Distinct Failure Patterns in Hypopharyngeal Cancer Patients Receiving Surgery-Based Versus Radiation-Based Treatment.

BACKGROUND: To cure advanced hypopharyngeal squamous cell carcinoma (HPSCC), primary operation followed by adjuvant (chemo-)radiotherapy (OP-CRT) or definitive chemoradiation (CCRT) are the two primary options. This study aimed to compare the failure patterns and long-term survival outcomes of HPSCC patients treated with these two strategies. PATIENTS AND METHODS: From 2007 to 2015, 198 pathologically confirmed HPSCC patients receiving either OP-CRT or CCRT were retrospectively reviewed. Failure patterns and survival outcomes stratified by the 7th American Joint Committee on Cancer staging system and treatment modalities were compared. RESULTS: One hundred and eighty-nine patients (95.4%) were stage III/IV and 62 patients (31.3%) received OP-CRT. Median follow-up duration was 4.9 years. Compared with CCRT, OP-CRT provided better 3-year local relapse-free survival for T3 (93 vs 48%, p < 0.0001), T4a (88 vs 37%, p = 0.0005) and better 3-year regional relapse-free survival for N2b+2c (93 vs 60%, p < 0.0001). Of note, for stage IVA subjects, OP-CRT provided better 3-year loco-regional relapse-free survival (85 vs 37%, p < 0.0001), marginal poor 3-year distant metastasis-free survival (62 vs 79%, p = 0.06), but comparable 3-year OS (52 vs 44%, p = 0.37) and 5-year OS (44 vs 31%, p = 0.15) compared with CCRT. CONCLUSIONS: For patients with advanced HPSCC, although OP-CRT and CCRT provided similar overall survival, failure patterns were distinct. OP-CRT provided better loco-regional control but was more likely to encounter distant metastases than CCRT. The detailed analysis of failure patterns will pave the way to improve this devastating disease.

Dissecting the mechanism of temozolomide resistance and its association with the regulatory roles of intracellular reactive oxygen species in glioblastoma.

Glioblastoma is the most common primary malignant brain tumor that is usually considered fatal even with treatment. This is often a result for tumor to develop resistance. Regarding the standard chemotherapy, the alkylating agent temozolomide is effective in disease control but the recurrence will still occur eventually. The mechanism of the resistance is various, and differs in terms of innate or acquired. To date, aberrations in O6-methylguanine-DNA methyltransferase are the clear factor that determines drug susceptibility. Alterations of the other DNA damage repair genes such as DNA mismatch repair genes are also known to affect the drug effect. Together these genes have roles in the innate resistance, but are not sufficient for explaining the mechanism leading to acquired resistance. Recent identification of specific cellular subsets with features of stem-like cells may have role in this process. The glioma stem-like cells are known for its superior ability in withstanding the drug-induced cytotoxicity, and giving the chance to repopulate the tumor. The mechanism is complicated to administrate cellular protection, such as the enhancing ability against reactive oxygen species and altering energy metabolism, the important steps to survive. In this review, we discuss the possible mechanism for these specific cellular subsets to evade cancer treatment, and the possible impact to the following treatment courses. In addition, we also discuss the possibility that can overcome this obstacle.

SOD2 Enhancement by Long-Term Inhibition of the PI3K Pathway Confers Multi-Drug Resistance and Enhanced Tumor-Initiating Features in Head and Neck Cancer.

