Rising incidence of HPV positive oropharyngeal cancer in Taiwan between 1999 and 2014 where betel nut chewing is common.

BACKGROUND: The incidence of human papillomavirus (HPV) positive oropharyngeal cancer (OPC) is rising but HPV negative OPC is decreasing in Western countries. In Taiwan, the incidence of HPV negative OPC is common but the incidence of HPV positive OPC remains unknown. The objective of this study is to estimate the incidence trend and the survival of HPV positive OPC in Taiwan. METHODS: Between 1999 and 2014, primary tumor tissues from 425 incident OPCs were obtained from 5 medical centers in Taiwan. 408 OPCs were evaluated by the EasyChip HPV genotyping (King-Car, I-Lan, Taiwan) and 369 OPCs by p16 staining. The clinical data were retrospectively obtained from the medical records. RESULTS: In our study, 29% of OPCs were HPV positive. The percentage of HPV positive OPC was stable from 1999 to 2014 (25% (1999-2002), 30% (2003-2006), 30% (2007-2010), 29% (2011-2014)). The estimated crude incidence rate of HPV positive OPC increased significantly from 0.62 (1999-2002), 1.06 (2003-2006), 1.52 (2007-2010) to 1.74 (2011-2014) per 100,000 person-year. The sensitivity and specificity of p16 staining for positive HPV infection were 92% and 91%, respectively. The 5-year overall survival rates for patients with HPV positive OPC and with HPV negative OPC were 67.8% and 49.0%, respectively (HR = 0.52 (0.35-0.76), p = 0.0005). Patients with HPV positive OPC but no betel nut/cigarette exposure had the best overall survival (5-year: 88.2%, p < 0.0001). Patients with HPV negative OPC and betel nut/cigarette exposure had the worst overall survival (5-year: 46.6%, p < 0.0001). Patients with HPV positive OPC but also with betel nut/cigarette exposure had poorer 5-year overall survival (48.3%, p < 0.01). CONCLUSION: The incidence of HPV positive OPC is increasing along with HPV negative OPC, which leads to stably low percentage of HPV positive OPC in Taiwan. HPV positive OPC may become an important head and neck cancer when the incidence of HPV negative OPC declines in the near future. P16 is a useful surrogate marker for HPV infection in OPC and a good prognostic indicator for treatment outcome of OPC. Patients with HPV positive OPC but no betel nut/cigarette exposure has an excellent prognosis. Betel nut/cigarette exposure significantly worsens the prognosis of HPV positive OPC.

Incidence and prognostic significance of extranodal extension in isolated nodal recurrence of oral squamous cell carcinoma.

BACKGROUND: Extranodal extension (ENE) is a crucial prognostic factor of oral squamous cell carcinoma (OSCC). However, the role of ENE in regional recurrence (rENE) remains unclear. The purpose of our study is to assess the salvage outcome according to the presence of rENE in oral cancer patients with isolated nodal recurrence. METHODS: Oral cancer patients diagnosed with isolated nodal recurrence at the National Taiwan University Hospital between January 2010 and December 2015 were reviewed. All patients were classified into two groups: with and without rENE. The treatment included salvage neck dissection (ND) ± metronomic chemotherapy, salvage ND and radiation (RT)/concurrent chemoradiation (CCRT), Salvage RT/CCRT alone, metronomic chemotherapy, or supportive care. RESULTS: We analyzed 198 patients, 156 with rENE and 42 without rENE. rENE presented more frequently in patients with initial ENE+ (OR = 3.17, p = 0.04), prior RT+ (OR = 2.96, p = 0.02), initial N2/N3 (OR = 2.76, p = 0.01), and recurrent LN size >1.5 cm (OR = 2.33, p = 0.03). The extent of rENE were also significantly different in these patients. The 2-year disease-free survival for patients with and without rENE were 15.7% and 31.7%, respectively (p = 0.002). The 2-year overall survival for patients with and without rENE were 19.6% and 43.9%, respectively (p = 0.004). For patients without rENE, those received salvage ND had better survival outcome (p < 0.001). By contrast, for patients with rENE, those received salvage RT/CCRT had better survival outcome (p < 0.001). CONCLUSION: The rENE is frequently present (78.79%) in OSCC patients with isolated nodal recurrence. Individualized treatment modalities based on the presence of rENE should be recommended to achieve better salvage outcomes.

