Epilepsy with auditory features: Long-term outcome and predictors of terminal remission

Summary

Objective

To assess the long-term outcome of epilepsy with auditory features (EAF) and to identify the clinical predictors for prognosis.

Methods

The study involved consecutive EAF patients with a follow-up of ≥5 years. Terminal remission (TR) was defined as a period of ≥5 consecutive years of seizure freedom at the last follow-up. We used Kaplan-Meier estimate to calculate the cumulative time-dependent probability of conversion to TR. Log-rank test and multivariate Cox regression analyses were performed to study the association between time to TR and prognostic determinants.

Results

We included 123 EAF patients (male/female = 58/65) with a median follow-up of 11 years (1626.9 person-years). Most were sporadic cases (68.3%), whereas 31.7% reported a family history of epilepsy. At last assessment, 42 patients had achieved TR (34.1%). Of the remaining 81 cases with no TR (65.9%), 37% had been in remission for 1-4 years and 62.9% still had seizures within the past year. The cumulative rates of TR were 26.6%, 35.7%, and 51.6% at 10, 20, and 30 years from inclusion. On multivariate analysis, age at onset > 10 years (hazard ratio [HR] = 3.2, P = .028), auditory aura characterized by distortions only versus simple/complex hallucinations (HR = 2.9, P = .041), and unremarkable scalp electroencephalogram (EEG) versus EEG with focal epileptiform activity (HR = 3.5, P = .041) were associated with TR.

Significance

Our data show a wide prognostic spectrum of EAF, ranging from mild forms with spontaneous remission, to severely refractory epilepsy addressed to surgery. The outcome, less favorable than expected from previous studies, appears to be primarily a function of 3 prognostic negative risk factors: age at onset < 10 years, auditory aura characterized by complex auditory hallucinations, and focal epileptiform abnormalities on scalp EEG. These predictors, easy to collect even at the first visit, may inform both clinicians and patients about the long-term prognosis and aid patient management.

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Basal Cell Carcinoma Induced by Therapeutic Radiation for Tinea Capitis – Clinical Pathological Study

Abstract

Aims

An increased prevalence of aggressive histological subtypes, such as the micronodular and morpheaform, has been seen, irrespective of the clinical course, in basal cell carcinoma (BCC) following irradiation for tinea capitis. The aim of this study was to assess the histopathological features of BCCs among patients irradiated for tinea capitis and correlate them with the clinical course.

Methods and Results

The medical records and BCC biopsy specimens of individuals who were previously irradiated for tinea capitis were revised. Demographic data and clinical characteristics were retrieved. Biopsy specimens were evaluated for histological subtype classification and additional histopathological features. A telephone survey was conducted to assess the clinical behaviour of the tumours. Thirty-one patients (17 male, 14 female) were included. The average age at time of first biopsy was 56 years. The total number of lesions was 185, with 80% of subjects showing multiple lesions. Nodular subtype was the most prevalent, followed by superficial, micronodular, and mixed tumours. Third of the BCC could be classified as aggressive histologically. Stromal fibroplasia and melanin deposits were common. There was no mortality related to BCC. None of the 17 patients who completed the survey had evidence of local invasiveness or metastases.

Conclusions

BCCs following radiation therapy for tinea capitis show unique histological characteristics related to aggressive behaviour. These aggressive features did not reflect the clinical behaviour in the current cohort.

This article is protected by copyright. All rights reserved.

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Grade 4 asbestosis does not extend directly from the respiratory bronchiole to the peripheral lung

Abstract

Aim

To confirm whether or not grade 4 asbestosis progresses from the respiratory bronchiole to the peripheral lung.

Methods and results

We retrospectively examined the autopsy or lobectomy specimens from 31 cases (29 males; mean age 64 years) satisfying the pathological criteria of grade 4 asbestosis. Asbestos bodies (ABs) were quantified in samples of dissolved lung and in tissue preparations on glass slides. Respiratory bronchiolar lesions were graded as 0, 1, and ≥ grade 2. Grade 4 asbestosis was subdivided into an atelectatic induration (AI); and usual interstitial pneumonia pattern (UIP pattern). Five, 10, and 16 cases had grade 0, 1, or ≥2 lesions respectively, with mean respective numbers of ABs in dissolved lung of 117,000/g dry lung, 468,000/g, and 968,000/g; and in specimens on glass slides of 7 ABs/cm² of tissue slice, 34 ABs /cm², and 195 ABs /cm². The differences were significant. Fifteen and 16 cases showed AI and UIP patterns, respectively; with mean respective numbers of ABs in dissolved lung of 1,006,000/g dry lung and 354,000/g, and 186 and 56 ABs/cm² on glass slides. The differences were significant. AI patterns originated in subpleural lobules or subpleural zonal areas, and UIP patterns originated in subpleural, peripheral lobules.

Conclusions

Grade 4 asbestosis does not start in the respiratory bronchiole. The presence of a grade 1 lesion is not required for the diagnosis of grade 4 asbestosis.

This article is protected by copyright. All rights reserved.

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Primary perianal adenocarcinoma of intestinal type – a new proposed entity

Abstract

Aims

The currently recognised subtypes of anal canal/perianal adenocarcinoma are those arising from low rectal mucosa or columnar cuff, fistula-related tumours and anal gland carcinoma. This following report presents two examples of a hitherto undescribed subtype of perianal adenocarcinoma with an intestinal phenotype.

Methods and Results

A 74 year old man had a perianal tumour locally excised whereas a 73 year old female underwent an abdominoperineal resection for perianal Paget's disease with an underlying carcinoma. Neither patient had a history of perineal fistulae, Crohn's disease or previous gastrointestinal neoplasia, and neither showed clinical, radiological or endoscopic evidence of another abdominal or pelvic tumour. Both resection specimens contained adenocarcinoma which were similar in demonstrating an intestinal morphology and CDX2 immunopositivity. The man has shown a disease-free outcome thus far but the woman has suffered with nodal and pelvic recurrence within a few months of surgery.

Conclusions

The name 'primary perianal adenocarcinoma of intestinal type' is proposed for this previously unrecognised subtype of perineal neoplasia. Awareness of its distinct existence – by recognising its intestinal morphology and immunophenotype while excluding metastasis from the intestinal tract – should help collate data to determine its specific prognosis and to formulate its best management.

This article is protected by copyright. All rights reserved.

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A Genomic and Clinicopathologic Study of Non–Small Cell Lung Cancers with Discordant ROS1 Gene Status by Fluorescent In Situ Hybridization and Immunohistochemical Analysis

Abstract

Background

ROS1 immunohistochemistry (IHC) using D4D6 antibody is a useful tool for screening patients with non–small cell lung cancer (NSCLC) slated for targeted therapy. Many studies and our data have identified cases that express the ROS1 protein strongly but are negative for ROS1 by fluorescent in situ hybridization (FISH). The present study investigated the driver mutation and clinicopathologic characteristics of 26 discordant cases (ROS1 IHC-positive but FISH-negative) to find new clues for distinguishing real ROS1-rearranged cases.

Patients and Methods

Tumors from 26 discordant cases were analyzed for clinicopathologic characteristics, mutations in EGFR, KRAS, ERBB2, BRAF, and PIK3CA; fusions in ALK and RET; and amplifications in MET, ERBB2, and ROS1.

Results

ROS1-rearranged NSCLCs were significantly more likely to be found in younger patients and at an advanced stage; they showed cribriform features, extracellular mucus, and psammoma bodies, whereas ROS1-discordant cases were found in older patients at a relatively early TNM stage and showed a lepidic growth pattern (all P <.001). Most of ROS1-rearranged NSCLCs were no concurrent mutation, whereas 73% of discordant cases harbored genetic aberrations, including EGFR and ERBB2. Compared with general lung adenocarcinomas, ERBB-2 abnormality was disproportionately high in ROS1-discordant cases. Moreover, we optimized the scoring criteria for ROS1 IHC as "H score >150 and no concurrent mutations"; then the specificity was increased to 81.6%.

Conclusions

Compared with ROS1-rearranged cases, ROS1-discordant patients showed distinct clinical and morphologic features and often harbored another oncogenic driver alteration. The use of optimized screening criteria will increase the specificity of ROS1 antibody.

This article is protected by copyright. All rights reserved.

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Comparison between Corticosteroid and Lidocaine Injection in the Treatment of Tennis Elbow: A Randomized, Double-Blinded, Controlled Trial

No abstract available

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Outcome Trends of Adult Cancer Patients Receiving Inpatient Rehabilitation: A 13-year review

AbstractObjectiveThis study describes characteristics and trends of inpatient rehabilitation among cancer patients within the United States over a 13-year period.DesignThis was a retrospective study of data from the Uniform Data System for Medical Rehabilitation (UDSMR®) from 2002 to 2014. Patients over the age of 17 admitted to inpatient rehabilitation facilities with a diagnosis of malignant cancer were included. Trends of rehabilitation outcomes including length of stay, Functional Independence Measure (FIM®) Instrument scores, and discharge location were examined.ResultsData from 115,570 cancer patients was evaluated. Mean age was 66 ±14 and 49% were female. Mean length of stay decreased over time (2002: 14 days to 2014:13 days, p70%) were discharged to the community.ConclusionCancer patients receiving acute inpatient rehabilitation demonstrated significant improvements in functional outcomes from admission to discharge. Cancer patients became more independent in important activities of daily living, thereby potentially reducing caregiver burden and ensuring safer discharges back to the community. This study suggests potential benefit of inpatient rehabilitation for appropriate cancer patients. Objective This study describes characteristics and trends of inpatient rehabilitation among cancer patients within the United States over a 13-year period. Design This was a retrospective study of data from the Uniform Data System for Medical Rehabilitation (UDSMR®) from 2002 to 2014. Patients over the age of 17 admitted to inpatient rehabilitation facilities with a diagnosis of malignant cancer were included. Trends of rehabilitation outcomes including length of stay, Functional Independence Measure (FIM®) Instrument scores, and discharge location were examined. Results Data from 115,570 cancer patients was evaluated. Mean age was 66 ±14 and 49% were female. Mean length of stay decreased over time (2002: 14 days to 2014:13 days, p70%) were discharged to the community. Conclusion Cancer patients receiving acute inpatient rehabilitation demonstrated significant improvements in functional outcomes from admission to discharge. Cancer patients became more independent in important activities of daily living, thereby potentially reducing caregiver burden and ensuring safer discharges back to the community. This study suggests potential benefit of inpatient rehabilitation for appropriate cancer patients. Corresponding Author: Jeffrey C. Schneider, 300 1st Avenue, Charlestown, MA 02129. jcschneider@partners.org Disclosures: None Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

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Effects of anodal transcranial direct current stimulation on somatosensory recovery after stroke: a randomized controlled trial

