bluuebunny/crossref_metadata_2025 huggingface dataset:
Clinicopathological significance and prognostic value of intratumoral and peritumoral lymphocytes in endometrial cancer patients.
Authors: Ore-Arce Martin , Ballester Carmen Illueca , Lopez-Reig Raquel , Parra-Grande Monica , Romero Ignacio , Lopez-Guerrero Jose Antonio , Poveda Andres
Published: May 2019

e17116

Background: The characterization and prognostic relevance of immune cells in the tumor microenvironment of endometrial cancer (EC) remain unknown. Our aims are to analyze the presence of tumor infiltrating lymphocytes (TIL) and peritumoral lymphocytes (PTL) in tumoral tissue of patients with EC, and to identify the correlation between TILs and PTLs subsets with clinicopathologic features and its prognostic value Methods: CD3, CD4, CD8, CD20, and FOXP-3 was determined by immunohistochemestry (IHQ). A 4-point score was defined based on TIL counts per highpowered field: (negative, low, moderate, and high). We used 10% positive peritumoral lymphocytes as a low-high cutoff value. POLE mutation was identified by Sanger sequencing of the exonuclease domain (exons 9-14). Analysis of mismatch repair expression and TP53 gene mutation status were assessed. Results from IHQ and analysis mutation were correlated with clinicopathological parameters and survival. Results: We recovered tumor samples from 68 FIGO stage I–IV EC patients. POLE mutations were identified in 5 of 44 (11.4%) EC analyzed. Microsatellite instability (MSI) and TP53 mutation were found in 45% and 25 % of cases respectively. According PTL, MSI tumors were significantly associated with low CD4+ (p = 0.01). High CD8+ was significantly associated with endometrioid grade 1-2 tumors (p = 0.04). Low FOXP3+ was significantly associated with endometrioid grade 1-2 (p = 0.02), MSS tumors (p < 0.01), FIGO stage I-II (p < 0.01), POLE WT (p < 0.01), TP53 WT (p < 0.01), and negative lymphovascular space invasion (p < 0.01). Negative CD20+ TIL was associated with endometrioid grade 1-2 tumors (p < 0.01) and ≥50% myometrial invasion (p = 0.03). Moderate CD8+ TIL was associated with lower tumor stage (p = 0.01). High CD8+ TIL was associated with better 5-year overall survival (OS) rate (high: 100 % vs. low: 53%; p = 0.003). No significant association was observed between POLE status, TP53 status, MMR expression and survival. Conclusions: Regulatory and cytotoxic T cells subsets differs in EC patients. High CD8+ TILs was significantly associated with better 5-year OS.
Does mismatch repair (MMR) deficiency have prognostic significance in low-risk endometrioid endometrial cancers?
Authors: Kim Soyoun Rachel , Pina Annick , Albert Arianne , McAlpine Jessica N. , Wolber Robert , Gilks Cyril Blake , Carey Mark S , Kwon Janice S
Published: May 2019

e17122

Background: Mismatch repair (MMR) deficiency is observed in 25-30% of all endometrial cancers. This can be detected by the absence of MMR protein staining on immunohistochemistry (IHC), and is used in many jurisdictions as a screen for an inherited mutation in one of the MMR genes (Lynch Syndrome). Only 10% of women with MMR deficiency (MMRd) have Lynch syndrome, but MMRd may still have prognostic significance. The objective of this study was to compare clinical outcomes between MMR deficient and proficient low-risk endometrioid endometrial cancers (stage IA, grade 1/2). Methods: This was a retrospective population-based cohort study of all low-risk endometrial cancers from Vancouver Coastal Health authority region from 2011 to 2016 that were assessed for MMR deficiency (MMRd). Primary outcome measures were recurrence rates expressed per person-years (py), progression free survival (PFS) and overall survival (OS) calculated using Kaplan-Meier method and log-rank tests. Cox proportional hazards model estimated the association between MMRd and recurrence and death after adjustment for covariates, expressed as hazard ratios (HR). Results: There were 475 low-risk patients, including 131 MMRd (27.6%) and 345 MMRp (proficient) patients. Women with MMRd tumors had higher recurrence rates (3.53p100py vs 1.21p100py) and worse PFS (p = 0.0082) compared to women with MMRp tumors. After adjustment for age, LVSI status, adjuvant therapy, and post-operative grade, MMRd status remained associated with a higher risk of recurrence (HR 2.99, 95% CI 1.27-7.04). There was no significant difference in OS between MMR groups (HR 1.38, 95% CI 0.57-3.33). Conclusions: In low-risk stage IA grade 1 or 2 endometrioid endometrial cancers, MMR deficiency is associated with a higher recurrence rate than in MMR proficient cases, after adjustment for covariates, implying that MMR deficiency reflects a different biology in endometrial cancer.
Effects of nivolumab alone or combination with molecular targeting agents for recurrent and refractory endometrial cancers with biomarker analyses.
Authors: Takano Masashi , Yoshikawa Tomoyuki , Kouta Hiroko , Horikoshi Miyuki , Asakawa Takayoshi , Kudoh Kazuya , Kita Tsunekazu , Miyamoto Morikazu , Aoyama Tadashi , Matsuura Hiroko , Ishibashi Hiroki , Iwahashi Hideki , Kakimoto Souichirou , Ikeda Sayaka , Takasaki Kazuki , Suminokura Jin , Kikuchi Yoshihiro
Published: May 2019