The phosphoinositide-3-kinase (PI3K) pathway has widely been considered as a potential therapeutic target for head and neck cancer (HNC); however, the application of PI3K inhibitors is often overshadowed by the induction of drug resistance with unknown mechanisms. In this study, PII3K inhibitor resistant cancer cells were developed by prolonged culturing of cell lines with BEZ235, a dual PI3K and mammalian target of rapamycin (mTOR) inhibitor. The drug resistant HNC cells showed higher IC50 of the proliferation to inhibitors specifically targeting PI3K and/or mTOR, as compared to their parental cells. These cells also showed profound resistance to drugs of other classes. Molecular analysis revealed persistent activation of phosphorylated AKT at threonine 308 in the drug resistant cells and increased expression of markers for tumor-initiating cells. Interestingly, increased intra-cellular ROS levels were observed in the drug resistant cells. Among anti-oxidant molecules, the expression of SOD2 was increased and was associated with the ALDH-positive tumor-initiating cell features. Co-incubation of SOD inhibitors and BEZ235 decreased the stemness feature of the cells in vitro, as shown by results of the spheroid formation assay. In conclusion, dysregulation of SOD2 might contribute to the profound resistance to PI3K inhibitors and the other drugs in HNC cells.

Investigating the health disparities in the association between lifestyle behaviors and the risk of head and neck cancer.

Many studies have reported a positive association between lower socioeconomic status (SES) and higher head and neck cancer (HNC) risk. Fewer studies have examined the impact of SES on the association between alcohol or cigarette use and HNC risk. The current case-control study (1104 HNC cases and 1363 controls) investigated the influence of education, a SES indicator, on the association between HNC and the use of alcohol, cigarettes, or betel quids in Taiwan, a country with universal health care. Our results showed a larger increase in HNC risk associated with alcohol among those with lower educational level (odds ratio [OR] = 2.07; 95% confidence interval [CI], 1.53-2.80) than those with higher educational level (OR = 1.38; 95% CI, 1.04-1.85) (heterogeneity-P = .03). Educational level had an influence on the association between alcohol use and HNC risk among those with genetic susceptibility (ALDH2-deficient) to the carcinogenic effect of alcohol. The association between cigarette or betel quid use and HNC risk was similar between the high and low educational groups. National policies and social interventions have led to the decline in the prevalence of cigarette and betel quid users in Taiwan. In contrast, due to the lack of adequate alcohol control policies, alcohol consumption in Taiwan has continued to rise. A higher impact of alcohol on HNC risk among lower SES individuals even with universal health care could be the result of insufficient alcohol control policies in Taiwan.

Radiotherapy for inferior vena cava tumor thrombus in patients with hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) with inferior vena cava (IVC) involvement is a rare disease with poor prognosis. This study aimed to evaluate the outcome of HCC patients receiving radiotherapy (RT) to IVC tumor thrombus. METHODS: A total of 42 consecutive HCC patients treated with RT to IVC tumor thrombus between September 2007 and October 2018 were enrolled. Overall survival (OS), the response of IVC thrombus, prognostic factors and failure pattern were assessed. RESULTS: The median follow-up time was 4.4 months. The median RT equivalent dose in 2-Gy fractions was 48.75 Gy (range, 3.25-67.10). The objective response rate of IVC thrombus was 47.6% (95% confidence interval [CI], 33.3-64.3%). The OS rate at 1 year was 30.0%, with a median OS of 6.6 months (95% CI, 3.7-9.5) from the start of RT. On multivariate analysis, Child-Pugh class, lymph node metastasis, lung metastasis and objective response of IVC thrombus were independent predictors for OS. Lung was the most common site of first progression in 14 (33.3%) patients. For 32 patients without lung metastasis before RT, use of systemic treatment concurrent with and/or after RT was associated with a significantly longer lung metastasis-free survival (5.9 vs. 1.5 months, p = 0.0033). CONCLUSIONS: RT is effective for IVC tumor thrombus of HCC with acceptable adverse effects. RT might be a treatment option incorporated into combination therapy for HCC involving IVC.

Validation of Alcohol Flushing Questionnaire to Identify ALDH2 Status in a Case-Control Study of Head and Neck Cancer.

