HTLV-1 associated acute adult T-cell lymphoma/leukemia presenting as acute liver failure in Micronesian: A case report.

RATIONALE: Malignant infiltration accounts for 0.5% of acute liver failure cases, with non-Hodgkin's lymphoma the predominant cause. Adult T-cell lymphoma/leukemia (ATLL) is a rarer source of acute hepatitis, with only 3 cases reported and all resulting in immediate deterioration with death. ATLL rises from human T-lymphocytic virus-1 (HTLV-1), commonly found in Japan (southern and northern islands), the Caribbean, Central and South America, intertropical Africa, Romania, and northern Iran. In Micronesia, HTLV-1 infection amongst native-born is absent or exceedingly rare. PATIENT CONCERNS: A 77-year-old Marshallese man presented to the emergency department with a 1-week history of generalized weakness, fatigue, and nausea. The physical exam revealed a cervical papulonodular exanthem and scleral icterus. DIAGNOSIS: Laboratory studies were remarkable for aspartate-aminotransferase of 230 IU/L (reference range [RR]: 0-40), alanine-aminotransferase of 227 IU/L (RR: 0-41), alkaline phosphatase of 133 IU/L (RR: 35-129), and total bilirubin of 4.7 mg/dL (RR: 0-1.2), supporting acute liver injury. Platelet count was 11.6x104/µL (RR: 15.1-42.4 × 104), hemoglobin was 13.8 g/dL (RR: 13.7-17.5), and white blood cell count was 7570/µL (RR: 3800-10,800) with 81.8% neutrophils (RR: 34.0-72.0) and 10.4% lymphocytes (RR: 12.0-44.0). The peripheral blood smear demonstrated abnormal lymphocytes with occasional flower cell morphology. HTLV-1/2 antibody tested positive. The skin and liver biopsies confirmed atypical T-cell infiltrate. The diagnosis of ATLL was established. INTERVENTIONS: The patient elected for palliative chemotherapy with cyclophosphamide, vincristine, and prednisone (CVP). He began antiviral treatment with zidovudine 250 mg bis in die (BID) indefinitely. Ursodiol and cholestyramine were added for his hyperbilirubinemia. OUTCOMES: Four weeks from admission, the patient returned to near baseline functional status and was discharged home. LESSONS: This case highlights that ATLL can initially present as isolated acute hepatitis, and how careful examination of peripheral blood-smear may elucidate hepatitis etiology. We also present support for utilizing ursodiol with cholestyramine for treating a hyperbilirubinemia. Moreover, unlike prior reports of ATLL presenting as liver dysfunction, combined antiviral and CVP chemotherapy was effective in this case. Lastly, there are seldom demographic reports of HTLV-1 infection from the Micronesian area, and our case represents the first indexed case of HTLV-1-associated-ATLL presenting as acute liver failure in a Marshallese patient.

Transarterial Radioembolization for Hepatocellular Carcinoma with Major Vascular Invasion: A Nationwide Propensity Score-Matched Analysis with Target Trial Emulation.

PURPOSE: To examine National Cancer Database (NCDB) data to comparatively evaluate overall survival (OS) between patients undergoing transarterial radioembolization (TARE) and those undergoing systemic therapy for hepatocellular carcinoma with major vascular invasion (HCC-MVI). METHODS: One thousand five hundred fourteen patients with HCC-MVI undergoing first-line TARE or systemic therapy were identified from the NCDB. OS was compared using propensity score-matched Cox regression and landmark analysis. Efficacy was also compared within a target trial framework. RESULTS: TARE usage doubled between 2010 and 2015. Intervals before treatment were longer for TARE than for systemic therapy (mean [median], 66.5 [60] days vs 46.8 (35) days, respectively, P < .0001). In propensity-score-matched and landmark-time-adjusted analyses, TARE was found to be associated with a hazard ratio of 0.74 (95 % CI, 0.60-0.91; P = .005) and median OS of 7.1 months (95 % CI, 5.0-10.5) versus 4.9 months (95 % CI, 3.9-6.5) for systemically treated patients. In an emulated target trial involving 236 patients with unilobular HCC-MVI, a low number of comorbidities, creatinine levels <2.0 mg/dL, bilirubin levels <2.0 mg/dL, and international normalized ratio <1.7, TARE was found to be associated with a hazard ratio of 0.57 (95 % CI, 0.39-0.83; P = .004) and a median OS of 12.9 months (95 % CI, 7.6-19.2) versus 6.5 months (95 % CI, 3.6-11.1) for the systemic therapy arm. CONCLUSIONS: In propensity-score-matched analyses involving pragmatic and target trial HCC-MVI cohorts, TARE was found to be associated with significant survival benefits compared with systemic therapy. Although not a substitute for prospective trials, these findings suggest that the increasing use of TARE for HCC-MVI is accompanied by improved OS. Further trials of TARE in patients with HCC-MVI are needed, especially to compare with newer systemic therapies.

