bluuebunny/crossref_metadata_2025 huggingface dataset:
The efficacy and safety of nedaplatin single therapy in 30 patients with platinum-resistant ovarian cancer.
Authors: Kasamatsu Yuka , Takekuma Munetaka , Kado Nobuhiro , Yoshioka Emi , Kuji Shiho , Tanaka Aki , Takahashi Nobutaka , Abe Masakazu , Hirashima Yasuyuki
Published: September 2018

e17075

Background: This study aimed to investigate the efficacy and safety of Nedaplatin single therapy for patients with platinum-resistant ovarian, tubal and primary peritoneal cancer after completing standard chemotherapy. Methods: From September 2002 to August 2016, 30 patients who were diagnosed with platinum-resistant ovarian cancer, were treated with Nedaplatin single therapy after completing all standard chemotherapy at our institution. Nedaplatin (80-100mg/m2) was adiministered intravenously on day 1 of a 28 day cycle. We retrospectively investigated the response rate, toxicities, and survival based on the use of Nedaplatin single therapy. Results: The median age was 58.5 years (23-76). The median number of prior chemotherapy regimen was 3 (1-7). The median platinum-free interval between the final use of platinum analogues and starting Nedaplatin single therapy was 9.4 months (0.9-54.9). Among 22 patients who had measurable disease, 8 (36.4%) responded partially to Nedaplatin single therapy. Seven patients (23.3%) experienced hematological toxicities of Grade 3/4. Six patients (20.0%) experienced non-hematological toxicities Grade 2. No treatment-related death occurred. The median progression-free survival was 3.2 months (0-23.3), and over all survival was 9.2 months (1.1-56.4) after treatment with Nedaplatin single therapy. Age (<70 years, p=0.017) and platinum-free interval (<6 months, p=0.013) were the prognosis factors for survival in univariate analyses. Conclusions: Nedaplatin single therapy seemed to be an effective and safe chemotherapy regimen for platinum-resistant ovarian cancer after completing standard chemotherapy.
The activity of the conjugated antimetabolite 5-FdU-ECyd against platinum-resistant ovarian cancer.
Authors: Wimberger Pauline , Klink Barbara , Gruetzmann Konrad , Puppe Julian , Klotz Daniel , Schroeck Evelin , Kuhlmann Jan Dominik , Schott Sarah
Published: September 2018

e17077

Background: Primary or secondary resistance to platinum-based chemotherapy is an important clinical challenge in the treatment of ovarian cancer (OC) and limits survival. Therefore, the development of innovative drugs against platinum resistance is urgently needed. Our therapeutic concept is based on the conjugation of two chemotherapeutic compounds to a monotherapeutic pro-drug, which is taken up by cancer cells and is subsequently cleaved into several active cytostatic metabolites. Our in vitro study evaluates the effects of the conjugated antimetabolite 5-FdU-ECyd, consisting of 2-deoxy-5-fluorouridine (5-FdU) and ethynylcytidine (ECyd), on platinum-resistant OC cells. Methods: In vitro assays and RNA-Seq (Illumina) were applied for characterization of 5-FdU-ECyd treated platinum-sensitive A2780 and isogenic platinum-resistant A2780cis as well as independent platinum-resistant Skov-3-IP OC cells. Results: Nano molar 5-FdU-ECyd concentrations induced a rapid dose-dependent decline of cell viability in platinum-sensitive and platinum-resistant OC cells. The cytotoxicity of 5-FdU-ECyd was accompanied by the formation of DNA double strand breaks and by the induction of apoptosis, indicated by a strong increase of pro-apoptotic molecular markers (caspase-3/7 activation, PARP-cleavage). Moreover, 5-FdU-ECyd efficiently decreased cell migration of platinum-resistant OC cells and inhibited other tumor-associated cellular functions, such as clonogenic or spheroidal growth. Transcriptome analysis indicated that, independently of platinum-resistance status, 5-FdU-ECyd influences distinct cellular pathways, involved in cell cycle regulation, apoptosis, DNA-damage response and RNA/pyrimidine metabolism. Combination treatment of 5-FdU-ECyd and platin did not show a synergistic cellular response, suggesting the potential use of 5-FdU-ECyd as a monotherapeutic agent. Conclusions: Our data provide a rationale to characterize the effect of 5-FdU-ECyd in a pre-clinical in vivo setting. We hypothesize that this conjugate is a promising therapeutic option for OC patients with resistance to conventional platinum-based chemotherapy.
Synthetic lethality interaction between aurora kinases and CHEK1 inhibitors in ovarian cancer.
Authors: Alcaraz-Sanabria Ana Lucía , Nieto-Jimenez Cristina , Corrales-Sanchez Veronica , Serrano-Oviedo Leticia , Serrano-Heras Gemma , Pretel Fernando Andrés , Montero Juan Carlos , Burgos Miguel , Llopis Juan , Galan-Moya Eva María , Amir Eitan , Pandiella Atanasio , Ocana Alberto
Published: September 2018

e17089

Background: Ovarian cancer is characterized by frequent mutations at TP53. These tumors also harbor germline mutations at homologous recombination repair (HR) genes, so they rely on DNA-damage checkpoint proteins, like the Checkpoint kinase 1 (CHEK1) to induce G2 arrest. In our study, by using an in silico approach, we identified a synthetic lethality interaction between CHEK1 inhibitors and mitotic Aurora Kinase A and B (AURKA/B) inhibitors. Methods: Gene expression analyses were used for the identification of relevant biological functions. OVCAR3, OVCAR8, IGROV1 and SKOV3 were used for proliferation studies. Alisertib was tested as AURKA/B inhibitor and LY2603618 as CHEK1 inhibitor. Analyses of cell cycle and intracellular mediators were performed by flow cytometry and western-blot. Stem cell properties were evaluated with immunofluorescence. Results: Gene expression analyses followed by functional annotation identified cell cycle as a deregulated function. Identified druggable kinases within this function included AURKA/B, TTK kinase and CHEK1. CHEK1 and AURKA/B inhibitors showed a synergistic interaction in different cellular models. Combination of Alisertib and LY2603618 triggered apoptosis, reduced the stem cell population and increased the effect of taxanes and platinum compounds. AURKA and CHEK1 were amplified in 8.7% and 3.9% of ovarian cancers, respectively. Expression of these genes was linked with detrimental clinical outcome. Conclusions: Amplification of AURKA and CHEK1 was observed in more than 12% of ovarian tumors. Our data describes a synthetic lethality interaction between CHEK1 and AURKA/B inhibitors with potential translation to the clinic.
Clinicopathologic characteristics of endometrial carcinoma metastatic to the ovary compared to endometrial carcinoma with synchronous ovarian carcinoma.
Authors: Rodriguez Gomez Hidalgo Natalia , Soslow Robert A. , Weigelt Britta , Sioulas Vasileios , Aloisi Alessia , Abu-Rustum Nadeem , Mueller Jennifer Jean , Makker Vicky , Leitao Mario M.
Published: September 2018

