bluuebunny/crossref_metadata_2025 huggingface dataset:
Sonographic and histopathologic characteristics of MMR-deficient endometrial cancer.
Authors: Smith Daniel Arnold , Paspulati Raj M , Azar Nami R , Laukamp Kai , Kikano Elias , Avril Stefanie , Ramaiya Nikhil H.
Published: May 2019

e17111

Background: Mismatch repair (MMR) deficiency has emerged as a key biomarker in endometrial cancer with roles in prognosis and guiding therapy. However, the differences of sonographic features between MMR-deficient and MMR-proficient endometrial cancers at initial presentation have not been established. Methods: Transvaginal ultrasound studies of 103 endometrial cancers (60 MMR-deficient, 43 MMR-proficient) at initial presentation were retrospectively analyzed by two experienced radiologists. Histopathologic findings and sonographic features of endometrial morphology recorded according to IETA terminology were compared using Likelihood Ratio Chi-Square and Mann–Whitney U tests. Results: The MMR-deficient group comprised of 90% and the MMR-proficient group of 100% endometrioid subtypes. The following sonographic features were statistically different between MMR-deficient (age 45-95) and MMR-proficient (age 45-83) groups: uniform endometrial echogenicity/pattern, non-uniform endometrial echogenicity/pattern, endometrial midline morphology, presence of a bright edge, and endomyometrial junction morphology. Ultrasound findings of endometrial thickness, synechiae, intracavitary fluid, color Doppler score, and vascular pattern were not significantly different. Statistically significant differences in pathology features included FIGO grade, myometrial invasion, and lymphovascular invasion, while FIGO stage showed no difference. Conclusions: MMR-deficient endometrial cancer is characterized by several statistically different ultrasound and histopathologic features on initial presentation compared to MMR-proficient endometrial cancer.[Table: see text]
Transcriptomic characterization of endometrial cancer in order to find new therapeutic targets.
Authors: Parra-Grande Monica , Ore-Arce Martin , Llorca Cristina , Poveda Andres
Published: May 2019

e17113

Background: There are unmet needs for targeted therapy in Endometrial Cancer (EC). The integrated genomic characterization of EC provided insights into disease biology. Our primary objective is to identify potential actionable pathways to target therapeutically in EC according to the microsatellite status (microsatellite instability high = MSI-H, and microsatellite stable/microsatellite instability low = MSS/MSI-L). Methods: 375 RNAs from the genomic profile of EC within the TCGA database were used to perform RNA-seq analysis. We analyzed RNA-sequencing data with edgeR package to filter and normalize the data, followed by the limma package with its Voom method, linear modeling and empirical Bayes moderation to asses differential expression. Reactome FI Cytoscape app was used to perform pathway and network-based data analysis. Results: According to the microsatellite status, two groups were identified: Group 1 = MSI-H (127 patients) and Group 2 = MSS/MSI-L (248 patients). Significant expression differences were found in 2141 genes. In the Group 1 we identified 1194 genes overexpressed and 947 genes overexpressed in the Group 2. Group 1 includes genes associated with cell proliferation. Group 2 includes genes associated with genomic instability and apoptosis evasion (table 1). Conclusions: In EC patients, Cyclin-dependent kinase (CDK) pathways could be a potential therapeutic target, especially in patients with MSI-H tumors. Further studies are necessary in order to evaluate the activity of CDKs inhibitors in this population.[Table: see text]
Quality of care and survival of women with uterine cancer by Hispanic origin: An NCDB analysis.
Authors: Gamble Charlotte , Huang Yongmei , Tergas Ana Isabel , Ruiz Maria Paula , Hou June YiJuan , Collado Fady , St. Clair Caryn , Wright Jason Dennis
Published: May 2019

e17120

Background: In cancer research in the US, Hispanic patients are often analyzed as a homogeneous group despite significant diversity within this ethnic classification. Our objective was to assess the impact of place of origin on quality of care and overall survival for Hispanic women with uterine cancer living in the US. Methods: The National Cancer Database (NCDB) was used to identify all patients with uterine cancer from 2004-2015. Hispanic origin was classified based on NCDB subgroups: Mexican, Puerto Rican, Cuban, South or Central American, and Dominican Republic. Multivariable models were used to assess the adjusted relative risk (aRR) of receiving quality of care indicators. Thirty-day mortality and overall 5-year survival were calculated using multivariable log-Poisson and Cox proportional Hazard models. Results: A total of 5,411 Hispanic women and 288,111 non-Hispanic women were identified. Of Hispanic women, Mexican patients comprised the largest subgroup (n = 2,512), and increased from 34.5% to 49.7% over the study period. South or Central American (n = 1,217) and Dominican (n = 218) patients also increased modestly, while the volume of Puerto Rican patients remained unchanged (n = 877), and Cuban patients decreased from 23.3% to 5.6% (n = 587). Compared to non-Hispanic women, there were no significant differences in the rates of use of minimally invasive surgery, chemotherapy in early stage high risk disease, lymph node dissection, or 30-day readmission among the Hispanic subpopulations. Rates of chemotherapy for advanced stage disease were modestly increased for Dominican (aRR 1.37, 95%CI (1.23-1.54)) and South or Central American (aRR 1.16, 95%CI (1.05,1.29)) groups. Dominican patients had a statistically significant reduction in overall mortality at five years for stage III and IV disease with aHR 0.38, 95%CI (0.16-0.90) and aHR 0.28, 95%CI (0.09, 0.87), respectively. For all other Hispanic subgroups, there were no differences in stage-specific survival. Conclusions: The diversity within the Hispanic cohort of women with uterine cancer in NCDB is changing. Overall quality indicators and survival outcomes are comparable between each Hispanic origin group, with the exception of advanced stage Dominican women who are more likely to receive chemotherapy, and have superior survival outcomes.
Does systemic treatment add value to stereotactic body radiation therapy for locoregional control in head and neck squamous cell carcinoma patients?
Authors: Tufano Andrea M , Newman James , Gogineni Emile , Karten Jessie L , Paul Doru , Ghaly Maged , Seetharamu Nagashree
Published: May 2019