The differences of immunologic and TP53 mutant phenotypes between synchronous and metachronous head and neck cancer and esophageal cancer.

OBJECTIVE: To determine the tumor genomic, immunologic expression, and risk factors of treatment outcomes for patients with double head and neck squamous cell carcinoma (HNSCC) and esophageal squamous cell carcinoma (ESCC). METHODS: We reviewed patients with double HNSCC and ESCC between 1995 and 2014. The TP53 genomic mutation, CD8+ tumor infiltrating lymphocytes (TIL) and tumor programmed cell death ligand 1 (PD-L1) expression of paired HNSCC and ESCC were analyzed. RESULTS: A total of 116 patients (57 metachronous and 59 synchronous) were included. There were 88 (75.86%) patients with HNSCC and 80 (68.97%) with ESCC harboured TP53 disruptive mutation. Nearly 106 (91.38%) patients had different clonality of TP53 mutation in paired HNSCC and ESCC. The immunologic expression of synchronous and metachronous patients was significantly different. Compared to the metachronous patients, the synchronous patients had significantly higher HNSCC CD8+ TIL (p = 0.03), ESCC CD8+ TIL (p < 0.001), HNSCC PD-L1+ tumor proportion score (TPS, p = 0.04), and ESCC PD-L1+ TPS (p = 0.04). Furthermore, among the synchronous patients, the immunologic expression between HNSCC and ESCC was significantly correlated. The CD8+ TIL and PD-L1 TPS had strongly (r = 0.63, p < 0.0001) and moderately (r = 0.42, p = 0.001) positive correlations, respectively. Finally, advanced stage (III/IV) HNSCC was a significant factor for disease-free (p = 0.03) and overall survival (p = 0.005). CONCLUSION: In patients with double HNSCC and ESCC, nearly all HNSCC and ESCC were of multicentric origin. For the synchronous patients, there was more adaptive immune resistance in HNSCC and ESCC. The immunologic expression between paired HNSCC and ESCC was also significantly correlated.

Proteogenomics of Non-smoking Lung Cancer in East Asia Delineates Molecular Signatures of Pathogenesis and Progression.

Lung cancer in East Asia is characterized by a high percentage of never-smokers, early onset and predominant EGFR mutations. To illuminate the molecular phenotype of this demographically distinct disease, we performed a deep comprehensive proteogenomic study on a prospectively collected cohort in Taiwan, representing early stage, predominantly female, non-smoking lung adenocarcinoma. Integrated genomic, proteomic, and phosphoproteomic analysis delineated the demographically distinct molecular attributes and hallmarks of tumor progression. Mutational signature analysis revealed age- and gender-related mutagenesis mechanisms, characterized by high prevalence of APOBEC mutational signature in younger females and over-representation of environmental carcinogen-like mutational signatures in older females. A proteomics-informed classification distinguished the clinical characteristics of early stage patients with EGFR mutations. Furthermore, integrated protein network analysis revealed the cellular remodeling underpinning clinical trajectories and nominated candidate biomarkers for patient stratification and therapeutic intervention. This multi-omic molecular architecture may help develop strategies for management of early stage never-smoker lung adenocarcinoma.

Association of Programmed Death-Ligand 1 Expression with Fusion Variants and Clinical Outcomes in Patients with Anaplastic Lymphoma Kinase-Positive Lung Adenocarcinoma Receiving Crizotinib.