The value of CT, MRI, and PET-CT in detecting retropharyngeal lymph node metastasis of head and neck squamous cell carcinoma.

BACKGROUND: The diagnostic accuracies of the imaging studies should be clearly acknowledged in managing head and neck cancer patients; however, the accuracies of preoperative imaging studies in detecting retropharyngeal lymph node (RPLN) metastasis are still not clarified. This study was to evaluate diagnostic accuracies of computed tomography (CT), magnetic resonance imaging (MRI), and positron emission tomography-computed tomography (PET-CT) in detecting RPLN metastasis of head and neck squamous cell carcinomas. METHODS: For 123 patients who had performed RPLN dissection during the surgery of their squamous cell carcinoma of the head and neck, preoperative CT, MRI, and/or PET-CT were reviewed for RPLN metastasis in a blinded fashion by one experienced radiologist. Sensitivity, specificity, positive predictive value, negative predictive value, and overall accuracy of each imaging modality were assessed, by comparing with the histopathologic findings of the resected RPLNs that served as the standard of reference. RESULTS: RPLNs were pathologically positive for metastasis in 43 of the 123 patients (35%). Sensitivity, specificity, positive predictive value, negative predictive value, and overall accuracy in detecting metastasis to RPLN were 65, 94, 85, 83, and 84% for CT; 74, 94, 87, 87 and 87% for MRI; 83, 93, 89, 89 and 89% for PET-CT, respectively. When all the three imaging modalities were considered together (n = 74), they offered sensitivity of 90%, specificity of 91%, positive predictive value of 87%, negative predictive value of 93%, and accuracy of 91%. CONCLUSIONS: The preoperative imaging studies offered relatively high specificity rates, but rather low sensitivity rates. The three imaging modalities altogether increased diagnostic accuracies, which highlights the potential of the three studies when used altogether can minimize missed diagnoses of RPLN metastasis.

Clinical outcomes and prognostic factor analysis after salvage surgery for recurrent squamous cell carcinoma of the oral cavity.

The purpose of this study was to analyze the oncological outcomes and predictive factors for successful curative salvage surgery after recurrent oral cavity squamous cell carcinoma. A retrospective study was conducted involving 73 patients who received surgery-based salvage treatment. The pattern of failure for primary treatment was local failure in 29 patients, regional failure in 29 patients, and loco-regional failure in 15 patients. The 5-year overall, loco-regional failure-free, and disease-free survival rates were 54.8%, 58.9% and 49.3%, respectively. Patients with an advanced initial N stage, previous treatment with combined modality therapy, loco-regional recurrence, advanced recurrent T stage, a disease-free survival of less than 8 months prior to salvage, and recurrence in a previously treated field had a significantly worse prognosis. Given the potential surgical morbidity, salvage surgery should be undertaken after careful consultation with patients who have factors for a poor prognosis.

Role of integrin ß1 as a biomarker of stemness in head and neck squamous cell carcinoma.