e17505

Background: Stereotactic body radiotherapy (SBRT) has been shown to provide locoregional control in head and neck squamous cell carcinoma (HNSCC) patients (pts) who are not candidates for curative procedures due to poor performance status, comorbidities, or radiation dose limitations from prior treatment. The addition of chemotherapy (chemo) and/or cetuximab (CET) is hypothesized to improve outcomes compared to SBRT alone, but there is limited data on comparative effectiveness. We compared outcomes of pts treated with SBRT vs. SBRT + chemo and/or CET using retrospective observational data from our institution. Methods: We identified new and recurrent HNSCC pts treated with SBRT +/- systemic therapy from 2012 to 2018. Age, Charlson Comorbidity Index (CCI) and stage were recorded. Primary outcome was locoregional disease control rate based on Modified Response Evaluation Criteria in Solid Tumors on 3-month post-treatment imaging. Secondary outcome was overall survival (OS) at 1 year. Pts were divided into 4 groups: SBRT, SBRT+chemo, SBRT+CET, and SBRT+chemo+CET (cohorts A, B, C and D, respectively). Results: 90 pts with median age of 73 years and median follow-up of 11.5 months were included. 94.4% were stage III or IV, and 68.9% had recurrent disease. The most commonly utilized chemotherapy was carboplatin and paclitaxel. Cohorts A, B, C and D constituted 28.9%, 31.1%, 31.1% and 8.8% respectively. Groups were well matched except for pts in Cohort A being significantly older than those in Cohort B (74.9 vs. 68.4 years; p = 0.01). Average CCI estimated 10-year survival was 8.4%. There was a trend towards improved locoregional control at 3 months in Cohort B vs. A (57.1% vs. 34.6%, p = 0.09), and improved OS at 1 year (46.4% vs. 23.1%; p = 0.07). These trends were not observed in comparisons between other cohorts. Conclusions: Chemo + SBRT may improve disease control as well as 1 year OS in HNSCC pts who do not qualify for curative procedures. Given the younger age of pts receiving chemo, selection bias cannot be excluded. Prospective studies with larger patient cohorts are needed to further evaluate the benefits and toxicities of adding systemic treatment to SBRT in this population.
Comparison of mortality and second primary oropharyngeal malignancies by human papilloma virus (HPV) status in patients (pts) with oropharyngeal squamous cell carcinoma (OPSCC) using an updated Surveillance, Epidemiology, and End Results (SEER) database.
Authors: Holstead Ryan , Rasul Rehana , Golden Anne , Seetharamu Nagashree
Published: May 2019

e17518

Background: Prognosis and patterns of failure differ between HPV positive (pos) and HPV negative (neg) OPSCC. HPV neg have an increased risk of developing head, neck, and lung SPM due to field cancerization. Second primary OPSCC in HPV pos pts may be due to persistent risk for HPV-mediated carcinogenesis and compromised immune status. The rate and location of SPM in HPV pos pts is not as well described and HPV-specific surveillance guidelines are yet to be determined. Methods: Retrospective cohort study from a custom SEER database of OPSCC diagnosed from 2013-2015 was conducted. Differences in overall survival (OS) and SPM were compared by HPV status using Gray’s test. Cox proportional hazard models were performed, adjusting for age, race, sex, year of diagnosis, tumor grade, stage, and first treatment. Results: 12,895 pts were identified, with a mean age of 61.8 (SD = 9.97) years, mostly male (83.2%), and white (87.3%), with 45.0% HPV pos, 15.3% HPV neg, and 39.7% HPV unknown (unk). Proportion of HPV pos pts increased from 2013-2015 (40.7%-49.2%). HPV pos pts tended to have higher stage and grade of tumor. Most patients were treated with chemotherapy and radiation. Median duration of follow up was 13 (5-22) months. HPV pos had significantly lower unadjusted 2-year mortality compared to neg or unk (13.7% vs. 38.9% vs. 32.8%, p < 0.001). Median OS for HPV pos, HPV neg and HPV unk was 29 months (m), 25.6 m, and 24.45 m respectivey (p < 0.0001). From the multivariable Cox regression, HPV neg pts had 2.25 times the risk (95% CI: 1.99-2.54) of death compared to HPV pos pts. Incidence of OP SPM was similar (0.008-0.011%) in all three HPV cohorts (aHR = 0.87, 95% CI: 0.49-1.54). Conclusions: Our study strongly supports the prognostic value of HPV status. Incidence of OP SPM is similar in HPV pos and neg OPSCC suggesting that similar surveillance strategies should be employed for all OPSCC pts. Limitations of the study include lack of data on smoking and alcohol use, high rate of HPV unk pts, and SEER-imposed restriction to SPM occurring only in the OP region.
Selected molecular markers as indicators of clinical profile, tumor characteristics and treatment outcome in squamous cell carcinoma of the larynx.
Authors: Iype Elizabeth Mathew , S Lakshmi , Balakrishnan Rajan
Published: May 2019