e17124

Background: The immunotherapy drug, nivolumab, is now approved for several metastatic cancers, and has resulted in responses previously not seen with these cancers. Molecular targeting agents, such as mammalian target of rapamycin (mTOR) inhibitor, have also recently been shown to have modest activity for endometrial cancers, however, the efficacy was limited.　The present retrospective analysis is to evaluate the efficacy of Nivolumab alone or combination with molecular targeting agents for recurrent and refractory endometrial cancers. Methods: A retrospective evaluation for medical charts of the patients were conducted: (a) the cases with histologically confirmed endometrial cancers, (b) those that had recurrent diseases, (c) diagnosed as refractory for the previous chemotherapy, (d) those that were treated with combination therapy using tri-weekly Nivolumab (100mg/body, every 3 weeks) alone, or combination with molecular targeting agents. The association with serum markers and response was also investigated. Results: A total of 16 patients were identified: 5 cases with endometrioid G1/2, 4 cases with endometrioid G3, and the 6 cases with serous, and one case with mucinous histology. Median age was 61 years old (range:43-76), and median number of the previous chemotherapy was 4 regimens (range:1-5). Combined drugs included everolimus (n = 9), temozolomide (n = 1), trametinib (n = 1), and nintedanib (n = 1). Among 12 cases with evaluable disease, a complete response over 20 months was observed in one case: a case with endometrial carcinoma G2 treated with Nivolumab and evelorimus (5mg/day, continuously). Stable disease more than three months was achieved in 8 cases (67%), and clinical benefit rate (CR+SD > 3months) was achieved in 75% of the cases. Median progression-free survival was 5 months (range: 3-20+). Non-hematological adverse events included general fatigue, mucositis, dysgeusia, skin rash, edema, and liver dysfunction, but the toxicity greater than grade2 was observed and in a case with liver dysfunction (G3). There was no significant relationship between response and serum levels of VEGF, p53, and IL-6, however, clinical benefit was observed in higher abundance of endometrioid histology compared with serous subtype (86% vs. 50%). Conclusions: Combination therapy using Nivolumab with evelolimus could be a candidate for recurrent and refractory endometrial cancers. Biomarker analyses for the responders are mandatory for further investigation for larger clinical studies.
Is uterine cancer screening indicated or possible in high risk special populations?
Authors: Lee Susan , Delaveux Anquilla , Crosby Claud , Chen Yiju Amy , Khozaim Kareem , Buenconsejo Lee , Timoteo Ianeta , Matthews Roland , Del Priore Giuseppe
Published: May 2019

e17126

Background: Uterine cancer (UC) is being considered for screening by the CDC due to its relative ascendancy in incidence. We sought to determine its potential for screening using a vanguard of contemporary cancer risk with high non-communicable disease rates (American Samoa [AS]) as a model sample set, and then Grady Hospital (GH) as a test population for screening. Methods: Public access de-identified databases covering the entire national population of AS over several time periods and de-identified GH tumor registry data. Results: In 2014 AS reported 258 new cancers (9.4/10,000 women/yr) including UC (36%), breast (37.6%), cervix (6.6%), ovary (5.1%), and others (14.7%). UC was the leading cause of gynecologic deaths (1.6x > ovarian or cervical). From 2004 - 14 the incidence of UC increased 78.9% to 3.4 cases/10,000 women/yr while breast cancer increased 52.2% to 3.5 cases/10,000. In the most recent 24 months, UC was 2.5x more likely to be diagnosed than breast, 3.6x more than colon, 8x more than cervical and 10.7x more than ovarian cancers. Gyn cancers were the leading cause of cancer death among women after lung. Based on this high incidence of UC, we sought to determine if it would be possible to reach US patients for potential screening using an urban population with health disparities in a test sample of potential beneficiaries of screening for UC the GH Morehouse service (79% black; mean age 58 (33 - 88). From 2010-6, 197 UCs were treated at GH; 96% were GH patients prior to diagnosis with an average time from earliest hospital encounter to the UC diagnosis of 1.75 years (0 – 5.5). Changes from 1st GH encounter to UC diagnosis and treatment including BMI, age, co-morbidities, etc will be presented. Conclusions: Uterine cancer has similar characteristics to currently screened cancers with an incidence in some high-risk population just under breast and prostate, but ahead of lung and colon. An enriched population, eg. BMI combined with age, especially with disparities, could benefit most from changes in screening strategy and management. Patients with UC are accessible in the hospital of their treatment for potential screening years before diagnosis. This may be an opportunity to reduce cost and morbidity from a rapidly increasing cancer.
A differential response to cetuximab in patients with recurrent unresectable or metastatic head and neck cancer following immunotherapy (IO) exposure: An institutional experience.
Authors: Ali Haythem Y. , Abdel Rahman Zaid , Sheqwara Jawad
Published: May 2019

e17500

Background: Metastatic head and neck cancer is a diagnosis with poor prognosis and very little in terms of available active therapy. Until recently the mainstay of therapy was chemotherapy with or without cetuximab. The regimen of cetuximab (C), platinum (P) and 5FU has a response rate(RR) of 36% in the first line setting, and a PFS of 5.6 months and OS of 10.1 months. In the setting of post first line therapy immunotherapeutic agents (IO) have average RR of 15% and median OS of 8 months. Methods: We studied all patients with metastatic or recurrent head and neck cancer who were treated with an IO at our institution between May 2016 and July 2018 evaluating their entire history of therapy. 19 patient were treated with IO at our institution in the designated period of whom 9 received nivolumab (N) and 10 received pembrolizumab ( P ). Patients treated on trials were excluded. Patients who received less than 1 cycle of therapy were also excluded. 7 of the 19 patients received an IO in the first line setting after being refractory or resistant to platinum containing definitive therapy, 7 received the IO after a cetuximab (C) containing first line regimen, 1 patient received IO in second line but was naïve to C and 4 received IO in the third line setting. Results: 3 of 19 patients treated with IO had partial response, there were no complete responses, 6 patients had stable disease as their best response and 10 patients progressed at the time of their first evaluation. 11 of 19 patients received additional therapy post IO. 10 patients received taxane based therapy 5 of whom the taxane was combined with C. Of the 5 patients who received a taxane and C combination 2 had CR, 2 had PR and one had PD. Of the 5 who received other taxane regimens, 1 had PR 1 had SD and 1 had PD, 2 expired prior to their first evaluation. The patient who received a non taxane regimen all had progressive disease. Of the 4 responding patients to C regimens 1 had SD during IO therapy and 3 had PD. The longest response duration to a C regimen post IO was 628 days. Conclusions: We observe an unusual response rate among patients treated with a combination of taxanes and cetuximab after IO therapy. This finding may relate to a modifying effect of IO on sensitivity to subsequent therapy. This observation merits further investigation.
Preclinical study of PD-0332991 on EBV-positive NPC cell lines and xenografts.
Authors: Xue Zhichao
Published: May 2019