AbstractObjectiveTo evaluate the effect of anodal transcranial direct current stimulation (tDCS) over the primary somatosensory cortex on the recovery of somatosensation, motor function, and the activities of daily living (ADL) in patients with subacute stroke.DesignThis study was a prospective, randomized sham controlled, double-blinded study. Patients with subacute stroke having somatosensory deficits (N = 24) were enrolled and assigned randomly to the anodal and sham stimulation groups. Patients received 10 consecutive anodal or sham tDCSs over the primary somatosensory cortex on the side of the stroke lesion. Before and after each stimulation session, Nottingham sensory assessments, Semmes Weinstein monofilaments examination, and manual function tests were performed, and modified Brunnstrom classification, modified Barthel index, and functional ambulation categories were assessed.ResultsAlthough there was no clear significant difference between the two groups, when the changes from baseline to post-treatment evaluation were compared between the groups, we observed a partially significant improvement in the anodal stimulation group compared to the sham stimulation group. Interestingly, the tactile sensation of the unaffected side also improved. Moreover, the greater improvement in ADL function was observed in the anodal stimulation group too.ConclusionAnodal tDCS over the primary somatosensory cortex may be a useful adjuvant therapy for the recovery of somatosensation and ADL function in patients with sensory deficits after stroke. Objective To evaluate the effect of anodal transcranial direct current stimulation (tDCS) over the primary somatosensory cortex on the recovery of somatosensation, motor function, and the activities of daily living (ADL) in patients with subacute stroke. Design This study was a prospective, randomized sham controlled, double-blinded study. Patients with subacute stroke having somatosensory deficits (N = 24) were enrolled and assigned randomly to the anodal and sham stimulation groups. Patients received 10 consecutive anodal or sham tDCSs over the primary somatosensory cortex on the side of the stroke lesion. Before and after each stimulation session, Nottingham sensory assessments, Semmes Weinstein monofilaments examination, and manual function tests were performed, and modified Brunnstrom classification, modified Barthel index, and functional ambulation categories were assessed. Results Although there was no clear significant difference between the two groups, when the changes from baseline to post-treatment evaluation were compared between the groups, we observed a partially significant improvement in the anodal stimulation group compared to the sham stimulation group. Interestingly, the tactile sensation of the unaffected side also improved. Moreover, the greater improvement in ADL function was observed in the anodal stimulation group too. Conclusion Anodal tDCS over the primary somatosensory cortex may be a useful adjuvant therapy for the recovery of somatosensation and ADL function in patients with sensory deficits after stroke. Corresponding author: Chung Reen Kim M.D., MS, Department of Physical Medicine and Rehabilitation, Ulsan University Hospital, University of Ulsan College of Medicine, 877 Bangeojinsunhwan-doro, Jeonha 1(il)-dong, Dong-gu, Ulsan, Korea. E-mail: crkim@uuh.ulsan.kr, Tel : 82-52-250-8730, Fax : 82-52-250-8071 We certify that no party having a direct interest in the results of the research supporting this article has or will confer a benefit on us or on any organization with which we are associated. No funds were received in support of this manuscript. Additionally, no benefits in any form have been or will be received from a commercial party related directly or indirectly to the subject of this manuscript. Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

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Letter to the editor involving the article ‘’Comparison Between Corticosteroids and Lidocaine Injection in the Treatment of Tennis Elbow: A Randomised, Double-Blinded, Controlled Trial”

No abstract available

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The efficacy of adding targeted agents to neoadjuvant therapy for locally advanced rectal cancer patients: a meta-analysis

Abstract

Patients with locally advanced rectal cancer (LARC) are at tremendous risk of metastatic diseases. To improve the prognoses of LARC patients, the efficacy of adding targeted agents to neoadjuvant therapy has been investigated by many researchers but remains controversial. A literature search of relevant databases was conducted through December 2016, 804 studies were identified and 32 investigations were ultimately included. A total of 1196 patients from 31 cohorts of 29 studies were eligible for quantitative synthesis in this single-arm setting meta-analysis. As pathologic complete response (pCR) shows promise as a prognosis indicator, we focused on pCR rates to evaluate whether adding targeted agents to neoadjuvant therapies improves the outcome of LARC patients. In our study, we revealed pooled estimates of pCR of 27% (95%CI, 21–34%) and 14% (95%CI, 9–21%) for bevacizumab-relevant cohorts and cetuximab-relevant cohorts, respectively. The safety of adding targeted agents to neoadjuvant therapy was also evaluated by pooling the data of Grade 3/4 toxicity. In conclusion, our study revealed that adding bevacizumab to the neoadjuvant therapy regimens provides appreciable pCR for LARC patients. Meanwhile, the efficacy of cetuximab remains inconclusive, RCTs with larger scale and better study design that stress more on mutational status are needed.

Since pathologic complete response (pCR) shows promise as a prognosis indicator, in this meta-analysis we pooled the data of pCR rates extracted from the included studies to evaluate whether adding targeted agents to neoadjuvant therapies improves the outcome of LARC patients. Our study revealed that adding bevacizumab to the neoadjuvant therapy regimens provides an appreciable pCR for LARC patients. Meanwhile, cetuximab fails to benefit LARC patients when the administration is not conducted based on their KRAS status.

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Clinical impact of ulceration width, lymphovascular invasion, microscopic satellitosis, perineural invasion, and mitotic rate in patients undergoing sentinel lymph node biopsy for cutaneous melanoma: a retrospective observational study at a comprehensive cancer center

Abstract

The prognostic significance of the width of the ulceration in primary melanomas remains unclear, and there is a relative paucity of data for lymphovascular invasion (LVI), microscopic satellitosis (MS), perineural invasion (PNI), and mitotic rate when compared with other pathological elements currently required for reporting. To evaluate the prognostic importance of the ulceration width and other important pathologic measurements, a single-institutional retrospective study was conducted using records of cutaneous melanoma patients who underwent sentinel lymph node (SLN) biopsy at The University of Texas, MD Anderson Cancer Center between 2003 and 2008. We identified 1898 eligible patients with median tumor thickness of 1.25 mm and median follow-up of 6.7 years. By multivariable analyses, the strongest risk factor for SLN positivity was high tumor thickness followed by the presence of LVI. The pathologic measures with the strongest influence on recurrence-free survival (RFS) were tumor thickness and positive SLN status. Ulceration width and presence of MS were also significantly associated with RFS while PNI was not. Factors with the strongest influence on melanoma-specific survival (MSS) were positive SLN status and mitotic rate. In conclusion, SLN biopsy should probably be offered if the primary tumor has LVI. MS is an adverse prognostic factor for RFS, but its influence on outcome is modest. Ulceration width predicts RFS but loses its independent prognostic significance for MSS when adjusting for currently used clinicopathological factors. In view of its impact on MSS, mitotic rate should be recorded for cutaneous invasive melanomas across all T categories.

SLN biopsy should be offered if the primary tumor has LVI. MS is an adverse prognostic factor for RFS, but its influence on outcome is modest. Ulceration width predicts RFS but lost its independent prognostic significance for MSS when adjusting for other contemporary clinicopathological factors. In view of its impact on MSS, mitotic rate should be recorded for cutaneous invasive melanomas across all T categories.

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A blood tumor marker combination assay produces high sensitivity and specificity for cancer according to the natural history

Abstract

Diagnosis using a specific tumor marker is difficult because the sensitivity of this detection method is under 20%. Herein, a tumor marker combination assay, combining growth-related tumor marker and associated tumor marker (Cancer, 73(7), 1994), was employed. This double-blind tumor marker combination assay (TMCA) showed 87.5% sensitivity as the results, but a low specificity, ranging from 30 to 76%. To overcome this low specificity, we exploited complex markers, a multivariate analysis and serum fractionation by biochemical biopsy. Thus, in this study, a combination of new techniques was used to re-evaluate these serum samples. Three serum panels, containing 90, 120, and 97 samples were obtained from the Mayo Clinic. The final results showed 80-90% sensitivity, 84-85% specificity, and 83-88% accuracy. We demonstrated a notable tumor marker combination assay with high accuracy. This TMCA should be applicable for primary cancer detection and recurrence prevention.

Utilizing three kind of tumor marker combination assay(TMCA), combining specific tumor marker, associated tumor marker and growth-related tumor marker, we can get high sensitivity of detection, but low specificity. By utilizing TMCA, complex tumor marker, a multivariate analysis formula and protein serum fractionation, we can get high sensitivity and high specificity of detection.

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Cancers, Vol. 10, Pages 57: Recommendations and Choices for BRCA Mutation Carriers at Risk for Ovarian Cancer: A Complicated Decision

Cancers, Vol. 10, Pages 57: Recommendations and Choices for BRCA Mutation Carriers at Risk for Ovarian Cancer: A Complicated Decision

Cancers doi: 10.3390/cancers10020057

Authors: Kelsey Lewis Karen Lu Amber Klimczak Samuel C. Mok

Current ovarian cancer screening guidelines in high-risk women vary according to different organizations. Risk reducing surgery remains the gold standard for definitive treatment in BRCA mutation carriers, but research advancements have created more short-term options for patients to consider. The decisions involved in how a woman manages her BRCA mutation status can cause a great deal of stress and worry due to the imperfect therapy options. The goal of this review was to critically analyze the screening recommendations and alternative options for high-risk ovarian cancer patients and evaluate how these discrepancies and choices affect a woman's management decisions.

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Issue Information - TOC

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Fine needle aspiration of pilomatrixoma: Cytologic features on thinprep and diagnostic pitfalls

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Issue Information - Masthead

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Issue Information - Copyright

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Annals of Neurology: Volume 83, Number 2, February 2018

A raster display of repeated motor cortical evoked potentials with single pulses of deep brain stimulation in the globus pallidus, pars interna in a patient with cervical dystonia. Each line represents a single trial, with stimulation beginning at the left margin, and the length of each line equivalent to 50 msec of recording. Dark blue = 0 mV, lighter blue-green colors = negative voltage, purple-red colors = positive voltage. Note that the evoked potential is negative at about 10 msec, positive at about 25 msec, and then near zero again at 50 msec. See Ni et al., pp 352–362, this issue. Ann Neurol 2018;83:1–1

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Issue Information - TOC

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Reply to questions on “Serial two-year follow-up after lymphaticovenular anastomosis for the treatment of lymphedema”

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Nasal Structural and Aerodynamic Features that may Benefit Normal Olfactory Sensitivity

Abstract

Nasal airflow that effectively transports ambient odors to the olfactory receptors is important for human olfaction. Yet, the impact of nasal anatomical variations on airflow pattern and olfactory function are not fully understood. In this study, 22 healthy volunteers were recruited and underwent CT scans for computational simulations of nasal airflow patterns. Unilateral odor detection thresholds (ODT) to l-Carvone, phenylethyl alcohol (PEA) and d-Limonene were also obtained for all participants. Significant normative variations in both nasal anatomy and aerodynamics were found. The most prominent was the formation of an anterior-dorsal airflow vortex in some but not all subjects, with the vortex size being significantly correlated with ODT of l-Carvone (r=0.31, p<0.05). The formation of the vortex is likely the result of anterior nasal morphology, with the vortex size varying significantly with the nasal index (ratio of the width and height of external nose, r=-0.59, p<0.001) and nasal vestibule "notch" index (r=0.76, p<0.001). The "notch" is a narrowing of the upper nasal vestibule cartilage region. The degree of the notch also significantly correlates with ODT for PEA (r=0.32, p<0.05) and l-Carvone (r=0.33, p<0.05). ODT of d-Limonene, a low mucosal soluble odor, does not correlate with any of the anatomical or aerodynamic variables. The current study revealed that nasal anatomy and aerodynamics might have a significant impact on normal olfactory sensitivity, with greater airflow vortex and a narrower vestibule region likely intensifying the airflow vortex towards the olfactory region and resulting in greater olfactory sensitivity to high mucosal soluble odors.