e17522

Background: Laryngeal Squamous cell carcinoma is widely prevalent in India and is the fourth leading cancer in males. The possibility that specific tumour characteristics (demonstrable by immunohistochemistry) may aid the clinician in choosing optimal treatments for a specific tumour, holds great promise. Objectives of the present study were to study the expression of select molecular markers p53, Bcl-2 (Apoptotic markers), EGFR, Ki67, Cyclin D1 (Proliferation markers) and Cox-2 (Inflammatory marker) in LSCC so as to form a hypothesis that a particular group of markers will be useful in determining the prognosis of LSCC. Methods: We studied 72 cases of laryngeal squamous cell carcinoma in an attempt to determine relationship between their clinicopathological characteristics and treatment outcome with the six molecular markers. Samples from patients who underwent laryngectomy from Jan 2006 to Dec 2010 were taken and analyzed prospectively and followed up till Dec 2015 or till death. . Immunoreactivity in tissue sections was evaluated as negative when no positive cells were observed within the tumor, weak (1+) , moderate (2+) , and strong or intense (3+) . Data were analyzed using SPSS software package. Chi squared test or exact test were used to test the associations. Logistic regression analysis was used to estimate the odds ratios and 95% confidence intervals. The disease free survival time of each patient was calculated by taking the difference between the date of surgery and the recurrence date/ death date/ the last follow up date whichever is applicable. Results: Proliferation markers EGFR, Cyclin D1 and Ki 67, individually and collectively were predictive of extracapsular spread and perineural spread of tumour. Node negative patients having intense expression of Cyclin D1 or Ki 67 has bad prognosis.. The significant expression of Cox-2 was highly predictive of Node positivity. In older patients and in T4 stage the presence of P53 / Bcl-2 resulted in worse overall survival. Markers of aggressiveness were identified as p53, Bcl-2 Cox-2. Markers of invasiveness were EGFR, Cyclin D1 and Ki 67. Markers predicting survival were p53, BCl-2, Cyclin D1 and Ki 67. Conclusions: If Proliferation markers are detected preoperatively in biopsy specimens, has important implications in planning aggressive management Cyclin D1 or Ki 67 in Node negative patients indicate need for a neck dissection or irradiation. Cox-2 assessment will be useful in predicting the occult nodal metastasis for prophylactic treatment
PDL-1 expression in oral squamous cell carcinoma and implications for treatment.
Authors: Srinivasalu Vijay Kumar , Subramaniam Narayana , Iyer Subramania , Nambiar Ajit , Koyakutty Manzoor , Thankappan Krishnakumar , Das Manjula , Dhar Sujan Kumar , Balasubramanian Deepak , Keechilat Pavithran
Published: May 2019

e17527

Background: PDL-1 expression has been shown in multiple tumours to be a key factor in treatment response and immunogenicity. In oral squamous cell carcinoma (OSCC), its role is controversial; the expression levels, prognostic significance and therapeutic relevance are unclear. This study was performed to determine the incidence of PDL-1 expression in OSCC, and to determine its correlation with demographic, clinical and pathological features, recurrence and survival. Methods: PDL-1 IHC (Dako kit) was determined on 64 samples of OSCC obtained during curative intent resection. PDL-1 expression levels were determined in tumour (T) and tumour infiltrating lymphocytes (TILs). Statistical analysis was performed. Results were validated on the mRNA-seq data from the Cancer Genome Atlas (TCGA) for head and neck squamous cell carcinoma (HNSCC). Results: 64 patients were included in the final analysis with a mean age of 54 years. < 1% expression was the most common for T (92%) and TILs (56%). Tumour PDL-1 expression < 1% had higher risk of lymphovascular invasion (LVI) (p = 0.044) and bone invasion (p = 0.010). TIL PDL-1 expression < 1% was more common in patients ≤45 years (p = 0.023) with higher chances of local recurrence (p = 0.020) and reduced local recurrence free survival (p = 0.047). For the TCGA data, low ( < 1%) PDL-1 expression was associated with a significant reduction in OS and DFS in the young (≤45 years) (p = 0.0078 and 0.0089 respectively), but not for older patients ( > 45 years) (p = 0.21 and 0.88 respectively). Conclusions: PDL-1 expression in OSCC was low. TIL PDL-1 expression < 1% was more common in those ≤45 years, and associated with a higher chance of local recurrence and poorer survival. The role of PDL-1 expression in prognosis of OSCC is controversial, with our data being the first to correlate low PDL-1 expression and poorer outcomes with younger patients. These results were validated by the TCGA data for HNSCC across multiple subsites. Further study is required to determine if this pathway plays a significant role in local control and survival.
Predictive score for recurrence after complete resection in locally advanced oral cavity squamous cell carcinoma.
Authors: Lu Hsueh-Ju , Tseng Szu-Wen , Peng Chih-Yu , Tseng Hsien-Chun , Hsin Chung-Han , Huang Wei-Shiou , Wu Ming-Fang , Yang Muh-Hwa , Chang Mu-Hsin
Published: May 2019

e17536

Background: Early progression, usually defined disease-free interval (DFI) less than six months after completing adjuvant platinum-based chemoradiotherapy (CRT), has very poor outcome for oral cavity squamous cell carcinoma (OCSCC). But there are no biomarkers to predict such early progression. Methods: Locally advanced OCSCC patients, after complete surgical resection and followed-up platinum-based adjuvant CRT, were retrospectively enrolled from Chung Shan Medical University Hospital (CSMUH, training cohort) and Taipei Veterans General Hospital (TPE-VGH, validating cohort) in Taiwan. Clinicopathologic variables of patients with DFI < or ≥ 6 months were compared by using the χ2 test. The Cox proportional hazards model was applied to identify independent factors for DFI. Survival was estimated using the Kaplan-Meier method and log-rank test. Results: A total of 350 high-risk OCSCC patients were enrolled, including 146 patients in training cohort and 204 in validating cohort. In multivariate Cox regression, pN > 0, extracapular spread, and depth of invasion ( ≥ 1cm) were independent factors for DFI in training cohort. If each factor scored one point, the scoring system could effectively predict early progression that sensitivity/specificity/area under curve (AUC) of training and validating cohort were 57.7%/91.2%/0.771 and 58.1%/83.9%/0.730, respectively (the cutoff level ≤ 2 or > 2). DFI between lower- (score 0–2) and high- (score 3) risk groups were also significantly different in both training (median DFI, 59.6 vs. 4.5 months, P < 0.001) and validating cohorts (NA vs. 9.3 months, P < 0.001). Conclusions: The established score system was effective to predict early progression after adjuvant CRT for locally advanced OCSCC.
Risk of second primary neoplasia in patients with oropharyngeal carcinoma: Role of HPV status in the outcome.
Authors: Lopez-Pousa Antonio , Lopez V Montserrat , Garcia Jacinto , Farre Nuria , Gallego Rubio Oscar , Majercakova Katerina , Camacho Daniela , Borrell Maria , Molto Consolacion , Riudavets Mariona , Terés Raul , Bujosa Aida , SULLIVAN IVANA GABRIELA , Quer Miquel , Leon Xavier
Published: May 2019