e17506

Background: Originated from nasopharynx, nasopharyngeal carcinoma is a subtype of head and neck cancer, which is consistently associated with EBV infection. It is prevalent exclusively in south of China, Malaysia and southeast Asia. Previously, there was only one EBV positive cell line, c666-1, for NPC study, the new EBV positive cell lines and xenografts established by our lab recently represent better models for preclinical drug test. The objective of this preclinical study is to evaluate the therapeutic effect of specific CDK4/6 inhibitor PD-0332991 in our new established EBV positive NPC cell lines and Xenografts. Methods: Cell lines were cultured in both 2D and 3D condition, cytotoxic test was conduct by Resazurin in 2D and by cell titer-glo in 3D. Cell cycle was analyzed by Western blot and flow cytometry. In the animal study, PD-0332991 was first used as single drug administrated to xenograft mice daily by oral gavage. Secondly, SAHA as a HDAC inhibitor was used to combine with PD-0332991 in this study, which was i.p. injected into animal every other day. Tumor size, body weight well as micro-pets scan data was recorded. The data from each experiment was analyzed by ANOVA and unpaired t-test for significant drug responses. Results: PD-0332991 was first identified to be effective during in vitro study. Beside single drug effect, when combination with SAHA, a synergistic effect was observed both in vitro and in vivo. In single drug study, PD-0332991 can significantly inhibit tumor growth in 3 of our xenografts (XENO76: P < 0.0001, XENO32: P < 0.0001, XENO23: P = 0.0019). In combination study, through tumor size and micro-pets scan, combination treatment induced significant decrease in tumor size and tumor metabolism states in animal models compare to vehicle, PD-0332991 and SAHA treatment. Conclusions: PD-0332991 is identified to be effective in our preclinical test by using our new established EBV positive cell lines and xenografts, this could be a promising treatment for NPC patients after clinical trial.
Use of prophylactic percutaneous endoscopic gastrostomy (pPEG) tube in head and neck cancer (HNC) patients and correlation of weight loss with treatment interruptions.
Authors: Pandey Deepali , Gibbs Lisa , Sahu Kamal Kant , Siddiqui Ahmad Daniyal
Published: May 2019

e17509

Background: HNC patients are at risk for weight loss which can cause treatment interruptions, and poorer outcomes. There is no consensus on optimal timing of PEG tube placement in HNC patients undergoing concurrent ChemoTherapy (CT) and RadioTherapy (RT). The aim of this study is to determine if pPEG tube would decrease weight loss (WL) in HNC patients. We also analyzed correlation between WL and CT interruptions (CTI), RT interruptions (RTI), and intravenous fluid requirements (IVFr). Methods: This is a prospective study. A total of 16 HNC patients undergoing concurrent CT, RT were included. Before treatment initiation, a PEG tube placement was recommended as a mode of nutrition. 13 patients chose to get pPEG tube and 3 refused. We collected data on weight at 0 and 2 months, CTI, RTI, and IVFr. CTI included missed as well as reduced chemotherapy doses. RTI included missed radiations. Statistical tests used - t-test, Levene’s test for equality of variances and point biserial correlation. Results: Median age - 63 years; Gender: 14 Male/2 Female; Tumor location - Oral cavity - 31.3%; Oropharynx - 43.7%; Larynx - 25%; Nasopharynx and Hypopharynx- 0%. Stages were - II (6.2%), III (37.5%) and IV (56.3%). 2 patients were non-smoker and 4 were Human Papilloma Virus positive. Mean WL(lb) in pPEG (n = 11) vs non-PEG (n = 3) group was 10.3 vs 20.3 (p = 0.045, one-tailed t-test). Average percentage of WL: PEG vs non-PEG - 5.8 vs 8.2; RTI vs not - 8.9 vs 5.3; CTI vs not - 6.9 vs 5.8; IVFr vs not - 6.8 vs 4.5 ( > 7.5% WL over 3 months is significant (ADA/ASPEN)). CTI, RTI and IVFr were positively correlated to WL (correlation coefficient: 0.16; 0.32; 0.17 respectively). CTI and RTI in pPEG group were 23.1% and 38.5% respectively. CTI and RTI in non-PEG group were 33.3% and 66.7% respectively. 2 patients in pPEG group had average weight gain of 2.75 lb. Only 3 patients had PEG tube related complications - infections and clogging. Conclusions: pPEG tube decreases weight loss in locally advanced HNC patients. Patients with higher weight loss had more chemoradiation interruptions and IVFr. HNC patients undergoing concurrent CT, RT should be encouraged to maintain weight and get a PEG tube.
Quality of life assessment in dose escalating head and neck radiation therapy.
Authors: Hany Riham H. , Saad Ehab , Al sirafy Samy , Kader Yasser A. , Hassan Aly Mohamed Abdulla , Abdelhady Eman ,   Kasr Al Ainy, Cairo University Hospitals, Cairo, Egypt
Published: May 2019