e17105

Background: According to recent reports, sporadic synchronous endometrial and ovarian cancers (SEOCs) of endometrioid histology may be clonally related. We sought to characterize the clinicopathologic characteristics and outcomes of patients with SEOC compared to those with endometrial carcinoma felt to have metastasis to the ovaries. Methods: All patients with endometrial cancer who underwent primary surgery at our institution from 06/1993- 09/2014 were identified. We included cases with carcinoma in the endometrium and ovary. Pathology reports were reviewed to determine the pathologist’s assessment of whether the ovarian carcinomas were likely synchronous or metastatic. Patients with stage IV endometrial carcinoma, irrespective of presence of ovarian disease, were excluded. Appropriate statistical tests were performed. Results: We identified 76 eligible cases; 19 were deemed SEOCs and 57 endometrial carcinoma with ovarian metastasis (ECOM). Median age was 52 years (range, 32-71) and 63 years (range, 43-89), respectively (p = 0.4). Non-endometrioid histology was observed in 21% of SEOCs compared with 58% of ECOMs (p = 0.006). There was no myoinvasion in 32% of SEOCs compared with 9% of ECOMs (p = 0.01). Endometriosis was noted in 58% of SEOCs compared with 4% of ECOMs (p < 0.0001). The median follow-up time was 44.2 months (range, 0.4-201.4) for the entire cohort. The 4-year progression-free survival (PFS) rates were 82% (SE+/-9.5) for SEOCs and 51.6% (SE+/- 7) for ECOMs (p = 0.06). The 4-year overall survival (OS) rates were 94.7% (SE+/-5.1) for SEOCs and 69.8% (SE+/-6.2) for ECOMs (p = 0.046). The 4-year PFS rates for cases of endometrioid histology alone were 84% (SE+/-10.6) for SEOCs and 77.8% (SE+/-8.87) for ECOMs (p = 0.97). The 4-year OS rates for cases of endometrioid histology alone were 93.3% (SE+/-8.4) and 81.9% (SE+/-8.2), respectively (p = 0.3). Conclusions: SEOC was associated with more favorable endometrial factors and with the presence of endometriosis, consistent with the notion that these are likely dissemination by retrograde flux. SEOC was associated with better survival outcomes but not when analyzing endometrioid histology alone.
Molecular and clinicopathological classification of high risk endometrial cancer (EC) treated with concurrent chemoradiation therapy (CCT).
Authors: Gil-Martin Marta , Vidal-Bel August , Valle Laura , Velasco Ana , Pardo Beatriz , Recalde Sabela , Ventura Zaa Luz , Navarro-Perez Valentín , Sanz-Pamplona Rebeca , Marin i Borras Susanna , Ponce Jordi , Marti Lola , Barahona Marc , Rovira Jordi , Piulats Josep M. , Matias-Guiu Xavier
Published: September 2018

e17110

Background: Recently, TCGA proposed a molecular classification in EC that might hold prognostic significance. This project aim is to evaluate the outcome of high risk EC treated with CCT and its correlation with a surrogate molecular classification. Methods: A total of 49 patients (pts) treated from 2011 to 2016 were included in a prospective database. Pts were treated with 2 cycles (C) of cisplatin on days 1 and 28 concurrent with external beam radiotherapy (RT) of the pelvis, plus brachytherapy (BCT); followed by 4 C of paclitaxel and carboplatin every 3 weeks. The molecular classification into the 4 groups of TCGA (POLE mut, MSI, CN-low, CN-high/serous-like) has been performed in 38 pts using a surrogate classification that consists in POLE mutations detection by Sanger, and immunohistochemistry for p53 and MMR, as surrogate markers for TP53 mutations and MSI. Results: Pts median age was 67yo; Endometrioid pathology in 59%, serous 20% and others 20%; up to 73% were grade 3; and FIGO Stage III in 82%. All pts received full dose of RT, 80% BCT, and 75% completed 6C of CT. With a median follow-up of 39 months [17-65], 6% of pts experienced local recurrence, and 30% metastatic relapse. 3-year overall survival (OS) and cancer–specific survival (CSS) was 80%, and 3-year progression free survival was 74%. Median OS is not reached at this point. Pts were molecularly classified as: 0% POLE mut, 13% CN-low, 37% MSI and 50% CN-high. Survival data show that CN-low present an 3-y OS and CSS of 100%, MSI of 82% and CN-high of 67%. No statistically significant differences have been found, probably due to the low number of events and pts. It is remarkable the survival difference between endometrioid and serous tumors in the CN-high group (86% vs 50%, respectively). This tendency can be observed in TCGA pts as well. Conclusions: CCT followed by CT is an effective adjuvant therapy in high risk EC pts with an acceptable toxicity. Correlation with molecular prognostic classification has shown a big proportion of patients in the MSI and CN-high groups, known to have worse prognosis. Morphologic differentiation between endometrioid and serous carcinomas in CN-high group might still hold prognostic implications.
Norethindrone substituted for megestrol in the treatment of metastatic endometrial carcinoma: Three cases.
Authors: Trivedi Sumita , Williams Felicia , Read William L.
Published: September 2018

