed statistically significant association with longer extra-bladder recurrence free survival (p < 0.001) and overall survival (p < 0.001). In multivariate analyses, complete type was an independent prognostic factor for extra-bladder recurrence free survival and overall survival. EMT phenotype based on the combination of EMT-related markers may provide a useful prognostic marker for UTUC patients.



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Clinicopathological analysis of Large Cell Lung Carcinomas definitely diagnosed according to the New World Health Organization Criteria

Publication date: Available online 14 February 2018
Source:Pathology - Research and Practice
Author(s): Yalan Bi, Yang Qu, Zhiyong Liang, Zichen Liu, Hui Zhang, Xiaolong Liang, Yufeng Luo, Jinling Cao, Haiqing Zhang, Ruie Feng
ObjectiveThe definition of large cell lung carcinoma (LCC) has undergone an extensive modification in the World Health Organization (WHO) Classification (2015). Present study aimed to investigate the clinicopathological characteristics of patients diagnosed as LCC according to current WHO criteria.MethodsLCCs diagnosed based on the previous WHO classification were reevaluated, and 17 cases of LCC were finally identified at Peking Union Medical College Hospital and Beijing Chest Hospital between 2009 and 2015. The clinicopathologic features were examined and EGFR and KRAS mutations were tested. Survival of the patients was analyzed by Kaplan-Meier method.ResultsThe median age of the patients was 64 years (range: 40-78). Most patients were male (64.7%) and about half of the patients were at TNM stage III (47.1%). Morphologically, most cases (70.6%) were classic LCC. All patients were treated by lobectomy plus lymph node dissection, 2 with bi-lobectomy and 1 with complex lobectomy, and the other 2 patients were further treated by partial pericardiotomy. Ten patients received postoperative chemotherapy, while only 3 patients were treated with radiotherapy after surgery. Molecular analysis showed two cases of EGFR mutation (L858R) but without non-overlapping KRAS mutation. The 3-year overall survival rate was 48.4 ± 15.1%. Chemotherapy was the only predictive factor that is associated with the prognosis of the patients (P = 0.003).ConclusionThe clinicopathological characteristics of 17 cases of stringently diagnosed LCC were retrospectively analyzed. LCC in our study showed aggressive behavior with high recurrence and metastasis and poor prognosis. Chemotherapy was only predictive factor that is significantly associated with the prognosis of the patients. Future studies based on a larger series and long term follow-up are still needed to characterize it further.



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MiR-1260b promotes the migration and invasion in non-small cell lung cancer via targeting PTPRK

Publication date: Available online 14 February 2018
Source:Pathology - Research and Practice
Author(s): Limin Xu, Xuting Xu, Huilian Huang, Zhihong Ma, Shuangmei Zhang, Pingping Niu, Yingrong Chen, Jinliang Ping, Ping Lu, Caihua Yu, Lishan Min, Jing Chen, Licheng Dai, Shunli Dong
ObjectiveNon-small cell lung cancer (NSCLC) accounts for 80-85% of lung cancer cases which cause most of cancer-related deaths globally. As our previous study discovered miR-1260b can be regarded as a specific signature for metastasis in NSCLC patients. However, the molecular mechanisms of miR-1260b underlying NSCLC progression and metastasis remain dismal.MethodsThe expression of miR-1260b in NSCLC tissues and cell lines were examined by real-time PCR, the effects of miR-1260b on cell migration, invasion and proliferation were evaluated in vitro. Furthermore, luciferase reporter assay was performed to identify the targets of miR-1260b, and the association between miR-1260b and its target gene was determined by real-time PCR and western blot assay.ResultsThe results showed that miR-1260b was significantly upregulated in NSCLC cell lines. The inhibition of miR-1260b expression decreased the migratory and invasive rates in A549 cells while miR-1260b overexpression had the opposite effect. Furthermore, PTPRK was identified as a direct target of miR-1260b, and PTPRK expression was inversely correlated with miR-1260b in NSCLC cell lines and clinical tissues.ConclusionsThese results suggested that miR-1260b may play an important role in NSCLC metastasis progression and could serve as a putative target for diagnosis and treatment of NSCLC.



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Understanding the nuances of microwave ablation for more accurate post-treatment assessment

Future Oncology, Ahead of Print.


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Imaging after radiofrequency ablation of renal tumors

Future Oncology, Ahead of Print.


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Erratum

Future Oncology, Ahead of Print.


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Distal muscle activity alterations during the stance phase of gait in restless leg syndrome (RLS) patients

Publication date: Available online 15 February 2018
Source:Sleep Medicine
Author(s): Chloe Dafkin, Andrew Green, Benita Olivier, Warrick McKinon, Samantha Kerr
ObjectiveTo assess if there is a circadian variation in electromyographical (EMG) muscle activity during gait in restless legs syndrome (RLS) patients and healthy control participants.MethodsGait assessment was done in 14 RLS patients and 13 healthy control participants in the evening (PM) and the morning (AM). Muscle activity was recorded bilaterally from the tibialis anterior (TA), lateral gastrocnemius (GL), rectus femoris (RF) and biceps femoris (BF) muscles.ResultsA circadian variation during the stance phase in only TA (PM>AM, p<0.005) and BL (PM<AM, p=0.008) activity was observed in control participants. Conversely no circadian variation was seen in any muscles in the RLS patients. RLS patients had an increased TA and GL activity (RLS>Controls, p<0.05) during early stance and decreased GL activity (RLS<Controls, p<0.01) during terminal stance in comparison to control participants in the evening. No other significant differences were noted between RLS patients and control participants. Activation of GL during the swing phase was noted in 79% of RLS patients and in 23% of control participants in the morning compared to 71% and 38% in the evening, respectively.ConclusionEMG muscle activity shows no circadian variation in RLS patients. Evening differences in gait muscle activation patterns between RLS patients and control participants are evident. These results extend our knowledge about alterations in spinal processing during gait in RLS. A possible explanation for these findings is central pattern generator sensitization caused by increased sensitivity in cutaneous afferents in RLS patients.