BACKGROUND: Carriers of the ALDH2*2 allele have impaired alcohol metabolism and are more susceptible to the development of alcohol-related cancers, including head and neck cancer (HNC). Screening for ALDH2*2 allele may identify high-risk individuals for alcohol health education. Although genotyping of ALDH2 is the most accurate way to identify ALDH2 deficiency, it may not be practical due to the cost and requirement for genotyping service. METHODS: This study evaluated the accuracy of the alcohol flushing questionnaire to identify ALDH2 deficiency in a case-control study of HNC conducted in Taiwan using data collected from 904 patients with HNC and 1,078 controls. RESULTS: Overall, alcohol flushing questionnaire had a high sensitivity (89%) of identifying ALDH2*2 carriers among the control subjects and a good sensitivity (79%) among the patients with HNC. The sensitivity of the alcohol flushing questionnaire in identifying ALDH2*2 carriers was affected by alcohol use, with a lower sensitivity among individuals who consumed alcohol, particularly among current regular (drinking alcohol once per week or more) alcohol drinkers. CONCLUSIONS: The current validation study showed that the alcohol flushing questionnaire may be a reasonable method to identify ALDH2-deficient individuals. However, current regular users of alcohol who reported no alcohol flushing may need to undergo genotyping of ALDH2 for a more accurate assessment of the ALDH2 status.

Adjuvant Radiotherapy After Keloid Excision: Preliminary Experience in Taiwan.

BACKGROUND: Surgical excision with adjuvant radiotherapy has gained attention as an effective treatment of keloid. The Asian population is challenged with a high incidence of keloid occurrence with a specific genetic predominance. The annual reported incidence of new keloid cases in Taiwan is around 30,000, but the disease control rate and effectiveness by means of surgical excision with adjuvant radiotherapy is not yet clear. METHODS: A retrospective chart review of the included consecutive keloid patients receiving surgical excision and radiotherapy was performed from 2013 to 2016 in a single institute. The reported risk factors were collected to investigate according to the outcome analysis. The Vancouver Scar Scale and the Japan Scar Workshop (JSW) Scar Scale were used to evaluate the correlation with keloid recurrence. RESULTS: In this series, the overall recurrence rate was 32%, reported with an average follow-up of 28 months. Independent risk factors varied according to the different outcome variables. Only JSW classification score independently predicted the risk of keloid recurrence (odds ratio, 1.305; P = 0.02). Both the Vancouver Scar Scale and the JSW system showed a good correlation with keloid recurrence (correlation efficiency, 0.529 and 0.54; P = 0.0437 and 0.0165, respectively). CONCLUSIONS: This preliminary report revealed convincing evidence of feasibility and effectiveness of applying adjuvant radiotherapy after keloid excision in the Taiwanese population. A more delicate biological equivalent dose of radiotherapy with an effective local control should be considered to improve the final outcome.

The interplay between oral microbiome, lifestyle factors and genetic polymorphisms in the risk of oral squamous cell carcinoma.

Poor oral hygiene may lead to overgrowth of pathogenic oral bacteria, which may induce chronic inflammation to promote the oncogenesis of oral squamous cell carcinoma (OSCC). This study investigated the association between oral bacterial profile and OSCC risk in a case-control study of 138 OSCC cases and 151 controls (88 cases and 90 controls for the discovery group and 50 cases and 61 controls for the validation group). Oral bacterial profiles were characterized by targeted sequencing of the 16S rRNA gene. Three species of periodontopathogenic bacteria, Prevotella tannerae, Fusobacterium nucleatum, and Prevotella intermedia, were associated with an increased OSCC risk. This association was modified by the genetic polymorphisms of TLR2 and TLR4. Use of alcohol, betel quids and cigarettes and poor oral hygiene were associated with a higher percentage of oral periodontopathogenic bacteria. The association between alcohol and periodontopathogenic bacteria was modified by the genetic polymorphism of ALDH2, with a stronger positive association observed among the ALDH2-deficient individuals. The percentage of periodontopathogenic bacteria was positively correlated with the level of salivary IL1ß, an inflammatory cytokine. Overall, our results showed a positive association between periodontopathogenic bacteria and OSCC risk and this relationship may be influenced by lifestyle and genetic factors. Our results provided further biological support for the established association between poor oral hygiene and OSCC risk. This suggested that improving oral hygiene may reduce OSCC risk and should be part of a public health campaign to prevent the occurrence of OSCC.