e17111

Background: Megestrol (M) is an effective palliative treatment for endometrial carcinoma but causes weight gain via activity at the corticosteroid receptor. Norethindrone (N) is a progestin without corticosteroid activity. We report 3 women with metastatic endometrial cancer responsive to M for whom a switch to N decreased side effects with continued cancer control. Methods: Case-series Results: 1. 62 year old with endometrial adenocarcinoma underwent surgery and chemoradiation. Lung metastases were discovered 31 months later and she began M with complete response at 13 months. She suffered weight gain and lymphedema. M was switched to N and continued for 4 years to date with weight loss and without progression. 2. 54 year old with endometrial adenocarcinoma underwent surgery and radiation. Lung metastases developed 30 months later. Chemotherapy produced response but was complicated by cerebrovascular accident. lung lesions developed 3 years later and slowly grew over the ensuing year. M was started and continued for 8 months. Her lung lesions responded but weight gain impacted her already reduced mobility. She was switched to N which has continued 11 months to date, with stable disease, without further weight gain. 3. 64 year old with a history of metastatic squamous cell carcinoma of the lung developed what was thought to be a second primary endometrial adenocarcinoma. She received surgery and radiation with pelvic recurrence 34 months later. M was started and continued for 17 months with response in pelvic and lung lesions, which proved to be metastatic endometrial carcinoma presenting before her primary. Weight gain resulted in wheelchair dependence. She was switched to N with continuing response over the ensuing 2 years. 28 months after starting N, imaging showed progression and she was switched back to M, her poor performance status precluding other treatments. She died 5 months later. Conclusions: In patients with metastatic endometrial cancer responding to megestrol, switching to norethindrone improved palliative benefit. Prospective clinical trials of norethindrone or similar progestins without corticosteroid activity should be considered for this population.
miRNA profiling in a case: Control study of African American women with uterine serous carcinoma (USC).
Authors: Lee Larissa Janeen , Howitt Brooke E. , Fendler Wojciech , Stawiski Konrad , Bu Paula , Cho Linda , Chowdhury Dipanjan , Matulonis Ursula A. , Konstantinopoulos Panagiotis A.
Published: September 2018

e17116

Background: USC is an aggressive subtype of endometrial cancer associated with worse outcomes in African American patients. We evaluated differences in tumor miRNA expression by race, clinical and tumor characteristics, and survival outcomes. Methods: FFPE tumor tissue from hysterectomy specimens was identified for 29 African American cases. Case matching was performed by computer-based random assignment in a 1:1 ratio with Caucasian controls based on age ( < 70 vs. ≥70 years), stage (FIGO I/II vs. III/IV) and histologic subtype (pure vs. mixed). RNA was extracted from 77 specimens with sufficient tumor cellularity (54 tumors and 23 matched normal endometrium). miRNA array profiling was performed by microRNA Hi-Power Labeling (Hy3/Hy5) and hybridization to miRCURY LNA microRNA Array 7th Gen (Exiqon, Denmark). Analysis was performed with R/Bioconductor using a moderated t-statistic with multiple testing correction. Validation was done using the TCGA dataset. Results: Clinical and treatment characteristics were similar for cases and controls, although use of adjuvant radiation was less common in African Americans (p = 0.03). With a median follow-up of 43 months, 17 patients had recurrent or progressive disease. DFS and OS rates were similar by race (both logrank p > 0.5). Of 968 miRNAs analyzed, 649 were differentially expressed in normal endometrium vs. tumor. When compared by race, histologic subtype, stage or presence of LVI, no differentially expressed miRNAs were identified. In patients with disease recurrence at 3 years, miR-223 was significantly upregulated (fold change 1.5; p = 0.002). In validation using a TCGA dataset of 131 patients with mixed (n = 22) or pure serous (n = 109) histology, increased miR-223 expression ( > median) was associated with worse overall survival (HR 2.47; 95%CI 0.9-6.6). After adjustment for patient age and BMI, upregulation of miR-223 was a significant risk factor for death (adjusted HR 2.94; 95%CI 1.01-8.52). Conclusions: Upregulation of miR-223 was associated with disease recurrence in a cohort of women with uterine serous carcinoma and validated by TCGA data. miRNA profiling did not identify biological differences between African American and Caucasian patients.
Multi gene panel testing in unselected patients (pts) with endometrial cancer (EC).
Authors: Cadoo Karen Anne , DeLair Deborah , Mandelker Diana , Barakat Richard R. , Brown Carol L. , Chi Dennis , Gardner Ginger J. , Jewell Elizabeth Lin , Leitao Mario M. , Long Kara , Mueller Jennifer Jean , Sonoda Yukio , Zivanovic Oliver , Berger Michael F. , Zhang Liying , Robson Mark E. , Offit Kenneth , Aghajanian Carol , Abu-Rustum Nadeem , Stadler Zsofia Kinga
Published: September 2018