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Effect of Kidney Transplantation on Sleep Disordered Breathing in End Stage Renal Disease Patients: A Polysomnographic study

Publication date: Available online 15 February 2018
Source:Sleep Medicine
Author(s): Sanjiv Mahajan, Kartik Gupta, Sanjeev Sinha, Atul Malhotra, Sandeep Mahajan
BackgroundSleep Disordered Breathing (SDB) is seen at an increased rate in patients suffering from End Stage Renal Disease (ESRD). This SDB is multifactorial with associated comorbidities like hypertension, diabetes mellitus and obesity interplaying with metabolic derangements in the form of uremia, acidosis, and hypervolemia. The renal transplant has been observed to correct most of these metabolic derangements and control progression of co-morbidities. While SDB is highly prevalent among patients in thepre-transplant stage, it remains to be seen whether the beneficial aspects of transplant are extended to improvement in SDB in ESRD patients.Methods18 patients undergoing thrice weekly hemodialysis (HD) for ESRD at the Transplant Clinic of All India Institute of Medical Sciences (AIIMS), New Delhi underwent detailed clinical, laboratory and polysomnographic evaluation. The average number of episodes of apnea and hypopnea per hour of sleep i.e.,Apnea-Hypopnea Index (AHI) was used to define the severity of sleep apnea. All patients underwent polysomnography (PSG) within 24 hours of the last HD and after 3 months of live donor transplant.ResultsOut of 18 patients, there were 14 males and 4 females. The median age was 28 years (Range 19 to 50 years). They had already spent a median period of 6 months (Range 3 to 31 months) on HD prior to inclusion. The prevalence of SDB (AHI ≥ 5/h) was 44.4% (8/18) before transplant which decreased to 5.6% (1/18) after transplant (p = 0.016). Desaturation Index had a median value of 5.8 events/hour (Range 0.1 to 35.4) in pre-transplant stage which decreased to 0 events/hour (Range 0 to 6.6) post-transplant (p=0.035).ConclusionThere was a significant improvement in the prevalence and severity of SDB after transplant. Whether improvement in SDB is sustained on long-termfollow-up remains to be seen.



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The headache under-response to treatment (HURT) questionnaire, an outcome measure to guide follow-up in primary care: development, psychometric evaluation and assessment of utility

Headache disorders are both common and burdensome but, given the many people affected, provision of health care to all is challenging. Structured headache services based in primary care are the most efficient,...

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Incidence of venous thromboembolism and use of anticoagulation in hematological malignancies: Critical review of the literature

Publication date: April 2018
Source:Critical Reviews in Oncology/Hematology, Volume 124
Author(s): Ombretta Annibali, Mariasanta Napolitano, Giuseppe Avvisati, Sergio Siragusa
Venous Thromboembolism (VTE) frequently complicates the course of hematologic malignancies (HM) and its incidence is similar to that observed in high-risk solid tumors. Despite that, pharmacologic prophylaxis and treatment of VTE in patients with HM is challenging, mainly because a severe thrombocytopenia frequently complicates the course of treatments or may be present since diagnosis, thus increasing the risk of bleeding. Therefore, in this setting, safe and effective methods of VTE prophylaxis and treatment have not been well defined and hematologists generally refer to guidelines produced for cancer patients that give indications on anticoagulation in patients with thrombocytopenia. In this review, besides to summarize the incidence and the available data on prophylaxis and treatment of VTE in HM, we give some advices on how to use antithrombotic drugs in patients with HM according to platelets count.



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Molecular Pharmacodynamics-Guided Scheduling of Biologically Effective Doses: A Drug Development Paradigm Applied to MET Tyrosine Kinase Inhibitors

The development of molecularly targeted agents has benefited from use of pharmacodynamic (PD) markers to identify "biologically effective doses" (BEDs) below maximum tolerable doses, yet this knowledge remains underutilized in selecting dosage regimens and in comparing the effectiveness of targeted agents within a class. We sought to establish preclinical proof-of-concept for such PD-based BED regimens and effectiveness comparisons using MET kinase small molecule inhibitors. Utilizing PD biomarker measurements of MET signaling (tumor pY^1234/1235MET/total MET ratio) in a Phase 0-like preclinical setting, we developed optimal dosage regimens for several MET kinase inhibitors and compared their antitumor efficacy in a MET-amplified gastric cancer xenograft model (SNU-5). Reductions in tumor pY^1234/1235MET/total MET of 95-99% were achievable with tolerable doses of EMD1214063/MSC2156119J (tepotinib), XL184 (cabozantinib), and XL880/GSK1363089 (foretinib), but not ARQ197 (tivantinib), which did not alter the PD biomarker. Duration of kinase suppression and rate of kinase recovery were specific to each agent, emphasizing the importance of developing customized dosage regimens to achieve continuous suppression of the PD biomarker at the required level (here, > 90% MET kinase suppression). The customized dosage regimen of each inhibitor yielded substantial and sustained tumor regression; the equivalent effectiveness of customized dosage regimens that achieve the same level of continuous molecular target control represents preclinical proof-of-concept and illustrates the importance of proper scheduling of targeted agent BEDs. PD guided Biologically Effective Dosage Regimens (PD-BEDRs) potentially offer a superior alternative to pharmacokinetic guidance (e.g., drug concentrations in surrogate tissues) for developing and making head-to-head comparisons of targeted agents.

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Complete Remission with Reduction of High-risk Clones following Haploidentical NK Cell Therapy against MDS and AML

Purpose: To evaluate the safety, efficacy and immunobiological correlates of allogeneic NK cell-based therapy in primary chemotherapy-refractory or relapsed high-risk myelodysplastic syndrome (MDS), secondary AML (MDS/AML), and de novo AML patients. Experimental design: Sixteen patients received fludarabine/cyclophosphamide conditioning combined with total lymphoid irradiation followed by adoptive immunotherapy with IL-2-activated haploidentical NK cells. Results: NK cell infusions were well tolerated with only transient adverse events observed in the 16 patients. Six patients achieved objective responses with complete remission (CR), marrow CR or partial remission (PR). Five patients proceeded to allogeneic hematopoietic stem cell transplantation (HSCT). Three patients are still free from disease >3 years after treatment. All evaluable patients with objective responses (5/5 evaluable) had detectable donor NK cells at days 7/14 following infusion, and displayed reduction of tumor cell clones, some of which carried poor prognosis mutations. Residual lin-CD34+CD123+CD45RA+ blast cells in responders had increased total HLA class I- and HLA-E-expression. Responding patients displayed less pronounced activation of CD8+ T cells and lower levels of inflammatory cytokines following NK cell infusion. Intriguingly, despite omission of systemic IL-2, all patients displayed increased frequencies of activated Ki-67+CD127-FoxP3+CD25hiCD4+ Treg cells of recipient-origin following NK cell therapy. Conclusion: Overall, this study suggests that high-risk MDS is responsive to NK cell therapy and supports the use of haploidentical NK cell infusions as a bridge to HSCT in refractory patients. Objective clinical responses and reduction of high-risk clones was associated with detectable donor-derived NK cells, immunoediting of residual blast cells, and less pronounced host immune activation.