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STING activation enhances cetuximab-mediated NK cell activation and DC maturation and correlates with HPV+ status in head and neck cancer

Publication date: March 2018
Source:Oral Oncology, Volume 78
Author(s): Shanhong Lu, Fernando Concha-Benavente, Gulidanna Shayan, Raghvendra M. Srivastava, Sandra P. Gibson, Lin Wang, William E. Gooding, Robert L. Ferris
ObjectivesThe intracellular DNA sensor stimulator of interferon genes (STING) has recently been shown to play a vital role in anti-viral and anti-tumor immune responses stimulating cytokine production. While human papillomavirus (HPV) is a causative agent for a subset of head and neck squamous cell carcinoma (HNSCC) with unique etiology and clinical outcome, how the STING pathway is regulated in a virus-induced tumor microenvironment is not well understood. Since STING inactivation likely reflects immunoescape via innate immunity, we hypothesized that its restoration would improve efficacy of the immune modulatory monoclonal antibody (mAb), cetuximab.Materials and methodsWe correlated STING protein expression with clinical parameters by immunohistochemistry (n = 106) and its mRNA expression from The Cancer Genome Atlas (TCGA) in HNSCC tissue specimens. STING protein expression was tested for association with cancer-specific survival (CSS). We further examined the impact of STING activation on cetuximab-mediated immunity using an in vitro NK:DC:tumor cells co-culture system.ResultsIn this study, we found that expression of STING both at the protein and mRNA level was higher in HPV positive (HPV⁺) specimens but unrelated to TNM stage or cancer-specific survival. Our in vitro studies verified that STING activation enhanced cetuximab mediated NK cell activation and DC maturation.ConclusionOur findings suggest a novel role of STING in HPV-related carcinogenesis, in which activation of the STING signaling pathway may facilitate anti-tumor response in HNSCC patients, particularly in combination with therapeutic monoclonal antibodies (mAbs) such as cetuximab, an epidermal growth factor receptor (EGFR) inhibitor.



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Heterogeneity and irregularity of pretreatment 18F-fluorodeoxyglucose positron emission tomography improved prognostic stratification of p16-negative high-risk squamous cell carcinoma of the oropharynx

Publication date: March 2018
Source:Oral Oncology, Volume 78
Author(s): Nai-Ming Cheng, Yu-Hua Dean Fang, Din-Li Tsan, Li-Yu Lee, Joseph Tung-Chieh Chang, Hung-Ming Wang, Shu-Hang Ng, Chun-Ta Liao, Lan-Yan Yang, Tzu-Chen Yen
ObjectivesHuman papillomavirus-negative oropharyngeal squamous cell carcinoma (OPSCC) has unfavorable survival outcomes. Two outcomes have been identified based on smoking history and tumor stage. We investigate the prognostic role of pre-treatment positron emission tomography (PET) in high-risk OPSCC.Materials and MethodsWe enrolled 147 M0 OPSCC patients with p16-negative staining and a history of heavy smoking (>10 pack-years) or T4 disease. All patients completed primary chemoradiotherapy, and 42% maximum standard uptake values (SUVmax) were used as the threshold for primary tumor. Patients were classified into training and validation cohorts with a ratio of 1:1.5 according to the PET date. Heterogeneity and irregularity indices were obtained. PET parameters with significant impact on progression-free survival (PFS) in receiver operating characteristic curves and univariate Cox models were identified and included in recursive partitioning analysis (RPA) for constructing a prognostic model. The RPA-based prognostic model was further tested in the validation cohort using multivariate Cox models.ResultsFifty-eight and 89 patients were in the training and validation groups, respectively. Heterogeneity parameter, SUV-entropy (derived from histogram analysis), and irregularity index, and asphericity were significantly associated with PFS. The RPA model revealed that patients with both high SUV-entropy and high asphericity experienced the worst PFS. Results were confirmed in the validation group. The overall concordance index for PFS of the model was 0.75, which was higher than the clinical stages, performance status, SUVmax, and metabolic tumor volume of PET.ConclusionsPET prognostic model provided useful prediction of PFS for patients with high-risk OPSCC.

Graphical abstract

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Podoplanin emerges as a functionally relevant oral cancer biomarker and therapeutic target

Publication date: March 2018
Source:Oral Oncology, Volume 78
Author(s): Edward P. Retzbach, Stephanie A. Sheehan, Evan M. Nevel, Amber Batra, Tran Phi, Angels T.P. Nguyen, Yukinari Kato, Soly Baredes, Mahnaz Fatahzadeh, Alan J. Shienbaum, Gary S. Goldberg
Oral cancer has become one of the most aggressive types of cancer, killing 140,000 people worldwide every year. Current treatments for oral cancer include surgery and radiation therapies. These procedures can be very effective; however, they can also drastically decrease the quality of life for survivors. New chemotherapeutic treatments are needed to more effectively combat oral cancer. The transmembrane receptor podoplanin (PDPN) has emerged as a functionally relevant oral cancer biomarker and chemotherapeutic target. PDPN expression promotes tumor cell migration leading to oral cancer invasion and metastasis. Here, we describe the role of PDPN in oral squamous cell carcinoma progression, and how it may be exploited to prevent and treat oral cancer.



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Oncologic and functional outcomes of pretreatment tracheotomy in advanced laryngeal squamous cell carcinoma: A multi-institutional analysis

Publication date: March 2018
Source:Oral Oncology, Volume 78
Author(s): Serena A. Byrd, Mary J. Xu, Lauren M. Cass, Daniel J. Wehrmann, Matthew Naunheim, Kara Christopher, John J. Dombrowski, Ronald J. Walker, Lori Wirth, John Clark, Paul Busse, Annie Chan, Daniel G. Deschler, Kevin Emerick, Derrick T. Lin, Mark A. Varvares
ObjectivesDescribe the influence of pretreatment tracheotomy and treatment modality (surgical versus non-surgical) on oncologic and functional outcomes.Materials and methodsRetrospective study of previously untreated advanced-stage laryngeal squamous cell carcinoma patients at two academic tertiary care institutions from 1995 to 2014.ResultsPrimary outcomes evaluated were disease-free survival, disease-specific survival, and overall survival of pretreatment tracheotomy versus no pretreatment tracheotomy cohorts. Functional status, measured by tracheotomy decannulation and gastrostomy tube placement/removal, was assessed. Of the 226 patients, 31.4% underwent pretreatment tracheotomy. Five-year disease-specific survival was 72.9%, and overall survival was 48.8% for entire cohort. There was a statistically significant decrease in overall survival (p = .03) and disease-free survival (p = .02) for the pretreatment tracheotomy group compared to no pretreatment tracheotomy, which was largely explained by primary tumor stage. Pretreatment tracheotomy was associated with gastrostomy tube placement and was an independent predictor of worse odds of gastrostomy tube removal. Disease stage, distant metastasis, and age independently conferred worse odds of gastrostomy tube removal.ConclusionPatients undergoing pretreatment tracheotomy for primary T4 laryngeal cancer had decreased overall survival compared to patients without pretreatment tracheotomy. There was no difference in local recurrence rates based on tracheotomy status. Organ preservation with chemotherapy and radiation did not result in better functional outcomes than surgery in the pretreatment tracheotomy group as nearly half of patients treated with organ preservation remained tracheotomy dependent. Based on this data, pretreatment tracheotomy may impact oncologic and functional outcomes in advanced disease, and it should be a consideration in an informed decision-making process.



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Baseline peripheral blood leukocytosis: Biological marker predicts outcome in oropharyngeal cancer, regardless of HPV-status

Publication date: March 2018
Source:Oral Oncology, Volume 78
Author(s): Zeno A.R. Gouw, Jan Paul de Boer, Arash Navran, Michiel W.M. van den Brekel, Jan-Jakob Sonke, Abrahim Al-Mamgani
ObjectivesTo study the prognostic value of abnormalities in baseline complete blood count in patients with oropharyngeal cancer (OPC) treated with (chemo) radiation.Methods and materialsThe prognostic value of baseline complete blood count on outcome in 234 patients with OPC treated between 2010 and 2015 was examined in multivariate analysis together with other conventional prognostic variables including HPV-status, tumor stage, tumor and nodal size.ResultsThe 3-year overall survival (OS), disease-free survival (DFS), locoregional control (LRC), and distant control (DC) of the whole group were 74%, 64%, 79%, and 88%, respectively. Leukocytosis and HPV-status were the only significant prognosticators for OS and DFS at the multivariate analysis. Patients without leukocytosis had a significantly better DC compared to those with leukocytosis (92% and 70%, respectively, p < 0.001). Patients with HPV-negative OPC had significantly worse LRC compared to HPV-positive patients (67% and 90%, respectively, p < 0.001). The 3-year OS in HPV-positive group with leukocytosis compared to those without leukocytosis were 69% and 95%, respectively (p < 0.001). The figures for HPV-negative patients were 41% vs. 61%, respectively (p = 0.010).ConclusionsThis is the first study to date reporting the independent impact of leukocytosis and HPV-status on outcome of patients with OPC. The poor outcome of patients with leukocytosis is mainly caused by the worse DC. The significant impact of leukocytosis on outcome was even more pronounced in HPV-positive patients. These biomarkers could help identifying patients with poor prognosis at baseline requiring intensification of local and/or systemic treatment while treatment de-intensification might be offered to the low-risk group.