e17544

Background: Patients with HPV-positive oropharyngeal cancer (OPC) have better prognosis and a lower risk of appearance of second primary neoplasm (SPN) than HPV-negative OPC patients. The aim of our study was to analyze the risk of developing SPN in a large group of patients with OPC according to HPV status in the primary tumor and its relationship with toxic habits. Methods: This study includes patients from a prospective data-base: 484 OPC patients were treated from 1991 to 2017 for which the HPV DNA positivity was evaluated by PCR in available tumor specimens. HPV DNA positive samples were further tested for HPV E6*I mRNA detection and/or p16INK4a immunohistochemistry. The mean follow-up of patients included in the study was 4.9 years (SD 5.1 years). We estimated the incidence of SPN in all cancer sites and in cancer sites related to tobacco and alcohol consumption according to the HPV status in the primary tumor. Results: Ninety-nine (20.5%) out of 484 OPCs included in the study were HPV-related. During the follow-up period, 127 patients with HPV-negative tumors (33.0%) and 19 patients with HPV-positive tumors (19.2%) had a SPN. Considering only the tobacco/alcohol-related SPNs, 106 of the patients with HPV-negative tumors (27.5%), and 12 patients with HPV-positive tumors (12.1%) had a tobacco/alcohol-related SPN (P < 0.0001). Five-year and 10-year SPN-free survival for HPV-negative versus HPV-positive OPC patients was 61.0% versus 81.5%, and 37.6% versus 73.8%, respectively (P < 0.001). When restricting the analyses to tobacco/alcohol-related SPNs, the corresponding survival rates were 66.6% versus 86.8% and 45.9% versus 83.5% for 5-year and 10-year survival rates, respectively (P < 0.0001). The frequency of tobacco/alcohol-related SPNs occurrence throughout the follow-up period for patients with HPV-negative OPC was 27.5%, for patients with HPV-positive tumors with a previous history of severe tobacco and/or alcohol use was 21.4%, and for patients with HPV-positive tumors without a history of severe tobacco and/or alcohol consumption it was 8.5% (P < 0.0001). Conclusions: HPV status and previous toxic habits might allow classifying patients regarding the risk of tobacco/alcohol-related SPNs. HPV-related OPC patients without previous history of severe tobacco and/or alcohol use have a significant low risk of SPN development, particularly in those locations related to tobacco use or alcohol consumption
Multiplexed digital PCR for detection of HPV in tissue samples from oropharyngeal cancer patients.
Authors: Kumar Sunil , Chera Bhishamjit S. , Beaty Brian , Marron David , Jefferys Stuart , Amdur Robert , Sheets Nathan , Dagan Roi , Hayes David N. , Weiss Jared , Grilley-Olson Juneko E. , Zanation Adam M. , Hackman Trevor , Blumberg Jeffrey , Patel Samip , Weissler Mark Christian , Parker Joel S. , Tan Xianming , Mendenhall William M. , Gupta Gaorav
Published: May 2019

e17552

Background: p16 immunohistochemistry (IHC) is a commonly used method for identifying HPV-associated oropharyngeal squamous cell carcinoma (OPSCC). However, p16 overexpression in a minority of HPV negative OPSCC can give rise to false positive results. In contrast, HPV nucleic acid testing lacks adequate sensitivity for routine diagnostic testing. The goal of this study was to investigate whether a multiplexed digital PCR assay can detect and quantify HPV DNA in p16 positive OPSCC treated with definitive chemo-radiotherapy (CRT). Methods: Formalin-fixed paraffin embedded (FFPE) residual diagnostic biopsy specimens were collected from 57 patients. Macrodissection was performed to ensure tumor cellularity > 70%. Extracted genomic DNA was analyzed by next generation sequencing (NGS) using a hybrid capture assay (UNCSeq) targeting > 200 cellular genes and HPV 16/18 genomes. We also designed, validated, and implemented an multiplexed droplet digital PCR (dPCR) assay to detect and quantify HPV DNA (strains 16, 18, 31, 33 and 35) in tissue samples, relative to a genomic control locus (chromosome 6). Results: HPV strain 16 DNA was identified in 50 patients (87.7%), whereas 5 patients (8.8%) had HPV DNA from an alternative high-risk strain (18/31/33/35). HPV DNA was undetectable in 2 patients, indicating a false positive rate of 3.5% for p16 IHC testing in this cohort. HPV DNA copy number per diploid genome equivalent varied significantly across samples, with a median value of 19.7 (range 0.23-1712). A significant correlation was observed between the copies of HPV detected by dPCR and NGS (R2 = 0.5853, p < 0.0001). Evidence for HPV integration was detected by NGS in 23 out of 56 evaluable tumors (42%). There was a trend towards a higher prevalence of HPV integration in tumors with less than 10 HPV copies per diploid genome relative to cancers with > / = 10 HPV copy number (63% versus 34%, p = 0.07). Conclusions: Multiplexed digital PCR demonstrates excellent sensitivity for detection and typing of HPV DNA in diagnostic FFPE specimens from patients with p16 positive oropharyngeal cancer. HPV copy number varies significantly across samples, with a possible association with HPV integration status. Future investigations of potential correlation between HPV copy number, integration status, and clinical outcomes are warranted. Clinical trial information: NCT02281955, NCT03077243.
A phase II study of concurrent nimotuzumab and intensity-modulated radiotherapy in elderly patients with locoregionally advanced nasopharyngeal carcinoma.
Authors: Cao Caineng , Hu Qiaoying , Chen Xiaozhong
Published: May 2019

