bluuebunny/crossref_metadata_2025 huggingface dataset:
Bovine milk-derived exosomes mediated delivery of resibufogenin and its effect on platinum-resistant ovarian carcinoma.
Authors: Zhou Guannan , Ding Jingxin
Published: May 2019

e17065

Background: Platinum-resistant ovarian carcinoma presents poor prognosis owing to its chemotherapeutic resistance. Resibufogenin is a kind of traditional Chinese medicine with potential anti-cancer ability. Exosomes are naturally occurring membrane particles that mediate intercellular communication by delivering molecular information between cells. The purpose of the current study was to evaluate the effect of bovine-milk-derived exosomes as carriers of resibufogenin to Platinum-resistant ovarian carcinoma and investigate the mechanism. Methods: Exosomes were isolated from bovine-milk using differential centrifugation and characterized by electron microscopy, nanoparticle tracking analysis, and western blot. Drug screening among 172 traditional Chinese medicines to find out resibufogenin. The exosomes were loaded with resibufogenin and the effectiveness of exosome-mediated drug was assessed with viability assay, transwell assay and flow cytometry assay. The distribution of exosome-delivered resibufogenin in cells was inspected by confocal microscopy. Xenograft mouse models were constructed to clarify the treatment response in vivo. mRNA sequencing assay, qPCR assay, immunohistochemistry assay and western blotting assay were used to detect and verify the targeted pathways. Results: Our main finding that resibufogenin inhibits the proliferation, migration and invasion in platinum-resistant ovarian carcinoma. Bovine-milk-derived exosomes delivered resibufogenin into platinum-resistant ovarian carcinoma and enhanced the cytotoxicity of resibufogenin. In vivo experiment demonstrated that resibufogenin suppressed the growth of xenograft tumors, with lower ki-67 expression and higher tunel expression. The mRNA sequencing assay, qPCR assay, immunohistochemistry assay and western blotting assay showed that the PI3K/AKT and Regulation of actin cytoskeleton signaling pathways account for the results above. Conclusions: Bovine-milk-derived exosomes can be used as effective carriers of resibufogenin to platinum-resistant ovarian carcinoma. Bovine-milk-derived exosomes-loading resibufogenin inhibits platinum-resistant ovarian carcinoma growth and migration in vitro and in vivo through PI3K/AKT and Regulation of actin cytoskeleton signaling pathway.
Prognostic value of monocyte to lymphocyte ratio (MLR) in epithelial ovarian cancer (EOC).
Authors: Cucurull Marc , Felip Eudald , Garcia Juan Jose , Erasun Carlos , Angelats Laura , Teruel Iris , Martinez-Román Sergi , Hernández Joaquin , Esteve Anna , España Sofia , Romeo Margarita
Published: May 2019

e17066

Background: Identifying high-risk early-stage EOC patients (p) is a major issue. Also, controversy about the role of neoadjuvant chemotherapy prior to surgery in advanced EOC is still ongoing. A high MLR is related to poorer outcomes in several cancers, and also in ovarian cancer according to limited retrospective series. We explored the clinical value of MLR in a cohort of EOC p. Methods: We included all EOC p diagnosed in our center, from January 2008 to April 2017, who had undergone radical treatment. Overall survival (OS) was assessed by Kaplan Meyer. Maximally selected rank statistics was used to determine the MLR cut-off value for the greatest OS discrimination. The hazard ratio (HR) of death of MLR was explored by multivariate Cox regression models, adjusted by age at diagnosis, stage I/II versus (vs) III/IV, high grade serous carcinomas (HGSC) vs other, primary surgery vs interval surgery after neoadjuvant chemotherapy (PS, IS), residual disease < 1 vs > 1cm, year of diagnosis, and hemoglobin, neutrophils, platelets and MLR at diagnosis. Results: 124 p were included. Median age at diagnosis was 58.7 years; 55.6% were HGSC;67.7% stage III/IV; 69.3% received PS; 14.3% had residual disease > 1cm. Median OS was 75 months. MLR was the laboratory parameter that more significantly impacted on OS in our model (p = 0.02). Optimal MLR cut-off was 0.38. The MLR > 0.38 group (MLR-hi) had a higher-risk of death (HR = 2.9; 95% IC: 1.3–6.5) with respect to those with MLR < = 0.38 (MLR-lo). Median OS were 100 and 35 months, respectively. In the MLR-lo group, median age at diagnosis was 56.9 years (vs 61.9 in the MLR-hi, p 0.047), 44.8% were HGSC (vs 61.2%, p 0.134), and 49.97% were stages I/II (vs 14.2%, p 0.001). MLR-hi p who had undergone PS or IS had similar OS (p = 0.63). In contrast, among MLR-lo p, PS showed significantly higher OS than IS (p < 0.0001). Conclusions: In our cohort, MLR was an independent prognostic factor in EOC. Its potential role to identify high-risk early-stage p and to predict worse outcomes after PS among advanced-stage p need to be explored in larger cohorts.
Poly adenosine diphosphate ribose polymerase inhibitors maintenance in patients with ovarian cancer: A systematic review and meta-analysis of randomized controlled trials.
Authors: WIN Htut Thura , Tun Aung , Sultan Anita , Swarup Sriman , Zaw Myo , Hlaing Pwint Phyu , Myat Yin Mon , Jahan Nusrat , Mogollon-Duffo Francis , Rehman Shabnam , Hardwicke Fred L. , Thein Kyaw Zin
Published: May 2019