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Role of sequential chemoradiotherapy in stage II and low-risk stage III–IV nasopharyngeal carcinoma in the era of intensity-modulated radiotherapy: A propensity score-matched analysis

Publication date: March 2018
Source:Oral Oncology, Volume 78
Author(s): Cheng Xu, Rui Sun, Ling-Long Tang, Lei Chen, Wen-Fei Li, Yan-Ping Mao, Guan-Qun Zhou, Rui Guo, Ai-Hua Lin, Ying Sun, Jun Ma, Wei-Han Hu
ObjectivesTo investigate the role of sequential chemoradiotherapy (SCRT; induction chemotherapy [IC] followed by intensity-modulated radiotherapy [IMRT]) in stage II and low-risk stage III–IV nasopharyngeal carcinoma (NPC).Materials and methodsFour well-matched groups were individually generated using propensity score matching in patients (n = 689) with stage II (SCRT vs. concurrent chemoradiotherapy [CCRT], SCRT vs. IMRT alone) and low-risk stage III–IV NPC (SCRT vs. CCRT, SCRT vs. IC + CCRT). Five-year overall/disease-free/locoregional relapse-free/distant metastasis-free survival (OS/DFS/LRRFS/DMFS) and acute hematological toxicities were compared between groups. The value of SCRT was further investigated in multivariate analysis and subgroup analysis by adjusting for covariates and limiting IC-to-IMRT time interval, respectively.ResultsSCRT led to equivalent survival outcomes compared to CCRT/IMRT alone and CCRT/IC + CCRT in stage II and low-risk stage III–IV NPC, respectively (all P > .050). In multivariate analysis, patients with stage II NPC treated by SCRT obtained higher DMFS (AHR = 0.22, 95% CI = 0.05–1.00, P = .050), but not OS, DFS or LRRFS, compared to patients receiving CCRT; non-significant differences were observed between SCRT and other treatments. SCRT with short IC-to-IMRT time interval (≤70 days) achieved higher 5-year survival rates than IMRT alone (DMFS: P = .046), CCRT (stage II NPC; OS: P = .047; DMFS: P = .020) and IC + CCRT (DFS: P = .041). Moreover, SCRT was associated with higher, equivalent and lower frequencies of acute hematological toxicities than IMRT alone, CCRT and IC + CCRT, respectively.ConclusionSCRT is mainly beneficial in stage II NPC, leading to better DMFS and/or equivalent acute hematological toxicities compared to CCRT/IMRT alone. CCRT is still the best choice for low-risk stage III–IV NPC.



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Induction chemotherapy followed by concurrent chemoradiation versus concurrent chemoradiation alone in the definitive management of p16-positive oropharyngeal squamous cell carcinoma with low-neck or N3 disease

Publication date: March 2018
Source:Oral Oncology, Volume 78
Author(s): Onita Bhattasali, Jeannie Han, Lester D.R. Thompson, Gary L. Buchschacher, Iman A. Abdalla, Shawn Iganej
ObjectiveThe addition of induction chemotherapy (ICT) to concurrent chemoradiation (CCRT) has been investigated as a method of improving outcomes among patients with locally advanced head and neck squamous cell carcinoma. Previous studies have consisted of heterogeneous populations with both p16-positive and p16-negative disease and varying extent of nodal disease burden. We evaluated the role of ICT in p16-positive oropharyngeal squamous cell carcinoma (OPSCC) at high-risk of distant failure.Materials and methodsA retrospective review was conducted of 88 consecutive patients with p16-positive OPSCC with low-neck and/or N3 lymphadenopathy. Among these patients, 44 received ICT followed by CCRT, and 44 received CCRT alone with concurrent agents including Cisplatin, Carboplatin, and Cetuximab. Disease control and survival outcomes were reported after adjusting for age, T stage, N stage, and smoking status.ResultsMedian follow-up for surviving patients was 47 (range: 13–115) months. Patients who received CCRT alone were older than those who received ICT (61 years vs. 56 years; p = 0.02); the groups were otherwise similarly balanced. 3-year distant metastasis: 38% vs. 18% (adjusted hazard ratio (HR) = 0.32 [0.13–0.82]; p = 0.02). 3-year progression-free survival: 49% vs. 74% (adjusted HR = 0.46 [0.22–0.93]; p = 0.03). 3-year overall survival: 67% vs. 83% (adjusted HR = 0.48 [0.21–1.12]; p = 0.09).ConclusionAmong patients with p16-positive OPSCC with low-neck and/or N3 lymphadenopathy, ICT followed by CCRT may reduce the risk for distant failure over CCRT alone and lead to improved progression-free survival. Future trials should concentrate on patients at the highest risk of distant metastasis in order to appropriately assess the benefit of ICT.



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Phosphorylation of PI3K regulatory subunit p85 contributes to resistance against PI3K inhibitors in radioresistant head and neck cancer

Publication date: March 2018
Source:Oral Oncology, Volume 78
Author(s): Myung Woul Han, In Sun Ryu, Jong Cheol Lee, Song Hee Kim, Hyo Won Chang, Yoon Sun Lee, Seulkina Lee, Seong Who Kim, Sang Yoon Kim
Objectives: PI3K/Akt/mTOR pathway is commonly activated in most cancers and is correlated with resistance to anticancer therapies such as radiotherapy. Therefore, PI3K is an attractive target for treating PI3K-associated cancers. Material and Methods: We investigated the basal expression and the expression after treatment of PI3K inhibitor or Src inhibitor of PI3K/Akt pathway-related proteins in AMC-HN3, AMC-HN3R, HN30 and HN31 cells by performing immunoblotting analysis. The sensitivity to PI3K inhibitors or Src inhibitor was analyzed by MTT assay and clonogenic assay. To determine the antitumoral activity of combination treatment with PI3K inhibitor and Src inhibitor, we used using xenograft mouse model. Results: We found that PI3K regulatory subunit p85 was predominantly phosphorylated in radioresistant head and neck cancer cell line (HN31), which showed resistance to PI3K inhibitors. Next, we investigated mechanism through which PI3K p85 phosphorylation modulated response to PI3K inhibitors. Of note, constitutive activation of Src was found in HN31 cells and upon PI3K inhibitor treatment, restoration of p-Src was occurred. Src inhibitor improved the efficacy of PI3K inhibitor treatment and suppressed the reactivation of both Src and PI3K p85 in HN31 cells. Furthermore, downregulation of PI3K p85 expression by using a specific siRNA suppressed Src phosphorylation. Conclusions: Together, our results imply the novel role of the PI3K regulatory subunit p85 in the development of resistance to PI3K inhibitors and suggest the presence of a regulatory loop between PI3K p85 and Src in radioresistant head and neck cancers with constitutively active PI3K/Akt pathway.



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Comparison of clinical, radiological and morphological features including the distribution of HPV E6/E7 oncogenes in resection specimens of oropharyngeal squamous cell carcinoma

Publication date: March 2018
Source:Oral Oncology, Volume 78
Author(s): Hani Ibrahim Channir, Katalin Kiss, Niclas Rubek, Jane Andersen, Jeanette Bæhr Georgsen, Gulla Søby Rathje, Birgitte Wittenborg Charabi, Christian von Buchwald, Christel Bræmer Lajer
BackgroundHuman papillomavirus (HPV)-driven oropharyngeal squamous cell carcinoma (OPSCC) represents a distinct tumour entity in comparison to HPV-negative OPSCC. The clinical, radiological, morphological features and distribution of HPV E6/E7 mRNA were investigated in resected specimens of OPSCC.MethodsWe retrieved formalin-fixed, paraffin-embedded whole section slides from 24 p16/HPV-DNA positive and 18 p16/HPV-DNA negative primary tumours and 16 corresponding metastases in patients with early-stage OPSCC who underwent planned curative or diagnostic primary transoral robotic surgery. A detailed clinicoradiological and histopathological investigation of the tumours was performed along with detection of HPV E6/E7 mRNA by in situ hybridisation.ResultsHPV-driven OPSCC was characterised by non-keratinising morphology and was dominated by a cohesive invasion pattern at the leading edge of the tumour. Dysplastic zones of the squamous epithelium were strictly located in the tonsillar crypts in contrast to HPV-negative OPSCC which predominantly arised from the dysplastic surface epithelium. Thirteen HPV-driven OPSCC invaded through the tonsillar lymphoid compartment and into soft tissue, causing a stromal desmoplastic reaction. HPV mRNA was consistently but inhomogenously expressed in the entire tumour area and in the dysplastic squamous epithelium. There was no HPV expression in the adjacent normal epithelium and in the non-neoplastic tissues.ConclusionsThis study enhances the current understanding of HPV-driven OPSCC. Only tumours that invade through the lymphoid compartment induce a stromal desmoplastic reaction. A consistent but inhomogenous expression of E6 and E7 mRNA was found in tumour and dysplastic areas, emphasizing that the E6/E7 oncogenes are the driving factors in HPV-driven OPSCC.



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Do we need a different staging system for tongue and gingivobuccal complex squamous cell cancers?

Publication date: March 2018
Source:Oral Oncology, Volume 78
Author(s): Piyush Gupta, Jocelyn C. Migliacci, Pablo H. Montero, Daniella Karassawa Zanoni, Jatin P. Shah, Snehal G. Patel, Ian Ganly
ObjectivesTo determine the need for a separate staging system for gingivobuccal complex squamous cell cancers (GBCSCC) based on 5-year overall survival (OS), disease-specific survival (DSS), and recurrence-free survival (RFS) data from one institution.Patients and methodsAn Institutional Review Board (IRB)-approved retrospective analysis was performed on an oral cavity cancer patient database. Patients from 1985 to 2012 with primary surgical treatment for biopsy-proven squamous cell cancer (SCC) from either the oral tongue (TSCC Group) or gingivobuccal complex (GBCSCC Group), were selected as two separate subgroups. The clinicopathologic data were used to stage the patients based on the American Joint Committee on Cancer 7th edition. Survival outcomes including 5-year OS, RFS, and DSS were calculated and analyzed. A multivariate analysis was performed to identify if subsite was an independent predictor for the survival outcomes, adjusting for other variables. A p-value of less than .05 was considered statistically significant.Results936 patients with TSCC and 486 patients with GBCSCC were considered eligible for the analysis. Patients with GBCSCC were more likely to be older (p < .001) and presented with more advanced disease (p < .001) compared to patients with TSCC. Unadjusted hazard ratio (HR) suggested GBCSCC had poor OS compared to TSCC. However, after adjusting for other variables, the adjusted HR was not significant (p = .593). There was no difference in 5-year DSS or RFS in either of the study groups.ConclusionWith similar survival outcomes by stage, there is no justification for using a different staging system for GBCSCC.



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Evaluating oropharyngeal carcinoma with transcervical ultrasound, CT, and MRI

Publication date: March 2018
Source:Oral Oncology, Volume 78
Author(s): Farhoud Faraji, Stephanie F. Coquia, Meghan B. Wenderoth, Ericka S. Padilla, Dana Blitz, M. Robert DeJong, Nafi Aygun, Ulrike M. Hamper, Carole Fakhry
ObjectiveTo compare transcervical ultrasonography (US) to standard cross-sectional imaging for the visualization of human papillomavirus-related oropharyngeal cancer (HPV-OPC).Materials and methodsPatients with HPV-OPC and available standard imaging (CT and/or MRI) were identified in clinic and prospectively enrolled. US was performed to visualize the oropharynx and lymph nodes. Tumor characteristics across imaging modalities were evaluated (CT versus MRI, and US versus standard imaging (SI)).ResultsForty-three patients were included. The overall blinded detection rates for CT and MRI were 83% and 71%, respectively. The unblinded detection rate for US was 98%. Agreement of tumor anatomic subsite was moderate for both CT vs MRI (κ = 0.59) and US vs SI (κ = 0.47). Comparison of tumor size by CT and MRI showed statistically significant correlations in craniocaudal (CC), anteroposterior (AP), and mediolateral (ML) dimensions (RhoCC = 0.51, pCC = 0.038; RhoAP = 0.81, pAP < 0.0001; RhoML = 0.57, pML = 0.012). Tumor size estimates by US and SI showed statistically significant correlations in CC and AP, but not ML (RhoCC = 0.60, pCC = 0.003; RhoAP = 0.71, pAP < 0.0001; RhoML = 0.30, pML = 0.08). Tumor volume estimates improved correlations between US and SI (Rho = 0.66, p < 0.0001). Stratification of US patients into early and late imaging studies demonstrated an increase in correlation strength from early (Rho = 0.32, p = 0.32) to late groups (Rho = 0.77, p < 0.0001) demonstrating that ultrasound accuracy improved with experience.ConclusionsOur findings suggest that transcervical ultrasonography is a sensitive and relatively accurate adjunct to standard imaging for the evaluation of oropharyngeal tumors. Its cost, portability, and potential for in-clinic and serial imaging render US an attractive modality to further develop for imaging oropharyngeal tumors.