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Immunophenotyping of Newly Diagnosed and Recurrent Glioblastoma Defines Distinct Immune Exhaustion Profiles in Peripheral and Tumor-infiltrating Lymphocytes

Purpose: Immunotherapeutic treatment strategies for glioblastoma (GBM) are under investigation in clinical trials. However, our understanding of the immune phenotype of GBM-infiltrating T-cells (TILs) and changes during disease progression is limited. Deeper insight is urgently needed to therapeutically overcome tumor-induced immune exhaustion. Experimental Design: We used flow-cytometry and cytokine assays to profile TILs and blood lymphocytes (PBL) from GBM patients, comparing newly diagnosed or recurrent GBM to long-term survivors (LTS) and healthy donors. TCR sequencing was performed on paired samples of newly diagnosed and recurrent GBM. Results: We identified a clear immune signature of exhaustion and clonal restriction in the TIL of patients with GBM. Exhaustion of CD8+ TILs was defined by an increased prevalence of PD-1+, CD39+, Tim-3+, CD45RO+, HLA-DR+ marker expression and exhibition of an effector-/transitional memory differentiation phenotype, whereas KLRG1 and CD57 were underrepresented. Immune signatures were similar in primary and recurrent tumors, however, restricted TCR repertoire clonality and a more activated memory phenotype were observed in TIL from recurrent tumors. Moreover, a reduced cytokine response to PHA stimulation in the blood compartment indicates a dysfunctional peripheral T-cell response in GBM patients. LTS displayed a distinct profile, with abundant naïve and less exhausted CD8+ T-cells. Conclusions: TILs and PBLs exhibit contrasting immune profiles, with a distinct exhaustion signature present in TILs. While the exhaustion profiles of primary and recurrent GBM are comparable, TCR sequencing demonstrated a contracted repertoire in recurrent GBM, concomitant with an increased frequency of activated memory T-cells in recurrent tumors.

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Development and External Validation of Prediction Models for 10-Year Survival of Invasive Breast Cancer. Comparison with PREDICT and CancerMath.

Purpose: To compare PREDICT and CancerMath, two widely used prognostic models for invasive breast cancer, taking into account their clinical utility. Furthermore, it is unclear whether these models could be improved. Experimental Design: A dataset of 5729 women was used for model development. A Bayesian variable selection algorithm was implemented to stochastically search for important interaction terms among the predictors. The derived models were then compared in three independent datasets (n = 5534). We examined calibration, discrimination and performed decision curve analysis. Results: CancerMath demonstrated worse calibration performance compared to PREDICT in oestrogen receptor (ER)-positive and ER-negative tumours. The decline in discrimination performance was -4.27% (-6.39 - -2.03) and -3.21% (-5.9 - -0.48) for ER-positive and ER-negative tumours, respectively. Our new models matched the performance of PREDICT in terms of calibration and discrimination, but offered no improvement. Decision curve analysis showed predictions for all models were clinically useful for treatment decisions made at risk thresholds between 5% and 55% for ER-positive tumours and at thresholds of 15% to 60% for ER-negative tumours. Within these threshold ranges, CancerMath provided the lowest clinical utility amongst all the models. Conclusions: Survival probabilities from PREDICT offer both improved accuracy and discrimination over CancerMath. Using PREDICT to make treatment decisions offers greater clinical utility than CancerMath over a range of risk thresholds. Our new models performed as well as PREDICT, but no better, suggesting that, in this setting, including further interaction terms offers no predictive benefit.

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Seltene Differentialdiagnose einseitiger, frontotemporaler Cephalgien

Laryngo-Rhino-Otol
DOI: 10.1055/s-0044-100516

© Georg Thieme Verlag KG Stuttgart · New York

Article in Thieme eJournals:
Table of contents  |  Full text

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Skalenübergreifende Auswertung des Fragebogens zur Erfassung des stimmlichen Selbstkonzepts (FESS)

Laryngo-Rhino-Otol
DOI: 10.1055/s-0044-101837

Hintergrund Der Fragebogen zur Erfassung des stimmlichen Selbstkonzepts (FESS) bildet in drei Skalen das persönliche Erleben der eigenen Stimme ab. Dabei werden die Beziehung zur eigenen Stimme, die Bewusstheit im Umgang mit der Stimme und der Zusammenhang zwischen Stimme und Emotion bestimmt. Für die Auswertung des Fragebogens fehlte bisher eine skalenübergreifende Betrachtungsweise, um eine vereinfachte Interpretation der Ergebnisse zu ermöglichen. Material und Methoden Der FESS Fragebogen wurde bei 536 Lehrkräften eingesetzt und mittels einer Diskriminanz analyse auf gemeinsame Ausprägungsmerkmale in den Skalen untersucht. Für eine differenzierte Betrachtung von Zusammenhängen mit Stimmgesundheit, psychischer und körperlicher Gesundheit wurden ebenfalls der Voice Handicap Index (VHI), der Fragebogen zum arbeitsbezogenen Verhaltens- und Erlebensmuster (AVEM) und der Fragebogen zur gesundheitsbezogenen Lebensqualität (SF-12) herangezogen. Ergebnisse Die Analyse ergab vier verschiedene Gruppen des stimmlichen Selbstkonzepts: die Gruppe 1) mit stimmlich und psychisch gesunden Werten, die Gruppe 2) mit einem eher wenig ausgeprägtem stimmlichen Selbstkonzept und durchschnittlicher psychischer Gesundheit, die Gruppe 3) mit einer hohen Bewusstheit im Umgang mit der Stimme und durchschnittlicher psychischer Gesundheit und die Gruppe 4) mit hohen stimmlichen und psychischen Belastungen. Schlussfolgerung Die Ergebnisse zeigen, dass für eine Gesamtauswertung des Fragebogens zur Erfassung des stimmlichen Selbstkonzepts eine gemeinsame Betrachtung aller drei Skalen in Betracht gezogen werden kann. Die dargestellten Gruppen stellen dafür eine geeignete Herangehensweise zur Unterstützung in der Diagnostik zur Verfügung.
[...]