e17081

Background: Ovarian cancer is the deadliest of gynecologic cancers and many recur despite achieving a clinical response to initial platinum-based chemotherapy. The use of poly adenosine diphosphate ribose polymerase (PARP) inhibitors maintenance has shown to improve survival in ovarian cancer. Methods: MEDLINE, EMBASE databases and meeting abstracts from inception through January 2019 were queried. Phase 3 randomized controlled trials (RCT) which employed PARP inhibitors maintenance in ovarian cancer were incorporated in the analysis. A generic inverse variance method was used to calculate the estimated pooled hazard ratio (HR) for progression-free survival (PFS) with 95% confidence interval (CI). Heterogeneity was assessed with Cochrane Q -statistic. Random effects were used due to some heterogeneity among studies. Results: Four phase III RCTs with a total of 1792 patients were eligible. The study arm used olaparib or niraparib or rucaparib while the control arm utilized placebo. The randomization ratio was 2:1 in all studies. Participants were sensitive to platinum-based chemotherapy, as newly diagnosed in SOLO-1 trial and had been previously on two such regimens in the other trials, with an objective response. Almost all patients in the SOLO-2 and SOLO-1 trials had a gBRCA mutation, while there were patients with and without the said mutation in the other two studies. The pooled HR for PFS was statistically significant at 0.32 (95% CI: 0.27-0.38; P < 0.0001), including gBRCA cohort (HR, 0.28; 95% CI: 0.24-0.33; P < 0.0001) and non-gBRCA cohort (HR, 0.39; 95% CI: 0.32-0.48; P < 0.0001). Conclusions: Our meta-analysis demonstrated that the use of maintenance therapy with PARP inhibitors significantly improved PFS compared to placebo, regardless of the presence or absence of gBRCA mutation.
A retrospective review on extended carboplatin infusion and incidence of hypersensitivity reaction in gynecologic malignancies in a single institution.
Authors: Park Jennifer , Lee Matthew C. , Kockenmeister Erik , John Veena S.
Published: May 2019

e17102

Background: Carboplatin has been the standard treatment for advanced gynecologic malignancies in the first line setting as well as treatment of relapsed disease. Carboplatin induced hypersensitivity reaction (HSR) is observed more frequently in a second line setting and symptoms can range from rash to life threatening symptoms such as anaphylaxis, which could preclude further treatment. A retrospective study by O’Cearbhaill showed HSR rate with extended infusion protocol to be 3.4%. However, two subsequent prospective studies by Lax and O’Cearbhaill did not find that extended infusion reduced the risk or severity of HSR. We reviewed the incidence of HSR with three hour extended-infusion carboplatin at our institution. Methods: Our practice at the Monter Cancer Center changed from standard 1 hour carboplatin retreatment infusion to extended-infusion in 2011. We reviewed charts of 162 patients from 2011 to present who received a three hour extended infusion of carboplatin. All patients received prophylactic H1 and H2 blockers along with steroids. HSR was determined in two ways: 1) Identifying patients who reported clinical symptoms of HSR. 2) Identifying which patients had received diphenhydramine, hydrocortisone and/or epinephrine as indicated for an infusion reaction. Results: 162 patients were identified: 83 with ovarian cancer, 44 with uterine cancer, and 16 with fallopian tube cancer, 10 with primary peritoneal cancer, and 9 with cervical/vulvar cancer. Most had relapsed disease and were previously treated for stage IV (35%), or stage III (47%) with platinum doublet chemotherapy at least six months prior. Only 1 out of 162 (0.6%) had a grade 1 reaction with hives and was treated with dexamethasone and diphenhydramine. She was previously treated with carboplatin 17 months prior. Her current HSR occurred during her fifth cycle of retreatment. She was not re challenged with the drug and elected not to undergo desensitization. Conclusions: Hypersensitivity reactions develop in about 12-33% of women retreated with carboplatin peaking at eight cycles (Lax et al.). The mechanism behind HSR is unclear but considered to be from repeated exposure to free platinum metal concentration. Incidence of HSR at our institution was lowest ever-reported at 0.6%, suggesting that our extended infusion protocol with the appropriate premedication is appropriate for carboplatin-retreat patients. Further prospective studies to evaluate this regimen is warranted.
Real-world duration of maintenance therapy in 2nd-line and later ovarian cancer (OC).
Authors: Garofalo David , Aydin Ebru , Labrador Monica , Webster Jennifer , Donaldson Joseph , Varughese Prateesh , Smith Helen , Hagan Melissa , Malik Ash , Scott Jeffrey A.
Published: May 2019

e17103

Background: Recurrent OC patients may benefit from maintenance therapy, with the goal of inducing a lasting remission or extending the time interval before progression without any deleterious impact on quality of life1. This analysis, based on real world data sourced from US community oncology practices, was designed to compare the time to next treatment of available maintenance treatment options in recurrent OC. Methods: This analysis utilized the Integra Data Exchange (DTX) database, a deidentified data source from community oncology practice systems (EMR, claims). This retrospective study included 3,629 OC patients with at least two visits between 7/16/16 and 4/16/18. 1,767 patients started at least one 2nd line or later line of therapy and 577 of these patients had at least one line of maintenance treatment. Maintenance options were monotherapy PARP inhibitors, Bevacizumab, or non-platinum-chemotherapy. Patients who did not receive maintenance were categorized as observation. Time to next treatment (start of maintenance to start of next line of therapy) was compared through ANOVA and paired T-test analyses. Results: A statistically significant difference was seen in time to next treatment between PARPi (n = 151) and bevacizumab maintenance (n = 212) (p = < 0.0125) and between PARPi and cytotoxic maintenance (n = 163) (p = < 0.0001). Bevacizumab and PARPi maintenance had significantly longer duration when compared to observation (n = 1,626) (p = < 0.0001). Cytotoxic maintenance duration was not significantly different than observation (p = 0.93). Conclusions: Our real world analysis found that there was a statistically significant increase in time to subsequent lines of therapy when certain maintenance treatment (PARPi, Bevacizumab) is utilized following 2nd line and later treatment in OC. Further, between available maintenance options, PARPi had the longest time to next treatment when compared to other maintenance options.[Table: see text]
Universal endometrial cancer tumor typing: How much has immunohistochemistry, microsatellite instability, and MLH1 methylation improved the diagnosis of Lynch syndrome across the population?
Authors: Kahn Ryan , Gordhandas Sushmita , Maddy Brandon Paul , Baltich Nelson Becky , Askin Gulce , Christos Paul J. , Caputo Thomas A. , Chapman-Davis Eloise , Holcomb Kevin , Frey Melissa Kristen
Published: May 2019