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Identification of a gene expression signature predicting survival in oral cavity squamous cell carcinoma using Monte Carlo cross validation

Publication date: March 2018
Source:Oral Oncology, Volume 78
Author(s): John Schomberg, Argyrios Ziogas, Hoda Anton-Culver, Trina Norden-Krichmar
ObjectivesThis study aims to identify a robust signature that performs well in predicting overall survival across tumor phenotypes and treatment strata, and validates the application of Monte Carlo cross validation (MCCV) as a means of identifying molecular signatures when utilizing small and highly heterogeneous datasets.Materials and methodsRNA sequence gene expression data for 264 patient tumors were acquired from The Cancer Genome Atlas (TCGA). 100 iterations of Monte Carlo cross validation were applied to differential expression and Cox model validation. The association between the gene signature risk score and overall survival was measured using Kaplan-Meier survival curves, univariate, and multivariable Cox regression analyses.ResultsPathway analysis findings indicate that ligand-gated ion channel pathways are the most significantly enriched with the genes in the aggregated signature. The aggregated signature described in this study is predictive of overall survival in oral cancer patients across demographic and treatment strata.ConclusionThis study reinforces previous findings supporting the role of ion channel gating, interleukin, calcitonin receptor, and keratinization pathways in tumor progression and treatment response in oral cancer. These results strengthen the argument that differential expression of genes within these pathways reduces tumor susceptibility to treatment. Conducting differential gene expression (DGE) with Monte Carlo cross validation, as this study describes, offers a potential solution to decreasing the variability in DGE results across future studies that are reliant upon highly heterogeneous datasets. This improves the ability of studies reliant upon similarly structured datasets to reach results that are reproducible.



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Submental artery island flap versus free flap reconstruction of lateral facial soft tissue and parotidectomy defects: Comparison of outcomes and patient factors

Publication date: March 2018
Source:Oral Oncology, Volume 78
Author(s): Akshay V. Patel, Jason E. Thuener, Kate Clancy, Mustafa Ascha, Nauman F. Manzoor, Chad A. Zender
ObjectivesThe submental artery island flap (SIF) has recently been described in temporal bone defects. At our institution we have broadened the application of the SIF and modified the harvest technique for complex lateral facial and skull base defects. Our primary aim is to evaluate the outcomes of patients undergoing complex lateral facial soft tissue, parotidectomy, and temporal bone defects who are reconstructed with the SIF to a similar cohort undergoing free tissue transfer reconstruction.Materials and methodsNineteen patients undergoing SIF and 54 patients undergoing free tissue flaps for oncologic lateral facial, parotidectomy and temporal bone defects were retrospectively identified. Comparative statistics were used to analyze variables between the two cohorts, specifically operative time, flap size, length of stay, regional recurrence, disease free survival, and overall survival.ResultsNo significant difference in demographic and disease related variables was observed. Operative time was significantly lower in SIF group with mean of 412.9 (SD 93.4) minutes compared to 544.1 (SD 139.9) minutes in free flap group. Flap size was significantly larger in free tissue transfer, 32.4 (SD 17.5) cm² (SIF) compared to mean area of 105.2 (SD 53.2) cm² (Free tissue transfer). A significant difference in length of stay was also noted between groups. There was no regional recurrence of disease in level I–III in SIF group. There was no significant difference in DFS or OS between the two groups.ConclusionSIF is an oncologically sound option for reconstruction of lateral facial soft tissue, parotidectomy, and temporal bone defects.



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Proteome analysis reveals that de novo regenerated mucosa over fibula flap-reconstructed mandibles resembles mature keratinized oral mucosa

Publication date: March 2018
Source:Oral Oncology, Volume 78
Author(s): Vinay V. Kumar, Bonney L. James, Manuela Ruß, Stefan Mikkat, Amritha Suresh, Peer W. Kämmerer, Michael O. Glocker
AimThe aim of this study was to determine whether intra-oral de novo regenerated mucosa (D) that grew over free fibula flap reconstructed-mandibles resembled the donor tissue i.e. external skin (S) of the lateral leg, or the recipient site tissue, i.e. keratinized oral mucosa (K).Materials and methodsDifferential proteome analysis was performed with ten tissue samples from each of the three groups: de novo regenerated mucosa (D), external skin (S), and keratinized oral mucosa (K). Expression differences of cornulin and involucrin were validated by Western blot analysis and their spatial distributions in the respective tissues were ascertained by immunohistochemistry.ResultsFrom all three investigated tissue types a total of 1188 proteins were identified, 930 of which were reproducibly and robustly quantified by proteome analysis. The best differentiating proteins were assembled in an oral mucosa proteome signature that encompasses 56 differentially expressed proteins. Principal component analysis of both, the 930 quantifiable proteins and the 56 oral mucosa signature proteins revealed that the de novo regenerated mucosa resembles keratinized oral mucosa much closer than extra-oral skin. Differentially expressed cornification-related proteins comprise proteins from all subclasses of the cornified cell envelope. Prominently expressed in intra-oral mucosa tissues were (i) cornifin-A, cornifin-B, SPRR3, and involucrin from the cornified-cell-envelope precursor group, (ii) S100A9, S100A8 and S100A2 from the S100 group, and (iii) cornulin which belongs to the fused-gene-protein group.ConclusionAccording to its proteome signature de novo regenerated mucosa over the free fibula flap not only presents a passive structural surface layer but has adopted active tissue function.



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Prognostic significance and optimal candidates of primary tumor resection in major salivary gland carcinoma patients with distant metastases at initial presentation: A population-based study

Publication date: March 2018
Source:Oral Oncology, Volume 78
Author(s): Xiao Shi, Fan Dong, Wenjun Wei, Kehan Song, Naisi Huang, Zhongwu Lu, Bowen Lei, Pengcheng Yu, Wanlin Liu, Yu Wang, Guohua Sun, Yulong Wang, Qinghai Ji
ObjectivesTo investigate the prognostic significance and identify optimal candidates of primary tumor resection (PTR) for patients with metastatic major salivary gland carcinoma (MaSGC) at diagnosis.Materials and methodsPatients with metastatic MaSGC were identified from the Surveillance, Epidemiology and End Results (SEER) database. Kaplan-Meier analyses, log-rank tests and multivariate Cox regression models were employed to evaluate the therapeutic roles of PTR in the overall cohort and different subgroups.ResultsOverall, 255 patients were included in our study, among whom 80 (31.4%) received PTR. PTR was associated with decreased overall mortality (OM) and cancer-specific mortality (CSM) in the overall cohort (PTR vs No-PTR, HR: 0.363, 95%CI: 0.204–0.646, p = .001 for OM; HR: 0.439, 95%CI: 0.243–0.794, p = .006 for CSM). When we focused on site-specific metastases, receipt of PTR significantly reduced the risk of OM for patients with lung, bone or distant lymph node involvement (all p < .05), whereas this surgical procedure not only failed to bring survival benefit, but even seemed to insignificantly increase the mortality risk once liver metastases were presented (PTR vs No-PTR, HR: 1.109, 95%CI: 0.279–4.412 for OM; HR: 1.596, 95%CI: 0.364–7.004 for CSM). In addition, subgroup analyses showed that patients with stage T1-3 disease, younger age (<65), single-site metastases and high-risk pathologies might benefit from PTR.ConclusionOur study for the first time verifies the favorable prognostic impact of PTR for highly-selected patients with metastatic MaSGC at diagnosis and has the potential to be adopted in future clinical practice, although long-term prospective studies are warranted.



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Neck recurrence in clinically node-negative oral cancer: 27-year experience at a single institution

Publication date: March 2018
Source:Oral Oncology, Volume 78
Author(s): Aviram Mizrachi, Jocelyn C. Migliacci, Pablo H. Montero, Sean McBride, Jatin P. Shah, Snehal G. Patel, Ian Ganly
ObjectivesNeck failure in patients with oral squamous cell carcinoma (OSCC) carries a poor outcome, yet the management of patients who initially present with clinically node-negative (cN0) neck is not clearly defined.Patients and methodsRetrospective review of patients with cN0 OSCC treated at Memorial Sloan Kettering Cancer Center from 1985 to 2012, focusing on rate, pattern and predictors of neck failure, salvage treatment, and survival outcomes.ResultsOf 1,302 patients, 806 (62%) underwent elective neck dissection (END) and 496 (38%) had observation. 190 patients (15%) developed neck recurrence. Median follow-up was 58.5 months (range 1–343); 5-year neck recurrence-free survival (NRFS) was 85% and 80% for the END and observation group respectively (p = .06). Patients with neck failure had poorer outcomes than patients without neck failure (5-year overall survival, 37% vs. 74% [p < .001]; disease-specific survival [DSS], 41% vs. 91% [p < .001]). Independent predictors of neck failure were smoking, primary tumor subsite (hard palate and upper gum), and extranodal extension. 87% of patients underwent salvage treatment (END: 81.1%; observation: 94%). Salvage surgery with adjuvant (chemo) radiation had better DSS than surgery alone or nonsurgical salvage.ConclusionsIn our cohort of patients with initially cN0 OSCC triaged to END vs. observation using clinical parameters, 15% developed neck failure. Salvage treatment was feasible in most cases but survival was poorer compared to patients without neck failure. Surgery followed by adjuvant (chemo) radiation resulted in the best outcome.



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Combination of post-operative radiotherapy and cetuximab for high-risk cutaneous squamous cell cancer of the head and neck: A propensity score analysis

Publication date: March 2018
Source:Oral Oncology, Volume 78
Author(s): Joshua D. Palmer, Charles J. Schneider, Neil Hockstein, Alexandra L. Hanlon, Jordan Silberg, Jon Strasser, Elizabeth A. Mauer, Michael Dzeda, Robert Witt, Adam Raben
ObjectivesThe objective of this study was to investigate the safety, tolerability and preliminary efficacy of radiotherapy plus cetuximab in high risk CSCC patients.Materials and MethodsPatients with high-risk CSCC diagnosed between 2006 and 2013 were analyzed. Patients were divided into two groups: radiotherapy alone versus radiotherapy plus cetuximab. Among 68 patients meeting study criteria, we identified 29 treated with cetuximab plus RT and 39 with RT alone. Primary analysis examined disease-free and overall survival, freedom from local and distant recurrence in the propensity score matched cohort. Propensity score analysis was performed with weighted factors including: Charlson Comorbidity Index score, age. KPS, primary location, T and N stage, recurrent status, margin status, LVSI, PNI and grade. Toxicity was assessed using the CTCAE v4.0.ResultsMedian follow-up for living patients was 30 months. Patients in the cetuximab group were more likely to have advanced N stage, positive margins and recurrent disease. After propensity score matching the groups were well balanced. Six patients experienced ≥ grade 3 acute toxicity in the cetuximab group. The 1-year, 2-year and 5-year progression free survival (PFS) for patients in the cetuximab group were 86%, 72% and 66%, respectively. The 1-year, 2-year and 5-year overall survival (OS) for patients in the cetuximab group was 98%, 80% and 80%, respectively.ConclusionsAlthough limited by small numbers, the combination of cetuximab and radiotherapy in CSCC appears well tolerated there were more long-term survivors and less distant metastasis in the cetuximab group. These promising finding warrant further studies.



