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Background: For R/M HNSCC, the differences in prognosis and treatment options between distant metastasis (DM) and locoregional recurrence, especially in the DM group, remain unclear. Methods: From the Taiwan Head Neck Society registry database, patients who were diagnosed with R/M HNSCC and received cetuximab‐based frontline therapy were collected for analysis. Results: Among the enrolled patients, 59.3% (491/827) belonged to the DM group. The DM group had less primary site of oral cavity, less betel nut chewing, higher lactate dehydrogenase (LDH) levels, and higher LDH/albumin ratio compared with the non‐DM group. For the patients with primary site of oral cavity and current smokers, DM coexisted with poorer outcomes. In the DM group, EXTREME‐like regimen was more suitable for older patients, those with elevated LDH, and those with higher LDH/albumin ratio than TPExtreme‐like regimen. Conclusion: DM coexisted with poorer prognosis in certain groups. LDH‐associated biomarkers may aid treatment options for DM patients. [ABSTRACT FROM AUTHOR]

Large primary tumor volume has been identified as a poor prognostic factor of esophageal squamous cell carcinoma (ESCC) treated with definitive concurrent chemoradiotherapy (CCRT). However, when neoadjuvant CCRT and surgery are adopted, the prognostic impact of primary tumor and lymph node (LN) volume on clinical outcomes in ESCC remains to be elucidated. This study included 107 patients who received neoadjuvant CCRT and surgery for ESCC. The volume of the primary tumor and LN was measured using radiotherapy planning computed tomography scans, and was correlated with overall survival (OS), disease-free survival (DFS), and cancer failure pattern. The median OS was 24.2 months (IQR, 11.1–93.9) after a median follow-up of 18.4 months (IQR, 8.1–40.7). The patients with a baseline LN volume > 7.7 ml had a significantly worse median OS compared to those with smaller LN volume (18.8 vs. 46.9 months, p = 0.049), as did those with tumor regression grade (TRG) 3–5 after CCRT (13.9 vs. 86.7 months, p < 0.001). However, there was no association between OS and esophageal tumor volume (p = 0.363). Multivariate analysis indicated that large LN volume (HR 1.753, 95% CI 1.015–3.029, p = 0.044) and high TRG (HR 3.276, 95% CI 1.556–6.898, p = 0.002) were negative prognostic factors for OS. Furthermore, large LN volume was linked to increased locoregional failure (p = 0.033) and decreased DFS (p = 0.041). In conclusion, this study demonstrated that large LN volume is correlated with poor OS, DFS, and locoregional control in ESCC treated with neoadjuvant CCRT and esophagectomy. [ABSTRACT FROM AUTHOR]