OBJECTIVES: Signaling between cancer stem cells (CSC) and their extracellular matrix has a crucial role in CSC progression and maintenance. However, mediators of this signaling pathway in head and neck squamous cell carcinoma (HNSCC) are largely unknown. Here, we explored whether integrin ß1, which is one of the key regulators of the communication between cells and their microenvironment, affected the stemness of HNSCC cells. MATERIALS AND METHODS: We examined self-renewal capacity, chemoresistance, and xenograft tumorigenicity after knockdown of integrin ß1 in primary HNSCC cells. In addition, we studied the role of focal adhesion kinase (FAK), an intracellular downstream molecule of integrin signaling, in influencing stemness of HNSCC. The relevance of Notch1 and integrin ß1 interactions in HNSCC cells was also examined. Finally, immunohistochemical analysis was carried out to test whether the coexpression of integrin ß1 and Notch1 in the samples from HNSCC patients correlated with their survival. RESULTS: Targeting integrin ß1 in HNSCC cells inhibited self-renewal, chemoresistance, and in vivo tumor-forming capacity. Treatment with an inhibitor of FAK decreased self-renewal capacities and expression of various putative stem cell markers (Oct4, Sox2, and Nanog) in a dose-dependent manner. Moreover, knockdown of integrin ß1 decreased the expression of Notch1 and its target genes (Hey1 and Hes1). Notably, HNSCC patients demonstrating simultaneous expression of integrin ß1 and Notch1 in their tissue samples had significantly worse survival rate. CONCLUSION: Integrin ß1/Notch1 axis has a significant role in the regulation of stemness in HNSCC.

Long-term oncological and functional outcomes of induction chemotherapy followed by (chemo)radiotherapy vs definitive chemoradiotherapy vs surgery-based therapy in locally advanced stage III/IV hypopharyngeal cancer: Multicenter review of 266 cases.

OBJECTIVE: The aim of this study was to evaluate the treatment outcomes for stage III/IV locally advanced hypopharyngeal squamous cell carcinoma (SCC), comparing induction chemotherapy followed by (chemo)radiotherapy (ICT), definitive chemoradiotherapy (CRT) and surgery-based therapy (SRT). SUBJECTS AND METHODS: Two hundred sixty-six patients with stage III/IV locally advanced hypopharyngeal squamous cell carcinoma (SCC) who underwent ICT (n = 74), CRT (n = 53) or SRT (n = 139) from 1997 through 2014 at the Seoul National University Hospital (n = 127) and the Hallym University Medical Center (n = 139) were enrolled in the study. All surgical procedures in the SRT group were performed by a single surgeon to eliminate surgeon bias. RESULTS: The 5-year disease-free survival (DFS) and overall survival (OS) of all patients (n = 266) were 59.4% and 44%, respectively. The 5-year DFS rates after salvage treatment were 52.7% for ICT, 52.8% for CRT and 65.5% for SRT (p = 0.194). The OS rates were 44.6% for ICT, 39.6% for CRT and 45.3% for SRT group (p = 0.106). The salvage rates were 12.5% for ICT, 15.6% for CRT and 3.8% for SRT group. The final laryngeal preservation rate was significantly lower in the SRT group (44.6%) than in the ICT (71.6%) or CRT (71.7%) groups. All major postoperative complications were significantly higher in the salvage surgery group. CONCLUSION: Treatment outcomes in the ICT and CRT groups were comparable to that of the SRT group for stage III/IV hypopharyngeal SCC. However, the relatively low chance of cure and high risk of complications should be taken into account when considering salvage surgery.

The impact of the number of harvested central lymph nodes on the lymph node ratio.

OBJECTIVE: The purpose of this study was to analyze the impact of lymph node harvest on the lymph node ratio (LNR). METHODS: We retrospectively reviewed 106 patients diagnosed preoperatively with PTMC (papillary thyroid microcarcinoma), no evidence of central or lateral neck nodal metastasis, and who underwent a total thyroidectomy and bilateral central lymph node neck dissection (CND). RESULTS: The median number of retrieved lymph nodes in the central compartments was 7±6.59 (range: 1-42). The mean number of metastatic lymph nodes in the central compartments on pathology was 1.1±1.79 (range: 0-7). The high node volume group (>7) had a significantly higher rate of central lymph node (CLN) metastasis than the low node volume group (≤7) in the final pathologic report (p<0.001). With the linear regression method, the number of CLN metastasis increased as the number of retrieved lymph nodes increased (correlation coefficient=0.286, p=0.003). The multivariate analysis confirmed the number of retrieved lymph nodes in the central compartments was a risk factor for high LNR (p=0.008, odds ratio 3.737). The rates of vocal fold palsy and hypoparathyroidism did not differ according to the number of retrieved lymph nodes. CONCLUSION: The lymph node ratio in the final pathologic report is larger when a greater number of lymph nodes are retrieved during the central compartment neck dissection.

Three distinct genomic subtypes of head and neck squamous cell carcinoma associated with clinical outcomes.