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Pitfalls of post-treatment PET after de-intensified chemoradiotherapy for HPV-associated oropharynx cancer: Secondary analysis of a phase 2 trial

Publication date: March 2018
Source:Oral Oncology, Volume 78
Author(s): Kyle Wang, Terence Z. Wong, Robert J. Amdur, William M. Mendenhall, Nathan C. Sheets, Rebecca Green, Brian D. Thorp, Samip N. Patel, Trevor G. Hackman, Adam M. Zanation, Mark C. Weissler, Bhishamjit S. Chera
ObjectivesWe evaluated patterns of nodal response and positive predictive value (PPV) of 3 month post-treatment PET in patients with HPV-associated oropharyngeal cancer treated on a multi-institutional de-intensification trial.Materials and methodsEligibility criteria included: (1) T0-3, N0-2c, M0, (2) HPV+/p16+ oropharyngeal squamous cell carcinoma, and (3) ≤10 pack-years smoking or ≤30 pack-years and abstinent ≥5 years. Patients received 60 Gy radiation alone (T0-2, N0-1) or with concurrent weekly cisplatin 30 mg/m² and surveillance PET three months post-radiation. Nodal responses were categorized as complete (CR), equivocal (ER), or incomplete (IR) using both local and central radiographic review. A "true positive" was ER/IR with clinical/radiographic progression or positive pathology.Results79 node-positive pts (84% N2) were analyzed. Distribution of nodal CR, ER, and IR was 44 (56%), 27 (34%), and 8 (10%), respectively. 29 (37%) had ER/IR in pre-treatment node-positive neck levels, whereas 14 (18%) had ER/IR in pre-treatment node-negative levels. Of patients with ER/IR, 5 were observed clinically, 19 received repeat imaging, and 11 received either biopsy (1) or neck dissection (10). The PPV was 9% for ER/IR and 13% for IR, with 3 patients found to have persistent disease on neck dissection. There was no difference in nodal relapse rate in patients with nodal CR vs. nodal ER/IR.ConclusionPost-treatment PET may not accurately predict the presence of persistent disease in patients with favorable-risk oropharynx cancer. These results support close surveillance rather than surgical evaluation in most favorable-risk patients.



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Comparison between magnetic resonance and computed tomography in detecting mandibular invasion in oral cancer: A systematic review and diagnostic meta-analysis

Publication date: March 2018
Source:Oral Oncology, Volume 78
Author(s): José de Souza Brandão Neto, Felipe Toyama Aires, Rogério Aparecido Dedivitis, Leandro Luongo Matos, Claudio Roberto Cernea
BackgroundSuspicion of mandibular invasion directly influences perioperative strategy, requiring marginal or segmental mandibulectomy, or reconstruction in some cases. This has a considerable impact on outcome and quality of life. The aim of this study was to evaluate the accuracy of magnetic resonance and computed tomography in the prediction of mandibular invasion in patients with oral cavity cancer.MethodA systematic review was conducted, including diagnostic studies comparing magnetic resonance imaging with computed tomography in the prediction of bone invasion. Sensitivity, specificity, positive and negative likelihood values and summary receiver operating characteristic (sROC) curves were calculated.ResultsThe electronic and manual search identified 346 articles. Of these, 11 studies were included in the systematic review for a total of 477 patients. The sensitivity, specificity, and positive and negative likelihood values for MRI were 78%, 86%, 5.29 and 0.23, respectively. For CT, they were 76%, 89%, 6.00 and 0.28, respectively. The sROC curves for MRI and CT were 82.3% and 82.5%, respectively.ConclusionNo superiority was observed between the diagnostic methods regarding mandibular invasion detection.



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Expression of miR-634 in gastric carcinoma and its effects on proliferation, migration, and invasion of gastric cancer cells

Abstract

This study aims to observe the expression of microRNA (miR)-634 in different gastric cancer cell lines and tissues, and to study the effects of miR-634 on the proliferation, migration, and invasion of the gastric cancer cells. The miR-634 mimics and miR-634 inhibitors were transfected by lentivirus into human gastric cancer SGC-7901 and MGC-803 cells, and the miR-634 cells without transfection were used as the control group (NC group). The expression of miR-634 in the transfected cells was detected by qRT-PCR. Cell viability was measured by the CCK8 assay. The migration and invasion ability of the cells were detected by scratch assays and Transwell^® chamber assays, respectively, and the luciferase assay verified the binding of miR-634 to the target gene JAG1. The expression level of miR-634 in gastric cancer tissues and cell lines was significantly lower than that in normal adjacent tissues and control cells. The survival of cells was significantly decreased, and number of cells migrating and invading was decreased in the miR-634 mimics group. However, in the miR-634 inhibitor group, the opposite results were observed. Over-expression of miR-634 inhibited the proliferation, migration, and invasion of gastric cancer cell lines, and the miR-634 target gene was JAG1.

Over-expression of miR-634 inhibited the proliferation, migration, and invasion of gastric cancer cell lines, and the miR-634 target gene was JAG1.

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Pre-articulatory electrical activity associated with correct naming in individuals with aphasia

Publication date: February–March 2018
Source:Brain and Language, Volumes 177–178
Author(s): Tarkeshwar Singh, Lorelei Phillip, Roozbeh Behroozmand, Ezequiel Gleichgerrcht, Vitória Piai, Julius Fridriksson, Leonardo Bonilha
Picture naming is a language task that involves multiple neural networks and is used to probe aphasia-induced language deficits. The pattern of neural activation seen in healthy individuals during picture naming is disrupted in individuals with aphasia, but the time-course of the disruption remains unclear. Specifically, it remains unclear which anatomical and temporal aspects of neural processing are necessary for correct naming. Here, we tested two individuals with stroke induced aphasia, and compared the differences in the event-related potentials (ERPs) and current sources when they made correct vs. erroneous responses during picture naming. The pre-articulatory ERP activity was significantly different between the two responses. Current source analysis revealed that the ability to recruit left temporal and frontal areas within a 300–550 ms time window after stimulus onset contributed to correct responses. These results suggest that targeted neuromodulation in these areas could lead to better treatment outcomes in patients with aphasia.



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Editorial: Oncolytic Virus and Gene Thearapy Application: Update 2018.

Related Articles

Editorial: Oncolytic Virus and Gene Thearapy Application: Update 2018.

Curr Cancer Drug Targets. 2018;18(2):108

Authors: Abei M

PMID: 29457568 [PubMed - in process]

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Inflammatory Biomarkers During Bacterial Acute Rhinosinusitis

Abstract

Purpose of Review

Diagnosis of bacterial acute rhinosinusitis is difficult. Several attempts have been made to clarify the diagnostic criteria. Inflammatory biomarkers are easily obtainable variables that could shed light on both the pathophysiology and diagnosis of bacterial acute rhinosinusitis. The purpose of this review article is to assess literature concerning the course of inflammatory biomarkers during acute rhinosinusitis and the use of inflammatory biomarkers in diagnosing bacterial acute rhinosinusitis.

Recent Findings

We included C-reactive protein, erythrocyte sedimentation rate, white blood cell counts, procalcitonin, and nasal nitric oxide in this review and found that especially elevated C-reactive protein and erythrocyte sedimentation rate are related to a higher probability of a bacterial cause of acute rhinosinusitis. Still, normal levels of these two biomarkers are quite common as well, or the levels can be heightened even during viral respiratory infection without suspicion of bacterial involvement.

Summary

Elevated levels of C-reactive protein or erythrocyte sedimentation rate support diagnosis of bacterial acute rhinosinusitis, but due to a lack of sensitivity, they should not be used to screen patients for bacterial acute rhinosinusitis.

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Cutaneous Manifestations of Reactions to Biologics

Abstract

Purpose of Review

The goal of this paper is to review the major adverse cutaneous reactions that have been reported to the most commonly used biologics.

Recent Findings

Anti-TNF agents and immune checkpoint inhibitors have significant, immune-mediated cutaneous manifestations that can necessitate discontinuation. Anti-TNF agents, IL-6 inhibitors, and IL-12/23 inhibitors can paradoxically cause psoriasis flares or unmask previously undiagnosed psoriasis. IL-17 inhibitors are unique in increasing risk for Candida infections. Benign injection site reactions, non-specific rash, cellulitis, and hypersensitivity reactions are relatively common adverse events.

Summary

A wide variety of cutaneous reactions caused by biologics have been reported, ranging from benign injection site reactions to life-threatening cutaneous reactions necessitating discontinuation of the implicated biologic agent.

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Truncated glioma-associated oncogene homolog 1 (tGLI1) mediates mesenchymal glioblastoma via transcriptional activation of CD44

The molecular pathways driving mesenchymal glioblastoma (GBM) are still not well understood. We report here that truncated glioma-associated oncogene homolog 1 (tGLI1) is a tumor-specific transcription factor that facilitates GBM growth, is enriched in the mesenchymal subtype of GBM and glioma stem cells (GSC), and promotes mesenchymal GSC by upregulating transcription of CD44. In an orthotopic GBM xenograft mouse model, tGLI1-overexpressing tumors grew more aggressively with increased proliferation and angiogenesis compared to control and GLI1-overexpressing xenografts. tGLI1 was highly expressed in GBM clinical specimens but undetectable in normal brains, whereas GLI1 was expressed in both tissues. A tGLI1 activation signature (tGAS) correlated with glioma grade, tumor angiogenesis, and poor overall survival, and GBM with high tGAS were enriched with mesenchymal GBM/GSC gene signatures. Neurospheres contained increased levels of tGLI1, but not GLI1, compared to the monolayer culture; mesenchymal GSC expressed more tGLI1 than proneural GSC. Ectopic tGLI1 expression enhanced the ability of mesenchymal GSC to yield neurospheres in vitro and form tumors in mouse brains. Selective tGLI1 knockdown reduced neurosphere formation of GBM cells. tGLI1 bound to and transactivated the promoter of the CD44 gene, a marker and mediator for mesenchymal GSC, leading to its expression. Collectively, these findings advance our understanding of GBM biology by establishing tGLI1 as a novel transcriptional activator of CD44 and a novel mediator of mesenchymal GBM and GSC.