Programmed death-ligand 1 (PD-L1) is an immune checkpoint molecule that can regulate immune responses in the tumor microenvironment (TME); however, the clinical applications of PD-L1 in early-stage colorectal cancer (CRC) remain unclear. In this study, we aimed to investigate the relationship between PD-L1 expression and survival outcome and explore its relevant immune responses in CRC. PD-L1 expression was evaluated by immunohistochemical staining to determine the tumor proportion score and combined positive score (CPS) in a Taiwanese CRC cohort. The oncomine immune response research assay was conducted for immune gene expression analyses. CRC datasets from the TCGA database were reappraised for PD-L1-associated gene enrichment analyses using GSEA. The high expression of PD-L1 (CPS ≥ 5) was associated with longer recurrence-free survival (p = 0.031) and was an independent prognostic factor as revealed by multivariate analysis. High PD-L1 expression was related to six immune-related gene signatures, and CXCL9 is the most significant overexpressed gene in differential analyses. High CXCL9 expression correlated with increased infiltration levels of immune cells in the TME, including CD8+ T lymphocytes and M1 macrophages. These findings suggest that high PD-L1 expression is a prognostic factor of early-stage CRC, and CXCL9 may play a key role in regulating PD-L1 expression. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Lessons Learned: SCB01A is a novel microtubule inhibitor with vascular disrupting activity.This first‐in‐human study demonstrated SCB01A safety, pharmacokinetics, and preliminary antitumor activity.SCB01A is safe and well tolerated in patients with advanced solid malignancies with manageable neurotoxicity. Background: SCB01A, a novel microtubule inhibitor, has vascular disrupting activity. Methods: In this phase I dose‐escalation and extension study, patients with advanced solid tumors were administered intravenous SCB01A infusions for 3 hours once every 21 days. Rapid titration and a 3 + 3 design escalated the dose from 2 mg/m2 to the maximum tolerated dose (MTD) based on dose‐limiting toxicity (DLT). SCB01A‐induced cellular neurotoxicity was evaluated in dorsal root ganglion cells. The primary endpoint was MTD. Safety, pharmacokinetics (PK), and tumor response were secondary endpoints. Results: Treatment‐related adverse events included anemia, nausea, vomiting, fatigue, fever, and peripheral sensorimotor neuropathy. DLTs included grade 4 elevated creatine phosphokinase (CPK) in the 4 mg/m2 cohort; grade 3 gastric hemorrhage in the 6.5 mg/m2 cohort; grade 2 thromboembolic event in the 24 mg/m2 cohort; and grade 3 peripheral sensorimotor neuropathy, grade 3 elevated aspartate aminotransferase, and grade 3 hypertension in the 32 mg/m2 cohort. The MTD was 24 mg/m2, and average half‐life was ~2.5 hours. The area under the curve‐dose response relationship was linear. Nineteen subjects were stable after two cycles. The longest treatment lasted 24 cycles. SCB01A‐induced neurotoxicity was reversible in vitro. Conclusion: The MTD of SCB01A was 24 mg/m2 every 21 days; it is safe and tolerable in patients with solid tumors. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. In this validation study of the alcohol flushing questionnaire with subjects from a hospital‐based case‐control study of head and neck cancerconducted in Taiwan, we found that the alcohol flushing questionnaire had a high sensitivity (89%) of identifying ALDH2*2carriers among the control subjects and a good sensitivity(79%) among the HNC patients. The sensitivity of the alcohol flushing questionnaire in identifying ALDH2*2carriers was affected by alcohol use, with a lower sensitivity among current regular alcohol drinkers. [ABSTRACT FROM AUTHOR]

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. Poor oral hygiene was associated with a worse survival of head and neck cancer. TLR4 affected the survival of head and neck cancer due to poor oral hygiene. Poor oral hygiene is both a risk and a prognostic factor of head and neck cancer [ABSTRACT FROM AUTHOR]

Objectives: Although betel quid (BQ) is an established risk factor of head and neck cancer (HNC), insufficiencies exist in the literature regarding the dose-response, BQ types, HNC sites, and BQ cessation. The current study was conducted to fill these insufficiencies. Materials and Methods: A hospital-based case-control study was conducted to evaluate the association between BQ and HNC. In-person interview was conducted to collect data on BQ chewing. The current analysis included 487 men newly diagnosed with HNC and 617 male controls who were frequency-matched to the cases by age. The association between BQ and HNC was assessed using multivariable unconditional logistic regression. Results: Ever BQ chewing was associated with an increased HNC risk regardless of the BQ types. A non-linear positive association between BQ and HNC was observed, with a steep rise in HNC risk for the first 5 pack-years or 200,000 minutes of BQ consumption. Every year of BQ cessation was associated with a 2.9% reduction in HNC risk; however, the risk did not reduce to the level of non-BQ chewers even after 20 years of BQ cessation. Eliminating BQ chewing may prevent 51.6% of HNCs, 62.6% of oral cancers, and 41.3% of pharyngeal cancers in Taiwan. Conclusion: Our results supported the positive association between BQ and HNC. BQ cessation is effective in reducing HNC risk and should be encouraged. Because BQ cessation may not reduce the HNC risk to the level of non-BQ chewers, it is important to prevent the initiation of BQ chewing. [ABSTRACT FROM AUTHOR]