e17511

Background: Both Dose escalation and acceleration can achieve higher tumor control rates with uncertain role of addition of concurrent chemotherapy. We aimed at developing a protocol for patients unable to receive the standard CCRT with little toxicity profile. Toxicity and Quality of life assessment were our primary end points in this pilot phase II trial. It is known from literature that pre-treatment QOL affects survival. Also, changes in QOL after treatment predict survival in cancer patients. Methods: 63 locally advanced HNC patients were randomized to receive (Arm A) 70Gy/35fr/7wks at 2Gy/fx concurrently with weekly Cisplatin 40mg/m2 or to receive (Arm B) 74Gy/33fx/6.5wks at 2.24Gy/fx with calculation of the Biological equivalent doses. CTCEA v4.3 was used to assess toxicity and Functional Assessment Cancer Therapy-Head & Neck (FACT-H&N) questionnaire (39-item) was used to assess QOL. The Questionnaires were collected and their scorings were calculated to get the FACT-H&N Trial outcome index (TOI), FACT-G and FACT-H&N total score pre-radiotherapy, 3 and 6 months post-radiotherapy for each patient. Results: There were 33 patients in arm A vs. 30 patients in arm B with median follow up 24.2 months. Our results showed statistical significant decrease of chemotherapy related toxicities (nausea, vomiting, neutropenia and anemia), acute (mucositis, oral pain, voice alteration, fatigue and acute dysphagia) and some late toxicities (late xerostomia) in the investigational arm vs. the CCRT arm. Regarding the FACT QOL assessment and scorings of the different parameters, there was no statistical difference between both arms in all FACT-H&N TOI, FACT-G and FACT-H&N total scores at pre-treatment, 3 and 6 months post treatment. Also when analyzing the mean change with time across the two groups pre-radiotherapy, 3 and 6 months post radiotherapy, it was not statistically significant. Our results did not demonstrate any significant differences in 2-year disease local control, PFS and OS between both arms, with comparable patterns of relapse. Conclusions: Slightly dose escalated hypofractionated regimen could be an option in LA-HNC treatment without affecting QOL, which needs confirmation in prospective large multi-centric trials. Clinical trial information: NCT03699969.
Triple combination treatment with anti-EGFR monoclonal antibody, low-dose chemotherapy, and anti-PD1 immune check-point inhibitors for recurrent and/or metastatic head and neck squamous cell carcinoma: A single institute experience.
Authors: Lin Ying-Chu , Uen Wu-Ching , Hao Sheng-Po , Hsiao Chen-Yu , Lai Hung-Chih
Published: May 2019

e17514

Background: The 1st line treatment of recurrent and/or metastatic head and neck squamous cell carcinoma (R/M SCCHN) was EXTREME regimen established by Vermorken at al since 2008. Recently in ESMO 2018, Keynote-048 presented frontline pembrolizumab monotherapy or combined chemotherapy had a better overall survival than EXTREME regimen, though with poor PFS (3.2m-3.4m) and response rate (19-23%). But chemotherapy plus pembrolizumab showed a shorter duration of response than the pembrolizumab alone. Therefore, role of chemotherapy as a partner of IO is debated. We presented a retrospective report of triple combination treatment of cetuximab, low-dose chemotherapy and anti-PD1 check-point inhibitor for R/M SCCHN patients as a e-publication in ASCO 2018. This is a update report. Methods: We retrospectively reviewed charts of R/M SCCHN patients who started triple combination of cetuximab, low-dose chemotherapy and anti-PD1 therapy during the period of Feb. 2017 till Jan.31 2018. The contents of combinations, previous treatments, duration of combination treatments, best response, and adverse effects were recorded. Data cutoff is Jan.15 2019. Results: Total 15 patients reviewed. The mean age was 55.4 years (age range 32 – 71 years). Previous treatments included chemotherapy (80%), anti-EGFR (33.3%), anti-PD1 check-point inhibitor (53.3%). The median duration of follow up was 434 days (range 187–707 days). Complete response was observed in 3 patients (20%), partial response in 7 patients (46.7%), stable disease in 4 patients (26.6%) and disease progression in 1 (6.6%). Objective response rate(CR+PR) observed was 66.7%. Clinical benefit rate(CR+PR+SD) observed was 93.3% . Dose of Cetuximab was 250-500mg/m2 every 2-3 weeks. Combination of chemotherapy included PF, TP, or docetaxel monotherapy. Doses were Cisplatin 30-50mg/m2, 5-FU 600-1000mg/m2, or docetaxel 20-30mg/m2; all in every 2-3 weeks. Anti-PD1 immune check-point inhibitors included Nivolumab 1-3mg/kg or Pembrolizumab 1-2mg/kg, every 2-3 weeks. Six patients (40%) died: 2 due to progression of disease, 1 due to tumour bleeding, 2 due to pneumonia, and 1 due to fungemia. Conclusions: Our real-world report might suggest a possible role of ADCC effect of cetuximab and less-toxic chemotherapy as a partner of IO. Further prospective study of triple combination therapy with biomarker evaluation is recommended.
Patterns of local extension and nodal involvement from 1300 nasopharyngeal carcinoma patients: An imaging-based predictor of distant metastases.
Authors: Fan Dan , Wang Ying , Tian Yifu , Lee Nancy Y. , Shen Liangfang
Published: May 2019