BACKGROUND: Programmed death-ligand 1 (PD-L1) expression is associated with clinical outcomes of epidermal growth factor receptor (EGFR) mutant lung adenocarcinoma (ADC) treated with tyrosine kinase inhibitors (TKIs). However, whether PD-L1 expression plays a role in anaplastic lymphoma kinase (ALK)-positive lung ADC is unknown. We aimed to evaluate the impact of PD-L1 in patients with ALK-positive lung ADC receiving crizotinib. MATERIALS AND METHODS: PD-L1 expression was identified by immunohistochemistry (IHC). Reverse transcriptase-polymerase chain reaction was used for ALK variant detection, and immunofluorescence-based multiplex staining was applied for exploring immune cells in tumor microenvironments. RESULTS: A total of 78 patients with ALK-positive advanced ADC were enrolled in our study, of whom 52 received crizotinib. Compared with EGFR/ALK wild-type tumors, PD-L1 expression was lower in ALK-positive ADC. ALK fusion variants were identified in 32 patients, and those with variant 3 and 5 (short variants) had higher PD-L1 expression than those with other variants. The crizotinib objective response rate (ORR) and progression-free survival (PFS) was better in tumors with negative PD-L1 expression (ORR/PFS in PD-L1 0% vs. 1%-49% vs. 50%-100%: 60.7%/11.8 months vs. 38.5%/6.5 months vs. 36.4%/4.0 months, p = .007/.022). The multivariate Cox proportional hazards model revealed that PD-L1 0% (vs. ≥1%) was an independent factor for longer PFS (adjusted hazard ratio 0.322, 95% confidence interval 0.160-0.650, p = .002). Multiplex IHC in three cases showed a varied extent of immune cell infiltrations in tumors with different PD-L1 expression. CONCLUSION: Positive PD-L1 expression was associated with unfavorable clinical outcomes in patients with ALK-positive lung ADC receiving crizotinib. IMPLICATIONS FOR PRACTICE: Not all lung adenocarcinoma with sensitizing driver mutations experienced durable responses to small-molecule tyrosine kinase inhibitors (TKIs). Similar to the negative impact of programmed death-ligand 1 (PD-L1) in epidermal growth factor receptor mutant tumors treated with TKIs, this study demonstrated that positive PD-L1 expression was also associated with worse response rate and shorter progression-free survival of anaplastic lymphoma kinase (ALK)-positive adenocarcinoma treated with crizotinib. Among different ALK fusion partners, tumors with short variants (V3 and V5) had higher PD-L1 compared with long variants (V1, V2, and V6). Testing PD-L1 before initiating crizotinib for ALK-positive lung cancer could be a simple method to provide important prognostic information.

Clinical characteristics and treatment outcome of oropharyngeal squamous cell carcinoma in an endemic betel quid region.

The clinical characteristics of oropharyngeal squamous cell carcinoma (OPSCC) may be different between endemic and non-endemic regions of betel nut chewing. The impact of combined alcohol drinking/betel quid chewing/cigarette smoking (ABC) exposure on the survival of OPSCC remains unclear. We reviewed the medical records of OPSCC patients between 1999 and 2013. Immunohistochemical staining of p16 and HPV genotype detection by DNA Polymerase chain reaction were both performed for each tumor. A total of 300 eligible patients including 74 HPV+ OPSCC patients and 226 HPV- OPSCC patients were enrolled. The 5-year disease-free survival rates for the HPV-, HPV+ OPSCC with and without ABC patients were 49.8%, 58.4% and 94%, respectively. The 5-year overall survival rates for the patients with HPV-, HPV+ OPSCC with and without ABC patients were 46%, 57.4% and 86%, respectively. Advanced locoregionally disease (T3/T4, N2/N3), HPV- OPSCC, combined 2 or all ABC exposure were the independent adverse prognostic factors for disease-free and overall survival. Therefore, our data suggest that in an endemic region of betel quid chewing, HPV- OPSCC comprises the majority of OPSCC and has a worse survival. Combined 2 or all ABC exposure had a significant negative impact on disease-free and overall survival.

Association between programmed death-ligand 1 expression, immune microenvironments, and clinical outcomes in epidermal growth factor receptor mutant lung adenocarcinoma patients treated with tyrosine kinase inhibitors.