OBJECTIVES: Heterogeneity of head and neck squamous cell carcinomas (HNSCCs) results in unpredictable outcomes for patients with similar stages of cancer. Beyond the role of human papilloma virus (HPV), no validated molecular marker of HNSCCs has been established. Thus, clinically relevant molecular subtypes are needed to optimize HNSCC therapy. The purpose of this study was to identify subtypes of HNSCC that have distinct biological characteristics associated with clinical outcomes and to characterize genomic alterations that best reflect the biological and clinical characteristics of each subtype. MATERIALS AND METHODS: We analyzed gene expression profiling data from pan-SCC tissues including cervical SCC, esophageal SCC, lung SCC, and HNSCC (n = 1346) to assess the similarities and differences among SCCs and to identify molecular subtypes of HNSCC associated with prognosis. Subtype-specific gene expression signatures were identified and used to construct predictive models. The association of the subtypes with prognosis was validated in two independent cohorts of patients. RESULTS: Pan-SCC analysis identified three novel subtypes of HNSCC. Subtype 1 had the best prognosis and was similar to cervical SCC, whereas subtype 3 had the worst prognosis and was similar to lung SCC. Subtype 2 had a moderate prognosis. The 600-gene signature associated with the three subtypes significantly predicted prognosis in two independent validation cohorts. These three subtypes also were associated with potential benefit of immunotherapy. CONCLUSION: We identified three clinically relevant HNSCC molecular subtypes. Independent prospective studies to assess the clinical utility of the subtypes and associated gene signature are warranted.

The Updated AJCC/TNM Staging System for Papillary Thyroid Cancer (8th Edition): From the Perspective of Genomic Analysis.

BACKGROUND: Recently, the American Joint Committee on Cancer published the 8th edition of its Cancer Staging Manual with major changes regarding the staging of thyroid cancer, including the raising of the age cutoff from 45 to 55 years. Using the clinical and genetic data of 505 papillary thyroid cancer (PTC) cases, we aimed to compare overall survival (OS) and recurrence-free survival (RFS) with different age cutoff values, and also investigate the efficacy of the new staging system on a genomic level. METHODS: We downloaded gene expression data, somatic mutation profile, copy number alteration data and clinical data of 505 PTC patients from The Cancer Genome Atlas data portal. We used multiple statistical analysis and multiplatform genomic analysis to evaluate the efficacy of the 8th edition. RESULTS: When using 55 years as the cutoff value for analyzing RFS, the Kaplan-Meier plot showed a significant p value but not when using 45 years (p = 0.006 vs. p = 0.493), but both cutoff values were significant when analyzing OS (p = 1.1 × 10-9 with age 55 vs. p = 4.4 × 10-5 with age 45). When looking at stage-dependent survival, both the 7th and 8th edition had significant p values (p = 0.048 vs. p = 3.1 × 10-9 in RFS and p = 5.9 × 10-10 vs. p = 2.2 × 10-10 in OS). Multiplatform genomic analysis showed patients ≥55 years had 103 differently expressed genes when compared with other age groups. Signaling pathway analysis revealed that patients ≥55 years had altered pathways associated with aggressiveness of thyroid cancer. CONCLUSION: In conclusion, this is the first study to show clinical and genetic evidence supporting the altered age cutoff point of 55 years in the AJCC 8th edition for PTC patients.

Clinical implication of programmed cell death-1 ligand-1 expression in tonsillar squamous cell carcinoma in association with intratumoral heterogeneity, human papillomavirus, and epithelial-to-mesenchymal transition.