Epinephrine is known as a weak, but important, agonist for platelet activation. It has been reported that the responsiveness of platelets to epinephrine was markedly impaired in 6% of Caucasians and in 16% of Japanese. The purpose of this study was to screen and characterize this abnormality in healthy Taiwanese Chinese volunteers. We used aggregometry, flow cytometry and platelet function analyzer (PFA)-100 system to assess in 50 healthy male volunteers the responsiveness of platelets to epinephrine stimulation. Using α2A adrenoceptor antagonist BRL44408 maleate competition and a [3H]yohimbin binding assay, we evaluated α2A adrenoceptors on platelets. The aggregation of platelets after stimulation with 10 μM of epinephrine indicated two distinct groups of study participants: 24 (48.0%) good- and 26 (52.0%) impaired-responders to epinephrine. Flow cytometric analysis of platelets after stimulated with 1 μM epinephrine showed that glycoprotein (GP) IIb/IIIa and P-selectin expression of epinephrine good- and impaired-responders were 27.1 ± 11.0% vs. 9.9 ± 5.4% (p = 0.003) and 12.2 ± 6.2% vs. 3.6 ± 3.5% (p < 0.001), respectively. The PFA-100 system showed that epinephrine-impaired-responders had a longer collagen-epinephrine induced closure time. Good-responder platelets incubated with BRL44408 maleate had an impaired response to epinephrine stimulation. [3H]yohimbine binding studies showed fewer α2A adrenoreceptors on the platelets of epinephrine-impaired-responders than on those of good-responders. The prevalence of impaired responsiveness to epinephrine was high and probably due to α2A adrenoreceptor deficiency in male Taiwanese Chinese. [ABSTRACT FROM AUTHOR]

Objectives: Host immunity likely plays a role in preventing progression of diffuse large B-cell lymphoma (DLBCL). Analysis of host immune cells may provide useful information for assessing prognosis or possibly clinical management.Methods: Peripheral blood samples from 77 patients with DLBCL and 30 healthy volunteers were analyzed using flow cytometry immunophenotyping. CBC counts, T-cell subsets, and dendritic cells (DCs) were detected, and the results were correlated with clinicopathologic characteristics.Results: Compared with healthy volunteers, patients with DLBCL had significantly higher leukocyte and monocyte counts (P < .001); higher percentages of neutrophils (P < .001), "natural" regulatory T cells (Tregs; CD3+Foxp3+, P < .001), and immature DCs (CD83-CD1a+, P = .005); and lower percentages of lymphocytes (P < .001) and helper T cells (P = .038). In univariate analysis, high neutrophil counts (≥6,000/μL, P = .014) and "induced" Tregs (CD4+CD25+, P = .026) were poor survival factors along with high International Prognostic Index scores (P < .001) and other high-risk clinical parameters. In multivariate analysis, high Tregs retained significance. Suppression of lymphocytes correlated with poor clinical factors; higher natural Tregs correlated with a lower CD4+/CD8+ ratio (P = .035) and more immature DCs (P = .055).Conclusions: Changes in blood immune cells occur in patients with DLBCL. The results also support a suppressive role of Tregs in adaptive immunity and correlate with poor-risk prognostic factors. [ABSTRACT FROM AUTHOR]

Background: The current study evaluated the association between tea consumption and head and neck cancer (HNC) in Taiwan, where tea is a major agricultural product and a popular beverage. Methods: Interviews regarding tea consumption (frequency, duration, and types) were conducted with 396 HNC cases and 413 controls. Unconditional logistic regression was performed to estimate the odds ratio (OR) and 95% confidence interval (CI) of HNC risk associated with tea drinking, adjusted for sex, age, education, cigarette smoking, betel quid chewing, and alcohol drinking. Results: A reduced HNC risk associated with tea drinking (OR for every cup per day = 0.96, 95% CI: 0.93–0.99; OR for ≧5 cups per day = 0.60, 95% CI: 0.39–0.94) was observed. The association was especially significant for pharyngeal cancer (OR for every cup per day = 0.93, 95% CI: 0.88–0.98; OR for ≧5 cups per day = 0.32, 95% CI: 0.16–0.66). A significant inverse association between HNC and tea consumption was observed particularly for green tea. Conclusions: This study suggests that tea drinking may reduce the risk of HNC. The anticancer property of tea, if proven, may offer a natural chemopreventive measure to reduce the occurrence of HNC. [ABSTRACT FROM AUTHOR]