e17562

Background: The purpose of this study was to evaluate the feasibility of concurrent nimotuzumab to intensity-modulated radiotherapy (IMRT) in elderly patients with locoregionally advanced nasopharyngeal carcinoma (NPC). Methods: According to the eighth edition of the American Joint Committee on Cancer staging system, elderly patients with stage III–IVA NPC were given concurrent nimotuzumab (200 mg/week, starting 1 week before IMRT) with IMRT. They completed a geriatric assessment tool (function, comorbidity, cognition, psychological state, social activity/support, and nutritional status) before initiation of protocol therapy. Results: Thirty patients [median age of 70.5 (65-95) years] with stage III (60%), and IVA (40%) NPC were enrolled between March 2017 and November 2018. The mean scores on the comorbidity scale and instrumental activities of daily living scale were 7 (range, 1 to 12) and 12 (range, 8 to 14), respectively. Grade 3 mucositis occurred in 10 (33%) patients and 1 (3%) patient had grade 3 radiotherapy-related dermatitis. Grade 3 pneumonia occurred in 3 patients (10%) and no patients had nimotuzumab-related acneiform rash. There were 20 complete responses and 10 partial responses 1month after the completion of IMRT. Conclusions: Concurrent administration of nimotuzumab and IMRT is effective and well-tolerated for elderly patients with locoregionally advanced NPC. Clinical trial information: NCT03025958.
Single institute analysis of squamous cell carcinoma of the head and neck treated with concurrent chemoradiation with either cisplatin versus cetuximab.
Authors: Jeong Il Seok , Kim Matthew , Nguyen Anthony L. , Mo Huan , Hayton Bruce , Xu David , Cao Huynh Le
Published: May 2019

e17571

Background: Squamous cell carcinoma of the head and neck (SCCHN) is currently the sixth most common cancer in the world and is linked to tobacco, alcohol and human papillomavirus (HPV). Cisplatin (Cs)-based concurrent chemoradiation is currently the standard treatment for locally advanced disease with a desire for organ preservation. In 2006, cetuximab (Cx) with radiation was approved as another option for this indication. We performed a single institute retrospective analysis to explore the difference in efficacy between Cs and Cx regimens with respect to P16 and smoking status. Methods: We retrospectively reviewed pts in Loma Linda University Medical Center (LLUMC) with locally advanced SCCHN who received concurrent chemoradiation with either Cx or Cs as first-line treatment from 2006 to present. We excluded patients with nasopharyngeal cancers, and patients having surgery as first line of treatment. Overall survival (OS) and disease free survival (DFS) with respect to p16 status and smoking status are the two primary endpoints. Results: Based on our study criteria, 115 out of 1545 screened pts qualified. The average age at diagnosis was 60 years. 75.7% were males and 24.3% were females. Median follow-up is 26 months. There are overall 55 DFS events and 23 OS events. Comparing between smokers (S, n = 44) and non-smokers (NS, n = 42), there is no significant difference in OS (NS: HR = 0.73 [0.28-1.92], p = 0.52) while the DFS was significantly better in the NS (NS: HR = 0.53 [0.29-0.98], p = 0.043). The overall median OS of the P16-pos pts (n = 49) is not reached while that of P16-neg pts (n = 12) is 36 mo (P16-neg: HR = 6.431 [1.71-24.13], p = 0.0058). The overall median DFS of the P16-pos pts is not reached while that of P16-neg pts is 6.5 mo (P16-neg: HR = 5.39 [2.32-12.54], p < 0.001). Overall, the median OS of Cx is 132 mo while that of Cs is not reached (Cs: HR = 0.38 [0.16-0.90], p = 0.027). The median DFS is 30 mo for Cs and 25 mo for Cx. Within P16-pos population, there are 4 OS events in Cx (n = 18) while 0 in Cs (n = 31)(p = 0.0062, favors Cs); there are 5 DFS events in Cx while 9 in Cs (Cs: HR = 1.17 [0.39-3.51], p = 0.78). The median OS and DFS for both groups are not reached. Conclusions: Our analysis of retrospective single institute data shows that positive P16 significantly associates with better OS. These findings are consistent with previous reports. Compared to Cx, the Cs regimen significantly associates with a better OS but not DFS in both overall and P16-pos populations.
Potential role of botanical drug APG-157 as immune adjuvant in patients with oral squamous cell carcinoma.
Authors: Shin Daniel Sanghoon , Srivatsan Eri , Nasser Hassan , Tosevska Anela , Jacobs Jonathan , Pellegrini Matteo , Wang Marilene
Published: May 2019