© Georg Thieme Verlag KG Stuttgart · New York

Article in Thieme eJournals:
Table of contents  |  Abstract  |  Full text

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Frugal Malleable Microdissectors and Arachnoid Knives for Microneurosurgery

Publication date: April 2018
Source:World Neurosurgery, Volume 112
Author(s): Deepak K. Jha
BackgroundSimilar to most of the other medical and surgical fields, neurosurgery has changed drastically in recent decades, especially in instrumentation and equipment. Safety, scope of treating initially considered nontreatable neurosurgical conditions, and prognosis of most neurosurgical procedures have improved significantly. Newer instruments and equipments are being introduced exponentially, leading to tremendous cost escalation of neurosurgical treatment. However, equitable distribution of neurosurgical services in society is far from reality. We need to look back and learn from our teachers and forefathers of neurosurgery their innovative ways to accomplish difficult procedures without advanced tools and techniques. Microneurosurgery is considered a highly skilled technique, and instruments used for it are delicate, precise, and costlier than similar instruments for macroneurosurgery.Technique and ConclusionFrugal innovative techniques and tools are presented for making stainless steel wire and plate microdissectors that are effective for microneurosurgical procedures and can be helpful for neurosurgeons working in resource-poor settings.



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Integration of Real-Time Intraoperative Contrast-Enhanced Ultrasound and Color Doppler Ultrasound in the Surgical Treatment of Spinal Cord Dural Arteriovenous Fistulas

Publication date: April 2018
Source:World Neurosurgery, Volume 112
Author(s): Giuseppe Maria Della Pepa, Giovanni Sabatino, Carmelo Lucio Sturiale, Enrico Marchese, Alfredo Puca, Alessandro Olivi, Alessio Albanese
BackgroundIn the surgical treatment of spinal dural arteriovenous fistulas (DAVFs), intraoperative definition of anatomic characteristics of the DAVF and identification of the fistulous point is mandatory to effectively exclude the DAVF.Case DescriptionIntraoperative ultrasound and contrast-enhanced ultrasound integrated with color Doppler ultrasound was applied in the surgical setting for a cervical DAVF to identify the fistulous point and evaluate correct occlusion of the fistula.ConclusionsIntegration of intraoperative ultrasound and contrast-enhanced ultrasound is a simple, cost-effective technique that provides an opportunity for real-time dynamic visualization of DAVF vascular patterns, identification of the fistulous point, and assessment of correct exclusion. Compared with other intraoperative tools, such as indocyanine green videoangiography, it allows the surgeon to visualize hidden anatomic and vascular structures, minimizing surgical manipulation and guiding the surgeon during resection.



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Management of Penetrating Brain Injury Caused by a Nail Gun: Three Case Reports and Literature Review

Publication date: April 2018
Source:World Neurosurgery, Volume 112
Author(s): Ruhong Wu, Yun Ye, Chunbo Liu, Changchun Yang, Huaping Qin
BackgroundPenetrating brain injury (PBI) caused by a nail gun is an extremely rare neurosurgical emergency that poses a challenge for neurosurgeons because of its rarity and complexity.Case DescriptionHere we present 3 cases of PBI caused by a nail gun. In the first case, the nail entered through the right parietal bone and lodged in the right parietal lobe and basal ganglia. In the second case, the nail entered through the right occipital bone and lodged in the right occipital lobe. In the third case, the nail entered through the right parietal bone and lodged in the right frontal and parietal lobes. All patients underwent surgical removal of the nail. The first patient presented with reduced left-side strength, whereas the second and third patients were neurologically intact on presentation.ConclusionsPBI caused by a nail gun can present with differing clinical manifestations, and most cases require immediate surgery. A rational management strategy should provide a good postoperative prognosis with minimal neurologic deficits in these patients.



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Decreased short-interval intracortical inhibition correlates with better pinch strength in patients with stroke and good motor recovery

Publication date: Available online 14 February 2018
Source:Brain Stimulation
Author(s): Karina Nocelo Ferreiro de Andrade, Adriana Bastos Conforto
BackgroundDeeper short-interval intracortical inhibition (SICI), a marker of GABAA activity, correlates with better motor performance in patients with moderate to severe hand impairments in the chronic phase after stroke.ObjectivesWe evaluated the correlation between SICI in the affected hemisphere and pinch force of the paretic hand in well-recovered patients. We also investigated the correlation between SICI and pinch force in controls.MethodsTwenty-two subjects were included in the study. SICI was measured with a paired-pulse paradigm. The correlation between lateral pinch strength and SICI was assessed with Spearman's rho.ResultsThere was a significant correlation (rho = 0.69, p = 0.014) between SICI and pinch strength in patients, but not in controls. SICI was significantly deeper in patients with greater hand weakness.ConclusionsThese preliminary findings suggest that decreased GABAA activity in M1AH correlates with better hand motor performance in well-recovered subjects with stroke in the chronic phase.



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Reversal of drug-induced gingival overgrowth by UV-mediated apoptosis of gingival fibroblasts — an in vitro study.

Publication date: May 2018
Source:Annals of Anatomy - Anatomischer Anzeiger, Volume 217
Author(s): Casey Ritchhart, Anita Joy
Gingival overgrowth (GO) is an undesirable result of certain drugs like Cyclosporine A (CsA). Histopathology of GO shows hyperplasia of gingival epithelium, expansion of connective tissue with increased collagen, or a combination. Factors such as age, gender, oral hygiene, duration, and dosage also influence onset and severity of GO. One of the mechanisms behind uncontrolled cell proliferation in drug-induced GO is inhibition of apoptotic pathways, with a consequent effect on normal cell turnover. Our objective was to determine if UV photo-treatment would activate apoptosis in the gingival fibroblast component. Human gingival fibroblast cells (HGF-1) were exposed to 200ng/ml or 400ng/ml CsA and maintained for 3, 6, and 9 days, followed by UV radiation for 2, 5, or 10min (N=6). Naïve (no CsA or UV), negative (UV, no CsA), and positive controls (CsA, no UV) were designated. Prior to UV treatment, growth media was replaced with 1M PBS to prevent absorption of UV radiation by serum proteins, and cells were incubated in growth media for 24h post-UV before processing for TUNEL assay, cell proliferation assays, or immunofluorescence. Data showed a temporal increase in proliferation of HGF-1 cells under the influence of CsA. The 200ng/ml dose was more effective in causing over-proliferation. UV treatment for 10min resulted in significant reduction in cell numbers, as evidenced by counts and proliferation assays. Our study is a first step to further evaluate UV-mediated apoptosis as a mechanism to control certain forms of GO.