Regular recreational physical activity and risk of head and neck cancer.

BACKGROUND: Although substantial evidence supports a 20-30% risk reduction of colon cancer, breast cancer, and endometrial cancer by physical activity (PA), the evidence for head and neck cancer (HNC) is limited. Three published studies on the association between PA and HNC have generated inconsistent results. The current study examined the association between recreational PA (RPA) and HNC risk with a more detailed assessment on the intensity, frequency, duration, and total years of RPA. METHODS: Data on RPA were collected from 623 HNC cases and 731 controls by in-person interview using a standardized questionnaire. The association between RPA and HNC risk was assessed using unconditional logistic regression, adjusted for sex, age, educational level, use of alcohol, betel quid, and cigarette, and consumption of vegetables and fruits. RESULTS: A significant inverse association between RPA and HNC risk was observed in a logistic regression model that adjusted for sex, age, and education (odds ratio (OR) = 0.65, 95% confidence interval (CI): 0.51-0.82). However, after further adjustment for the use of alcohol, betel quid, and cigarette, and consumption of vegetables and fruits, RPA was no longer associated with HNC risk (OR =0.97, 95% CI: 0.73-1.28). No significant inverse association between RPA and HNC risk was observed in the analysis stratified by HNC sites or by the use of alcohol, betel quid, or cigarette. CONCLUSION: Results from our study did not support an inverse association between RPA and HNC risk. The major focus of HNC prevention should be on cessation of cigarette smoking and betel chewing, reduction of alcohol drinking, and promotion of healthy diet that contains plenty of fruits and vegetables.

Allergy symptoms, serum total immunoglobulin E, and risk of head and neck cancer.

PURPOSE: Allergy symptoms have been associated with a reduced head and neck cancer (HNC) risk, while elevated blood immunoglobulin E (IgE) levels have been associated with an increased HNC risk. According to the "prophylaxis hypothesis," allergic reaction is the body's way of expelling carcinogens. IgE level may be increased by exposure to environmental carcinogens, including alcohol and cigarette smoke. We hypothesized that individuals with elevated serum IgE without allergy symptoms (i.e., asymptomatic atopic) would have the highest HNC risk. METHODS: A case-control study of HNC (576 cases and 740 controls) was conducted to evaluate the association between allergy symptoms or serum total IgE and HNC risk and the effect modification of allergy symptoms on the association between serum total IgE and HNC risk. RESULTS: Elevated serum total IgE was associated with a significantly increased HNC risk [odds ratio (OR) 1.71, 95 % confidence interval (CI) 1.21-2.42]. Having allergy symptoms was associated with a significantly reduced HNC risk (OR 0.56, 95 % CI 0.43-0.73). Compared to subjects with normal serum total IgE and no allergy symptoms, asymptomatic atopic individuals had a significantly increased HNC risk (OR 2.12, 95 % CI 1.33-3.35). CONCLUSIONS: Our results provided further evidence to support the "prophylaxis hypothesis." Further investigations regarding the immune profiles of asymptomatic atopic individuals may provide additional clues for the biological mechanisms underlying the association between allergy symptoms, IgE, and HNC risk.

The interplay between alcohol consumption, oral hygiene, ALDH2 and ADH1B in the risk of head and neck cancer.