INTRODUCTION: Besides being a predictive biomarker of response to immunotherapy in lung cancer in general, programmed death-ligand 1 (PD-L1) is not so well correlated with treatment outcomes of lung adenocarcinoma (ADC) harbouring epidermal growth factor receptor (EGFR) mutations, as reported studies are inconclusive and seldom addressed the issues of response to treatment and resistance. The primary objective is to evaluate the association of PD-L1 and EGFR tyrosine kinase inhibitor (TKI) efficacy, resistance, and relevant clinical outcomes. The secondary objective is to further explore the tumour microenvironments of EGFR mutant tumours with different PD-L1 expression. METHODS AND MATERIALS: Using immunohistochemical (IHC) staining, we retrospectively tested PD-L1 expression (Dako 22C3) in the pre-treatment tumours from advanced EGFR mutant lung ADC patients, of whom all were treated with TKIs. Multiplex IHC assay was applied for exploring immune cells in tumour microenvironments. RESULTS: A total of 153 Taiwanese patients were enrolled in our study, of whom a majority of cases were female (58.9%) and non-smokers (75.8%). The objective response rate (ORR) to EGFR TKI and progression-free survival (PFS) were better in patients with PD-L1 expression <50% (ORR/PFS in PD-L1 0% versus 1-49% versus ≥50%: 65.6%/12.5 months versus 56.4%/12.8 months versus 38.9%/5.9 months, P < 0.05). The multivariate analysis showed that PD-L1 <50% was an independent prognostic factor for longer PFS (hazard ratio (HR) 0.433, 95% confidence interval (CI) 0.250-0.751, P = 0.003). Furthermore, tumours with higher PD-L1 expression were less likely to develop a secondary T790M mutation (T790M+ in PD-L1 0% versus 1-49% versus ≥50%: 53.7% versus 35.7% versus 10%, P = 0.024). Multiplex IHC tests were applied in 15 cases and revealed a potential correlation between PD-L1, immune cells, and EGFR TKI responses. CONCLUSIONS: Lower pre-treatment PD-L1 is associated with better ORR, PFS, and higher frequency of T790M resistance in EGFR TKI-treated lung ADC patients.

Hypoxia-induced Slug SUMOylation enhances lung cancer metastasis.

BACKGROUND: The Slug-E-cadherin axis plays a critical role in non-small-cell lung cancers (NSCLCs) where aberrant upregulation of Slug promotes cancer metastasis. Now, the post-translational modifications of Slug and their regulation mechanisms still remain unclear in lung cancer. Hence, exploring the protein linkage map of Slug is of great interest for investigating the scenario of how Slug protein is regulated in lung cancer metastasis. METHODS: The Slug associated proteins, Ubc9 and SUMO-1, were identified using yeast two-hybrid screening; and in vitro SUMOylation assays combined with immunoprecipitation and immunoblotting were performed to explore the detail events and regulations of Slug SUMOylation. The functional effects of SUMOylation on Slug proteins were examined by EMSA, reporter assay, ChIP assay, RT-PCR, migration and invasion assays in vitro, tail vein metastatic analysis in vivo, and also evaluated the association with clinical outcome of NSCLC patients. RESULTS: Slug protein could interact with Ubc9 and SUMO-1 and be SUMOylated in cells. Amino acids 130-212 and 33-129 of Slug are responsible for its binding to Ubc9 and protein inhibitor of activated STAT (PIAS)y, respectively. SUMOylation could enhance the transcriptional repression activity of Slug via recruiting more HDAC1, resulting in reduced expression of downstream Slug target genes and enhanced lung cancer metastasis. In addition, hypoxia could increase Slug SUMOylation through attenuating the interactions of Slug with SENP1 and SENP2. Finally, high expression Slug and Ubc9 levels were associated with poor overall survival among NSCLC patients. CONCLUSIONS: Ubc9/PIASy-mediated Slug SUMOylation and subsequent HDAC1 recruitment may play a crucial role in hypoxia-induced lung cancer progression, and these processes may serve as therapeutic targets for NSCLC.

Mixed squamous cell and glandular papilloma of the lung: A case report of a novel mutation in the BRAF gene and coexistent HPV infection, possible relationship to ciliated muconodular papillary tumor.