e17119

Background: Universal tumor testing for defective DNA mismatch repair (MMR) is recommended for all women diagnosed with endometrial cancer (EC) to identify those with underlying Lynch syndrome (LS). However, since its implementation in 2013, the effectiveness of this screening method on identifying individuals with LS across the population has not been well studied. The aim of this study was to evaluate outcomes of MMR immunohistochemistry (IHC), MLH1 methylation, and microsatellite instability (MSI) analysis among EC patients. Methods: We conducted a complete systematic search of online databases PubMed, Embase, Medline, and Cochrane Library between 1990-2018. A DerSimonian–Laird random-effects model meta-analysis was utilized to estimate the weighted prevalence of LS diagnoses. Results: The comprehensive search produced 3,427 publications. 29 peer-review studies met the inclusion criteria. 6,649 EC patients were identified, 206 (3%) were confirmed to have LS following positive universal tumor molecular screening.5,917 patients underwent tumor IHC, 28% had abnormal staining. 3,140 patients underwent MSI analysis, 31% had MSI instability. Among EC patients with deficient IHC staining or positive MSI analysis, the weighted prevalence of LS was 15% and 19% respectively. 1159 patients exhibited loss of MLH1 staining, 143 (13.7%) were found to be MLH1 methylation negative, 32 demonstrated a germline MLH1 mutation (2.8% of all MLH1 absent staining; 22.4% of all MLH1 methylation negative). 43% of EC patients diagnosed with LS via tumor typing would have been missed by family history-based screening alone. Conclusions: Despite widespread implementation of universal tumor testing in EC, data regarding results have previously been limited. For the first time, this study provides large-scale predictive values that will help practitioners evaluate abnormal results in the context of LS and aid in patient counseling. [Table: see text]
Differential vaginal wall dosing in high-dose rate brachytherapy for endometrial cancer: The potential for superior coverage of at-risk areas while preserving organs at risk—An analysis of simulated data.
Authors: Sinha Dhiraj , Alleyne-Mike Kellie , De_four Sherisse , Ratan Naveen , Ramesh Shashidhar
Published: May 2019

e17121

Background: The treatment of curable endometrial cancer (EC)involves surgery with adjuvant radiotherapy. Histology of EC is a major determining factor for intracavitary brachytherapy (ICRT) treatment volume in early stage EC. Many guidelines recommend ICRT treatment of an extended volume up to the whole length of the vaginal stump (VS) for cases of high risk histologies (HRH) wherein a differential dosing of proximal and distal VS has the potential to achieve targeted therapeutic doses to at risk areas without compromise to critical structures.We present a simulated novel way to treat the VS by ICRT in cases of EC with HRH. Analysis of the simulated and approved plans allow us to compare the doses to organs at risk (OAR’s). Methods: Seventy-five cases from July 2017-August 2018 were reviewed and twenty-five (25) met the criteria for inclusion in this study. All these cases received External Beam Radiation Therapy (EBRT) dose of 50.4Gy/28. The ICRT simulation CT data-set was subsequently used to generate the study plan which was then compared to the actual treatment plan. In order to treat the whole VS but spare OARs a club-shaped design was proposed. This technique involved treating the upper 1/3 with a prescription point at 0.5cm lateral to the applicator surface and the lower 2/3 with a prescription point at the applicator surface. The length of the VS was defined from the tip of the applicator to 2cm superior to the introitus. The D2cc values for the contoured bladder and rectum were extracted from the treatment plan and used along with the D2cc values from the EBRT treatment to calculate OAR EQD2. QUANTEC Constraints used were (ICRU 83): EQD2 bladder: 90Gy; EQD2 rectum: 75Gy. Once calculated, the results were analyzed and the percent deviation between the proposed plan and the constraints as well as the approved plan were determined. Results: Twelve (12) of twenty-five (25) cases were HRH cases. The club-shaped design to treat the whole VS didn't further compromise the OAR (EQD2: 22% below constraints) or the rectum (EQD2: 1% below constraints). There was only a 2% difference between the final constraints in both treatment techniques. Conclusions: This technique to treat the full VS length can be used without adversely affecting OAR toxicities with superior coverage to at risk areas while maintaining dose constraints to OAR. Results, however, are limited by the small sample size.
Incidence of comorbidities on death certificate data in women with gynecological cancers.
Authors: McLaughlin Mary Elizabeth , Suneja Gita , Chino Junzo P.
Published: May 2019