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The Meckel Collections (Die Meckelschen Sammlungen), Rüdiger Schultka

Publication date: May 2018
Source:Annals of Anatomy - Anatomischer Anzeiger, Volume 217
Author(s): Friedrich Paulsen




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Reliability and construct validity of the Ottawa valve collapse scale when assessing external nasal valve collapse

Nasal valve collapse is a common cause of nasal obstruction in otolaryngology practice. Common examination methods, such as the Cottle Maneuver and modified Cottle Maneuver are available. However, these method...

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Bilateral Piriform sinus fistulas: a case study and review of management options

Piriform sinus fistulas occur due to developmental abnormalities of the third and fourth branchial arches, and almost always occur unilaterally. They generally present as recurrent abscesses in the anterior-in...

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Endoscopic Endonasal Resection of Tuberculum Sellae Meningioma with Utilization of Indocyanine Green

J Neurol Surg B
DOI: 10.1055/s-0038-1625939

We present the case of a 67-year-old female with an incidental finding of a left-sided tuberculum sellae meningioma on a brain magnetic resonance imaging (MRI) for an unrelated complaint. Formal visual field testing showed a small defect in the inferior nasal and temporal fields of the left eye, compatible with mass effect on the optic nerve by the tumor.An endoscopic endonasal transtuberculum approach with decompression of the left optic nerve was performed using a standard binostril four-hand technique, with the patient positioned supine with the head turned to the right side and tilted to the left, fixed in a three-pin head clamp, under imaging guidance. After exposure, we drilled the tuberculum sellae and the floor of the sella and after opening the dura, the tumor and optic nerve came into view. The tumor was completely removed and we confirmed the patency of all perforating vessels using indocyanine green. Reconstruction was done in a multilayered fashion, using collagen matrix and a nasoseptal flap.Patient had an uneventful postoperative stay and was discharged on postoperative day 3, neurologically stable with no new hormonal deficits. Pathology report confirmed a WHO Grade I meningioma with K i-67 of 1% and 3-month postoperative MRI confirmed a gross total resection and visual fields exam showed a complete recovery.The link to the video can be found at: https://youtu.be/zRmt2aIvX5c.
[...]

Georg Thieme Verlag KG Stuttgart · New York

Article in Thieme eJournals:
Table of contents  |  Abstract  |  open access Full text

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Fluoroscopy-Assisted Transnasal Onyx Occlusion of the Eustachian Tube for Lateral Skull Base Cerebrospinal Fluid Leak Repair

J Neurol Surg B
DOI: 10.1055/s-0038-1625975

Objectives To describe transnasal Eustachian tube (ET) occlusion with a liquid embolic solution for lateral skull base cerebrospinal fluid (CSF) leaks. Design A lateral skull base CSF fistula model was developed by the authors using fresh cadaveric heads. Using a transtympanic needle, regulated pressurized pigmented saline was continuously instilled into the middle ear space and visualized endoscopically in the nasopharynx. An angioembolization catheter was then placed through the cartilaginous ET orifice just medial to the bony ET. Under endoscopic and fluoroscopic guidance, a column of liquid embolic agent was deployed into the bony ET segment up to the middle ear space. Setting Tertiary care academic center. Participants Cadaveric specimens. Main Outcome Measures Cessation of CSF flow after occlusion at supraphysiologic pressures. Results In two cadavers, a CSF fistula model was developed and endoscopic visualization of irrigant flow into the nasopharynx was confirmed. Fluoroscopy provided adequate anatomic views of the ET and middle ear, in addition to dynamic views of embolization. Cessation of flow after occlusion was successfully achieved with pressures up to 25 mm Hg, which exceeds normal physiological intracranial pressure. Conclusion Eustachian tube occlusion with a liquid embolic solution is feasible in a novel cadaveric CSF leak model. In the future, this relatively short, straightforward procedure may become an outpatient alternative to manage intermittent or low-flow CSF fistulae following lateral skull base surgery.
[...]

Georg Thieme Verlag KG Stuttgart · New York

Article in Thieme eJournals:
Table of contents  |  Abstract  |  Full text

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Orbitopterional Approach with Extradural Clinoidectomy for the Resection of a Tuberculum Sellae Meningioma: Adapting the Strategy to the Microsurgical and Pathological Anatomy

J Neurol Surg B
DOI: 10.1055/s-0038-1623523

Objectives To describe the orbitopterional approach with extradural clinoidectomy for the resection of a tuberculum sellae meningioma, with an emphasis on the microsurgical and pathological anatomy of such lesions. Design After completing the orbitopterional craniotomy in one piece, the optic nerve is identified extradurally, unroofed, and the clinoid process resected. The falciform ligament is divided and the optic nerve is decompressed extradurally. Opening the frontotemporal dura exposes the tumor in the subfrontal region. The tumor is followed along the ipsilateral and contralateral optic nerves, and its dural tail is cut and coagulated at the level of the tuberculum. Care is taken to preserve the optic nerve perforators during the dissection. Photographs of the region are borrowed from Dr Rhoton's laboratory to illustrate the microsurgical anatomy. Participants The surgery was performed by the senior author assisted by Dr. Jaafar Basma, neurosurgery fourth-year resident. The video was edited by Dr. Vincent Nguyen, neurosurgery third-year resident. Outcome Measures Outcome was assessed with the extent of resection and visual symptoms. Results A near-total resection of the tumor was achieved. A small part of tumor significantly adherent to the optic nerve was intentionally left behind. The patient had a stable vision examination postoperatively. Conclusions Understanding the microsurgical anatomy of the suprasellar region and the pathological anatomy of the tuberculum sellae meningioma is necessary to achieve a good resection of these tumors while preserving functionality of the optic apparatus. The orbitopterional approach with anterior clinoidectomy provides the appropriate access for such endeavor.The link to the video can be found at: https://youtu.be/WtAP8uqSW0M.
[...]