e17119

Background: Inherited mutations (muts) in Lynch Syndrome genes (LS) & PTEN are associated with EC. The prevalence of other cancer predisposition genes is unclear. The majority of studies have selected pts by age, family history or specific tumor features. We sought the prevalence of cancer predisposition genes in unselected pts attending for surgical consultation. Methods: 03/2016-10/2016, pts with new EC diagnosis were offered to consent to an IRB approved protocol. Tumor-normal sequencing, was performed via a custom next-generation sequencing panel (MSK-IMPACT) with return of results for 76 cancer predisposition genes. Per institutional standard, all ECs undergo reflex screening for LS with IHC for mismatch repair proteins (MMR P). Results:77 pts consented, median age 60 (27-84), median BMI 27 (16-66), 27% Ashkenazi Jewish (AJ) descent. Tumors: 56 (73%) stage 1, remainder stage 3 or 4, majority (52, 68%) endometrioid histology, of which 31 (60%) grade 1. 15 pathogenic germline variants were identified in 14 pts (18%) including 3 (4%) in LS genes (2 MSH6, 1 MLH1) with corresponding abnormal MMR P. One pt with a known BRCA1 mutation, without prior cancer, with prior risk reducing salpingo-oophorectomy had stage III grade 3 endometrioid EC at 47 yo, tumor LOH at BRCA1 was identified. Of the 4 pts with high-penetrance muts, 3 met criteria for genetic testing for the implicated gene due to personal/family cancer history, 1 pt with MSH6 mutation was identified via absent MMR P only. The remaining 11 pathogenic variants were incremental findings in moderate penetrance ( CHEK2 I157T, MRE11, ATM, APC I1307K, MUTYH) or autosomal recessive genes ( MUTYH, RECQL4, ATM). 5 pt had moderate penetrance variants in known AJ founder muts. Conclusions: In this cohort of unselected EC pts the prevalence of LS was as expected & reflex IHC screening captured all pts appropriately. While all high-penetrance muts were captured by clinical criteria, the incremental identification of moderate penetrance muts in these largely early stage/ low risk EC pts may alter personal & at-risk family member breast & colon cancer screening recommendations. Continuing accrual will reveal the extent to which additional high penetrance genes are seen in unselected EC pts.
Impact of metformin on survival and mTOR pathway in head and neck cancer patients: An updated analysis.
Authors: Gulati Shuchi , Takiar Vinita , Mark Jonathan , Butler Randall , NeCamp Joshua , Wise-Draper Trisha Michel
Published: September 2018

e17500

Background: Metformin is hypothesized to suppress tumor cell growth by mTOR pathway inhibition, which mediates the phosphoinositide 3-kinase/Akt signaling pathway (frequently deregulated in human cancers). This effect is mediated by activation of the AMP protein kinase (AMPK). Despite knowledge of the mechanism, various retrospective studies show conflicting results about effect of metformin on survival in head and neck squamous cell carcinoma (HNSCC) patients (pts). Methods: We analyzed a retrospective cohort of 1500 consecutive pts (between 2009-2015) with HNSCC. We added about 1000 pts to previously presented data (e17514-ASCO 2016). These pts included those with diabetes (DM) on metformin (MET) or other anti-diabetic agents. Descriptive statistics were used for demographic and pt data. Kaplan-Meier method was used to calculate median overall survival (OS) and progression free survival (PFS), 95% CI. Cox model was used to test association between MET (or DM) and OS (or PFS) (using SPSS-24 (IBM)). Results: Of the 1500 pts with HNSCC, 329 had advanced cancer (stage III/ IV), and received definitive chemo-radiation (CRT). Of these, majority were Caucasian (90%), males (90%) and smokers (70%). Mean age at diagnosis was 57 years (SD 10). 53 pts had DM, of which 37 were on MET. Statistical results are shown in Table 1. Conclusions: This retrospective study showed no statistically significant difference between various subgroups described in the table. Given the low number of diabetics, and pts on MET, data is limiting. However, further subset analyses are ongoing to determine whether a difference in treatment (RT vs. cetuximab vs. cisplatin) had an impact on outcomes. Future experiments will utilize tissue microarrays to evaluate for association with mTOR pathway aberrations. [Table: see text][Table: see text]
Unmet needs in head and neck cancer patients: Unmet needs, emotional disorders, and pain.
Authors: Airoldi Mario , Ostellino Oliviero , Raimondo Luca , Pecorari Giancarlo , Franco Pierfrancesco , Rampino Monica , Succo Giovanni , Denegri Martina , Tosi Chiara , Botto Rossana , Torta Riccardo , Ieraci Valentina
Published: September 2018

e17501

Background: knowledge is still lacking about head and neck patients’ unmet needs and their association with the other debilitating symptomatologies that worsen Quality of Life (QoL), compliance to treatments and prognosis. The aim of this research, so, it was to investigate the unmet needs of this type of patients in accordance with sympomts. Beside this study tried to evaluate if patients’ needs were correctly understood by their caregivers, nurses and oncologist. Methods: we surveyed 100 patients (80 men and 20 women) with head and neck cancer, during the active phase of chemotherapy treatmet,58 caregivers’ patients, nurses and the oncologist. The axious symptomatology and the depressive symptomatology were assessed by the Hospital Anxiety and Depression Scale (HADS). Distress was assessed by the Distress Thermometer (DT). Unmet needs were assessed from patients and their caregivers by Supportive Care Needs Survey-short Form (SCNS-SF34); nurses and the oncologist had to answer only to the 5 questionnaire’s macro-areas. Pain was assessed using the answer given to the SCNS-SF34’s first item. Results: having unmet needs in the psychological area is associated with the presence of symptoms in the preceding 24 hours (c2 = 10.213 , p = .001). Unmet needs in the communicative and informative area are associated with pain (c2 = 5.260 , p = .022). Unmet needs in physical conditions and daily living area are associated with pain (c2 = 9.962 , p = .002) and the presence of symptoms in the preceding 24 hours (c2 = 6.760 , p = .009). Unmet needs in patient support and health care area is associated with: distress (c2 = 4.459 , p = .035), anxious symptomatology (c2 = 4.071 , p = .044) and pain (c2 = 14.733 , p = .000). Unmet needs in sexuality area are associated with anxious symptomatology (c2 = 7.328 , p = .007) and pain (c2 = 4.833 , p = .028). Feelings about death and dying are associated with anxious symptomatology (c2 = 6.451 , p = .011) and depressive symptomatology (c2 = 5.317 , p = .021). Caregivers and patients both detect the presence of unmet needs in many areas. Conclusions: there tare several associations found between unmet needs and main symptomatologies that negatively impact with patient’s QoL and prognosis.
Could neutrophil to lymphocyte ratio (NLR), derived neutrophil to lymphocyte ratio (dNLR), platelet to lymphocyte ratio (PLT), and lymphocyte to monocyte ratio be common independent prognostic factors in head and neck squamous cell carcinoma?
Authors: Manikhas Georgy M. , Kutukova Svetlana I. , Beliak Natalia P. , Popova Natalia V. , Zhukova Natalia V. , Ivaskova Julia V. , Erdniev Sanal
Published: September 2018