Alcohol consumption is an established risk factor for head and neck cancer (HNC). The major carcinogen from alcohol is acetaldehyde, which may be produced by humans or by oral microorganisms through the metabolism of ethanol. To account for the different sources of acetaldehyde production, the current study examined the interplay between alcohol consumption, oral hygiene (as a proxy measure for the growth of oral microorganisms), and alcohol-metabolizing genes (ADH1B and ALDH2) in the risk of HNC. We found that both the fast (*2/*2) and the slow (*1/*1+ *1/*2) ADH1B genotypes increased the risk of HNC due to alcohol consumption, and this association differed according to the slow/non-functional ALDH2 genotypes (*1/*2+ *2/*2) or poor oral hygiene. In persons with the fast ADH1B genotype, the HNC risk associated with alcohol drinking was increased for those with the slow/non-functional ALDH2 genotypes. For those with the slow ADH1B genotypes, oral hygiene appeared to play an important role; the highest magnitude of an increased HNC risk in alcohol drinkers occurred among those with the worst oral hygiene. This is the first study to show that the association between alcohol drinking and HNC risk may be modified by the interplay between genetic polymorphisms of ADH1B and ALDH2 and oral hygiene. Although it is important to promote abstinence from or reduction of alcohol drinking to decrease the occurrence of HNC, improving oral hygiene practices may provide additional benefit.

Comparison of concurrent chemoradiotherapy versus neoadjuvant chemotherapy followed by radiation in patients with advanced nasopharyngeal carcinoma in endemic area: experience of 128 consecutive cases with 5 year follow-up.

BACKGROUND: Combined radiotherapy and chemotherapy is considered the standard of care for locally advanced nasopharyngeal carcinoma (LA-NPC) in Epstein-Barr virus infection endemic area. This study compared the long-term outcomes between LA-NPC patients treated with neoadjuvant chemotherapy followed by radiotherapy (NACT) and those treated with concurrent chemoradiotherapy (CCRT). METHODS: From 2003 to 2007, a total of 128 histopathologically proven LA-NPC patients receiving either NACT or CCRT were consecutively enrolled at the National Cheng Kung University Hospital in Taiwan. NACT consisted of 3-week cycles of mitomycin, epirubicin, and cisplatin on day 1 and fluorouracil and leucovorin on day 8 (MEPFL) or weekly alternated cisplatin on day 1 and fluorouracil and leucovorin on day 8 (P-FL). CCRT comprised 3-week cycles of cisplatin (Cis 100) or 4-week cycles of cisplatin and fluorouracil (PF4). The first failure site, disease free survival (DFS), overall survival (OS), and other prognostic factors were analyzed. RESULTS: Thirty-eight patients (30%) received NACT. Median follow-up duration was 53 months. More patients with advanced nodal disease (N2-N3) (86.8% vs 67.8%, p =0.029) and advanced clinical stage (stage IVA-IVB) enrolled in the NACT group (55.2% vs 26.7%, p =0.002). For NACT, both MEPFL and P-FL had similar 5-year DFS and OS (52.9% vs 50%, p =0.860 and 73.5% vs 62.5%, p =0.342, respectively). For CCRT, both PF4 and Cis 100 had similar 5-year DFS and OS (62.8% vs 69.6%, p =0.49 and 72.9% vs 73.9%, p =0.72, respectively). Compared to CCRT, NACT had similar 5-year DFS and OS (51.5% vs 65.1%, p =0.28 and 71.7% vs 74.3%, p =0.91, respectively). Among patients who were recurrence-free in the first 2 years after treatment, those treated with NACT experienced poorer locoregional control compared to those treated with CCRT (Hazard ratio =2.57, 95% confidence interval: 1.02 to 6.47, p =0.046). CONCLUSIONS: For LA-NPC, both CCRT and NACT were similarly efficacious treatment strategies in terms of long-term disease control and survival probability. Close locoregional follow-up is recommended for patients receiving NACT, because these patients are more prone to develop locoregional failure than patients receiving CCRT.

Impact of Alcohol and Smoking on Outcomes of HPV-Related Oropharyngeal Cancer.