Background: Although the relationship between allergy and cancer has been investigated extensively, the role of allergy in head and neck cancer (HNC) appears less consistent. It is not clear whether allergies can independently influence the risk of HNC in the presence of known strong environmental risk factors, including consumption of alcohol, betel quid, and cigarette. Methods: The current paper reports results from: 1) an original hospital-based case-control study, which included 252 incident cases of HNC and 236 controls frequency-matched to cases on sex and age; and 2) a meta-analysis combining the results of the current case-control study and 13 previously published studies (9 cohort studies with 727,569 subjects and 550 HNC outcomes and 5 case-control studies with 4,017 HNC cases and 10,928 controls). Results: In the original case-control study, we observed a strong inverse association between allergies and HNC [odds ratio = 0.41, 95% confidence interval (CI): 0.27–0.62]. The meta-analysis also indicated a statistically significant inverse association between HNC and allergies [meta-relative risk (RR) = 0.76, 95% CI: 0.63–0.91], particularly strong for allergic rhinitis (meta-RR = 0.55, 95% CI: 0.40–0.76). In addition, the inverse association between allergies and HNC was observed only among men (meta-RR = 0.67, 95% CI: 0.54–0.84) but not among women (meta-RR = 0.98, 95% CI: 0.81–1.18). Conclusions: These findings suggest that immunity plays an influential role in the risk of HNC. Future studies investigating immune biomarkers, including cytokine profiles and genetic polymorphisms, are warranted to further delineate the relationship between allergies and HNC. Understanding the relationship between allergies and HNC may help devise effective strategies to reduce and treat HNC. [ABSTRACT FROM AUTHOR]

Intratumoral heterogeneity in epidermal growth factor receptor (EGFR)-mutant mutant non-small-cell lung cancer (NSCLC) explains the mixed responses to EGFR-tyrosine kinase inhibitors (TKIs). However, some studies showed tumors with low abundances of EGFR mutation still respond to EGFR-TKI, and the mechanism remained undetermined. Extracellular vesicles (EVs) can transmit antiapoptotic signals between drug-resistant and drug-sensitive cells. Herein, we profiled EVs from EGFR-mutant cells to identify a novel mechanism explaining why heterogenous EGFR-mutant NSCLC patients still respond to EGFR-TKIs. We first demonstrated that the EVs from EGFR-mutant changes the wild-type cells' sensitivity to gefitinib by adding EV directly or coculturing EGFR wild-type (CL1-5) cells and EGFR-mutant (PC9) cells. In animal studies, only the combined treatment of PC9 EV and gefitinib delayed the tumor growth of CL1-5 cells. MicroRNA analysis comparing EV miRNAs from PC9 cells to those from CL1-5 cells showed that mir200 family members are most abundant in PC9 EVs. Furthermore, mir200a and mir200c were found upregulated in plasma EVs from good responders to EGFR-TKIs. Finally, the transfection of CL1-5 cells with miR200c inactivates downstream signaling pathways of EGFR, the EMT pathway, and enhances gefitinib sensitivity. Overall, our results suggest that in heterogeneous EGFR-mutant NSCLC, tumor cells transmit EV miRNAs that may affect sensitivity to EGFR-TKIs and provide potential prognostic biomarkers for EGFR-mutant NSCLC. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Owing to the high mortality and rapidly growing costs related to lung cancer, it is worth examining the health benefits of prevention for major types of lung cancer. This study attempts to quantify the quality-adjusted life expectancy (QALE), loss-of-QALE, and lifetime healthcare expenditures of patients with different pathological types of lung cancer.Methods: A national cohort consisting of 66,535 patients with pathologically verified lung cancer was followed for 13 years (1998-2010) to obtain the survival function, which was further extrapolated to lifetime. Between 2011 and 2012, EuroQol 5-dimension questionnaires were used to measure the quality of life (QoL) for 1,314 consecutive, cross-sectional samples. After multiplying the lifetime survival function by the utility values of QoL, we estimated the QALE and loss-of-QALE. We also collected the monthly healthcare expenditures, which included National Health Insurance-reimbursed and out-of-pocket direct medical costs, for 2,456 patients from 2005 to 2012. These values were multiplied by the corresponding survival probabilities to calculate lifetime healthcare expenditures after adjustments with medical care inflation rates and annual discount rates.Results: The QALE for patients with small cell lung cancer, squamous cell carcinoma, and adenocarcinoma were 1.21, 2.37, and 3.03 quality-adjusted life year (QALY), with the corresponding loss-of-QALE of 13.69, 12.22, and 15.03 QALY, respectively. The lifetime healthcare expenditures were US$ 18,455 ± 1,137, 20,599 ± 1,787, and 36,771 ± 1,998, respectively.Conclusions: The lifelong health impact and financial burdens in Taiwan are heavier for adenocarcinoma than for squamous cell carcinoma. The cost-effectiveness of prevention programs could be directly compared with that of treatment strategies to improve patient value. And the methodology could be applied to other chronic diseases for resources planning of healthcare services. [ABSTRACT FROM AUTHOR]