e17519

Background: The purpose of our study was to investigate prognostic role of neutrophil to lymphocyte ratio (NLR), derived neutrophil to lymphocyte ratio (dNLR), platelet to lymphocyte ratio (PLR), and lymphocyte to monocyte ratio in PFS and OS, and immunological tumor’s microenvironment in patient with HNSCC. Methods: We analysed medical records an tumor samples of 60 patients with HNSCC with stage I - IVB (37 men, 23 women; median age 59). All patients were under standard clinical complex protocol. All patients were under our supervision from 2010 to 2015. We examined demographic data, clinical stage, tumor morphological characteristics and specific level of expression of CD8(+) T-cells, in the tumor and microenvironment, and baseline level of WBC, neutrophil, lymphocyte, monocyte and PLT . Also we analysed calculated value of NLR, dNLR, PLR, and LMR. Results: The median value of NLR was 2.03 (95% CI: 1.66-2.59), dNLR - 1.44 (95% CI: 1.23-1.70), PLR - 144.58 (95% CI: 107.59-179.32) and LMR - 6.79 (95% CI: 5.34-8.17). Median of 1-year OS and PFS was non significantly lower in pts with NLR < 2.03 (16.0 vs 18.0 month, p = 0.6020 and 5.00 vs 7.00 month, p = 0.5383). But NLR correlate with expression of CD8(+) T-cell in tumor (p = 0.05). Median of 1-year OS was the same in both group (16.0 vs 17.0 month, p = 0.5453), PFS was non significantly lower in pts with dNLR < 1.44 (16.0 vs 18.0 month, p = 0.6020 and (5.00 vs 7.00 month, p = 0.7435). NLR correlate with expression of CD8(+) T-cell in tumor (p = 0.0337). Analyse of LMR showed trend of best 1-year OS in pts with LMR < 6.79 (18.0 vs 15.0 month, p = 0.4674) and equal PFS (6.00 vs 7.00 month, p = 0.4914). PFS and 1-year OS were better (nonsignificant) in pts with PLT > 144.58 (9.0 vs 5.0 month, p = 0.5854) and (18.0 vs 16.0 month, p = 0.5836). Conclusions: Important role of indicators of systemic inflammation is obvious for patient with HNSCC, but our study showed that only baseline characteristics couldn’t be strong prognostic factors by different degree of intratumor inflammation.
Human papillomavirus (HPV)-related oropharyngeal cancer cofactors: Viral co-infections, second cancers, and survival trends—A single Veterans Administration (VA) institution.
Authors: Dawson George Anthony , Zhang Yue Hua , Laurio Angela , Smith Patricia , Dellatto Michael , Innis-Gordon Fiona T. , Reino Anthony
Published: September 2018

e17531

Background: Oropharyngeal cancers related to HPV are increasing in number. Common factors associated with HPV related head and neck cancers include ethnicity, young age, and low usage of alcohol and tobacco. All are typical of HPV+ related Oropharyngeal cancer in non-VA populations. Methods: This IRB approved chart review of 73 documented patients with Oropharyngeal cancers from co-HPV infections from 01/01/2011 - 12/31/2016. In this version of report we discuss second cancers, trends and other co-factors. Results: Overall trend was notable for a reversal (more HPV+ / less HPV- ) cases. All cancers were squamous cell variety. 2011 /2012 /2013/ 2014/2015/2016 HPV +: 4 / 4 / 0 / 6 / 11 / 7. HPV -: 6 / 8 / 4 / 8 / 6 / 5. Clinical stage: Evident adenopathy - (N2 to N3) was noted in 51/73(70%) cases: HPV+ 30/36 (83%) / HPV- 21/37(57%). As noted, there are ~40 co-factor events in each group with no clear association with HPV + or – status numbers of cases were too small for meaningful analysis. Second Cancers HPV+: PROSTATE 7 / BLADDER 2 / TESTICULAR 1 / RENAL 1 / LUNG 1 / SKIN 4. HPV- : FOM 2 / LARYNX 2 / TONSILLAR 1 / PAROTID 1 / BLADDER 1 / SKIN 5 / PROSTATE 1 / LUNG 1. Survival data results: There was evidence in our data that survival was prolonged in patients who are HPV negative, but this sample was too small to show statistical significance. Further, it appears white race improves the odds of survival p-value 0.073, however, not statistically significant, due to the small sample. Conclusions: As in the non-VA community, our data noted an increase in HPV+ oropharyngeal cancers treated at the Bronx VA during review period. Further, our HPV+ group had predominant advanced adenopathy, and whites had longer survival regardless of HPV status. Second cancers in HPV- group followed field cancerization effects in regards number new or old head / neck cancer events. Interestingly, with almost equal tobacco / alcohol use in both groups, no 2nd head and neck cancers in the HPV+ group were discovered. Potential immuno-protection for HPV+ 2nd h and N cancers.[Table: see text]
Mutational profile of HPV-driven head and neck cancers according to tobacco consumption.
Authors: Mirghani Haitham , Lacroix Ludovic , Casiraghi Odile , Auperin Anne , Rossoni Caroline , Villepelet Aude , Lacave Roger , Marty Virginie , Even Caroline
Published: September 2018