e17127

Background: Risk factors for the development of gynecological cancers are known to vary; however, the effect on mortality is uncertain. Methods: Using CDC Wonder Database, death certificate data, all women who died of cancer in the United States from 2003-2016 were included if a cancer diagnosis was listed as a primary or contributing cause. Cases were then divided into gynecological (GYN) cancer or not, and thereafter characterized as cervical, ovarian, uterine, or other. Other causes contributing to death (comorbidities were then captured via ICD10 codes listed on death certificates and grouped into similar disease states. Chi-squared and Mann-Whitney U tests were performed for statistical significance. Results: Of 35,324,091 death certificates, 4,177,823 deaths were women with cancer listed as a cause of death. 440,792 were gynecological cancer, with cervical cancer in 62,807; uterine cancer in 134,420; ovarian cancer in 221,119; and other gynecological cancers in 25,946. Women with GYN cancers were more likely to have intestinal obstruction (2.7% vs 0.7%, OR 4.05), ascites (0.7% vs 0.2%, OR 3.30), HIV (0.1% vs 0.05%, OR 1.53), kidney disease (4.7% vs 3.6%, OR 1.33), and thrombo-embolic disorders (4.3% vs 3.5%, OR 1.25) when compared to non-GYN cancers (all p < 0.00001). Uterine cancer was more likely to have diabetes-related comorbidities (6.4% vs 3.8%, OR 1.75), metabolic syndrome (9.5% vs 6.1%, OR 1.60), thrombo-embolic disorders (5.5% vs 3.8%, OR 1.48), ischemic heart disease (5.0% vs 3.6%, OR 1.43), than other GYN cancers (all p < 0.00001). Cervical cancer was more associated with HIV (0.3% vs 0.03%, OR 10.73) and tobacco-related disorders (4.7% vs 1.9%, OR 2.56). Ovarian cancer was more associated with ascites (1.1% vs 0.4%, OR 2.93), intestinal obstruction (3.5% vs 1.8%, OR 2.04), and pleural effusion (1.1% vs 0.6%, OR 1.92) (all p < 0.00001). Conclusions: Comorbidities contributing to death significantly differ amongst gynecological cancers and non-gynecological cancers, which has relevance to strategies that can be differentially employed to reduce mortality. In particular, women with uterine cancer may benefit from reduction in risk of diabetes, ischemic heart disease, and embolic disorders; those with cervical cancer may benefit from smoking cessation and optimal HIV management.
Prognostic models for prediction of overall survival after first-line platinum-based chemotherapy for primary metastatic nasopharyngeal carcinoma.
Authors: Li Wang-Zhong , Liu Guo-Ying , Liang Hu , Lv Shu-Hui , Lv Xing , Guo Xiang , Xia Wei-Xiong , Yanqun Xiang
Published: May 2019

e17501

Background: Platinum-based chemotherapy remains the main treatment strategy for patients with primary metastatic nasopharyngeal carcinoma (mNPC). However, survival outcomes are heterogeneous. The present study sought to develop clinical predictive models for overall survival (OS) in mNPC. Methods: Institutional database was queried for patients with mNPC who received first-line platinum-based chemotherapy between 2008 and 2015. Eligible patients (n = 460) were split into a training (2008-2013, n = 296) and an internal validation cohort (2014-2015, n = 164) according to the period of diagnosis. Potential prognostic factors for OS were evaluated using univariate and multivariate analyses. The performance of prognostic models was assessed by discrimination and calibration. The clinical usefulness of prognostic models was evaluated by decision curve analysis. Results: We established two nomogram-based prognostic models to predict OS probability, the first (baseline model) based on baseline factors, the second (composite model) incorporating posttreatment plasma Epstein-Barr virus DNA (EBV DNA) and objective response (OR) to first-line chemotherapy. The incorporation of posttreatment plasma EBV DNA and OR to the model improved the predictive accuracy. The C-index of composite model for predicting OS was 0.767 (P < .001), which was statistically higher than the C-index values for baseline model (0.686). The results were confirmed in the internal validation cohort. Conclusions: We developed and validated two prognostic models that can be used before and after completion of first-line chemotherapy, respectively. The proposed models can be used for prognosis prediction and better selection of patient into clinical trials.
Induction chemotherapy (IC) followed by concurrent chemoradiotherapy (CCRT) in nasopharyngeal carcinoma(NPC) patients treated between 2004 and 2016: Patient and treatment characteristics and long term outcome.
Authors: Altun Musa , Kaval Gizem , Ibis Kamuran , Ozkaya Kubra , Meral Rasim , Karadeniz Ahmet Nafiz , Sari Murat , Ekenel Meltem , Basaran Mert , Bavbek Sevil E.
Published: May 2019

e17507

Background: Standard treatment of locoregionally advanced nasopharyngeal carcinoma (LRA-NPC) is CCRT with or without adjuvant chemotherapy (CT). The value of adding IC to CCRT in LRA-NPC is unclear. We aimed to retrospectively evaluate LRA-NPC patients treated with IC followed by CCRT and analyse patient, tumor, treatment characteristics and outcome. Methods: Between 2004 and 2016, 202 patients with nonmetastatic LRA-NPC (stage 3-4), 144 males and 58 females ranging from 17 to 75 (median 49) years old were treated with IC followed by CCRT. Eleven (%5.4) patients had keratinised (WHO I), and 191 (%94.6) had nonkeratinised or undiffrentiated (WHO II-III) carcinoma. Cumulative radiation dose to primary tumor ranged from 60 to 74 (median 70) Gy. Ninety-one (%45) of the patients received 2-dimensional and 111 (%55) received intensity modulated radiotherapy (IMRT). IC consisted of taxane (T)(75 mg/ m2) and platinum (P)(75 mg/m2) combination (199 patients) or P and fluoruracil or epirubicine (3 patients) combination and 188 of the patients received 3 cycles of IC. Concomittant P was used either weekly (40 mg/m2, 25 patients) or every 3-weekly (100 mg/m2, 177 patients) application. Follow-up ranged from 5 to 167 months (median, 72.5 months). Results: Treatment failure was observed in 52 (%25.7) of the patients (21 local, 13 regional and 27 distant failures). Distant failure rate of all the patients exceeds 13%. Five and 10 years disease free survival (DFS) rates are 75.2% and 70.4% and overall survival (OS) rates are 78.9% and 64% respectively. In univariate analysis patient age favoring those below 49 and stage of disease favoring WHO II-III were all significant predictors of DFS and OS. In addition pathology was a significant predictor of DFS. Conclusions: LRA-NPC patients treated with IC followed by CCRT have a high locoregional control rate. Despite the use of systemic (induction) chemotherapy distant control remains insufficient and continues to be a challenge in NPC treatment. Besides improving locoregional control more effective systemic therapy is needed. [Table: see text]
Synchronous esophageal cancer impact on survival of head and neck squamous cell carcinoma (HNSCC) patients.
Authors: Amor Divino Paulo Henrique , Matos Gustavo Duarte Ramos , Lima Karolina , Castro Gilberto , Nader Marta Gustavo , Takeda Flavio Roberto , Cecconello Ivan , Braghiroli Oddone Freitas Melro , Mak Milena Perez
Published: May 2019