e17516

Background: Distant metastasis is a main determinant of prognosis in patients with nasopharyngeal carcinoma(NPC). We explored the patterns of disease spread in NPC patients and identified the pattern correlates with distant metastases. Methods: The imaging documents of 1300 consecutive newly diagnosed nasopharyngeal carcinoma between 2012 and 2016 were reviewed. According to the incidence rates of tumor invasion, the anatomic sites were classified into high-risk group (≥50%), medium-risk group (≥10%~ < 50%) and low-risk group ( < 10%). The location of lymph nodes was determined by 2013 updated guidelines for neck node levels. Additionally, we developed a novel classification based on tumor spreading patterns, as shown in Table. Moreover, we validated the prognostic accuracy of the classification in a validation cohort from a different institution, 241 non-metastatic NPC patients were retrospectively enrolled. Kaplan-Meier method and log-rank test were used to analyze all time-to-event data. Results: The incidence rates of tumor invasion were 0.2% ~91.2%, 95.2% cases across the midline. If anatomic sites in high-risk group or median-risk group were involved, the incidence rates in adjacent medium-risk sites or low-risk group were increased. On the contrary, the incidence rates were decreased when the adjacent high-risk sites or median-risk group were not involved. 85.9% cases had involved lymph nodes. Only 3.9% had skip metastases. The incidence rates of nodal involvement were increased when adjacent upper nodal level was involved. In validation cohort, distant metastases were present in 32/241 NPC patients (13.3%) and 3-year distant metastasis-free survival(DMFS) in local, superior, inferior, and mixed type were 95.0%, 91.3%, 89.0%, and 78.7%, respectively. Cumulative survival curves for former three patterns were relatively similar and were clearly separated from mixed type. DMFS was significantly lower for patients with mixed type pattern than for those with other patterns(P = 0.018). Conclusions: Local disease in NPC patients spreads stepwise from proximal sites to more distal sites. The frequency of metastases in the jugular lymph node chains decreased in the cranio-caudal direction. Based on the patterns of tumor extension, an imaging-based predictor of distant metastases was developed and may be used as a prognostic marker for selecting patients to further systemic treatments. [Table: see text]
QOL assessment in head and neck cancer patients undergoing neoadjuvant chemotherapy and its impact on overall survival.
Authors: Dhumal Sachin , Patil Vijay Maruti , Noronha Vanita , Joshi Amit , Bhattacharjee Atanu , Roy Somnath , Das Sudeep , Prabhash Kumar
Published: May 2019

e17519

Background: NACT (neoadjuvant chemotherapy) is one of the treatment options in advanced head and neck cancer (H&N cancer); however there is limited quality of life data available in these patients. Methods: Between August 2013- April 2014, 90 technically unresectable H&N cancer patients who were underwent NACT at our centre were selected for this analysis. EORTC QLQ-C30 and HN35 version 3.0 was used for quality of life assessment at baseline and after 02 cycles of NACT. PFS and OS was estimated by Kaplan Meier method. The mean change in QOL at various domains was calculated with 95% CI. The relationship between change in QOL domain and OS was analysed. Results: The median age of the cohort was 45 years (Range 21-65 years). The predominant subsite was oral cavity, in 62 patients (68.9%).The median PFS and OS was 10.53 months (95%CI 8.1-13.0) and 20.8 months (95%CI 15.1-26.5). The mean scores for all domains of QOL are shown in table 1. Conclusions: NACT leads to improvement in QOL in patients treated with head and neck cancers and its has impact on OS.[Table: see text]
Biomarkers of resistance to cetuximab in head and neck squamous cell carcinoma (HNSCC).
Authors: Surikova Ekaterina I. , Kit Oleg I. , Neskubina Irina V. , Frantsiyants Elena M. , Vladimirova Liubov Yu , Lyanova Aza A. , Engibaryan Marina A. , Shalashnaya Elena V. , Aedinova Irina V. , Ulianova Yulia V. , Volkova Viktoriya L. , Pustovaya Irina Viktorovna , Ezhova Maria
Published: May 2019

e17523

Background: Treatment of advanced HNSCC (T3 and T4) involves the use of anti-EGFR monoclonal antibodies targeting the EGF-EGFR and VEGF-VEGFR cascades responsible for the cell proliferation, differentiation, invasion, metastasis, angiogenesis and apoptosis. The purpose of the study was the search for biomarkers of resistance to cetuximab in HNSCC patients. Methods: Tumor biopsy was performed in patients with HNSCC (n = 40) (Т3-4N0-1M0) before and after two cycles of chemotherapy with cetuximab - 400 mg/m2 administered on day 1 and 250 mg/m2 per week, cisplatin 100 mg/m2 on day 1, fluorouracil 1000 mg/m2 - 96-hour continuous infusion. Patients were divided into group 1 (progression, n = 11) and group 2 (stabilization and partial remission, n = 29). Levels of VEGF-A (pg/mL) (BenderMedSystem, Austria) and TGF-β (pg/mL) (eBioscience, USA) were determined in biopsy samples by ELISA, and the VEGF-A/TGF-β ratio was calculated. Statistical analysis of the results was performed using the Statistica 10.0 program with M±m determination. Differences were considered significant at p < 0.05. Results: Before treatment, levels of VEGF-A in biopsy samples were 634.8±37.2, TGF-β – 1092.5±71.9, and VEGF-A/TGF-β – 0.58±0.03. After 2 cycles of chemotherapy with cetuximab, results in group 1 for VEGF-A were 680.3±41.2, TGF-β – 1773.7±111.4, and VEGF-A/TGF-β – 0.384±0.021; in group 2: VEGF-A – 487.7±26.1, TGF-β – 572.3±34.7, and VEGF-A/TGF-β – 0.85±0.043. Thus, after 2 cycles of chemotherapy with cetuximab, TGF-β in group 1 increased by 1.6 times and VEGF-A/TGF-β – by 1.5 times (p < 0.05). In group 2, VEGF-A decreased by 1.3 times, TGF-β by 1.9 times, and VEGF-A/TGF-β increased by 1.46 times (p < 0.05). Conclusions: Decreased levels of markers and increased VEGF-A/TGF-β can predict cetuximab efficacy. Increased TGF-β and reduced VEGF-A/TGF-β allow predicting resistance to chemotherapy with cetuximab.
Changes in KRAS mutations in patients with oral mucosa and tongue cancer (OMTC) undergoing medical treatment with cetuximab (Cet).
Authors: Lyanova Aza A. , Kit Oleg I. , Enin Yaroslav S. , Timoshkina Natalya N. , Engibaryan Marina A. , Aedinova Irina V. , Volkova Viktoriya L. , Bauzhadze Mamuka V. , Chertova Natalia A. , Vladimirova Liubov Yu
Published: May 2019