e17535

Background: HPV-driven oropharyngeal cancer (OPC) patients are characterized by a better prognosis than their HPV-negative counterparts. However, this significant survival advantage is not homogeneous and studies have highlighted that among HPV-positive patients those with a smoking history have a significantly increased risk of disease progression and death compared to those who have never smoked. The reason why tobacco consumption impacts negatively the prognosis is still elusive. Tobacco might induce additional genetic alterations leading to a more aggressive phenotype. The purpose of this study is to characterize the mutational profile of HPV-positive OPC by smoking status. We hypothesize a higher frequency of mutations affecting among smokers. Methods: Targeted next-generation sequencing of 38 oncogenes/tumor suppressor genes that are commonly mutated in cancers caused by tobacco/alcohol consumption was performed in 62 HPV-driven OPC cases stratified by smoking status. Results: The study population included 37 (60%) non-smokers and 25 (40%) smokers distributed as follows: 1 (4%) patient smoked <10 pack-year (PY), 8 (32%) patients between 10-20 PY and 16 (64%) >20 PY. Twenty (31%) patients had no mutation, 14 (23%) had 1 mutation and 28 (46%) had 2 or more mutations. The most commonly mutated genes regardless of tobacco consumption were PIK3CA (20%), MLL2 (20%), TP53 (8%), FAT 1 (15%), FBXW7 (16%), NOTCH 1 (9%) and FGFR3 (9%). Mutation rate was not significantly different in smokers compared to non-smokers even when analyses focused on heavy smokers (>20 pack-years compared to <20 pack-years). Similarly there was no significant difference in mutations patterns according to tobacco consumption. The 3 years overall survival, disease-specific-survival and loco-regional-control rates for the whole cohort are respectively 88% (95% CI: 76.4-94.1), 88% (95% CI: 76.4-94.1) and 80.6% (95% CI: 67.5-88.8). Despite a median follow-up was 4.5 years (6 months to 11.7 years), the few number of events (13 relapses, 13 deaths including 10 due to OPC) precludes detailed prognosis analyses. Conclusions: HPV-driven OPC patients with a smoking history have a comparable mutational rate than non-smokers. Smoking impact on the prognosis isn’t attributable to the mutational burden. Further studies are warranted.
Lymphocyte apoptosis as a predictive biomarker for radiotherapy de-intensification in EBV-associated nasopharynx cancer.
Authors: Chua Kevin Lee Min , Shihabuddeen Waseem Ahamed , Shwe Than Than , Tan Sze Huey , Wee Joseph , Tan Terence , Chua Melvin
Published: September 2018

e17545

Background: Emerging evidence in viral-associated head and neck cancers supports the concept of dose de-intensification in these radiosensitive tumors, but different strategies exist in selecting patients for treatment de-intensification. We hypothesize that patients who develop severe late toxicities (LT) to radiation (RT) have better tumor control, due to a common radiosensitivity index. Here, we investigate the utility of a normal tissue radiosensitivity assay (RT-induced lymphocyte apoptosis, RILA) in predicting clinical outcomes (tumor control and normal tissue toxicity) of patients with EBV-associated nasopharynx cancer (NPC). Methods: RILA assay was assessed in a cohort of locally advanced NPC patients from a randomized controlled phase III trial (N = 172, NCC0901) of cisplatin-RT with or without induction gemcitabine, carboplatin and paclitaxel. LT was assessed by CTCAE v.2 at the following intervals (2 mo yr 1, 4 mo yr 2, 6 mo yr 3-5, annually thereafter). We performed the RILA assay (48 h post 8 Gy) in a subset of cases (N = 87). Results: At a median follow-up of 5.7y, DFS (3y 74.9% GCP vs 67.4% Control, p = 0.362) and incidence of severe Grade ≥3 LT did not differ between the treatment arms. In keeping with our hypothesis, onset of severe LT was associated with reduced risk of disease relapse; OR 0.19 (95% CI = 0.02 – 1.59, p = 0.168). High %RILA, stratified by top quartile, was associated with severe LT (OR 1.92 [95% CI = 0.67-5.5], p = 0.26); and lower rate of recurrence (4.5% (1/22), high %RILA vs19.7% (12/61), low %RILA, p = 0.086). Interestingly, subset analyses revealed that CD8+, but not CD4+ subpopulation of immune cells, was strongly associated with recurrence; OR 8.58 for low %CD8-RILA (p = 0.001). Conclusions: Herein, we showed that %RILA may be a useful biomarker for tumor and normal tissue radiosensitivity of EBV-associated NPC. If validated, this predictive assay will enable precision matching of RT-sensitive patients for de-intensification in EBV- and other viral-associated head and neck cancers. The association between tumor control and CD8-subset of immune cells suggests an immune dependency for RT.
Phase II trial of valproic acid combined with cisplatin-based chemoradiation in locally advanced (LA) head and neck squamous cell carcinoma (HNSCC) patients (pts).
Authors: Mak Milena Perez , Pasini Fatima Solange , Diao Lixia , Garcia Fabyane Oliveira Teixeira , Takahashi Tiago Kenji , Amadio Alex Vitorio , Siqueira Sheila Aparecida Coelho , Sichero Laura , Snitcovsky Igor M. L. , Kulcsar Marco Aurelio Vamondes , Wang Jing , Castro Gilberto
Published: September 2018

e17546

Background: Cisplatin-based chemoradiation (CRT) offers LA HNSCC pts a high local control rate, however, relapses are frequent. Here we evaluated if epigenetic regulation by VA, a histone deacetylase inhibitor (HDACi), combined with CRT in LA HNSCC improves response rate (RR). Methods: Patients with unresectable oropharynx (OP) and oral cavity LA HNSCC were included in this Simon two-stage phase II trial. After two weeks of VA (P1), CRT was initiated. Primary goal was RR at 8 weeks after CRT+VA (P2) by RECIST v 1.1. 8/20 and 25/32 responses were needed in the first and second stages for the trial to be considered positive (α = 0.05, β = 0.2). MicroRNA (miR) PCR-array profiling in plasma samples at baseline, P1 and P2, was compared to healthy controls by two sample t-test for each miR. Distribution of p-values was analyzed by beta-uniform mixture. HDAC2 and HR23B tumor immunohistochemistry were also evaluated. Results: Ten LA p16 negative OP pts were included. High-risk HPV was detected in 3 pts samples. Median age was 55 years (41-65). All pts were male, smokers or ex-smokers and with previous moderate/high alcohol intake. Due to significant toxicities seen in an interim safety analysis, accrual was terminated. A RR of 88% was achieved in 9 evaluable pts. A total of 169 miRs were differently expressed among pts and controls (FDR 0.05), including lower expression of known tumor suppressors (TS) such as miR-31, -222, -let-7b and -145. There were no significant differences in the pattern of miR expression at P1 vs. baseline. P2 vs. baseline had lower levels of miR-31, particularly in responders (p 0.007). TCGA HNSCC pts with low levels of miR-31 had a trend towards higher relapse free survival (HR 1.11, 95% CI 0.99-1.25; p = 0.073). Non-responders had no difference in miR expression between baseline and P2. HDAC2 H-score above 170 was 90% accurate in predicting 6-month disease free survival. Conclusions: Although improved RR was seen with VA+CRT, prohibitive toxicities prevented the trial from continuing. Cancer pts and controls had distinct pattern of miR expression, mainly with low levels of TS targeting TP53. miR-31 deregulation in HNSCC needs to be further elucidated. Clinical trial information: NCT01695122.
Prediction model for cervical lymph node metastasis using CT characteristics in patients with head and neck squamous cell carcinoma.
Authors: Choi Young Jun , Chung Mi Sun , Lee Jeong Hyun
Published: September 2018