Georg Thieme Verlag KG Stuttgart · New York

Article in Thieme eJournals:
Table of contents  |  Abstract  |  open access Full text

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Endoscopic Endonasal Resection of a Suprasellar Pituitary Adenoma Mimicking Tuberculum Sellae Meningioma in a Patient with an Intrasellar Persistent Trigeminal Artery

J Neurol Surg B
DOI: 10.1055/s-0038-1625943

A 50-year-old female with an incidentally diagnosed suprasellar lesion was initially managed conservatively due to the presence of an intrasellar persistent trigeminal artery going through the dorsum sellae and fundamentally forming the blood supply of the entire posterior circulation. Serial follow-up brain magnetic resonance imaging (MRI) revealed progressive enlargement of the suprasellar lesion over 4 years period. Surgery was indicated after the initial tumor growth; however, the patient refused surgery for fear of complications related to the persistent trigeminal artery. Two-and-a-half years later, she presented with deterioration of vision. Formal visual field testing revealed a right temporal field defect. Brain MRI demonstrated significantly enlarged suprasellar lesion, most consistent with tuberculum sellae meningioma, exerting mass effect on the optic apparatus.The patient underwent endoscopic endonasal resection of the lesion through a transplanum/transtuberculum approach. Intraoperatively, absence of hypertrophic McConnel arteries, hyperostosis, and the fact that the dura was soft and not under tension was against the diagnosis of tuberculum sellae meningioma. Additionally, the tumor consistency was similar to a pituitary adenoma. A complete resection was accomplished and multilayer skull base reconstruction was performed with no complications. On postoperative day 1 (POD 1), she was operated upon for the evacuation of small suprasellar hematoma associated with vision deterioration. Histopathological examination confirmed the diagnosis of atypical pituitary adenoma with K i-67 labeling index of 4 to 5%. The patient ultimately recovered well with improved vision, and was discharged on POD 4 with no new neurological deficits. At 4 years follow-up, her vision was normalized and brain MRI showed no residual or recurrent lesion.The link to the video can be found at: https://youtu.be/QZmzctjAEbw.
[...]

Georg Thieme Verlag KG Stuttgart · New York

Article in Thieme eJournals:
Table of contents  |  Abstract  |  open access Full text

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Extended Endoscopic Endonasal Resection of a Suprasellar and Third Ventricular Retrochiasmatic Craniopharyngioma with a Narrow Pituitary Gland–Optic Chiasm Interval: Techniques to Optimize Resection

J Neurol Surg B
DOI: 10.1055/s-0038-1625946

The extended endoscopic endonasal approach can be utilized to surgically treat pathology within the suprasellar space. This relies on a sufficient corridor and interval between the superior aspect of the pituitary gland and the optic chiasm. Tumors located in the retrochiasmatic space and within the third ventricle, however, may not have a widened interval through which to work. With mass effect on the superior and posterior aspect of the optic chiasm, the corridor between the chiasm and the pituitary gland might even be further narrowed. This may negate the possibility of utilizing the endoscopic endonasal approach for the management of pathology in this location. We present a case of a retrochiasmatic craniopharyngioma with a narrow resection corridor that was treated with the extended endoscopic approach and we review techniques to potentially overcome this limitation.The link to the video can be found at: https://youtu.be/ogRZj-aBqeQ.
[...]

Georg Thieme Verlag KG Stuttgart · New York

Article in Thieme eJournals:
Table of contents  |  Abstract  |  open access Full text

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Lateral Supraorbital Craniotomy for Tuberculum Sella Meningioma Resection

J Neurol Surg B
DOI: 10.1055/s-0038-1623530

Tuberculum sella meningioma can be approached by either open or endoscopic approaches. The aim of this video case presentation is to highlight the nuances of the lateral supraorbital craniotomy for tuberculum sella meningioma resection. The authors present a 34-year-old female patient who presented with decreased right eye visual acuity (20/60), afferent pupillary defect, and nasal field cut due to a tuberculum sella meningioma. The tumor was partially encasing the left A1 artery, severely displacing the optic apparatus, and minimally invading the right optic canal. The lateral supraorbital craniotomy was considered the most suitable approach to this tumor. The operative nuances and pitfalls of this approach are detailed in the video. Gross total resection of the tumor was achieved and confirmed with postoperative MRI. The patient's vision gradually improved and she was discharged on the fourth postoperative day. The minimally invasive lateral supraorbital craniotomy for tuberculum sella meningioma is a suitable approach in selected cases.The link to the video can be found at: https://youtu.be/yG8q6YH2D9k.
[...]

Georg Thieme Verlag KG Stuttgart · New York

Article in Thieme eJournals:
Table of contents  |  Abstract  |  open access Full text

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Microsurgical Resection of Suprasellar Craniopharyngioma—Technical Purview

J Neurol Surg B
DOI: 10.1055/s-0038-1625941

Objectives Complete surgical resection is an important prognostic factor for recurrence and is the best management for craniopharyngioma. This operative video demonstrates the technical nuances in achieving complete resection of a suprasellar craniopharyngioma. Design and Setting The surgery was performed in a middle-aged lady who presented with the history of progressive bitemporal hemianopia and excessive sleepiness over 8 months. On imaging, suprasellar craniopharyngioma was identified. The tumor was approached through opticocarotid cistern and lamina terminalis. Exposure of bilateral optic nerves, right internal carotid artery, anterior cerebral artery, and its perforator branches was then afforded and the tumor was gross totally resected. Results The author demonstrates step-by-step technique of microsurgical resection of suprasellar craniopharyngioma. The narrow corridor to deeper structures, intricacies of multiple perforator vessels, and the technique of arachnoid and capsule dissection are the main challenging factors for the gross total resection of craniopharyngioma. The tumor portion which lies under the ipsilateral optic nerve is a blind spot region with a high chance of leaving residual tumor. Mobilization of optic nerve may endanger visual function too. The use of handheld mirror ['mirror-technique'] helps in better visualization of this blind spot and achieve complete excision. Conclusions The technical pearls of craniopharyngioma surgery include the optimum utilization of translamina terminalis route, wide opening of the cisterns, meticulous separation of deep perforator vessels, capsular mobilization/traction avoidance, and the use of "mirror-technique" for blind-spot visualization. These surgical strategies help to achieve complete resection without causing neurological deficit.The link to the video can be found at: https://youtu.be/9wHJ4AUpG50.
[...]

Georg Thieme Verlag KG Stuttgart · New York

Article in Thieme eJournals:
Table of contents  |  Abstract  |  open access Full text

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Endoscopic Endonasal Transoculomotor Triangle Approach for the Resection of a Pituitary Adenoma with Ambient Cistern Extension

J Neurol Surg B
DOI: 10.1055/s-0038-1625942

Objectives The current video presents the nuances of the endoscopic endonasal transoculomotor triangle approach for the resection of a pituitary adenoma with extension into the ambient cistern. Design The video analyzes the presentation, preoperative workup and imaging, surgical steps and technical nuances of the surgery, the clinical outcome, and follow-up imaging. Setting The patient was treated by a skull base team consisting of a neurosurgeon and an ENT surgeon at a teaching academic institution. Participants The case refers to a 62-year-old female who presented with vision loss and headaches, and was found to have a pituitary adenoma with extension into the ambient cistern. Main Outcome Measures The main outcome measures consist of the reversal of the patient symptoms (headaches), the recurrence-free survival based on imaging, as well as the absence of any complications. Results The patient's headaches improved. There was no evidence of recurrence. Conclusions The endoscopic endonasal transoculomotor triangle approach is safe and effective for addressing pituitary tumors which extend into the ambient cistern.The link to the video can be found at: https://youtu.be/EBLwEWhohxY.
[...]