e17524

Background: Mutations in KRAS are known to be predictors of anti-EGFR therapy efficacy. Besides the mutation status of the treatment-naive tumors the changes in the level of mutant DNA during medical treatment are also of clinical interest for the individualization of the treatment. The purpose of the study was to detect somatic single nucleotide polymorphism (SNP) activating mutations in KRAS exon 2 in patients (pts) with OMTC undergoing chemotherapy (CT)±Cetuximab (Cet). Methods: Extracellular DNA samples were obtained from plasma of pts with OMTC (T3-4No-1Mo) undergoing CT (CDDP+5FU)+Cet (group A) before treatment and in 2 weeks after. Patients undergoing CT (CDDP+5FU, no Cet) were included in Group B. 7 activating mutations in KRAS exon 2 were detected by Droplet Digital PCR method (DD PCR) with "KRAS Screening Multiplex Kit" (BioRad, USA). Results: Samples from 28 pts were included. The frequency of SNP activating in KRAS exon 2 before treatment was 25%. In the group A (n = 12) KRAS mutations were not found or the level of mutant DNA did not exceed 1%. No significant changes were found in this group after treatment. The group B (n = 16) had some KRAS variations the majority of which did not change after treatment. However, 2 pts had a sharp increase in mutant DNA: from 0.03% before CT in both cases to 17.04% and 56.38% -after treatment (p < 0.01). Conclusions: Medical treatment, especially CT, could cause the changes in activating mutations in KRAS exon 2 in pts with OMTC. Revealing of these changes is of great importance for the following treatment options. Detection of mutant extracellular DNA by DD PCR could be valuable to monitor their status during the treatment.
Analysis of race and gender disparities in mortality trends from patients diagnosed with nasopharyngeal, oropharyngeal and hypopharyngeal cancer from 2000 to 2014.
Authors: Badin Kristine , Nayak Kapoor Asha , Guddati Achuta Kumar
Published: May 2019

e17533

Background: Squamous cell carcinoma of the nasopharynx, oropharynx and hypopharynx constitutes a majority of head neck malignancies. The incidence-based mortality across different races has been noted to be divergent. This study analyzes the trend in incidence-based mortality from the years 2000 to 2014 amongst both the genders in Caucasian/White and African American/Black patients. Methods: The Surveillance, Epidemiology, and End Results (SEER) Database was queried to conduct a nation-wide analysis for the years 2000 to 2014. Incidence-based mortality for all stages of nasopharyngeal, oropharyngeal and hypopharyngeal cancer was queried and the results were grouped by race (Caucasian/White, African American/Black, American Indian/Alaskan native and Asian/Pacific Islander) and gender. All stages and ages were included in the analysis. T-test was used to determine statistically significance difference between various subgroups. Linearized trend lines were used to visualize the mortality trends of all sub groups. Results: Incidence-based mortality rates (per 1000) for nasopharyngeal, oropharyngeal and hypopharyngeal cancer all races and both the genders is shown in the table below. The male to female gender disparity in mortality is~ 1:3 in patients with nasopharynx across all races and becomes worse to ~1:4 and ~1:5 for patients with oropharyngeal and hypopharyngeal cancers respectively. Notably the highest incidence based mortality for nasopharyngeal cancers is seen in Asian/pacific Islander males and a similar peak is noted for hypopharyngeal cancers in African American/Black males. Conclusions: A significant gender disparity exists in all there pharyngeal cancers across all races. It is unclear if female gender is protective but further study is warranted in a stage- specific and age-specific manner to better understand this disparity.[Table: see text]
Genome-wide study of salivary microRNAs as potential noninvasive biomarkers for detection of nasopharyngeal carcinoma.
Authors: Wu Lirong , He Xia
Published: May 2019

e17535

Background: Since recent studies reported that blood-based microRNAs (miRNAs) could detect cancers and predict prognosis, a new field has been opened for circulating miRNAs as potential biomarkers in cancers. In this pilot study, we evaluated to our knowledge for the first time whether salivary miRNAs might be applicable as innovative biomarkers for Nasopharyngeal carcinoma (NPC) detection. Methods: By high throughput label-free microarray contained 2025 human miRNA probes, 12 down-regulated miRNAs from saliva samples from 22 newly diagnosed NPC patients and 25 healthy controls were selected. Then, their target genes enriched by gene ontology and pathway were used to construct a regulatory and interaction networks. The receiver operating characteristic analyses (ROC) and logistic regression were calculated to assess discriminatory accuracy. Results: Advanced bioinformatics analysis was conducted to understand the most significant hub gene is TP53 that probably regulated by the 12 dysregulated miRNAs. The ROC including the 12 miRNAs as well as the 6 significant deregulated miRNAs separated NPC patients from healthy controls with a very high (areas under the receiver operating characteristic curve [AUC] = 0.999, sensitivity = 100.00%, specificity = 96.00%) and high accuracy (AUC = 0.941, sensitivity = 95.45%, specificity = 80.00%), respectively. Conclusions: Differentially expressed miRNAs might play critical roles in NPC by regulating their target genes, and may have the potential to become diagnostic biomarkers.
Comparison of the seventh and eighth editions of the American Joint Committee on Cancer (AJCC) staging for oropharyngeal squamous cell carcinomas (OPSCC): A Surveillance, Epidemiology and End Results Program (SEER) database analysis.
Authors: Trivedi Sumita , Song Haocan , Liu Yuan , Steuer Conor Ernst , Stokes William , Kaka Azeem , Patel Mihir , Chen Zhuo Georgia , Shin Dong Moon , Aiken Ashley , Beitler Jonathan Jay , Saba Nabil F.
Published: May 2019