e17513

Background: Optimal treatment of synchronous tumors (ST) of the aerodigestive tract is debatable and care is often individualized. Our goal was to characterize patients with HNSCC and esophageal cancer (EC) ST and to establish prognostic factors that could aid therapeutic decision. Methods: In this retrospective observational study, we evaluated data from 1650 consecutive patients diagnosed with HNSCC from 2008 to 2016. Patients with ST of HNSCC and esophagus with an interval of ≤ 6 months between both diagnoses were included. Patients ≥ 6 months between both diagnoses, incomplete treatment information and presence of another tumor site were excluded. Results: 52 patients were eligible. Median age was 57 years (39-91). Most were male (98%), with smoking and drinking habits (98%) and ECOG 0-1 (73%). HNSCCs were mainly in oropharynx (54%) and locally advanced disease (LA, III-IVB) (88%). In contrast, EC was early stage (I-II, 62%), located in the thorax (94%) and squamous histology (96%). 14 (27%) had LA in both primaries. Most LA HNSCCs (85%) were treated with radiotherapy (RT) with a median dose of 70Gy (5-70Gy). 50% received platinum and taxane induction chemotherapy. 81% of initial EC received at least surgery, mucosectomy or RT (median 50.4Gy). Hospitalization due to toxicity occurred in 12 (23%) and 7 (14%) of HNSCC and EC treatments, respectively. 16 patients (31%) had no definitive treatment directed to EC, without apparent impact on survival. Median time to progression was 13.8 months, being HNSCC the most frequent site of progression/relapse (40%). Median survival was 23.9 months (IC 95% 9.2-38.6). Early HNSCC survival was comparable to LA HNSCC (17.3 vs. 23.9 mo, p = 0.98). In LA HNSCC, LA vs. initial EC carried a worse prognosis (16 vs. 36.3 mo, p = 0.008). Anemia, BMI, tobacco exposure had no impact on survival. Conclusions: The occurrence of EC and HNSCC ST leads to a dismal survival, even in patients with early stage HNSCC. The presentation of LA in both sites is particularly challenging and associated with worse prognosis. Given the rate of treatment-related toxicity in this population, cautious efforts should be employed when planning definitive treatment in ST pts.
Efficacy and safety of apatinib as second-line or beyond therapy in patients with recurrent and/or metastatic head and neck squamous cell carcinoma.
Authors: Qin You , Ding Qian , Xu Xinhua , Cao Fengjun , Ning Siqing , Zhou Haibo , Chen Guiming , Huang Jing , Peng Gang , Yang Kunyu
Published: May 2019

e17517

Background: The aim of this study was to evaluate the efficacy and safety of apanitib in the treatment of patients with recurrent and/or metastatic head and neck squamous cell carcinoma (HNSCC) who failed from one or more lines of therapy. Methods: Patients with recurrent and/or metastatic HNSCC after failure of at least one line of therapy were recruited in this open-label exploratory study. Subjects were initially given apatinib 250mg qd until disease progression or unacceptable toxicity. Dose reduction to 125 mg was allowed. Herein, we reported the preliminary results at the cut-of date of Jan 31, 2019. Results: Between Jul 2017 to Dec 2018, 17 patients were enrolled. The median age was 59 years; 94% were male; 88% had more than 2 lines of chemotherapy. The median PFS and OS were 5.71 and 7.86 months, respectively. Most treatment related adverse events (AEs) were in grade ½. The grade ¾ AEs were hypertension (1/17, 5.88%), fistula (2/17, 11.76%), mouth mucositis (2/17, 11.76%), proteinuria (2/17, 11.76%), and f bleeding (6/17, 35.29%). Conclusions: Apatinib showed promising efficiency with tolerable toxicity for recurrent and/or metastatic HNSCC patients who failed from one or more lines of therapy. Clinical trial information: ChiCTR1800015278.
Determining the biomarker landscape and its impact on outcomes in HPV+ head and neck cancer after primary resection.
Authors: Khanna Suchin Rajeev , Wise-Draper Trisha Michel
Published: May 2019

e17520

Background: Human Papillomavirus (HPV) has emerged as a risk factor for oropharyngeal squamous cell carcinoma (OPSCC). Despite the better prognosis, HPV OPSCC is managed the same as HPV-negative cancer with toxic multimodality therapy. Numerous clinical trials are ongoing in an attempt at de-escalation treatment strategies in this population. However, the population is heterogenous in that 25% of patients still do poorly despite aggressive therapy. Tools to accurately separate this subset with poorer prognosis remain elusive. Finding the molecular means of prognosticating and risk-stratifying HPV OPSCC patients is an area of emerging interest to help better identify suitable candidates for de-escalation. We conducted an exploratory analysis of biomarkers with this goal in mind, specifically looking at HPV OPSCC patients that underwent definitive resection as their primary treatment. Methods: Tumor specimens from 26 patients with HPV OPSCC that underwent primary definitive resection were clinically annotated with variables of interest including patient demographics, presence of adverse pathological features, and recurrence and survival outcomes. A tissue microarray (TMA) was generated and tissue was stained by immunohistochemistry (IHC) with highly specific antibodies for molecular markers with known involvement in the pathogenesis of OPSCC. Pathologists reviewed the slides and assessed both the percentage of positive cells and the intensity of immunoreactivity. Scores were given based on these values. Results: Decreased pAMPk IHC expression portended better progression free survival (PFS), with hazard ratio (HR) of 0.004 with p = 0.09 trending towards statistical significance. The HR for biomarker expression and outcomes for ERCC1, p4EBP1, pMTOR, PI3K, PTEN, pAkt, pS6 did not achieve statistical significance. Conclusions: Decreased expression of pAMPk appeared to signify better PFS with a trend towards statistical significance. This was an exploratory analysis and was not powered to detect a difference in expression in any particularly studied biomarker, and the sample size was a limitation. Further studies should be powered to specifically detect a meaningful difference of pAMPk expression as it relates to outcomes.
Nationwide treatment patterns of oropharyngeal cancer in the human papillomavirus era.
Authors: Yang Kailin , Ward Matthew C. , Reddy Chandana A. , Burkey Brian B. , Adelstein David J. , Koyfman Shlomo A.
Published: May 2019