Programmed cell death-1 ligand-1 (PD-L1), essential for immune evasion, is a potential candidate for pathogenesis and therapeutic target of human papillomavirus (HPV)-positive tonsillar squamous cell carcinomas (TSCCs). MET/hepatocyte growth factor signaling and transcription factors involved in epithelial-to-mesenchymal transition (EMT) upregulate PD-L1, which can contribute to clinical outcome. Intratumoral heterogeneity of PD-L1 expression is of clinical importance in selection bias due to false-negative patient enrollment. However, the clinicopathological features, prognostic value, and coexpressed molecules of PD-L1 remain unclear in TSCCs. PD-L1 expression was evaluated via immunohistochemistry using a specific monoclonal antibody (SP142) between whole-tissue and tissue microarray (TMA) sections of 79 tumors (5% cutoff value with weak staining). Expressions of EMT markers (TWIST1, Snail, and SNIP1) and MET/hepatocyte growth factor were also analyzed. Staining of the TMA sections showed 78.5% concordance rate to the whole section. PD-L1 positivity and its intratumoral heterogeneity were 29.1% and 15.2% of TSCCs by whole section, respectively. PD-L1 positivity was prevalent in females, HPV-positive tumors without base of tongue invasion, and SNIP1-overexpressed tumors. SNIP1 overexpression, unmethylated TWIST1, smoking, and poorly differentiated tumors were predictive for PD-L1 overexpression. PD-L1 positivity was a favorable independent prognostic factor. Subgroup analyses according to the coexpression of PD-L1 with HPV, SNIP1, or unmethylated TWIST1 indicated the best clinical outcome than any other subgroups. In conclusion, intratumoral heterogeneity of PD-L1 expression was frequent, warranting a caution in punching TMA cores. A combined analysis of PD-L1 with EMT and HPV may define a characteristic subset of patients and prognostic group.

Predictive gene signatures of nodal metastasis in papillary thyroid carcinoma.

BACKGROUND: Cervical lymph node metastases (LNM) in papillary thyroid carcinomas (PTCs) are common and develop in approximately 30-80% of PTCs. The presence of cervical LNM significantly increases the rate of locoregional recurrence in PTCs. OBJECTIVE: To search for predictive gene signatures for nodal metastasis in PTCs. METHODS: We used unsupervised clustering with unbiased manner to compare molecular profiles between PTCs with nodal metastasis and PTCs without nodal metastasis using mRNA-seq of TCGA data. Using gene ontology (GO) and logistic regression test, we generated 12-predictive genes for nodal metastasis in PTCs. RESULTS: Unsupervised clustering of mRNA-seq (training set, N = 158) revealed that PTCs with nodal metastasis showed different gene expression patterns compared to PTCs without nodal metastasis. We generated 12 predictive genes and these gene signatures showed consistency for predicting nodal metastasis when we applied them to a validation set (N = 80). Based on multivariate analysis, these 12 predictive gene signatures showed more significant odds ratio compared to other variables. CONCLUSIONS: These 12 gene signatures could be used to predict the chance of nodal metastasis in PTCs in preoperative evaluation using fine needle aspiration biopsy (FNAB) so that appropriate plan such as central neck dissection could be made.

BRAFwild papillary thyroid carcinoma has two distinct mRNA expression patterns with different clinical behaviors.

BACKGROUND: Using a large set of genomic data from The Cancer Genome Atlas (TCGA), we classified BRAFwild papillary thyroid carcinomas (PTCs) into 2 subtypes with distinct molecular patterns and different clinical behaviors. We also suggested gene signatures (RAS-score) to predict molecular subtypes and clinical behaviors of BRAFwild PTC. METHOD: Integrated genomic analysis was done using all genomic data of PTC in TCGA data portal (https://tcga-data.nci.nih.gov) and cancer browser (https://genome-cancer.ucsc.edu). Using Gene Ontology and a logistic regression test, we selected gene signatures (RAS-score) and applied this prediction model to the validation cohort (GSE60542). RESULT: When we performed multiplatform genomic analysis, BRAFwild PTCs were divided into 2 molecular subtypes. Each subtype showed distinct molecular patterns and clinical behaviors. Gene signatures successfully predicted molecular subtype in another validation cohort. CONCLUSION: We found that BRAFwild PTCs were divided into 2 molecular subtypes and each subtype showed distinct molecular patterns, different activated pathways, and different clinical behaviors.

Patterns and predictors of emergency department visits among older patients after breast cancer surgery: A population-based cohort study.