e17547

Background: Lymph node metastasis is a major prognostic determinant for patients with head and neck squamous cell cancer (HNSCC). This study aimed to construct a predictive model using CT characteristics of lymph node and tumor for patients with HNSCC to stratify the risk of lymph node metastasis. Methods: The study population was obtained from historical cohort of 472 cervical lymph nodes from 191 patients with HNSCC in a tertiary referral hospital. We analyzed preoperative CT images of lymph nodes according to diameter, ratio of long-to-short axis diameter, necrosis or cystic change, conglomeration, infiltration to adjacent soft tissue, and laterality (ipsilateral vs contralateral) and analyzed T stage. Reference standard was surgical pathologic results. Multivariate logistic regression analysis was performed to predict whether nodules were diagnosed as metastasis or benign. Results: CT features of lymph nodes, including minimal axial diameter, ratio of long-to-short axis diameter, necrosis or cystic change, and T stage were selected as predictors for lymph nodes metastasis. A 10-point risk scoring system was developed, and the risk of malignancy ranged from 7.3% to 99.8%, which was positively associated with increases in risk scores. The areas under the receiver operating characteristic curve of the development and validation sets were 0.886 and 0.879, respectively. Conclusions: We have devised a simple predictive model using the CT characteristics of lymph nodes and tumor for HNSCC to stratify the risk of cervical lymph node metastasis. [Table: see text]
Immune-related saliva micro-RNA’s to predict clinical response to a combination of cetuximab and low-dose chemotherapy in head and neck cancer (HNSCC) patients (pts) with poor performance status (PS).
Authors: Bonomi Marcelo Raul , Ado Safoa , Kooshki Mitra , Ahmed Tamjeed , Sullivan Christopher , Waltonen Joshua , Triozzi Pierre
Published: September 2018

e17548

Background: Recurrent/Metastatic HNSCC is an immunosuppressive disease, especially in the group of patients with poor performance status. Recent studies have shown that low dose chemotherapy, which is much better tolerated than full dose cytotoxic chemotherapy, can increase the anti-tumor immune response and cause tumor regression. In this study we assessed the immune-effects of weekly cetuximab in combination with low dose weekly chemotherapy in HNSCC pts with poor PS by measuring saliva and plasma immune modulatory micro RNAs (miRs). Methods: Patients with recurrent/metastatic HNC with an ECOG PS of 2 or 3 were treated with low-dose weekly carboplatin (AUC 1) and paclitaxel (25 mg/m2) along with weekly cetuximab (400mg/m2 followed by 250 mg/m2). Seven immune modulatory miRs (146a, 155, 181, 20a, 223, 335, 125b) were measured in the saliva and plasma by quantitative PCR prior to treatment and at week 5. Results: Between 4/2016 and 1/2017, 30 patients were enrolled in this study. 24 patients were evaluable for response. Mean age was 69 years (range 51-89), Male/Female: 14/8. ECOG PS 2/3: 13/9. Site of disease: oral cavity 7, pharynx 9, larynx 4, para-nasal 2, unknown 2. Treatment was well tolerated. The most common dose limiting toxicity was skin rash in 10/24 pts (41.5%). Response: partial response 12 (50%); stable disease 4 (16.5%); progressive disease 8 (33.5%). Reduction in miR levels by week 5 were associated with clinical response. Reduction in saliva levels of miRs 146a and 181 correlated with clinical benefit (PR+SD). Pre-treatment saliva levels of miR 146a also showed to be a predictor of tumor response to therapy. Plasma levels of the immune modulatory miRs tested were not associated with response to therapy. Conclusions: The combination of cetuximab and low-dose chemotherapy is active and well tolerated in HNSCC patients with poor PS. Reduction in saliva levels of immune modulatory miRs 146a and 181 were associated with clinical benefit to therapy.
Effect of cetuximab on development of viral infectious complications in laryngeal cancer.
Authors: Vladimirova Liubov Yu , Zykova Tatiana , Ryadinskaya Ludmila A. , Engibaryan Marina , Storozhakova Anna E , Abramova Natalya A , Popova Irina L , Tikhanovskaya Natalya Mikhailovna , Agieva Aza , Pustovaya Irina Viktorovna , Ulianova Yulia
Published: September 2018