Georg Thieme Verlag KG Stuttgart · New York

Article in Thieme eJournals:
Table of contents  |  Abstract  |  open access Full text

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Patient satisfaction and oral health-related quality of life 10–15 years after orthodontic-surgical treatment of mandibular prognathism

Publication date: Available online 14 February 2018
Source:International Journal of Oral and Maxillofacial Surgery
Author(s): E. Schilbred Eriksen, K. Moen, P.J. Wisth, S. Løes, K.S. Klock
This study investigated 36 patients at 10–15 years after they had undergone mandibular setback surgery by intraoral vertical ramus osteotomy (IVRO) and subsequent intermaxillary fixation for 6 weeks. The patients completed a 37-item structured questionnaire to evaluate patient satisfaction and possible long-term effects of the treatment. Visual analogue scales were used to measure self-perceived changes in seven items concerning oral function and appearance. Oral health-related quality of life was assessed using the Oral Impacts on Daily Performance (OIDP) index. The main reasons for seeking treatment were to improve chewing function and appearance. The treatment had resulted in significant improvements regarding chewing function, appearance, bullying, and self-confidence in social settings (all P<0.05). All patients were either very satisfied (61%) or reasonably satisfied (39%) with the treatment result. The mean OIDP frequency score was 8.49 on a scale from 8 to 40. Seventy-four percent of the patients reported no oral impacts on quality of life. In conclusion, 10–15 years after combined orthodontic and IVRO surgical treatment of mandibular prognathism, the patients were satisfied, and oral health-related quality of life was reported to be good.



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Base of tongue cancer—is it tongue cancer located at the base of the tongue, or is it a type of lingual tonsil cancer? The perspective from a genomic analysis

Publication date: Available online 13 February 2018
Source:International Journal of Oral and Maxillofacial Surgery
Author(s): K. Kim, K.Y. Choi, J.H. Kim, I.S. Park, Y.S. Rho, D.J. Lee
The aim of this study was to determine whether base of tongue (BOT) cancer is tongue cancer located at the base of the tongue or lingual tonsil cancer originating from tonsil tissue. This was a retrospective study using data from The Cancer Genome Atlas (TCGA). The genomic patterns of three primary cancers (BOT, oral tongue, and tonsil) were compared to determine their similarities and differences. Gene expression data (n=193; 26 BOT, 125 oral tongue, and 42 tonsil cases), copy number alteration data (n=142; 19 BOT, 96 oral tongue, and 27 tonsil cases), and somatic mutation data (n=187; 25 BOT, 122 oral tongue, and 40 tonsil cases) were analyzed using the t-test, heatmap analysis, and OncoPrint, respectively. Clinical information for the three tumour groups was included in the analyses. When using multiplatform analysis, BOT cancer showed nearly the same genomic pattern as tonsil cancer, but not oral tongue cancer. The χ² test and survival analysis revealed that BOT cancer had the same clinical and survival patterns as tonsil cancer. In conclusion, BOT cancer showed a genomic pattern similar to that of tonsil cancer, but different to that of oral tongue cancer. Further prospective studies are warranted before the results of this study can be applied in a clinical setting.



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Usefulness of reconstructed 3D images for cochlear implantation in a case with a facial nerve anomaly

Facial nerve anomalies are a potential problem in patients with cochleovestibular malformations. A case of cochlear implant (CI) surgery in the presence of intra-temporalbone facial nerve bifurcation is presented. During the first surgery, the facial nerve bifurcation obscured the promontory and round window. It was difficult to perform cochleostomy because of the lack of landmarks of the basal turn of the cochlea, and the first surgical attempt at cochleostomy was abandoned. A repeat CT scan was performed after the first surgery with reconstructed 3D images of the temporal bone and the cochlea, and then the cochlea was successfully opened at revision surgery.

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Adjustment of the Vocal Tract Shape via Biofeedback: A Case Study

In this study, an adjustment of the vocal tract shape toward selected sound waves in the frequency range of the first and second formants without phonation is discussed. The sound waves of a loudspeaker in front of the open mouth and amplified by the vocal tract are used as biofeedback signals. It is shown that the resonance amplification of the vocal tract complies with the concept of forced oscillation, with the driver being the sound source and the resonator being the vocal tract. An adjustment toward increased amplification via vocal tract resonance can be related to smaller bandwidths and lower damping.

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Prevalence and clinical presentation at the onset of type 1 diabetes mellitus among children and adolescents in AL-Baha region, Saudi Arabia

Journal Name: Journal of Pediatric Endocrinology and Metabolism
Issue: Ahead of print


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Outcomes of mitochondrial derived diseases: a single-center experience

Journal Name: Journal of Pediatric Endocrinology and Metabolism
Issue: Ahead of print


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Bing-Neel syndrome presenting as gait problems due to spinal cord involvement

Publication date: April 2018
Source:Clinical Neurology and Neurosurgery, Volume 167
Author(s): Karen Vermeiren, Marc Lemmerling, Henk Louagie, Mia Vantomme, Marjan Petrick, Frank Bouttens, Koenraad Verstraete




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Advanced MRI study of migrainous infarction presenting as cortical laminar necrosis – case report and literature review

Publication date: Available online 14 February 2018
Source:Clinical Neurology and Neurosurgery
Author(s): Ricardo Morais, Filipe Sobral, Gil Cunha, Olga Brito, Isabel Santana




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Sialic Acid Binding Immunoglobulin-Like Lectin-1 mRNA in Peripheral Blood Leukocytes Is Related to Chance of Relapse in Graves’ Disease

Clinical Thyroidology Feb 2018, Vol. 30, No. 2: 69-73.


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RAI Ablation Has Decreased for Low-Risk Thyroid Cancers in California

Clinical Thyroidology Feb 2018, Vol. 30, No. 2: 85-87.