BACKGROUND: The aim of this study was to evaluate the impact of adverse lifestyle factors on outcomes in patients with human papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (OPSCC). METHODS: From 2010 to 2019, 150 consecutive non-metastatic OPSCC patients receiving curative treatment in our institution were retrospectively enrolled. HPV positivity was defined as p16 expression ≥75%. The effects of adverse lifestyle factors on overall survival (OS) and disease-free survival (DFS) on OPSCC patients were determined. RESULTS: The median follow-up duration was 3.6 years. Of the 150 OPSCCs, 51 (34%) patients were HPV-positive and 99 (66%) were HPV-negative. The adverse lifestyle exposure rates were 74.7% (n = 112) alcohol use, 57.3% (n = 86) betel grid chewing, and 78% (n = 117) cigarette smoking. Alcohol use strongly interacted with HPV positivity (HR, 6.00; 95% CI, 1.03-35.01), leading to an average 26.1% increased risk of disease relapse in patients with HPV-positive OPSCC. Heavy smoking age ≥30 pack-years was associated with increased risk of death (HR, 2.05; 95% CI, 1.05-4.00) and disease relapse (HR, 1.99; 95% CI, 1.06-3.75) in OPSCC patients. In stratified analyses, the 3-year absolute risk of disease relapse in HPV-positive OPSCC patients reached up to 50% when alcohol use and heavy smoking for ≥30 pack-years were combined. CONCLUSIONS: Alcohol acted as a significant treatment-effect modifier for DFS in HPV-positive OPSCC patients, diluting the favorable prognostic effect of HPV positivity. Heavy smoking age ≥30 pack-years was an independent adverse prognostic factor of OS and DFS in OPSCC patients. De-intensification treatment for HPV-related OPSCC may be avoided when these adverse lifestyle factors are present.

Association of Primary Treatment Modality for Advanced-Stage Oropharyngeal Squamous Cell Carcinoma With Survival Outcomes.

Importance: Definitive chemoradiotherapy and upfront surgical treatment are both accepted as the standard of care for advanced-stage oropharyngeal squamous cell carcinoma. However, the optimal primary treatment modality remains unclear. Objective: To evaluate the comparative effectiveness of definitive chemoradiotherapy and upfront surgical treatment for advanced-stage oropharyngeal cancer. Design, Setting, and Participants: This retrospective comparative effectiveness analysis used data from the population-based Taiwan Cancer Registry. Included patients were diagnosed with clinical stage III or IV oropharyngeal squamous cell carcinoma from 2007 to 2015 and were identified from the registry. Patients with T4b or N3 disease were excluded. Data were analyzed from June 2019 through December 2020. Interventions: Definitive chemoradiotherapy or upfront surgical treatment. Main Outcomes and Measures: The primary outcome was overall survival, for which data were available through December 31, 2018. Secondary outcomes were progression-free survival, locoregional recurrence-free survival, and distant metastasis-free survival. Results: Among 1180 patients, 694 patients (58.8%) were in the definitive chemoradiotherapy group and 486 patients (41.2%) were in the upfront surgical treatment group. The median (interquartile range) follow-up was 3.62 (1.63-5.47) years, and most patients were men (1052 [89.1%] men) with a primary tumor in the tonsils (712 patients [60.3%]), moderately differentiated histology (604 patients [51.2%]), clinical N2 disease (858 patients [72.7%]), and clinical stage IVA disease (938 patients [79.5%]). The mean (SD) age was 54.59 (10.35) years. Primary treatment with an upfront surgical procedure was associated with a decreased risk of death during the study period (hazard ratio [HR], 0.81; 95% CI, 0.69-0.97; P = .02). However, when adjusted for age, subsite, histological grade, and T and N classification, upfront surgical treatment was no longer associated with an increased risk of death during the study period (HR, 0.96; 95% CI, 0.80-1.16; P = .70). Progression-free survival was worse in the group receiving upfront surgical treatment than in the group receiving chemoradiotherapy (HR, 1.64; 95% CI, 1.09-2.46; P = .02), and this difference persisted after adjusting for other factors associated with prognosis (ie, age, tumor subsite, histological grade, and T and N classification) (HR, 1.72; 95% CI, 1.12-2.66; P = .01). Conclusions and Relevance: This study found that definitive chemoradiotherapy was associated with effectiveness that was comparable with that of upfront surgical treatment when adjusted for baseline factors associated with prognosis. These findings suggest that definitive chemoradiotherapy should be considered to avoid accumulating toxic effects associated with surgical treatment and chemoradiotherapy.