e17578

Background: Cytostatic treatment was shown to influence significantly reactivation of latent viral infections. Our purpose was to study the possible effect of cetuximab on activation of herpesvirus infections. Methods: The blood serum of patients with histologically confirmed laryngeal squamous cell carcinoma was studied before and after chemotherapy. The main group included 9 pts receiving cetuximab+cisplatin+5-fluorouracil, the control group – 9 pts, cisplatin+5-fluorouracil. Antibodies (AB) against viral proteins were detected by ELISA. Results: 6 (66.7%) pts of the main group had primary advanced cancer, 3 (33.7%) – recurrent laryngeal cancer; in control group - 7 (77.7%) and 2 (22.2%), respectively. All pts in both groups were seropositive for HSV 1,2, CMV and EBV before chemotherapy; 4 (44.4%) pts in main group and 7 (77.8%) controls were HPV 6 seropositive. Serological markers of activation of herpes virus infection (IgM or IgG against early viral proteins) after chemotherapy were detected in the main group in 8 (88.9%): HSV 1,2 - 5 (55.6%), CMV - 2 (22.2%), EBV - 3 (33.3%). HSV 1,2, CMV and EBV infections in the control group were activated equally often and found in 3 (33.3%) pts. Clinical signs of herpes virus infection were not observed in either group. A sharp decline in AB titers, sometimes up to their complete disappearance, was registered in 3 (33.3%) pts in the main group and in 6 (66.7%) controls. 1 pt of the main group showed a decline in EBV AB titers and absence of HPV 6 AB titers, 1 pt - a decline in CMV and EBV AB, 1 pt - a decline in HSV 1,2, CMV and EBV AB and absence of HPV 6 AB titers. 2 pts of the control group showed a decrease in HPV 6 AB, 2 pts – their absence, 2 pts – absence of HPV 6 AB and a decline in HSV 1,2, CMV and EBV AB. It could be associated with a greater degree of bone marrow hematopoiesis inhibition during cytostatic therapy. Lymphopenia was registered in the control group more frequently than in the main one. Conclusions: Cetuximab inclusion into chemotherapy does not have an additional negative impact on the development of viral infectious complications. A higher rate of registration of specific antibodies typical of the acute infection phase in the cetuximab group could indicate an adequate response to viral infection.
Changes in blood parameters of patients with laryngeal squamous cell carcinoma during polychemotherapy with cetuximab.
Authors: Vladimirova Liubov Yu , Guskova Nailya , Ryadinskaya Ludmila A. , Engibaryan Marina , Donskaya Aliya K. , Guskova Ekaterina , Gusareva Marina A. , Golomeeva Nadezhda , Abakumova Svetlana V. , Tselishcheva Irina V. , Avanesova Kristina , Nozdricheva Anastasia , Zakharchenko Viktoria , Belgova Svetlana V. , Gornostaeva Ekaterina
Published: September 2018

e17579

Background: Our purpose was to evaluate changes in blood parameters in patients with laryngeal squamous cell carcinoma (LSCC) during polychemotherapy (PCT) with cetuximab. Methods: Levels of white blood cells (WBC), immature granulocytes (IG) and neutrophils (Ne), as well as levels of C-reactive protein (CRP), lactate dehydrogenase (LDH) and creatinine were studied in the blood of 20 patients with stage I-III LSCC before therapy with cetuximab/cisplatin+5-fluorouracil and on days 2, 9 and 16 of the therapy. The control group (21 patients) received similar PCT without cetuximab. Treatment was assessed using the RECIST criteria. Results: Partial response was observed in 16 (80%) patients of the main group and in 5 (23.8%) controls, stabilization - 4 (20%) and 12 (57.4%), respectively, progression – in 4 (19%) patients of the control group. Patients of the main group with treatment effect showed WBC increase by 2 times after every cetuximab injection (days 2, 9, 16) compared with the initial levels due to Ne and IG increase by 2.7 and 4 times, respectively. WBC and IG levels measured on days 2, 9 and 16 were 13.40±2.86×109/L, 13.52±1.88×109/L, 12.25±2.08×109/L and 0.044±0.021×109/L, 0.056±0.015×109/L, 0.060±0.008×109/L, respectively (p < 0.001). A transient increase in the indexes was replaced by their decrease to the initial values, with the values similar to the reference ones by the end of the treatment. At the same time, we observed decrease in CRP and creatinine levels up to the reference levels (7.69±3.28 mg/L and 74.75±6.54 umol/L, respectively); LDH did not increase. Stabilization was characterized by unchanged WBC levels, positive dynamics of IG and slow decline of CRP level exceeding the reference one (10.0 mg/L) by the treatment end. Reduction of WBC and increase in IG and CRP levels were noted in the controls regardless of the PCT results which could be explained by severity of intoxication syndrome, partially due to the disease and partially due to PCT toxicity. Conclusions: A dual transient increase in WBC and IG levels, reduction of CRP and creatinine during the treatment and unchanged LDH indicate minimization of myelotoxic and general toxic effects of PCT in combination with cetuximab.
A new combination therapy using recombinant human adenovirus p53 injection (rAd-p53) to manage advanced thyroid cancer.
Authors: Zhu Jingqiang
Published: September 2018

e17585

Background: Although most thyroid cancers have good clinical outcomes, there still have some advanced and radioiodine-resistant thyroid cancers being lack of effective treatment. In this study, we reported a new combination therapy including recombinant adenovirus-p53 (rAd-p53) to treat advanced thyroid cancers. Methods: Two types of unresectable cancers (one advanced PTC and one ATC) received preoperative intratumoral injection of rAd-p53 combined with radiotherapy to shrink the tumor and surgery to remove the tumor. In the matched controlled clinical trial, 82 advanced PTC patients accorded with the inclusive criteria and exclusion criteria were included and matched into experimental group (EG, n = 41) and control group (CG, n = 41). Compared CG received surgery only, EG received preoperative intratumoral injection of 2×1012rAd-p53 viral particles (VP) per 3 days for 5 times and surgery. Results: In the advanced PTC case, the combination treatments including rAd-p53 gene therapy combined with radiotherapy evidently shrunk the tumor and improved the operative condition. Finally, the patient received a successful surgery to remove the tumor totally. In the ATC case, rAd-p53combined radiotherapy obvious relieved enlargement of the lump in the neck and shrunk the tumor. More importantly, the program of surgery to excise the tumor was deemed suitable for this ATC patient through a series of treatments and severity evaluation. In the matched controlled clinical study, compared the control group (CG), rAd-p53 significantly increased the radically operative rate in experiment group (EG) (92.7% vs73.2 %, P= 0.021, n = 41). The 7 years follow-up data showed rAd-p53 decreased locoregional recurrence rate (19.51% vs 36.59%) and new metastasis rate (7.32% vs 17.07%) and increased the median time to locoregional recurrence (24.5 M vs 23.27 M) and new metastasis (19.0 M vs 9.2 M) and the disease-free survival rate (75.61% vs 46.34%) for patients in EG. Conclusions: The combination therapy improved the prognosis to patients with advanced thyroid cancer, indicating this combination therapy including rAd-p53 has an important implication for managing advanced thyroid cancer.