Mixed squamous cell and glandular papilloma (mixed papilloma) is a very rare tumor, with fewer than 25 cases having been reported in the literature. Although a scattering of cases of p16Ink4a overexpression have been described to date, no human papillomavirus (HPV) DNA has been detected in these tumors, either by in situ hybridization (ISH) or polymerase chain reaction (PCR). This is the first case of mixed papilloma with PCR-confirmed HPV genotype 16, 35, 51 infections in an 18-year-old non-smoking male, coexisting with multiple atypical adenomatous hyperplasias (AAHs). Histologically, this tumor shows a predominant papillary architecture, covered by a mixture of stratified squamous cells, ciliated or non-ciliated cuboidal to columnar cells, mucous cells, and scattered goblet cells. Immunohistochemically, the squamous component was positive for p40, and the glandular cells were focally positive for TTF-1. Both components were diffusely immunoreactive to CK7. In addition, BRAF V600E mutation was also first demonstrated in mixed papilloma, but not in the AAHs. These findings suggest that HPV infection and the BRAF mutation may be important in the pathogenetic role in young non-smoking patients.

The Differences in Clinicopathologic and Prognostic Characteristics Between Surgically Resected Peripheral and Central Lung Squamous Cell Carcinoma.

BACKGROUND: Pulmonary peripheral-type squamous cell carcinoma (p-SqCC) has been increasing in incidence. However, little is known about the clinicopathologic features of p-SqCC. This study aimed to investigate the clinicopathologic characteristics and clinical outcomes of p-SqCC compared with central-type SqCC (c-SqCC) in a large cohort of surgically resected lung SqCC patients with long-term follow-up results. METHODS: The study included 268 patients with SqCC who underwent surgical resection at the authors' institute from January 1990 to September 2013. The mean follow-up period was 67.1 months. The clinicopathologic and genetic characteristics were investigated in relation to their association with progression-free survival (PFS) and overall survival (OS) based on tumor location. RESULTS: The study cohort included 120 patients with p-SqCC and 148 patients with c-SqCC. Compared with c-SqCC, p-SqCC was correlated with older age (p = 0.002), female sex (p = 0.033), better performance status (p < 0.001), smaller tumor (p = 0.004), less lymph node metastasis (p < 0.001), and an earlier pathologic stage (p < 0.001). Despite the clinicopathologic differences, tumor location was not significantly correlated with clinical outcomes. For the p-SqCC patients, the multivariate analysis showed a significant correlation of lymphovascular invasion (PFS, p < 0.001; OS, p < 0.001) and lymph node metastasis (p = 0.007; OS, p = 0.022) with poor PFS and OS, but a significant correlation of incomplete tumor resection (PFS, p = 0.009) only with poor PFS. CONCLUSIONS: The clinicopathologic features differed between the p-SqCC and c-SqCC patients. Lymphovascular invasion and lymph node metastasis were independent prognostic factors of p-SqCC. These prognostic factors may be potentially used as indicators for adjuvant therapies to be used with patients who have p-SqCC.

Prognostic significance of tumor-infiltrating lymphocytes in patients with operable tongue cancer.

BACKGROUND: Our aim was to investigate the prognostic significance of tumor-infiltrating lymphocytes (TILs) in operable tongue cancer patients. METHODS: The presence of CD3+, CD4+, CD8+, and forkhead box protein P3-positive (FOXP3+) TILs in tumor tissues obtained from 93 patients during surgery was examined using immunohistochemistry. RESULTS: The 3-year overall survival (OS) of patients with a low CD8/FOXP3 ratio was significantly lower than that of patients with a high CD8/FOXP3 ratio (63.8% vs. 87.3%, p = 0.001). Patients with high FOXP3 had a significantly lower 3-year regional recurrence-free survival (RRFS) than did patients with low FOXP3 (49.3% vs. 87.3%, univariate log rank p = 0.000). A low CD4/FOXP3 ratio (68.4% vs. 93.7%, univariate log rank p = 0.002) was significantly unfavorable prognostic factors for 3-year distant metastasis-free survival (DMFS). CONCLUSIONS: In addition to clinicopathological characteristics, TIL markers represent prognosticators for clinical outcomes.

M1 macrophages decrease in the deciduae from normal pregnancies but not from spontaneous abortions or unexplained recurrent spontaneous abortions.