OBJECTIVES: To characterize rates, reasons for, and associated predictors for emergency department (ED) visits after breast cancer (BC) surgery. METHODS: All women over 65 years undergoing curative surgery for non-metastatic incident BC (1998-2012) were identified using Quebec's universal healthcare administrative databases. Reasons for ED visits within 45days of operation were reported. Associated factors were estimated using Cox regression. RESULTS: Of 24,463 patients, 12.8% had postoperative ED visits. Most frequent reasons were: superficial infection, noninfectious gastrointestinal, trauma or wound (other than breast), noninfectious respiratory, and breast wound disruption. Significant predictors included localized (aHR, 1.24, CI 1.04-1.49) or regional disease (aHR 1.64, CI 1.41-1.92), mastectomy (aHR 1.22, CI 1.10-1.34), each operation before definitive oncologic control (aHR 1.12, CI 1.03-1.21), lower institutional volume (aHR 1.23, CI 1.09-1.38), having 6-10 prescriptions (aHR 1.23, CI 1.15-1.31) or >10 (aHR 1.53, CI 1.33-1.77), benzodiazepine use (aHR 1.09, CI 1.01-1.18), anticoagulant use (aHR 1.29, CI 1.13-1.46), cardiovascular disease (aHR 1.15, CI 1.05-1.26), diabetes (aHR 1.11, CI 1.00-1.24), past hospitalization (aHR 1.25, CI 1.17-1.34), and lower income (aHR 1.12, CI 1.04-1.20). CONCLUSION: Identification of risk factors in older patients before BC surgery could help prevent postoperative ED visits.

The one-hundred most-cited articles focused on thyroid research: a bibliometric analysis.

INTRODUCTION: The number of citations that an article has received reflects its impact on a particular research area. EVIDENCE ACQUISITION: We determined the one-hundred most-cited articles in thyroid research via the Institute for Scientific Information Web of Knowledge database, using the search term. The following parameters were used to analyze the characteristics of the 100 most-cited articles: publication year, journal (including subject category and impact factor), number of citations and annual citations, authors, department, institution, country, type of study, and topic. EVIDENCE SYNTHESIS: The number of citations for the 100 most-cited articles ranged from 2521 to 412 (mean, 643.4) and the number of annual citations ranged from 392.9 to 7.1 (mean, 38.0). The majority of articles were published in 2000-2009 (32%), published in endocrinology journals (29%), originated in the USA (70%), were clinical observation study (31%), and dealt with nodular thyroid disease (32%). Department of Internal Medicine, Johns Hopkins University School of Medicine and Department of Internal Medicine, Ohio State University College of Medicine (N.=6 each) were the leading institutions and Mazzaferri EL (N.=7) was the most prolific author. CONCLUSIONS: Our study presents a detailed list and analysis of the 100 most-cited thyroid research articles, which provides a unique insight into the historical development in this field.

Clinicopathological factors influencing the outcomes of surgical treatment in patients with T4a hypopharyngeal cancer.

BACKGROUND: The purpose of this study was to determine prognostic factors influencing outcomes of surgical treatment in patients with T4a hypopharyngeal cancer. METHODS: The present study enrolled 93 patients diagnosed with T4a hypopharyngeal cancer who underwent primary surgery between January 2005 and December 2015 at six medical centers in Korea. Primary tumor sites included pyriform sinus in 71 patients, posterior pharyngeal wall in 14 patients, and postcricoid region in 8 patients. Seventy-two patients received postoperative radio(chemo)therapy. RESULTS: Five-year disease-free survival (DFS) and disease-specific survival (DSS) rates were 38% and 45%, respectively. In univariate analysis, 5-year DFS was found to have significant and positive correlations with margin involvement (p < 0.001) and extracapsular spread (p = 0.025). Multivariate analysis confirmed that margin involvement (hazard ratio (HR): 2.81; 95% confidence interval (CI): 1.49-5.30; p = 0.001) and extracapsular spread (HR: 2.08; 95% CI: 1.08-3.99; p = 0.028) were significant factors associated with 5-year DFS. In univariate analysis, cervical lymph node metastasis (p = 0.048), lymphovascular invasion (p = 0.041), extracapsular spread (p = 0.015), and esophageal invasion (p = 0.033) were significant factors associated with 5-year DSS. In multivariate analysis, extracapsular spread (HR: 2.98; 95% CI: 1.39-6.42; p = 0.005) and esophageal invasion (HR: 2.87; 95% CI: 1.38-5.98; p = 0.005) remained significant factors associated with 5-year DSS. CONCLUSION: Margin involvement and extracapsular spread are factors influencing recurrence while extracapsular spread and esophageal invasion are factors affecting survival in patients with T4a hypopharyngeal cancer treated by primary surgery.