Investigating the association between serum human papillomavirus type 16 E7 antibodies and risk of head and neck cancer.

Human papillomavirus (HPV) is recognized as a major cause of oropharyngeal cancer (OPC) in Western countries. Less is known regarding its contribution to the OPC occurring in Asia. The current study aimed to investigate the association between antibody responses to HPV16 E7 and head and neck cancer (HNC) risk in a hospital-based case-control study conducted in Taiwan with 693 HNC cases and 1,035 controls. A positive association was observed between seropositivity to HPV16 E7 and OPC risk, whereas no significant association was found in the non-OPC cases. The increased OPC risk associated with seropositivity to HPV16 E7 was more significant among nonbetel quid or noncigarette users. Seropositivity to HPV16 E7 showed moderate agreement with P16 expression in OPC. OPC patients that were seropositive to HPV16 E7 or p16 positive were more highly educated and less likely to use alcohol, betel quids, and cigarettes compared to HPV16 E7 seronegative or p16 negative OPC patients. Furthermore, patients with p16 positive OPC were more likely to be women compared to patients with p16 negative OPC, likely owing to the low prevalence of alcohol, betel quid, and cigarette users among women. Overall, this study suggested that similar to Western countries, HPV may also be an important risk factor of OPC in Taiwan. With the declining consumption of betel quids and cigarettes in Taiwan, a higher percentage of OPC cases in Taiwan will be attributed to HPV in the future. Public health measures, including HPV vaccination, need to be implemented to prevent the occurrence of HPV-positive OPC.

Delivery of chemotherapeutic agents using drug-loaded irradiated tumor cells to treat murine ovarian tumors.

BACKGROUND: Ovarian cancer is the leading cause of death among women with gynecologic malignancies in the United States. Advanced ovarian cancers are difficult to cure with the current available chemotherapy, which has many associated systemic side effects. Doxorubicin is one such chemotherapeutic agent that can cause cardiotoxicity. Novel methods of delivering chemotherapy without significant side effects are therefore of critical need. METHODS: In the current study, we generated an irradiated tumor cell-based drug delivery system which uses irradiated tumor cells loaded with the chemotherapeutic drug, doxorubicin. RESULTS: We showed that incubation of murine ovarian cancer cells (MOSEC) with doxorubicin led to the intracellular uptake of the drug (MOSEC-dox cells) and the eventual death of the tumor cell. We then showed that doxorubicin loaded MOSEC-dox cells were able to deliver doxorubicin to MOSEC cells in vivo. Further characterization of the doxorubicin transfer revealed the involvement of cell contact. The irradiated form of the MOSEC-dox cells were capable of treating luciferase-expressing MOSEC tumor cells (MOSEC/luc) in C57BL/6 mice as well as in athymic nude mice resulting in improved survival compared to the non drug-loaded irradiated MOSEC cells. Furthermore, we showed that irradiated MOSEC-dox cells was more effective compared to an equivalent dose of doxorubicin in treating MOSEC/luc tumor-bearing mice. CONCLUSIONS: Thus, the employment of drug-loaded irradiated tumor cells represents a potentially innovative approach for the delivery of chemotherapeutic drugs for the control of ovarian tumors.

The Role of Pretreatment Serum Neutrophil-to-Lymphocyte Ratio in Hypopharyngeal Cancer Treated with Definitive Chemoradiotherapy: A Pilot Study.