BACKGROUND/PURPOSE: To investigate the M1/M2 polarity of macrophages in the endometrium among different menstrual cycles, normal and abnormal pregnancies, and unexplained recurrent spontaneous abortions (RSAs). METHODS: Endometrial tissue was obtained from 43 patients undergoing hysterectomy, either in the follicular phase (Group 1, n = 23) or in the luteal phase (Group 2, n = 20). In addition, decidual tissue was obtained from 53 pregnant women during the first trimester, either of normal pregnancies (Group 3, n = 12) or abnormal pregnancies (Group 4: spontaneous abortions, n = 20; Group 5: unexplained RSA, n = 21). Using immunofluorescence to examine the M1 and M2 macrophages in the endometrium and deciduae from cases with different menstrual phases and various pregnancy outcomes, respectively, we endeavored to learn the possible pathophysiology of abortions. RESULTS: M1 macrophages were abundant in the deciduae of spontaneous abortions and unexplained RSA, whereas the frequency of M2 macrophages was significantly higher in the endometrium of luteal phase and normal pregnancies. CONCLUSION: M2 polarization is important for early successful pregnancies in humans.

Globo H expression is associated with driver mutations and PD-L1 expressions in stage I non-small cell lung cancer.

BACKGROUND: Globo H is a tumor-associated carbohydrate antigen exclusively expressed in cancer cells rather than normal tissue. Globo H has been found on many cancers of epithelial origins, and become an attractive target for cancer vaccine. OBJECTIVES: We aimed to study the expression of Globo H in non-small cell lung cancer (NSCLC) patients, and correlated its expression with common driver mutations, clinical outcomes, and status of immune checkpoint, programmed death-ligand 1 (PD-L1). METHODS: The study enrolled 228 patients with surgically resected stage I NSCLC, including 139 patients with adenocarcinoma (ADC) and 89 patients with squamous cell carcinoma (SqCC). Using immunohistochemistry, tumors with moderate to strong membranous staining in ⩾ 1% tumor cells per section were scored as positive Globo H expression. Driver mutations including EGFR, KRAS, BRAF were detected by direct sequencing, while ALK, PI3KCA, FGFR1 and PD-L1 expression was detected by immunohistochemical (IHC) staining. RESULTS: Positive Globo H expression was detected in 88 of the 228 (38.6%) patients. These included 51 of 139 (36.7%) patients with ADC and 37 of 89 (41.6%) patients with SqCC. Positive Globo H expression was significantly associated with EGFR mutation and PD-L1 expression in the ADC group, and PI3KCA overexpression in the SqCC group. The survival analysis showed that Globo H expression was not an independent prognostic factor in stage I NSCLC. CONCLUSIONS: Globo H expression was correlated with specific driver mutations in ADC and SqCC NSCLC tumors, as well as PD-L1 status. Immunotherapy targeting Globo H may have potential application in lung cancer treatment.

The immunologic advantage of recurrent nasopharyngeal carcinoma from the viewpoint of Galectin-9/Tim-3-related changes in the tumour microenvironment.

Given salvage treatment for recurrent nasopharyngeal carcinoma (NPC) remains a clinical dilemma, immunotherapy targeting NPC-specific immunosuppression may bring new hope. We analyzed the expression of CD8, CD4, Foxp3 and Tim-3 in lymphocytes, and of Galectin-9 in tumour cells between paired primary and recurrent NPC from 95 patients and we noted that there was significant increase in the expression of Galectin-9+ tumour cells (p < 0.001) and Foxp3+ lymphocytes (p < 0.001) but a significant decrease in the expression of CD8+ lymphocytes (p = 0.01) between paired primary and recurrent NPC. Of all patients, 53 patients (55.79%) and 57 patients (60%) had increased percentages of Galectin-9+ tumour cells and of Foxp3+ lymphocytes, respectively. Conversely, 42 patients (44.21%) had decreased percentages of CD8+ lymphocytes. The patients with high Galectin-9 expression in recurrent NPC frequently also had high Tim-3 (p = 0.04) and Foxp3 (p = 0.01), and low CD8 (p = 0.04) expression in lymphocytes. After multivariate analyses, low CD8 expression in lymphocytes was an independent risk factor for relapse-free survival (p = 0.002) and overall survival (p = 0.02). Our data suggests that recurrent NPC may had more immunologic advantage than primary NPC, especially the Galectin-9/Tim-3 pathway. The immunotherapies targeting Galectin-9/Tim-3/Foxp3 interaction may serve as a potential salvage treatment for recurrent NPC.