e17572

Background: Natural botanical drugs, such as curcumin, resveratrol and related flavonoids, are under clinical studies. Previous pilot study of curcumin, a polyphenol, for normal and patients with oral squamous cell carcinoma (OSCC) showed significant inhibition of inflammatory cytokines in saliva. Phase I investigation was performed on APG-157 to evaluate the potential utility an as oral drug for the treatment of OSCC. Methods: A double-blind, randomized, placebo-controlled phase I clinical trial was conducted with a botanical preparation containing a combination of curcumin related polyphenol molecules (pharmaceutical name APG-157). 12 Subjects with oral cancer and 13 normal control subjects were recruited. Two doses of the drug, 3x100 mg and 3x200 mg, were tested. The drug was administered orally each hour for 3 consecutive hours. Blood and saliva were collected pre-treatment and 1, 2, 3, and 24 hours post-treatment. Salivary cells and supernatants were analyzed for the expression of cytokines by multiplex ELISA and microbial content by 16S RNA sequence. Pre- and post-treatment tumor biopsies of one subject were studied for expression using the RNA seq and immunofluorescence (IF). Results: This study did not reveal any toxicity and there was a dose dependent inhibition of inflammatory cytokines, IL-1β, TNF-alpha and IL-8 in the salivary supernatant of cancer subjects treated with the drug. Tumor RNA-seq revealed down regulation of gene ontologies of cell adhesion, cell cycle and cell division and up regulation of generation of precursor metabolite/energy in the post-treatment tumor sample. Microbiome study showed significant decrease in Bacterioides after 24 hours of treatment. There was also a trend of decreasing Bacteroides among other cancer subjects treated with APG-157. IF showed a marked increase in the number of CD4, CD8 T cells in post-treatment tumor. PD-L1 expression was up-regulated in the post-treatment tumor sample. Conclusions: APG-157 is found to be safe and toxicity was not observed. The drug has shown a decrease in inflammatory cytokines. Moreover, there was a markedly increased CD4, CD8 T cells infiltration on a subject and decreased Bacteriodes microbial population after APG-157 treatment suggesting that it might have potential synergistic effect with immune checkpoint blockade immunotherapy. Decreased expression of cell growth related genes and increased expression of growth inhibitory genes pointed to a potential anti-tumor activity of APG-157.
Chemotherapy in the management of olfactory neuroblastoma/esthesioneuroblastoma: An analysis of the surveillance, epidemiology, and end results (SEER) 1973-2015 database.
Authors: Cranmer Lee D. , Chau Bonny
Published: May 2019

e17573

Background: Olfactory neuroblastoma (ON) is a malignant tumor of nasal cavity arising in sensory neuroectodermal olfactory cells. Chemotherapy (CT) has been proposed as an adjunct to primary local therapy. Here, we investigated the role of CT in primary ON treatment. Methods: SEER was searched for ON (ICD-3 9522). Inclusion criteria were (1) unique cases; (2) primary nasal cavity tumor; (3) staging information; and (4) ability to derive Kadish stage. Abstracted covariates included sex, age, tumor grade, nodal status, year of diagnosis, derived Kadish stage, and treatment (surgery, radiotherapy (RT), CT). Outcomes included disease-specific (DSS) and overall (OS) survival. In SEER, CT and RT are classified as Yes vs No/Unknown. Uni- and multi-variable Cox analyses assessed CT treatment on DSS and OS, controlling for covariates noted above. To account for proportional hazards violations, such variables were either stratified or time-varying. Multiple imputation addressed missing data. A p < 0.05 was designated for statistical significance. Analyses were conducted using Stata ver 12. Results: 797 ON cases were included. In univariable analysis, CT treatment (yes vs no/unknown) was associated with inferior DSS (HR 2.81, 95% CI 2.11 3.74, p < 0.001) and OS (HR 2.03, 95% CI 1.63 2.54, p < 0.001). In multivariable analyses, CT was again associated with inferior DSS (HR 1.74, 95% CI 1.21, 2.51, p = 0.003) and OS (HR 1.71, 95% CI 1.26, 2.32, p = 0.001). Limiting analysis to those with local/regional disease treated with local therapy (surgery and/or radiation), CT remained associated with inferior outcomes [DSS (HR 2.78, 95% CI 1.63, 4.74, p < 0.001) and OS (HR 2.17, 95% CI 1.45, 3.27, p < 0.001)]. Sensitivity analyses ruled out chemotherapy misclassification as an explanation for our results. Conclusions: Our analysis does not support the use of chemotherapy to improve either DSS or OS in primary ON treatment. We controlled for known ON prognostic factors available from SEER. Other prognostic and treatment selection factors could exist for which we did not control. Chemotherapy may also beneficially affect outcomes other than DSS or OS. While concerns have been expressed regarding CT treatment misclassification in SEER, our analyses did not identify such misclassification as an explanation.
Targeted next-generation sequencing in papillary thyroid carcinoma of Chinese Han population.
Authors: Liu Jie , Li Huizheng , Du Rong , Fang Nan , Zhang Jingbo , Tang Yu , Wang Jianwei , Wu Qixi
Published: May 2019