e17538

Background: The recently released eighth edition of the American Joint Committee on Cancer (AJCC) Staging Manual, Head and Neck Section, incorporates significant changes to the prior seventh edition. The changes reflect the improved understanding of tumor biology, prognostic factors and molecular markers that effect outcomes in Head and Neck cancers. A key update restages OPSCC by human papilloma virus (HPV) positive and negative cancers as data demonstrated that these tumors have significantly different biology and outcomes. Methods: Using SEER data from 2004 – 2014, we identified male patients with squamous cell carcinomas of the tonsil, base of tongue and soft palate aged between 21 and 64 years old (those clinical characterizes were considered as surrogate markers for HPV positive status). We classified them by the AJCC 8th edition staging for HPV positive OPSCC and by AJCC 7th edition staging. The prediction performance by two staging editions were compared regarding overall survival (OS) and Disease free survival (DFS). Kaplan-Meier method and Cox proportional hazard model were applied, and the discrimination performance was measured by the concordance statistics (C-statistics). Results: A total of 8202 eligible patients were included in the analysis with a median follow up period of 51 months. 7415 (90.4%) patients had previously received radiation and 7038 (85.8%) patients had previously received chemotherapy. The median age of patients was 56 years. Distribution of stage I disease increased from 2% to 19.6% in AJCC 8th edition. 10-year overall survival (OS) for AJCC 8th stages I (74%), II (78%), III (55%) and IV (32%). Using Stage I as reference, the hazard ratio for stage II, III, and IV is 0.98 (95%CI: 0.87-1.09), 2.29 (95%CI: 2.04-2.57), and 5.88 (95%CI: 4.96-6.98). Similar results were noted for ten year disease free survival. The C-statistics measured overall discrimination for 8th edition is 0.68 and 0.63 for the 7th edition (P < 0.001). Conclusions: Based on this SEER analysis, the overall performance of discrimination improved from AJCC 7th to 8th edition; but in this study population, AJCC 8th edition does not distinguish stage I and II sufficiently as expected as it does for stages III and IV disease. Limitations of the SEER database include the surrogate for P16 status and under reported and incomplete data.
Translating transcriptome to immunophenotype in head and neck squamous cell carcinoma (HNSCC) to identify pathways promoting T-cell infiltration.
Authors: Rampias Theodoros , Kontos Christos K. , Polyzos Alexandros , Giotakis Aris , Giotakis Evangelos , Scorilas Andreas , Kirodimos Euthymios , Foukas Periklis , Psyrri Amanda
Published: May 2019

e17542

Background: We sought to analyze the transcriptional landscape of HNSCC in an attempt to identify tumor-intrinsic oncogenic pathways that appear to mediate T-cell infiltration of tumor tissue. In this direction, we employ a methodology that integrates histopathology data of the tumor microenvironment with its corresponding transcriptome. Methods: 32 frozen HNSCCs were subjected to RNA-seq and corresponding FFPE were scored for plasma cells, tertiary lymphoid structures and CD8a+ TILs (center, invasive margin). RNA-seq data were analyzed to identify differentially expressed genes (DEGs) between tumors scored by immunohistochemistry (IHC) as CD8a high and CD8a low. Gene ontology analysis (GO) was performed based on DEGs > 1.5 fold expression change between CD8a high and CD8a low groups. Candidate genes were investigated by hierarchical clustering in TCGA RNA-seq data and further validated by IHC and quantitative RT-PCR in our cohort. Results: 32 HNSCCs were either scored as CD8a high or CD8a low based on IHC detection of CD8a+ cells in invasive margin of tumors. Comparative analysis of mRNA expression data between CD8a high and CD8a low groups in our cohort revealed that Muc1/16 overexpression and glycosylation was highly enriched in T cell infiltrated group of tumors. This finding was further validated using antibodies that detect glycosylated epitopes for both mucins. Analysis of TCGA RNA-seq data indicated that Muc1/16 overexpressing tumors share signatures of early keratinocyte differentiation and stem cell identity and co-express high levels of enzymes that promote Muc1/16 glycosylation. Interestingly, loss of CDH1 and acquisition of epithelial mesenchymal transition (EMT) markers in the cluster of Muc1/16 overexpressing tumors is strongly correlated with elevated CD8a, IDO1, CD274 and CXCL10 mRNA levels (P < 0.0001). Conclusions: Muc1/16 overexpressing tumors represent a very immunogenic HNSCC cluster. Previous studies have shown that mucins 1 and 16 in cancer cells expose glycosylated-specific epitopes that are recognized by T cells as cancer antigens. To this end, MUC1/16 expression may serve as predictive biomarkers for response to immunotherapy and MUC-targeted immunotherapy may function as an attractive partner to checkpoint inhibitors in HNSCC.
TREM-1 expression in HPV-related oropharyngeal squamous cell carcinoma.
Authors: Airoldi Mario , Raimondo Luca , Azzimonti Barbara , Chiusa Luigi , Pecorari Giancarlo , Cappello Paola , Cena Tiziana , Valente Guido
Published: May 2019