e17521

Background: Human papillomavirus-mediated (HPV+) oropharyngeal cancer is now defined as a clinically distinct entity from HPV-unrelated (HPV-) disease in the 8th edition AJCC staging system, which more accurately informs prognosis for HPV+ patients. Treatment decisions are currently made according to the AJCC 7th ed staging. HPV+ patients are associated with favorable outcome. This study aims to analyze the national pattern of practice for HPV+ disease. Methods: Patients with oropharyngeal squamous cell carcinoma (OPSCC) diagnosed from 2010-2012 were identified from the National Cancer Database (NCDB). Patients were staged using the AJCC 7th system. Chemotherapy, radiotherapy and surgery were counted as treatment modalities. Fisher’s exact test and chi-squared test were used to assess treatment patterns over time. Overall survival (OS) was compared with Cox proportional hazards model. Results: 5,928 HPV+ OPSCC patients were identified. Single modality (surgery or radiation) was the most common treatment choice, used in 53.6% of stage I and 48.8% of stage II patients. For stage I, the use of dual modality therapy (70.8% received surgery with radiation) decreased from 36% in 2010 to 19% in 2012 (p = 0.05), though no significant difference in OS was seen between dual modality and single modality. Dual modality with chemoradiation was the main approach for stage III (58.6%) and stage IVA (67.5%) disease. Use of trimodality decreased from 2010 to 2012 in both stage III (p = 0.03) and stage IVA (p < 0.01). Conclusions: Using a national cohort of HPV+ patients from the NCDB, we showed that single modality was the most common for stages I/II and dual modality was the mainstay for stages III/IVA. Usage of aggressive approaches (dual modality for stages I/II and trimodality for stages III/IVA) decreased over time. Prospective studies would be needed to determine the optimized therapeutic choice for HPV+ patients given favorable outcome.
Osimertinib and dihydroartemisinin: A novel drug combination targeting head and neck squamous cell carcinoma.
Authors: Rosell Rafael , Chaib Imane , Cai Xueting , Llige David , Santarpia Mariacarmela , Jantus-Lewintre Eloisa , Filipska Martyna , Pedraz Carlos , Yang Jie , Miao Jing , Sun Rongwei , Bracht Jillian , Ito Masaoki , Aguilar Andrés , de Aguirre Itziar , Codony-Servat Jordi , Cardona Zorrilla Andres Felipe , Karachaliou Niki , Cao Peng
Published: May 2019

e17526

Background: Recurrent and metastatic head and neck squamous cell carcinoma (HNSCC) has a dismal prognosis with limited progression-free survival and overall survival, even when treated with different combinations of chemotherapy, targeted therapies and immunotherapy. We explored in vitro and in vivo the effect of the epidermal growth factor (EGFR) inhibitor, osimertinib, alone and in combination with dihydroartemisinin (DHA) in HNSCC. Methods: The combination of osimertinib with DHA was tested in the FaDu and CAL27 HNSCC cell lines. Tumor cell proliferation assays were conducted in cultured cells and mouse xenografts. Western blotting analysis of related signal pathways was performed to investigate the molecular mechanisms of the inhibitory effect of DHA and the combination. Other compounds, which inhibit signal transducer and activator of transcription 3 (STAT3), Src-family kinases (SFKs), sphingosine kinase 1 (SPHK1), or the receptor tyrosine kinase (RTK) AXL were also combined with osimertinib in vitro. Results: Osimertinib exerted synergistic cytotoxicity toward FaDu and CAL27 HNSCC cells when combined with DHA. DHA reversed the osimertinib-induced STAT3 and Src, phosphorylation. The double combination inhibited AXL expression. The anticancer potential of osimertinib plus DHA combination was validated in vivo on FaDu and CAL27 xenografts in mice without notable side effects. Conclusions: The results illustrate that the combinatory therapy of osimertinib and DHA, as a repurposing anticancer drug, could be a novel therapeutic strategy for recurrent and/or metastatic HNSCC patients. The findings indicate that a clinical trial is warranted to confirm the benefit of the combination.
Clinical prognostic factors in patients with recurrent or metastatic carcinoma of the head and neck treated with immune checkpoints therapies.
Authors: Resteghini Carlo , Cavalieri Stefano , Rametta Alessandro , Alfieri Salvatore , Galbiati Donata , Platini Francesca , Locati Laura Deborah , Bossi Paolo , Bergamini Cristiana , Granata Roberta , Orlandi Ester , Piazza Cesare , Mancinelli Moela , Licitra Lisa F.
Published: May 2019