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Patient Age Is Associated with Papillary Thyroid Cancer Mortality Only in Patients with BRAF V600E Mutation

Clinical Thyroidology Feb 2018, Vol. 30, No. 2: 53-55.


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Surgeon-Performed Ultrasound Is Important in the Preoperative Nodal Assessment of Patients with Potential Thyroid Malignancy

Clinical Thyroidology Feb 2018, Vol. 30, No. 2: 77-79.


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Current ATA Thyroid Cancer Guidelines Are Poor Predictors of the Extent of Thyroidectomy

Clinical Thyroidology Feb 2018, Vol. 30, No. 2: 56-58.


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Editorial: What's Ahead for Clinical Thyroidology in 2018

Clinical Thyroidology Feb 2018, Vol. 30, No. 2: 51-52.


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Does a Patient with a Normal FT4 but a TSH of 7 or Higher Have An Increased Risk of Cardiac Complications After Percutaneous Coronary Artery Interventions?

Clinical Thyroidology Feb 2018, Vol. 30, No. 2: 59-61.


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Levothyroxine May Decrease the Risk of Miscarriage in Women with High TPOAb Titers, Older Age, and Female Infertility Cause

Clinical Thyroidology Feb 2018, Vol. 30, No. 2: 74-76.


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Targeted Therapy Offers a Glimmer of Hope for Patients with Anaplastic Thyroid Cancer Even Outside of a Clinical Trial

Clinical Thyroidology Feb 2018, Vol. 30, No. 2: 62-65.


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Ultrasound Shear Wave Elastography May Help Reduce Frequency of Fine-Needle Biopsy in Low-Risk Thyroid Nodules

Clinical Thyroidology Feb 2018, Vol. 30, No. 2: 80-84.


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A Low-Iodine Diet During Methimazole Treatment Worsens Graves’ Disease Outcomes

Clinical Thyroidology Feb 2018, Vol. 30, No. 2: 66-68.


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U.S. Newborn Screening Programs for Congenital Hypothyroidism Vary Widely

Clinical Thyroidology Feb 2018, Vol. 30, No. 2: 88-89.


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New York Surgeon Gets 13 Years in Prison for Medicare Fraud

A federal judge also ordered Syed Imran Ahmed, MD, to pay millions in restitution and fines. The court found he billed more than $85M for procedures he never performed and upped charges with a false code.
Medscape Medical News

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For Rare Melanoma, Checkpoint Inhibitors May Hold Substantial Promise

A new study suggests that patients with a rare form of melanoma, called desmoplastic melanoma, may be particularly likely to benefit from treatments known as immune checkpoint inhibitors. An NCI-sponsored clinical trial is already testing one such drug in patients with this cancer.

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Communication Activities of Daily Living (CADL-3) versión española. Adaptación al contexto español y análisis de fiabilidad

Publication date: January–March 2018
Source:Revista de Logopedia, Foniatría y Audiología, Volume 38, Issue 1
Author(s): Clàudia Roca, Ignasi Ivern, Olga Bruna, Mercedes Velasco
IntroducciónActualmente no se usa ninguna prueba estandarizada que proporcione la cuantificación de la comunicación funcional del paciente con afasia castellanohablante. El estudio tiene como principales objetivos la traducción y adaptación al contexto español y el análisis de fiabilidad del instrumento de evaluación llamado Communication Activities of Daily Living (CADL-3).MétodosSe llevó a cabo con una muestra de 107 pacientes con afasia. La media de edad fue 60.68 (DE=15.104). A todos ellos se les administró individualmente la prueba CADL-3 versión española. Este incluyó fases de traducción, adaptación y fiabilidad.ResultadosLa versión final de la prueba CADL-3 versión española incluye 50 ítems con calificaciones positivas en la revisión de expertos. Se obtuvo una alta fiabilidad con una alfa de Cronbach de .949 y un coeficiente de fiabilidad test-retest .903 (p<.001).ConclusiónLa prueba CADL-3 versión española facilita la evaluación de la capacidad del paciente para comunicarse funcionalmente, con la finalidad de desarrollar programas de rehabilitación que respondan de forma más específica a las necesidades del paciente.IntroductionAt present, no standardized test is used to provide quantification of functional communication of Spanish-speaking patients with aphasia. The aim of the study is to translate and adapt the assessment instrument called Communication Activities of Daily Living (CADL-3) for use in the Spanish context and to conduct reliability analysis of the instrument.MethodsThe study was conducted with 107 patients with aphasia. The mean age was 60.68 (SD=15.104). The CADL-3 test Spanish version was individually administered. The study included stages of translation, adaptation and reliability.ResultsThe final version of the CADL-3 test Spanish version included 50 ítems with positive ratings in the expert review. The CADL-3 coefficient alpha was .949 and test-retest reliability was .903 (p<.001).ConclusionThe CADL-3 test Spanish version could provide the evaluation of patients' ability to communicate functionally and help in the development of rehabilitation programs that respond more specifically to patient needs.



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Regarding the Use of the Term “Cementum” in Pathologic Proliferations

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Monitoring of mechanical errors and their dosimetric impact throughout the course of non-coplanar continuous volumetric-modulated arc therapy

Volumetric-modulated Dynamic WaveArc therapy (VMDWAT) is a non-coplanar continuous volumetric modulated radiation therapy (VMAT) delivery technique. Here, we monitored mechanical errors and their impact on dos...

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Tutorial and Guidelines on Measurement of Sound Pressure Level in Voice and Speech

Purpose

Sound pressure level (SPL) measurement of voice and speech is often considered a trivial matter, but the measured levels are often reported incorrectly or incompletely, making them difficult to compare among various studies. This article aims at explaining the fundamental principles behind these measurements and providing guidelines to improve their accuracy and reproducibility.

Method

Basic information is put together from standards, technical, voice and speech literature, and practical experience of the authors and is explained for nontechnical readers.

Results

Variation of SPL with distance, sound level meters and their accuracy, frequency and time weightings, and background noise topics are reviewed. Several calibration procedures for SPL measurements are described for stand-mounted and head-mounted microphones.

Conclusions

SPL of voice and speech should be reported together with the mouth-to-microphone distance so that the levels can be related to vocal power. Sound level measurement settings (i.e., frequency weighting and time weighting/averaging) should always be specified. Classified sound level meters should be used to assure measurement accuracy. Head-mounted microphones placed at the proximity of the mouth improve signal-to-noise ratio and can be taken advantage of for voice SPL measurements when calibrated. Background noise levels should be reported besides the sound levels of voice and speech.

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