The Pretreatment Neutrophil-to-Lymphocyte Ratio is a Prognostic Determinant of T3-4 Hypopharyngeal Squamous Cell Carcinoma.

OBJECTIVE: This study aimed to investigate the clinicopathological factors that influence recurrence and survival in patients who undergo operations for T3-4 hypopharyngeal squamous cell carcinomas (SCCs). MATERIALS AND METHODS: One hundred and five patients who underwent surgery between 2001 and 2008 for advanced hypopharyngeal SCCs were consecutively enrolled and reviewed. RESULTS: The pretreatment neutrophil-to-lymphocyte ratio (NLR; median 3.22, range 0.62-46.50) was associated with disease recurrence and patient survival. A difference in the 5-year cumulative disease recurrence rate between patients with high (≥3.22) and low (<3.22) NLRs was significant (60.4 and 36.5%, respectively; p = 0.004). A multivariate analysis confirmed that an NLR ≥3.22 was an independent indicator of a poor prognosis for advanced hypopharyngeal SCC, as per the following parameters: overall survival (hazard ratio [HR] 2.53, 95% confidence interval [CI] 1.48-4.30, p = 0.001), disease-specific survival (HR 2.45, 95% CI 1.38-4.34, p = 0.002), and disease-free survival (HR 2.18, 95% CI 1.24-3.83, p = 0.007). Additional prognostic factors per the survival analyses included lymph node density, surgical margin, lymphovascular invasion, and perineural invasion. CONCLUSIONS: An NLR ≥3.22 is associated with a higher risk of disease recurrence and poor survival in patients with T3-4 hypopharyngeal SCCs. We propose the use of the NLR to broaden the current TNM staging system; the development of a more effective treatment protocol for patients with high NLRs will be essential.

Evaluation of geranylgeranylacetone against cisplatin-induced ototoxicity by auditory brainstem response, heat shock proteins and oxidative levels in guinea pigs.

This study aims to assess whether geranylgeranylacetone (GGA) could reduce ototoxicity induced by cisplatin through upregulation of not only heat shock protein(HSP)-70, but also HSP-27 and HSP-40, and to study if GGA would reduce cisplatin-induced increase in oxidative stress. 48 guinea pigs were used in this study and treated with the following regimen: 0.5% CMC (sodium carboxymethyl cellulose) control for 7days, GGA (600mg/kg/d) for 7days, a combination of GGA (600mg/kg) for 7days and then one dose of 10mg/kg cisplatin (GGA+Cis), and a combination of CMC for 7days and then 10mg/kg cisplatin (cisplatin group). Auditory brainstem response (ABR) measurement was performed in each animal at time before treatment and 7days after the last dose. Additionally, HSPs, nitric oxide (NO), and lipid peroxidation (LPO) levels in cochlear membranous tissues were assessed. The mean ABR thresholds in the cisplatin group were significantly (p<0.05) increased when compared to the other three groups. In guinea pigs receiving both GGA and cisplatin, the mean threshold shift (TS) were smaller (p<0.05) than those of the cisplatin group, but larger (p<0.05) than those of the CMC control or GGA only group with statistical significance. Compared to the GGA only group or the group treated with GGA+Cis, the cisplatin group had the highest (p<0.05) oxidative stress (NO and LPO levels), and the lowest (p<0.05) mean HSPs expression levels. It can be concluded that GGA attenuate ototoxicity induced by cisplatin through upregulation of HSP-27, -40, and -70. Moreover, increased oxidative stress induced by cisplatin in the cochlea membranous tissue could be reduced by pre-treatment of GGA.

High PD-L1 expression is associated with stage IV disease and poorer overall survival in 186 cases of small cell lung cancers.