e17574

Background: Papillary Thyroid Carcinoma (PTC) is the most common type of thyroid cancer. Developments in next-generation sequencing (NGS) technology can help to disclose the genotype of PTC in the Chinese Han population. Methods: A total of 50 patients with PTC who underwent thyroidectomy in 2015-2018 at the Affiliated Dalian Friendship Hospital of Medical University were enrolled. Total DNA was extracted from formalin-fixed, paraffin-embedded tissue sections and quantified. Targeted regions of 57 thyroid cancer-associated genes were amplified, barcoded and sequenced using an Illumina MiSeq 500 platform. Results: A total of 591 mutations were detected in 50 samples, including 514 missense mutations (87%), 39 frameshift mutations (6.6%), 22 stop-gain (3.7%) and 16 indel (2.7%) variants. Among them, only 64 mutations have been studied with cancer clinical relevance. The BRAF V600E mutation was present in 42 of 50 (84%) patients, and was the most common mutation. The CHEK2 mutation was present in 27 of 50 (54%) patients. The 10 most important genes with mutations included AKT1 (34%), EIF1AX( 30%), ATM (20%) , MED12 (18%) , NF1 (18%), RET (18%), RBM10 (16%) and TERT (12%). Among them, the CHEK2, AKT1 and EIF1AX mutations were always concomitant with the BRAF V600E mutation, which is controversial to previous studies. Only two samples had no mutation tested. The medium mutation is 11 muts/sample. Six samples had more than 10 occurrences of gene mutations. However, the mutation burden has no relevance to lymph node metastasis or other pathological prognostic factors. Conclusions: BRAF V600E is the most common and important mutation in PTC, but there are also many other genes that mutate in this disease. The gene mutation in PTC varies in different patients, but no relevance between pathological factors and gene mutations have been founded . However, the discovery of the gene mutation spectrum in the Han Chinese population with PTC could enhance the understanding of this disease’s clinical behavior.
Safety of denosumab in patients with refractory differentiated thyroid cancer and advanced medullary thyroid cancer.
Authors: Wassermann Johanna , Mathy Elise , Lescaille Geraldine , Slim Marine , Buffet Camille , Saie Clotilde , Braik-Djellas Yasmin , Simon Jean-Marc , Ménégaux Fabrice , Tresallet Christophe , Chami Linda , Lussey-Lepoutre Charlotte , Hervé Geneviève , Bernier Marie-Odile , Spano Jean-Philippe , Leenhardt Laurence
Published: May 2019

e17578

Background: Few data exist regarding the use of denosumab in patients with bone metastases from radioactive iodine (RAI) refractory differentiated thyroid cancer (DTC) and advanced medullary thyroid cancer (MTC). We aimed to describe adverse events of specific interest - osteonecrosis of the jaw (ONJ) and severe hypocalcemia - in this rare setting. Methods: We retrospectively reviewed the charts of all the patients treated with denosumab for bone metastases from RAI-refractory DTC and advanced MTC in our institution. All patients had a calcium measurement and a clinical and radiological dental screening before denosumab initiation. All patients without hypercalcemia received a calcium supplementation. We assessed associations between ONJ or severe hypocalcemia ( < 1.75mmol/L) and suspected risk factors by Fisher exact tests. Results: Between 2014 and 2018, 23 patients were treated with denosumab. Two-thirds of patients were male (n = 16), median age was 69 years (range 43-87). Histology was DTC and MTC in 19 (83%) and 4 (17%) patients, respectively. DTC patients had received a median cumulated dose (CD) of 300 mCi of RAI (range 100-700). Ten patients (43%) had at least one cervical surgery for recurrence or persistence, and 6 (26%) had cervical radiotherapy. Four patients had hypoparathyroidism before denosumab initiation. Two-thirds of patients ( n =15) received a tyrosine kinase inhibitor (TKI) in association with denosumab. The median duration of denosumab was 20 months (range 1-47). ONJ occurred in 6 patients (26%) and severe hypocalcemia in 3 patients (13%). Conclusions: Patients with RAI-refractory DTC and advanced MTC are at high risk of ONJ and severe hypocalcemia under denosumab treatment. Benefit/risk ratio should be highly weighted particularly when treatment is prolonged. Patients should be closely monitored for the risk of ONJ and hypocalcemia. [Table: see text]
Analysis of trends in mortality in patients with lymphoepithelial carcinoma of the head and neck.
Authors: Weldon Marcus Kyle , Komiya Takefumi , Guddati Achuta Kumar
Published: May 2019

e17583

Background: Squamous cell carcinoma is the most common subtype of malignancy found in patients with Head and Neck malignancy. There are other rare subtypes which are not adequately reported in medical literature. Lymphoepithelial carcinoma consists of lymphocytic infiltration in a background of undifferentiated carcinoma cells and has a high malignant potential. They are most often seen in salivary glands but can also be found in other structures of the head and neck region. This analysis reports the nation-wide mortality of patients diagnosed with lymphoepithelial carcinoma of the Head and Neck. Methods: Data was extracted from the Surveillance, Epidemiology, and End Results (SEER) Database from the years 2000 to 2014. Incidence-based mortality for all stages was queried and results were grouped by gender and race (Caucasian/White, African American/Black, American Indian/Alaskan native and Asian/Pacific Islander). Paired T-test was used to determine statistically significance difference between various subgroups. Results: Incidence-based mortality has been improving for African American/Black patients and has been worsening for Caucasian/White, American Indian/Alaskan native and Asian/Pacific Islander for the period of 2000 to 2014. The differences in mortality trends were statistically different (P < 0.05). The highest mortality rate per 1000 patients was seen in Asian/Pacific Islander population, followed by African American/Black, American Indian/Alaskan native and the least mortality was noted in Caucasian/White patients. When a similar analysis with linearized trend lines on gender was conducted, only African American/Black males and Asian/Pacific Islander females showed an improving trend in mortality. The sample size was a major limitation of this study (Caucasian/White - 134, African American/Black - 30, American Indian/Alaskan native - 5 and Asian/Pacific Islander – 87). Conclusions: Lymphoepithelial carcinoma is a rare subtype of Head and Neck malignancies whose incidence-based mortality showed a worsening trend. This study showed significant race and gender disparity amongst patients with lymphoepithelial carcinoma. Due to its rarity, this subtype warrants further study; especially with regards to its etiology, clinical course and cure rates.
Rising thyroid cancer incidence in Kerala: Is it real or over diagnosis?
Authors: Raghuram Saadvik , Ponnada Bharadwaj , Keechilat Pavithran
Published: May 2019