e17530

Background: Immunotherapy (IT) provides advantages in a small proportion of recurrent / metastatic head and neck squamous cell carcinoma (RM HNSCC) patients (pts). Predictive biomarkers are still an unmet need. We aimed to determine if known prognostic clinical factors in RM HNSCC as well as new variables hold prognostic value in the IT era. Methods: We conducted a retrospective analysis of a cohort of 106 RM HNSCC pts enrolled into IT trials at National Cancer Institute of Milan-Italy between Oct 2014 - Jul 2018. Using Log Rank test and Cox proportional hazard model we computed univariate and multivariate analysis (UVA; MVA) of demographics, clinical and biological data to assess their prognostic value for progression free survival (PFS) and overall survival (OS). Results: Ninety-three pts (M 75; F: 18) were included in the final analysis with a median follow up of 20.8 months. The majority (96%) were treated in platinum-refractory setting. Approximately half of pts received anti-PD-1 or anti-PDL-1 monotherapy while the remaining 52% received them in combination with other IT agents. Median OS and PFS were 6.5 (CI 95%: 4.6-10.4) and 2.1 months (CI 95%: 1.8-2.2), respectively. Statistically significant factors at UVA for PFS were smoking history - both pos vs neg and < vs ≥ 30 PY, disease subsite, weight loss > 5%, Karnosfky performance status (PSK), occurrence of any and G3-G4 drug related (DR) toxicities, neutrophil to lymphocytes ratio (NLR). Without stratification for disease subsite, MVA showed independent predictive value of prolonged PFS for positive smoking history (HR 0.5, p 0.02) and any DR toxicities (HR 0.43, p < 0.01). Several factors reached significance for OS in UVA (smoking history and PY, weight loss > 5%, ECOG PS, PSK, occurrence of any toxicities, CRP, baseline C-reactive protein, antibiotic use, steroid use in the 30 days before IT). Of these, PSK (HR 0.95, p 0.01) and any DR toxicities (HR 0.3, p < 0.01) resulted to be predictive in the MVA. Conclusions: Clinical parameters, especially pretreatment PSK, smoking history and occurrence of any DR toxicities, appear to be strong predictors of outcome in RM HNSCC pts treated with IT. These results should be validated in an independent cohort.
A novel mechanism of miRNA-mediated CBX8 associated with tumorigenesis in head and neck squamous cell carcinoma.
Authors: Shiah Shine-Gwo , Chou Sung-Tau , Kuo Ching-Chuan , Chi Ya-Hui
Published: May 2019

e17534

Background: Polycomb group (PcG) proteins influence the development and progression of cancer. However, the mechanism that contributes to tumorigenesis have not been fully understood in head and neck squamous cell carcinoma (HNSCC). Methods: The expression of chromobox 8 (CBX8), a member of the polycomb group (PcG) of proteins, on OSCC patients was determine by quantitative real-time PCR (qRT-PCR) and immunohistochemistry. Specific targeting by miRNAs was determined by software prediction, luciferase reporter assay, and correlation with target protein expression. The functions of miR-410-3p and CBX8 were accessed by transwell migration and invasion analyses using gain- and loss-of-function approaches. Results: Here we found that CBX8 is upregulated in HNSCC tissues and cell lines. Using CBX8 knockdown cDNA microarray, we identify a CBX8-mediated target gene MIPOL1 which is inversely correlated with CBX8 expression in HNSCC tissues. Ectopic expression of MIPOL1 could inhibit tumor invasion and migration, whereas MIPOL1 silencing suppressed these effects in CBX8-knockdown HNSCC cells. Otherwise, depletion of CBX8 also induced p53 activity and increased the expression level of p21 and p27 through MIPOL1-independent manner, which result in cell cycle arrest in G2M phase. Silencing of p53 could inhibit p21 and p27 accumulation in CBX8 knockdown cells. Furthermore, we demonstrated that down-regulation of miR-410-3p promoted HNSCC cells migration and invasion through directly targeting CBX8. Overexpression of miR-410-3p decreased CBX8 expression and reduced migration and invasion, while ectopic expression of CBX8 rescued the miR-410-3p-reduced migration and invasion. In clinical samples, miR-410-3p level closely inversely correlated with CBX8 and positively correlated with MIPOL1. Conclusions: Collectively, our findings indicate that miR-410-3p may act as a tumor suppressor via negatively regulating CBX8. The newly identified miR-410-3p/CBX8/MIPOL1 and miR-410-3p/CBX8/p53 signaling axes may suggest new therapeutic strategies against HNSCC.
Retrospective analysis of baseline clinical factors associated to CDDP-nephrotoxicity in locally advanced head and neck cancer (LAHNC) patients.
Authors: Platini Francesca , Barretta Francesco , Alfieri Salvatore , Cavalieri Stefano , Resteghini Carlo , Galbiati Donata , Locati Laura Deborah , Bergamini Cristiana , Granata Roberta , Calareso Giuseppina , Iacovelli Nicola Alessandro , Quattrone Pasquale , Incandela Fabiola , Bossi Paolo , Licitra Lisa F.
Published: May 2019

e17537

Background: CDDP is the standard of care for HNC. We performed a retrospective analysis related to baseline clinical characteristics and CDDP-nephrotoxicity in LAHNC patients (pts) treated in a curative setting with CDDP and concomitant RT (CRT) or with CDDP as part of induction chemotherapy. Methods: We collected data of LAHNC pts treated between 2008 and 2018 at the National Cancer Institute of Milan. CDDP was administered 100 mg/sm every 3 weeks or 50 mg/sm once a week during CRT, or 75 mg/sm during induction. Nephrotoxicity was assessed using creatinine increase (CreaIncr) recorded at day 6-20 post CDDP, graded according to CTCAE v4.0 and analyzed as a dichotomous variable (Grade>0 vs Grade = 0). We used univariable logistic regression to investigate associations between CreaIncr and clinical variables. Continuous variables were modeled using 3-knots restricted cubic splines. Results: Overall, 204 pts were considered. Male: 74%; median age: 56 yrs [IQR 51-63]. CRT was performed in 179 pts (88%). Three-weekly schedule was performed in 75% of pts. The median CDDP dose was 250 mg [IQR 200-300]. One fourth had history of hypertension and 9% were on diuretics. At baseline, median [IQR] creatinine was 0.80 mg/dL [0.69-0.89], creatinine clearance 109 mL/min [98-129] and uricaemia 4.90 mg/dL [4.11-5.74]. In total, 44% pts suffered from CreaIncr (G1: 46 pts; G2: 39 pts; G3-G4: 5 pts) all of them occurred within the first 2 cycles. CreaIncr was observed in 92% of pts treated with CRT, 84% received 3-weekly CDDP. Baseline creatinine clearance, azotaemia and hypertension were not significantly associated with CreaIncr. Loop diuretics alone appeared a potential relevant factor [OR 4.72;95%CI 0.96-23.32;p = 0.057]. Concomitant drugs (ACE inhibitors, Sartans, Ca-blockers) [OR 1.48;95%CI 1.00-2.18;p = 0.050] and uricaemia [OR 1.95;95%CI 1.27-3.0;p = 0.006] were statistically significantly associated to CreaIncr. Conclusions: In our selected population we found that concomitant medications and uricaemia were significantly related to CreaIncr. A better understanding of clinical baseline factors may improve decision making in a setting where CDDP has a curative significance.
Association of low neutrophil-to-lymphocyte ratios (NLR) and high lymphocyte-to-monocyte ratios (LMR) with overall survival and response to induction chemotherapy (IC) when used to select patients (pts) with locally advanced squamous cell of the larynx (LSCC) for combined chemoradiation (CRT).
Authors: Risch Zachary , Bellile Emily , Townsend Ryan , Swiecicki Paul , Casper Keith , Malloy Kelly M , Hogikyan Norman D , Spector Matthew E , Shuman Andrew , Stucken Chaz , Chinn Steven Bennett , Chepeha Douglas Brian , Jolly Shruti , Mierzwa Michelle Lynn , Bradford Carol Rossier , Eisbruch Avraham , Carey Thomas E. , Prince Mark E , Wolf Gregory T. , Worden Francis P.
Published: May 2019