BACKGROUND: Small cell lung cancer (SCLC) is an aggressive malignancy with a distinct natural history and dismal prognosis. SCLC is characterized as a recalcitrant neoplasm with limited therapeutic options and platinum-based chemotherapy is the treatment of choice. Programmed cell death-ligand 1(PD-L1)-mediated immune escape may be a suitable target for specific therapy, but its role in SCLC is unclear. MATERIALS AND METHODS: In total, 186 SCLC cases were investigated. Paraffin-embedded tumor sections were stained with a PD-L1 antibody. PD-L1 overexpression was denoted by moderate-to-strong PD-L1 membrane staining in ≥ 5% of tumor cells. Tumor cells and infiltrating lymphocytes were scored separately. RESULTS: The overall frequency of PD-L1 overexpression, in tumor cells and tumor infiltrating lymphocytes (TILs) was 78.0% and 54.3%, respectively. High tumor PD-L1 expression was significantly correlated with high TIL PD-L1 expression (P=0.001) and stage IV disease (P=0.048). Multivariate analysis revealed that high tumor PD-L1 expression and stage IV disease were two independent risk factors for poor overall survival. CONCLUSIONS: High PD-L1 expression was observed in SCLCs compared with their expression in conventional NSCLCs. The aggressive behavior of SCLC could be partially related to PD-L1-mediated immune escape. High PD-L1 expression correlated with poor prognosis and may provide a rationale for immunotherapy for high-grade SCLC.

Attenuation of lymphocyte immune responses during Mycobacterium avium complex-induced lung disease due to increasing expression of programmed death-1 on lymphocytes.

Mycobacterium avium complex-induced lung disease (MAC-LD) becomes important due to its increasing prevalence. Attenuated cellular immunity associated with programmed cell death (PD)-1 may play a pathophysiological role in MAC-LD but lacks of investigation. We enrolled 80 participants in this prospective study, including 50 with MAC-LD and 30 healthy controls. Peripheral blood mononuclear cells (PBMCs), lymphocytes and monocyte-derived macrophages were used for MAC antigen stimulation. Patients with MAC-LD had lower tumor necrosis factor-α and interferon-γ responses compared to the healthy controls in PBMC stimulation assays with MAC bacilli. These responses improved after MAC treatment. The PD-1 and PD ligand expressions and apoptosis were higher in the lymphocytes of the patients with MAC-LD compared to the controls. Both PD-1 and apoptosis on T lymphocytes were significantly increased in the patients with MAC-LD, either by direct MAC stimulation or by MAC-primed macrophage activation. Partially blocking PD-1 and the PD ligand with antagonizing antibodies in the stimulation assay significantly increased the cytokine production of IFN-γ and decreased the apoptosis on T lymphocytes. In conclusion, the patients with MAC-LD have attenuated lymphocyte immunity, which might be associated with increasing activation of PD-1 and PD-1 ligand. Regulating such activation might improve the lymphocytic secretion of IFN-γ and reduce apoptosis.

Lymph Node Ratio Predicts Recurrence and Survival for Patients with Resectable Stage 4 Hypopharyngeal Cancer.

BACKGROUND: This study aimed to investigate the clinicopathologic prognostic predictors of stage 4 hypopharyngeal cancer and to extend the traditional tumor-node-metastasis classification system to advance its predictive ability. METHODS: The study enrolled 120 patients with pathologically stage 4 hypopharyngeal cancer treated with pharyngolaryngectomy and neck dissection between 2001 and 2007. RESULTS: The study showed a 5-year overall survival (OS) of 44.6%, a disease-specific survival (DSS) of 51.6%, and a disease-free survival (DFS) of 48% for all the patients. In the multivariate analysis, a lymph node (LN) ratio of 0.113 or higher was a significant poor prognostic factor for OS (hazard ratio [HR] 1.89; 95% confidence interval [CI] 1.17-3.05; p = 0.009), DSS (HR 2.17; 95% CI 1.29-3.64; p = 0.003), and DFS (HR, 2.24; 95% CI 1.12-4.52; p = 0.024) in stage 4 hypopharyngeal cancer. In addition, pretreatment neutrophil-lymphocyte ratio, lymphovascular invasion, and margin status also were predictors of survival outcomes. Furthermore, the study found that disease recurrence differed significantly between the patients with a LN ratio of 0.113 or higher (68.2%) and those with a LN ratio lower than 0.113 (39.5%) (p = 0.002). CONCLUSIONS: A LN ratio of 0.113 or higher is a strong predictor of disease recurrence and survival for patients with stage 4 hypopharyngeal cancer.