Serum neutrophil-to-lymphocytes ratio (NLR) is a potential predictive and prognostic marker in head and neck cancers. This study aimed to determine the role of pretreatment serum NLR in patients with hypopharyngeal cancer (HPC) treated with definitive chemoradiotherapy. We retrospectively investigated the correlation between clinicopathological parameters and NLR status and analysed its impact on therapeutic response and survival. A total of 120 patients treated at a single institution between 2009 and 2015 were included. The median follow-up time was 24.1 months. High NLR (NLR ≥ 4) was associated with advanced T classification (p = 0.01*) and advanced stage (p = 0.02*) based on chi-square test. We also found that high pretreatment NLR was correlated with poor treatment response (HR = 2.42, 95% CI: 1.08-5.44, p = 0.03*). Pretreatment NLR was also an independent prognostic factor for progression-free survival (HR = 1.71, 95% CI: 1.01-2.90, p = 0.046*) and overall survival (HR = 1.99, 95% CI: 1.21-3.28, p = 0.01*) while correcting for known prognostic factors. Overall, these findings support that NLR is a potential biomarker for host response to tumour aggressiveness, therapeutic response to chemoradiotherapy and survival in HPC patients. This study is limited by its retrospective nature and further validation is warranted.

The Influence of Prediagnosis Alcohol Consumption and the Polymorphisms of Ethanol-Metabolizing Genes on the Survival of Head and Neck Cancer Patients.

BACKGROUND: Although alcohol drinking is an established risk factor of head and neck cancer (HNC), less is known about its role in the prognosis of HNC. The current study investigated the association between pretreatment alcohol consumption and the overall survival (OS) of HNC patients. METHODS: Cox proportional hazards models were performed to evaluate the association between prediagnosis alcohol drinking and the OS of HNC patients. In addition, the influence of the polymorphisms of two ethanol-metabolizing genes, ADH1B and ALDH2, on this relationship was also evaluated. RESULTS: The results showed a significant positive dose-response relationship between prediagnosis alcohol use and worse OS of HNC patients. This association was more significant for oropharyngeal cancer, hypopharyngeal cancer, and laryngeal cancer than for oral cancer. The association between alcohol use and the poorer OS of HNC patients was mainly through its association with a higher stage of HNC at diagnosis. The worst OS associated with alcohol use was observed among HNC patients with the fast ADH1B and the slow/nonfunctional ALDH2 genotype combination. CONCLUSIONS: Our analysis showed a significant positive dose-response relationship between prediagnosis alcohol use and a worse OS of HNC. This association was mainly due to the higher stage of HNC among alcohol drinkers. In addition, the polymorphisms of the ethanol-metabolizing genes, ADH1B and ALDH2, modified the relationship between prediagnosis alcohol use and the OS of HNC patients. IMPACT: Prediagnosis alcohol use may be a prognostic indicator of HNC.

Oral hygiene and the overall survival of head and neck cancer patients.

Poor oral hygiene is an established risk factor of head and neck cancer (HNC); however, its role in the survival of HNC patients is unclear. This study evaluated the association between oral hygiene habits, including regular dental visits, frequency of tooth brushing, and use of dental floss, and the overall survival (OS) of HNC patients using interview data collected from 740 HNC patients. In addition, the interactions between oral hygiene and the polymorphisms of TLR2 and TLR4 on the OS of HNC patients were assessed. The analysis indicated that poor oral hygiene was significantly associated with poorer OS of HNC patients (hazard ratio (HR) = 1.38, 95% confidence interval (CI): 1.03-1.86). This association was modified by a single nucleotide polymorphism, rs11536889, of TLR4. A significant association between poor oral hygiene and worse survival of HNC was observed among those with the CG or CC genotype (HR = 2.32, 95% CI: 1.41-3.82) but not among those with the GG genotype (HR = 0.95, 95% CI: 0.65-1.40). Our results suggested that poor oral hygiene is not only a risk factor but may also be a prognostic factor of HNC.