e17539

Background: University of Michigan Cancer Center (UMCC) protocol 9520 treated pts with stage III/IV LSCC with 1 cycle of cisplatin & 5-FU (PF) to select pts for definitive therapy. Pts whose tumors attained a ≥ 50% response after 1 cycle of PF underwent CRT. Those who had a < 50% response to IC were treated with total laryngectomy + RT. Correlative science from UMCC 9520 demonstrated that an increased percentage of CD4+ cells predicted response to PF & suggested improved survival. Published retrospective data also has demonstrated that lower NLR & higher LMR are associated with improved prognosis in p16- SCC of the oropharynx & pyriform sinus, while cancers with higher NLR & lower LMR have a worse prognosis. Similar to our previous correlative analysis, this study is also a secondary analysis of the predictive value of NLR & LMR in a prospective trial of bio-selective IC. Methods: NLR & LMR were calculated from pre-treatment CBC for all pts (N = 87) enrolled onto UMCC 9520. Results: All 87 pts received IC with PF. 65/87 (75%) responded to IC & received CRT. Results of response to IC compared the NLR & LMR ratios by logistic regression analysis & was used to create NLR & LMR cut points. Among pts with LMR ≥ 3, the response rate (RR) was 89% while the RR was 64% with LMR < 3 (p = 0.008). Among pts with NLR < 4.7, the RR was 79% while the RR of pts with > 4.7 was 58% (p = 0.06). Overall & disease specific survivals were greater in pts with LMR ≥ 3, (log rank p = 0.04, p = 0.03, respectively). Conclusions: Higher LMR & lower NLR are associated with favorable responses to IC & LMR ≥ 3 is associated with improved survival. This data correlates strongly with our published results from UMCC 9520, whereby elevated circulating CD4+ lymphocytes predict response to IC & survival. This important information may help direct the design of future laryngeal preservation protocols.
Impact of reactive gastrostomy tube placement on clinical course of oropharynx cancer patients treated with chemoradiation.
Authors: Dave Ami A , Mozer Marisa A , Zhang Yanyu , Sen Neilayan , Bojko Monica , Huff Amanda A , Al-Khudari Samer , Stenson Kerstin , Fidler Mary J.
Published: May 2019

e17540

Background: Prophylactic percutaneous gastrostomy tube (PEG) insertion reduces toxicity from chemoradiation to the head and neck but is thought to increase long term feeding tube dependence. This study retrospectively examines incidence and risk factors for treatment related complications of oropharynx cancer patients with and without prophylactic PEGs. Methods: Rush University Medical Center oropharynx cancer patients who received definitive chemoradiation treatment between 2007-2018 were included. Classifications were: “therapeutic” PEG (pretreatment for immediate use due to inability to swallow), prophylactic PEG, reactive PEG (patient/physician preference or 10% weight loss from baseline), and no PEG inserted on treatment. We compared patients with reactive or no PEG to (1) patients with prophylactic PEG, and (2) patients with prophylactic PEG and therapeutic PEG. Multivariate linear and logistical regression models were used to test PEG effect on weight loss, hospital admission, and incidence of acute kidney injury (AKI). Models were adjusted for covariates (age, gender, race, HTN, CAD, DM, other comorbidity). Acute kidney injury (AKI) was creatinine 1.5-2x above baseline. Results: In all, 104 patients were included with mean age 60.1 (SD = 8.65) and baseline BMI 29.6 (SD = 5.62). 53.4% (N = 55) had a prophylactic PEG, 38.8% (N = 40) had reactive or no PEG, 7.8% (N = 8) had a therapeutic PEG. 80 (76.9%) were treated with cisplatin. For all patients, analyses showed that reactive PEG or no PEG patients were more likely to develop AKI during treatment compared to patients with a prophylactic PEG (OR:3.2, p = 0.03), and to patients with prophylactic PEG and therapeutic PEG combined (OR:3.5, p = 0.02). There were no statistically significant differences between PEG groups for weight loss and hospital admission rate. In cisplatin treated patients, reactive PEG or no PEG patients were more likely to be admitted to the hospital compared to prophylactic PEG patients (OR:3.8, p = 0.04). Compared to patients with prophylactic and therapeutic PEG combined, however, there was no statistically significant difference. Patients with reactive or no PEG were more likely to have AKI than prophylactic PEG (OR:5.2, p < 0.01), and as compared to patients with therapeutic or prophylactic PEG (OR:4.4, p = 0.02). Conclusions: Reactive PEGs were associated with increased AKI and hospitalizations compared with prophylactic PEG. With a reactive PEG model, patients may need to have routine lab work and monitoring adjusted to reduce treatment complications.