e17545

Background: Immunotherapy in head and neck squamous cell carcinoma (SCC) is a hot topic and PD1/PDL-1 checkpoint blockade is a promising approach even if there is a lack of robust progno-stic/predictive biomarkers and treatment benefits in overall survival are variable. Triggering Receptor Expressed on Myeloid cell 1 (TREM-1) reverses the M2-polarizing effect of hypoxia imparting a M1-skewed pro-inflammatory phenotype to macrophages that controls tumour growth. Aim of this study is to evaluate the prognostic role of TREM-1 in oropharyngeal (OP) SCC. Methods: In 25 patients with stage III-IV HPV+ OPSCC we evaluated, with immunohistochemistry, in surgical specimens the following immunologic parameters in intratumoral (IT) and peritumoral (PT) environment: PD1-PDL-1 (1+ = < 20% positive cells (pc); 2+ = 21-50% pc; 3+ = > 50% pc) CD4, CD8, FOXP3 (1+ = < 10% pc; 2+ = 10-20% pc ; 3+ = > 20% pc) IL22 (1+ = 1-33% pc, 2+ = 34-67% pc, 3+ = > 67% pc) and TREM ( 1+ = 1-50% pc, 2+ = > 50% pc). The McNemar test was used to assess differences between IT and PT environment. Results: CD4 IT 0/1+ = 12% 2+/3+ = 88% PT 0/1+ = 6% 2+/3+ = 94% FOXP3 IT 0/1+ = 88% 2+/3+ = 12% PT 0/1+ = 65% 2+/3+ = 35% CD8 IT 0/1+ = 12% 2+/3+ = 88% PT 0/1+ = 48% 2+/3+ = 52% PD1 IT 0/1+ = 100% 2+/3+ = 0% PT 0/1+ = 100% 2+/3+ = 0% PDL1 IT 0/1+ = 53% 2+/3+ = 47% PT 0/1+ = 6% 2+/3+ = 94% IL22 IT 0/1+ = 59% 2+/3+ = 41% PT 0/1+ = 29% 2+/3+ = 71% TREM-1 IT 0/1+ = 94% 2 + = 6% PT 0/1+ = 82%* 2+ = 18% * 1+ = 64% Statistical analysis showed a concordant expression of CD4, CD8 and PDL-1 both in IT and PT while TREM-1 was more expressed in PT (p = .001) and PD-1 in IT (p = 0.12).There was no correlation between TREM-1 pc and CD68 and CD35 pc. Tumours with low PT TREM-1 positivity have a lowest risk of relapse (p = .01). Conclusions: HPV+ OPSCC is promoted by inflammatory infiltrate anergy. TREM-1 PT positivity has unfavourable impact on relapse.
Associations between pretreatment body mass index and presence of post-treatment nutrition impact symptoms in head and neck cancer survivors.
Authors: Douglas Katherine G. , Crowder Sylvia L. , Rozek Laura S. , Wolf Gregory T. , Arthur Anna
Published: May 2019

e17547

Background: The objective of this study was to determine if pre-treatment body mass index (BMI) is associated with the presence of self-reported, nutrition impact symptoms (NIS) 1-year post-treatment in head and neck cancer (HNC) survivors. We hypothesize that higher pre-treatment BMI may be associated with fewer reported NIS post treatment. Methods: This was a longitudinal study of 430 HNC survivors recruited from the University of Michigan Head and Neck Specialized Program of Research Excellence (HN-SPORE) study. Participants completed a pre-treatment health questionnaire which included self-reported height and weight. NIS were assessed at 1-year post-treatment using a Likert scale ranging from 1 (not at all) vs 5 (extremely) bothered by symptoms. Eight individual NIS were assessed (trismus, xerostomia, bothered chewing, dysphagia liquids, dysphagia solids, taste changes, mucositis, and shoulder or neck pain). Individual symptoms were summed to create a symptom summary score. Self-reported pre-treatment height and weight were used to calculate BMI in kg/m2. BMI was categorized as 1) underweight, 2) normal weight, 3) overweight and 4) obese. Pearson partial correlations between pre-treatment BMI status and individual post-treatment NIS and post-treatment NIS summary score were examined. Covariates included age, sex, tumor site, disease stage, smoking, alcohol consumption, and HPV status. Results: BMI was significantly inversely associated with bothered chewing, dysphagia liquids, dysphagia solids, taste alterations, and shoulder pain (p < 0.05). BMI was also significantly inversely correlated with the overall symptom summary score. Conclusions: Higher pre-treatment BMI may be associated with reduced risk of post-diagnosis symptom burden in HNC survivors. Funding: NIH/NCI P50CA097248; Hatch project 1011487; Carle-Illinois Cancer Scholars for Translational and Applied Research Fellowship.
Prognostic neutrophil-to-lymphocyte and platelet-to-lymphocyte ratio in locally advanced oropharyngeal cancer: a retrospective experience of two institutions.
Authors: Espeli Vittoria G. , Martucci Francesco , Richetti Antonella , Pastore Alessia
Published: May 2019

e17548

Background: the Neutrophil-to-Lymphocytes ratio (NLR) and the Platelet-to-Lymphocytes ratio (PLR) represent potential prognostic markers in different tumor types. The purpose of our study was to investigate the prognostic role of the pretreatment inflammatory markers NLR and PLR in patients with locally advanced squamous cell oropharyngeal cancer (OPSCC) treated with curative concomitant chemoradiotherapy (CRT). Methods: between 2004 and 2016, all patients with OPSCC diagnosed at the University Hospital of Varese and the Oncology Institute of Southern Switzerland were reviewed retrospectively. CRT consisted of Intensity-Modulated Radiation Therapy (IMRT) to a dose of 66-70 Gy concomitant to 3 doses of 3-weekly cisplatin. Pre-treatment NLR and PLR were registered from blood samples obtained within 14 days before treatment. 3-year disease free survival (DFS) was analyzed. Results: ninety-two patients were identified. Median follow-up was 39 months. Median NLR was 3 and median PLR was 153. The 3 year DFS was 82.9%. Univariate analysis showed that HPV status and PLR were statistically significant factors in determining 3-year DFS (p 0.01 and 0.04 respectively). Multivariate analysis showed that only HPV status was a statistically significant factor for 3-year DFS (p 0.009). High NLR and high PLR were correlated with lower DFS: patients with NLR > 4 had a 3-years DFS of 50% versus 75%in the group with NLR ≤ 4(p = 0.04) and patients with PLR > 150 had a 3-years DFS of 65% versus 82% in the group with PLR ≤ 150 (p = 0.04). Conclusions: in our case series, NLR and PLR were significantly associated with clinical outcome. Additional data are necessary to investigate the prognostic value of inflammatory markers and to identify the ideal cut-off of both markers.