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A novel mechanism for activation of GLI1 by nuclear SMO that escapes anti-SMO inhibitors

Small molecule inhibitors of the Hedgehog (HH) pathway receptor Smoothened (SMO) have been effective in treating some patients with basal cell carcinoma (BCC), where the HH pathway is often activated, but many patients are poorly responsive. In this study, we report the results of investigations on PTCH1 signalling in the HH pathway that suggest why most BCC patients respond poorly to SMO inhibitors. In immortalised human keratinocytes, PTCH1 silencing led to the generation of a compact, holoclone-like morphology with increased expression of SMO and the downstream HH pathway transcription factor GLI1. Notably, while siRNA silencing of SMO in PTCH1-silenced cells was sufficient to suppress GLI1 activity, this effect was not phenocopied by pharmacological inhibition of SMO, suggesting the presence of a second undefined pathway through which SMO can induce GLI1. Consistent with this possibility, we observed increased nuclear localisation of SMO in PTCH1-silenced cells as mediated by a putative SMO nuclear/nucleolar localisation signal (N(o)LS). Mutational inactivation of the N(o)LS ablated this increase and suppressed GLI1 induction. Immunohistological analysis of human and mouse BCC confirmed evidence of nuclear SMO, although the pattern was heterogeneous between tumours. In PTCH1-silenced cells, >80% of the genes found to be differentially expressed were unaffected by SMO inhibitors, including the putative BCC driver gene CXCL11. Our results demonstrate how PTCH1 loss results in aberrant regulation of SMO-independent mechanisms important for BCC biology, and highlights a novel nuclear mechanism of SMO-GLI1 signalling that is unresponsive to SMO inhibitors.

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Comment on Hall et al. (2017), “How to Choose Between Measures of Tinnitus Loudness for Clinical Research? A Report on the Reliability and Validity of an Investigator-Administered Test and a Patient-Reported Measure Using Baseline Data Collected in a Phase IIa Drug Trial”

Purpose

The purpose of this letter, in response to Hall, Mehta, and Fackrell (2017), is to provide important knowledge about methodology and statistical issues in assessing the reliability and validity of an audiologist-administered tinnitus loudness matching test and a patient-reported tinnitus loudness rating.

Method

The author uses reference textbooks and published articles regarding scientific assessment of the validity and reliability of a clinical test to discuss the statistical test and the methodological approach in assessing validity and reliability in clinical research.

Results

Depending on the type of the variable (qualitative or quantitative), well-known statistical tests can be applied to assess reliability and validity. The qualitative variables of sensitivity, specificity, positive predictive value, negative predictive value, false positive and false negative rates, likelihood ratio positive and likelihood ratio negative, as well as odds ratio (i.e., ratio of true to false results), are the most appropriate estimates to evaluate validity of a test compared to a gold standard. In the case of quantitative variables, depending on distribution of the variable, Pearson r or Spearman rho can be applied.

Conclusion

Diagnostic accuracy (validity) and diagnostic precision (reliability or agreement) are two completely different methodological issues. Depending on the type of the variable (qualitative or quantitative), well-known statistical tests can be applied to assess validity.

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Capecitabine efficacy is correlated with TYMP and RB expression in PDX established from triple-negative breast cancers

Purpose: triple-negative breast cancer (TNBC) patients with residual disease after neoadjuvant chemotherapy have a poor outcome. We developed patient-derived xenografts (PDX) from residual tumors to identify efficient chemotherapies and predictive biomarkers in a context of resistance to anthracyclines and taxanes-based treatments. Experimental Design: PDX were established from residual tumors of primary breast cancer patients treated in neoadjuvant setting. TNBC PDX were treated by anthracyclines, taxanes, platins and capecitabine. Predictive biomarkers were identified by transcriptomic and immunohistological analysis. Downregulation of RB1 was performed by siRNA in a cell line established from a PDX. Results: residual TNBC PDX were characterized by a high tumor take, a short latency and a poor prognosis of the corresponding patients. With the exception of BRCA1/2 mutated models, residual PDX were resistant to anthracyclines, taxanes, and platins. Capecitabine, the oral prodrug of 5-FU, was highly efficient in 60% of PDX with two models showing complete responses. Prior treatment of a responder PDX with 5-FU increased expression of thymidylate synthase and decreased efficacy of capecitabine. Transcriptomic and IHC analyses of 32 TNBC PDX, including both residual tumors and treatment-naïve derived tumors, identified RB and TYMP proteins as predictive biomarkers for capecitabine response. Finally, RB1 knockdown in a cell line established from a capecitabine-responder PDX decreased sensitivity to 5-FU treatment. Conclusions: we identified capecitabine as efficient chemotherapy in TNBC PDX models established from residual disease and resistant to anthracyclines, taxanes and platins. RB positivity and high expression of TYMP were significantly associated with capecitabine response.

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Molecular lymph node status for prognostic stratification of prostate cancer patients undergoing radical prostatectomy with extended pelvic lymph node dissection

Purpose: Molecular lymph node (LN) analysis using quantitative polymerase chain reaction (qPCR) detects LN metastases with higher sensitivity than histopathology. However, the prognostic role of molecular LN status in prostate cancer (PCa) patients treated with radical prostatectomy (RP) and extended pelvic LN dissection (ePLND) is unclear. To investigate the association of molecular compared to histopathologic LN status with biochemical recurrence. Experimental Design: Patients with intermediate and high risk PCa were prospectively enrolled and underwent RP with ePLND including obturator, internal, external and common iliac region. LNs ≥3mm were bisected and examined by standard histopathology and qPCR for Kallikrein3 (KLK3) expression. Biochemical recurrence was defined by confirmed postoperative PSA>0.2ng/ml. Results: In 111 patients, 2411 of 3173 removed LNs were examined by both methods. Histopathology detected 68 LN metastases in 28 (25%) patients. Molecular analysis confirmed elevated KLK3 expression in 65 histopathologic LN metastases of all 28 pN1-patients (pN1/molN1) and additionally reclassified 224 histopathologic negative LNs and 32 (29%) pN0-patients as LN-positive (pN0/molN1). At a median follow-up of 48 months 52 (47%) patients developed biochemical recurrence. Median biochemical recurrence-free survival (bRFS) was 9 months [95%CI0.0-20.1] in pN1/molN1-patients, 24 months [95%CI1.7-46.3] in pN0/molN1 patients and was not reached in pN0/molN0 patients (p<0.001). On multivariable Cox regression analysis, molecular LN status (HR 4.1 [95%CI1.9-8.8],p<0.001) but not histopathologic LN status (HR 1.5 [95%CI0.8-3.0],p=0.198) was confirmed as independent predictor of biochemical recurrence. Conclusion: Molecular LN analysis identified pN0-patients with a high risk of biochemical recurrence and provided superior prognostic information in comparison with histopathology alone.

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The Airway Transcriptome as a Biomarker for Early Lung Cancer Detection

Lung cancer remains the leading cause of cancer-related death due to its advanced stage at diagnosis. Early detection of lung cancer can be improved by better defining who should be screened radiographically, and determining which imaging-detected pulmonary nodules are malignant. Gene expression biomarkers measured in normal-appearing airway epithelium provide an opportunity to use lung cancer associated molecular changes in this tissue for early detection of lung cancer. Molecular changes in the airway may result from an etiologic field of injury and/or field cancerization. The etiologic field of injury reflects the aberrant physiological response to carcinogen exposure that creates a susceptible microenvironment for cancer initiation. In contrast, field cancerization reflects effects of "first-hit" mutations in a clone of cells from which the tumor ultimately arises or the effects of the tumor on the surrounding tissue.  These fields might have value both for assessing lung cancer risk and diagnosis. Cancer-associated gene expression changes in the bronchial airway have recently been used to develop and validate a 23-gene classifier that improves the diagnostic yield of bronchoscopy for lung cancer among intermediate-risk patients. Recent studies have demonstrated that these lung cancer-related gene expression changes extend to nasal epithelial cells that can be sampled non-invasively. While the bronchial gene expression biomarker is being adopted clinically, further work is necessary to explore the potential clinical utility of gene-expression profiling in the nasal epithelium for lung cancer diagnosis, risk assessment, and precision medicine for lung cancer treatment and chemoprevention.

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Concurrent Inhibition of Neurosphere and Monolayer Cells of Pediatric Glioblastoma by Aurora A Inhibitor MLN8237 Predicted Survival Extension in PDOX models

Purpose: Pediatric glioblastoma (pGBM) is highly aggressive tumor in need of novel therapies. Our objective was to demonstrate the therapeutic efficacy of MLN8237 (Alisertib), an orally available selective inhibitor of Aurora A kinase (AURKA), and to evaluate which in vitro model system (monolayer or neurosphere) can predict therapeutic efficacy in vivo. Experimental Design: AURKA mRNA expressions were screened with qRT-PCR. In vitro anti-tumor effects were examined in 3 matching pairs of monolayer and neurosphere lines established from patient derived orthotopic xenograft (PDOX) models of the untreated (IC-4687GBM), recurrent (IC-372GBM) and terminal (IC-R0315GBM) tumors; and in vivo therapeutic efficacy through log rank analysis of survival times in 2 models (IC-4687GBM and IC-R0315GBM) following MLN8237 treatment (30 mg/kg/day, p.o., 12 days). Drug concentrations in vivo, mechanism of action and resistance were also investigated. Results: AURKA mRNA over-expression was detected in 14 pGBM tumors, 10 PDOX models and 6 cultured pGBM lines as compared with 11 low grade gliomas and normal brains. MLN8237 penetrated into pGBM xenografts in mouse brains. Significant extension of survival times were achieved in IC-4687GBM of which both neurosphere and monolayer were inhibited in vitro, but not in IC-R0315GBM of which only neurosphere cells responded (similar to IC-3752GBM cells). Apoptosis mediated MLN8237 induced cell death, and the presence of AURKA-negative and CD133+ cells appears to have contributed to in vivo therapy resistance. Conclusions: MLN8237 successfully targeted AURKA in a subset of pGBMs. Our data suggest that combination therapy should aim at AURKA-negative and/or CD133+ pGBM cells to prevent tumor recurrence.

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Androgen Deprivation Therapy Potentiates the Efficacy of Vascular Targeted Photodynamic Therapy of Prostate Cancer Xenografts

Purpose: WST11 vascular targeted photodynamic therapy (VTP) is a local ablation approach relying upon rapid, free radical-mediated destruction of tumor vasculature. A phase III trial showed that VTP significantly reduced disease progression when compared to active surveillance in patients with low-risk prostate cancer (PCa). The aim of this study was to identify a druggable pathway that could be combined with VTP to improve its efficacy and applicability to higher risk PCa tumors. Experimental Design: Transcriptome analysis of VTP treated tumors (LNCaP-AR xenografts) was used to identify a candidate pathway for combination therapy. The efficacy of the combination therapy was assessed in mice bearing LNCaP-AR or VCaP tumors. Results: Gene Set Enrichment Analysis (GSEA) identifies the enrichment of androgen responsive gene sets within hours post-VTP treatment, suggesting that the androgen receptor (AR) may be a viable target in combination with VTP. We tested this hypothesis in mice bearing LNCaP-AR xenograft tumors by using androgen deprivation therapy (ADT), degarelix, in combination with VTP. Compared to either ADT or VTP alone, a single dose of degarelix in concert with VTP significantly inhibited tumor growth. A sharp decline in serum PSA confirmed AR inhibition in this group. Tumors treated by VTP and degarelix displayed intense TUNEL staining 7 days post-treatment, supporting an increased apoptotic frequency underlying the effect on tumor inhibition. Conclusions: Improvement of local tumor control following androgen deprivation combined with VTP provides the rationale and preliminary protocol parameters for clinical trials in patients presented with locally advanced PCa.