e17589

Background: There has been an increase in the incidence of thyroid cancer in India and in high income countries. One of the reasons for this has been attributed to the large number of screening programs. Kerala state ranks second highest in the incidence of thyroid cancer in India. Screening provides the advantage of early detection of cancer and successful treatment but also tends to over diagnose. Methods: To study the trend of incidence of primary thyroid cancer among newly diagnosed cancer patients and its association with the mode of detection, we retrospectively reviewed hospital based cancer registry data of patients with thyroid cancer who were treated at AIMS (Amrita Institute of Medical Sciences), Kochi between 2004-2014. All patients who were newly diagnosed with primary thyroid cancer at our center or referred to us after initial surgery were included in this analysis. Patients with recurrent cancer/metastases were excluded. Results: We analyzed the records of 2,315 newly diagnosed thyroid cancer patients. Median age was 44.1yrs (range 13-90yrs). There were 619 males and 1696 females. Papillary type was the most common 85.8% followed by follicular type 7.4%. 1235 cases were operated at AIMS. 74 cases (3.2%) were diagnosed incidentally by Ultrasonography/PET scan/CT scan. All others (97% n = 2,245) presented with neck swelling. It was seen that the proportion of new cases of thyroid cancer among all new cancer cases was increasing serially from 4.6 % (n = 106, 95% 2004) to 7.4% (n = 195) to13.7% (n = 317, 2014). There was a significant increase in the number of cases of T1a and T1b at the time of diagnosis during the study period (n = 1235, p value < 0.001 and p value for trend < 0.001 respectively) which indicates that there was early diagnosis. 97% of the cases presented with thyroid related symptoms indicating that clinical presentation has still been the main mode of detection in our series. Conclusions: Our data shows that there may be a true increase in the number of cases of thyroid cancer as majority presented with clinical symptoms, except few detected incidentally. As it is a single institution based data we need further studies to see if over use of USG based imaging for any thyroid swelling is responsible for an apparent increase in the number of thyroid cancer cases.
Learnings from a pragmatic study to evaluate benefit of performing reflex clinical trial matching and providing clinical decision support to physicians.
Authors: Jain Neha M , Culley Alison , Osterman Travis John , Levy Mia Alyce
Published: May 2019

e18006

Background: Clinical trial enrollment is an assiduous process and requires active initiation and maintenance efforts by providers, patients, trial investigators, or other clinical staff. Setting up automated process triggers to perform a reflex clinical trial matching can kick-start the process without requiring human intervention. Methods: Using a clinical trial matching service developed in collaboration with GenomOncology, we used the receipt of sequencing test results as a process trigger to perform reflex clinical trial matching on oncology patients. A research nurse performed additional refinements to these results using multi-faceted filtering and an initial manual prescreening. In this pragmatic study, providers were randomized to receive results of prescreening events. EMR messages were sent to the intervention cohort of providers with recommendations for clinical trials for their patients and suggested next steps. Provider responses and prescreening outcomes were recorded in a REDCap project. To iteratively refine the trial results, matching algorithm updates were deployed throughout the study. Results: In the pilot deployment of this trial, we performed prescreening on 60 patients. At the time of prescreening vital status of 17% of the patients was outdated. We observed that trial cohort related recruiting statuses were the highest contributors to false matches (44%) and provider response rate was 94%. Conclusions: It is not possible to make substantial improvements to the outcome of clinical trial enrollment events without investing in reliable publicly available resources that host updated recruiting status for trials at the arm/cohort level. Uptake of such efforts by NCI or NLM has the potential to radically change the accuracy of clinical trial matching services and thereby improve enrollment efficiencies.[Table: see text]
Triple blinded prospective study assessing the impact of genomics: EndoPredict and artificial intelligence Watson for Oncology (WFO) on MDT’s decision of adjuvant systemic therapy for hormone receptor positive early breast carcinoma.
Authors: Somashekhar S.P. , Yethadka Ramya , C Rohit Kumar , Rajgopal Ashwin K , Rauthan Amit , Patil Poonam
Published: May 2019

e18013

Background: : Decision on adjuvant systemic therapy in hormone positive early breast carcinoma is the only grey area in breast carcinoma management. This study was done to investigate the concordance between the results of genomic test, artificial intelligence and tumor board decision and implications of the same in clinical practice. Methods: This was a triple blinded, prospective study. Decision regarding the adjuvant systemic therapy was done by the multidisciplinary tumor board (MDT)after reviewing the pathology reports & the results correlated with Endopredict test reports & artificial intelligence(Watson for Oncology). Results: Total of 42 patients included. Mean age was 58.3 years, 71.4% were post-menopausal. Breast conservation was done in 47.6%. 64.2% were T1-2N0 stage. Infiltrating ducal carcinoma was major type (83.3%). Decision by MDT to give adjuvant chemotherapy was for 25 patients (59.5%) & hormonal therapy for rest. Recommendation by Watson for oncology was to give adjuvant chemotherapy in 50%. Endopredict score (EPclin) resulted in a low-risk group of 22 patients (52.3%), while 15(47.6%) had a high risk EPclin score. Discordance between the endopredict test, Watson & tumor board was for 11 patients (26.1%): 3 patients had high risk score, but the tumor board decision was to give hormonal therapy due to the age factor. 8 patients had low risk score, but tumor board decision was to give adjuvant chemotherapy. Extremes of age, premenopausal status, intermediate grade & high Ki 67% values were the factors associated with discordance. The treatment decision changed for 4 patients (4/11, 36%) after reviewing the endopredict test and Watson recommendation. Conclusions: Tumor board decision can be more scientific & evidence based with the help of genomics & a learnt colleague in the form of Watson for Oncology. Even though the clinical experience is the important determinant of adjuvant therapy, genomic test with artificial intelligence, which includes the scientific evidence, will guide in decision making. Long term follow up is needed for the validation in our clinical setting.