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Combination approach for detecting different types of alterations in circulating tumor DNA in leiomyosarcoma

Purpose: The clinical utility of circulating tumor DNA (ctDNA) monitoring has been shown in tumors that harbor highly recurrent mutations. Leiomyosarcoma (LMS) represents a type of tumor with a wide spectrum of heterogeneous genomic abnormalities; thus, targeting hotspot mutations or a narrow genomic region for ctDNA detection may not be practical. Here we demonstrate a combinatorial approach that integrates different sequencing protocols for the orthogonal detection of single nucleotide variants (SNVs), small indels and copy number alterations (CNAs) in ctDNA. Experimental design: We employed Cancer Personalized Profiling by deep Sequencing (CAPP-Seq) for the analysis of SNVs and indels, together with a genome-wide interrogation of CNAs by Genome Representation Profiling (GRP). We profiled 28 longitudinal plasma samples and 25 tumor specimens from 7 patients with LMS. Results: We detected ctDNA in 6 of 7 of these patients with >98% specificity for mutant allele fractions down to a level of 0.01%. We show that results from CAPP-Seq and GRP are highly concordant, and the combination of these methods allows for more comprehensive monitoring of ctDNA by profiling a wide spectrum of tumor-specific markers. By analyzing multiple tumor specimens in individual patients obtained from different sites and at different times during treatment, we observed clonal evolution of these tumors that was reflected by ctDNA profiles. Conclusions: Our strategy allows for a comprehensive monitoring of a broad spectrum of tumor-specific markers in plasma. Our approach may be clinically useful not only in LMS but also in other tumor types that lack recurrent genomic alterations.

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Integrated Pharmacokinetic/Pharmacodynamic Model of a Bispecific CD3xCD123 DART(R) Molecule in Nonhuman Primates: Evaluation of Activity and Impact of Immunogenicity

Purpose: Flotetuzumab (MGD006 or S80880) is a bispecific molecule that recognizes CD3 and CD123 membrane proteins, redirecting T-cells to kill CD123-expressing cells for the treatment of acute myeloid leukemia. In this study, we developed a mathematical model to characterize MGD006 exposure-response relationships and to assess the impact of its immunogenicity in cynomolgus monkeys. Experimental Design: 32 animals received multiple escalating doses (100-300-600-1000 ng/kg/day) via intravenous infusion continuously 4-days a week. The model reflects sequential binding of MGD006 to CD3 and CD123 receptors. Formation of the MGD006/CD3 complex was connected to total T-cells undergoing trafficking, whereas the formation of the tri-molecular complex results in T-cell activation and clonal expansion. Activated T-cells were used to drive the peripheral depletion of CD123-positive cells. Anti-drug antibody development was linked to MGD006 disposition as an elimination pathway. Model validation was tested by predicting the activity of MGD006 in 8 monkeys receiving continuous 7-day infusions. Results: MGD006 disposition and total T-cell and CD123-positive cell profiles were well characterized. Anti-drug antibody development led to the suppression of T-cell trafficking but did not systematically abolish CD123-positive cell depletion. Target cell depletion could persist after drug elimination owing to the self-proliferation of activated T-cells generated during the first cycles. The model was externally validated with the 7-day infusion dosing schedule. Conclusions:A translational model was developed for MGD006 that features T-cell activation and expansion as a key driver of pharmacological activity and provides a mechanistic quantitative platform to inform dosing strategies in ongoing clinical studies.

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TGF-{beta}1 genetic variants predict clinical outcomes of HPV-positive oropharyngeal cancer patients after definitive radiotherapy

Purpose. Transforming growth factor-β1 (TGF-β1) plays a critical role in inflammation and immune responses and treatment response and survival. TGF-β1 variants may affect its expression level or functional efficiency, thus modifying tumor status and survival in HPV-positive squamous cell carcinoma of the oropharynx (SCCOP). Experimental design. We determined tumor HPV16 status and genotyped three TGF-β1 polymorphisms in 564 incident SCCOP patients treated with radiotherapy or chemoradiation. Univariate and multivariable Cox models were used to evaluate the associations between the three polymorphisms and survival. Results. Overall, 85% of patients (482 of 564) had HPV16-positive SCCOP. We found that TGF-β1 rs1982073 had statistically significant associations with survival, while TGF-β1rs1800469 and TGF-β1rs1800471 did not. Patients with TGF-β1 rs1982073 CT/CC variant genotypes had significantly better overall, disease-specific, and disease-free survival compared with those with the corresponding common homozygous TT genotype (all log-rank: P <0.001). Furthermore, these genotypes were significantly associated with an approximately 5 times reduced risk of overall death, death owing to disease, and recurrence after multivariable adjustment. Moreover, the stratified analyses by tumor HPV status indicated that the significant effects of TGF-β1 rs1982073 polymorphism on survival were found among HPV16-positive SCCOP patients only. Finally, the functional relevance of these variants was further characterized. Conclusions. Our findings support that the TGF-β1 rs1982073 polymorphism plays a significant role in the prognosis of SCCOP, especially in HPV16-positive SCCOP patients treated with chemoradiation. Prospective studies with larger sample sizes are needed to confirm these findings.

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Prediction of the optimal dosing regimen using a mathematical model of tumour uptake for immunocytokine-based cancer immunotherapy

PURPOSE: Optimal dosing is critical for immunocytokine-based cancer immunotherapy to maximize efficacy and minimize toxicity. Cergutuzumab amunaleukin (CEA-IL2v) is a novel CEA-targeted immunocytokine. We set out to develop a mathematical model to predict intratumoral CEA-IL2v concentrations following various systemic dosing intensities. EXPERIMENTAL DESIGN: Sequential measurements of CEA-IL2v plasma concentrations in 74 patients with solid tumors were applied in a series of differential equations to devise a model that also incorporates the peripheral concentrations of IL-2 receptor-positive cell populations (i.e. CD8+, CD4+, NK and B cells) which affect tumor bioavailability of CEA-IL2v. Imaging data from a subset of 14 patients were subsequently utilized to additionally predict antibody uptake in tumor tissues. RESULTS: We created a PKPD mathematical model that incorporates the expansion of IL-2R-positive target cells at multiple doses levels and different schedules of CEA-IL2v. Model-based prediction of drug levels correlated with the concentration of IL-2R-positive cells in the peripheral blood of patients. The pharmacokinetic model was further refined and extended by adding a model of antibody uptake, which is based on drug dose and the biological properties of the tumor. In silico predictions of our model correlated with imaging data and demonstrated that a dose-dense schedule comprising escalating doses and shortened intervals of drug administration can improve intratumoral drug uptake and overcome consumption of CEA-IL2v by the expanding population of IL-2R-positive cells. CONCLUSIONS: The model presented here allows simulation of individualized treatment plans for optimal dosing and scheduling of immunocytokines for anti-cancer immunotherapy.

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Phase Ib Study of Glasdegib, A Hedgehog Pathway Inhibitor, in Combination With Standard Chemotherapy in Patients With AML or High-Risk MDS

Purpose: This open-label, multicenter, dose-finding, phase Ib study (NCT01546038) evaluated the safety, pharmacokinetics, pharmacodynamics, and clinical activity of the novel Hedgehog pathway Smoothened inhibitor glasdegib (PF-04449913) in patients (N = 52) with acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome (MDS). Experimental Design: Glasdegib 100 or 200 mg was administered orally, once daily in 28-day cycles, in combination with low-dose cytarabine (arm A) or decitabine (arm B) to newly diagnosed patients considered not suitable for standard induction chemotherapy, and in combination with cytarabine/daunorubicin (arm C) to fit patients. The study followed a standard 3+3 dose-escalation design. The primary endpoint was dose-limiting toxicity (DLT). Ten additional patients were enrolled in expansion cohorts of arms A (n = 23) and C (n = 22) to confirm the recommended phase II dose (RP2D). Results: No DLTs were observed in arms A and B; 1 DLT (grade 4 neuropathy) occurred in arm C. The most common treatment-related non-hematologic adverse events were mostly grades 1-2 in all arms. Muscle spasms, dysgeusia, and alopecia  were generally mild. Overall, sixteen (31%) patients achieved a complete remission (CR)/CR with incomplete blood count recovery. 100 mg daily was selected as the RP2D for glasdegib in combination with standard chemotherapies in the absence of an estimated maximum tolerated dose in this setting. Conclusions: Treatment with glasdegib in combination with standard chemotherapy was generally well-tolerated and consistent with prior findings, warranting further evaluation of glasdegib-based combinations in patients with AML or high-risk MDS.

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Foretinib overcomes entrectinib resistance associated with the NTRK1 G667C mutation in NTRK1 fusion-positive tumor cells in a brain metastasis model

Background: Rearrangement of the neurotrophic tropomyosin receptor kinase 1 (NTRK1) gene, which encodes tyrosine receptor kinase A (TRK-A), occurs in various cancers, including colon cancer. Although entrectinib is effective in the treatment of central nervous system (CNS) metastases that express NTRK1 fusion proteins, acquired resistance inevitably results in recurrence. CNS is a sanctuary for targeted drugs; however, the mechanism by which CNS metastases become entrectinib-resistant remains elusive and must be clarified to develop better therapeutics. Experimental design: The entrectinib-resistant cell line KM12SM-ER was developed by continuous treatment with entrectinib in the brain metastasis-mimicking model inoculated with the entrectinib-sensitive human colon cancer cell line KM12SM, which harbors the TPM3-NTRK1 gene fusion. The mechanism of entrectinib resistance in KM12SM-ER cells was examined by next-generation sequencing. Compounds that overcame entrectinib resistance were screened from a library of 122 kinase inhibitors. Results: KM12SM-ER cells, which showed moderate resistance to entrectinib in vitro, had acquired the G667C mutation in NTRK1. The kinase inhibitor foretinib inhibited TRK-A phosphorylation and the viability of KM12SM-ER cells bearing the NTRK1-G667C mutation in vitro. Moreover, foretinib markedly inhibited the progression of entrectinib-refractory KM12SM-ER-derived liver metastases and brain tumors in animal models, predominantly through inhibition of TRK-A phosphorylation. Conclusion: These results suggest that foretinib may be effective in overcoming entrectinib resistance associated with the NTRK1-G667C mutation in NTRK1 fusion-positive tumors in various organs, including the brain, and provide a rationale for clinical trials of foretinib in cancer patients with entrectinib-resistant tumors harboring the NTRK1-G667C mutation, including patients with brain metastases.

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