Inhibitor of DNA binding 2 is a novel therapeutic target for stemness of head and neck squamous cell carcinoma.

BACKGROUND: Head and neck squamous cell carcinomas (HNSCCs) are highly lethal epithelial tumours containing self-renewal cancer stem cells (CSCs). CSCs in HNSCCs are strongly associated with tumour initiation, invasion, and chemoradiation resistance. However, the important factors regulating stemness in HNSCCs remain unclear. Here, we investigated the molecular roles and clinical significance of inhibitor of DNA binding 2 (Id2) protein to determine if it constitutes a novel therapeutic target for ablating HNSCC cells with stemness. METHODS: We performed in vitro and in vivo studies of Id2 function and its effects on stemness using HNSCC cells. We also examined whether Id2 expression could be used as a prognostic indicator through immunohistochemical staining of 119 human HNSCC tumours. RESULTS: Expression of Id2 was higher in HNSCC cells with stemness compared with differentiated HNSCC cells. Overexpression of Id2 increased proliferation, self-renewal, and expression of the putative stemness marker CD44 in HNSCC cells in vitro and in vivo. In contrast, silencing of Id2 using short hairpin RNA attenuated the stemness phenotype of HNSCC cells by reducing self-renewal, CD44 expression, cisplatin chemoresistance, and xenograft tumourigenicity. Most importantly, increased expression of Id2 was closely associated with poorer post-treatment survival rates in HNSCC patients. CONCLUSIONS: Inhibitor of DNA binding2 represents a novel and promising therapeutic target for treating and improving the clinical outcomes for patients with HNSCC.

Risk Factors of and Treatments for Pharyngocutaneous Fistula Occurring after Oropharynx and Hypopharynx Reconstruction.

BACKGROUND: A pharyngocutaneous fistula is a common and difficult-to-manage complication after head and neck reconstruction. It can lead to serious complications such as flap failure, carotid artery rupture, and pharyngeal stricture, and may require additional surgery. Previous radiotherapy, a low serum albumin level, and a higher T stage have been proposed as contributing factors. We aimed to clarify the risk factors for pharyngocutaneous fistula in patients who underwent flap reconstruction and to describe our experiences in treating pharyngocutaneous fistula. METHODS: Squamous cell carcinoma cases that underwent flap reconstruction after cancer resection from 1995 to 2013 were analyzed retrospectively. We investigated several significant clinical risk factors. The treatment modality was selected according to the size of the fistula and the state of the surrounding tissue, with options including conservative management, direct closure, flap surgery, and pharyngostoma formation. RESULTS: A total of 127 cases (18 with fistulae) were analyzed. A higher T stage (P=0.048) and tube-type reconstruction (P=0.007) increased fistula incidence; other factors did not show statistical significance (P>0.05). Two cases were treated with conservative management, 1 case with direct closure, 4 cases with immediate reconstruction using a pectoralis major musculocutaneous flap, and 11 cases with direct closure (4 cases) or additional flap surgery (7 cases) after pharyngostoma formation. CONCLUSIONS: Pharyngocutaneous fistula requires global management from prevention to treatment. In cases of advanced-stage cancer and tube-type reconstruction, a more cautious approach should be employed. Once it occurs, an accurate diagnosis of the fistula and a thorough assessment of the surrounding tissue are necessary, and aggressive treatment should be implemented in order to ensure satisfactory long-term results.

Heavy alcohol drinking downregulates ALDH2 gene expression but heavy smoking up-regulates SOD2 gene expression in head and neck squamous cell carcinoma.

BACKGROUND: This study aims to determine the relationship between expression levels of ALDH2 and SOD2 genes and clinical parameters such as alcohol drinking, tobacco smoking, primary site of HNSCC, and human papilloma virus (HPV) state. METHODS: Gene expression data were obtained from gene expression omnibus (GEO accession number: GSE65858). Clinical data (N = 270) including survival result, gender, age, TNM stage, primary site of HNSCC, HPV status, alcohol drinking, and tobacco smoking habit were analyzed according to gene expression pattern. RESULTS: ALDH2 gene was expressed in low levels in patients with heavy alcohol consumption. It was expressed in high (p = 0.01) levels in patients with no or light alcohol consumption. ALDH2 gene was also expressed in low levels in patients with oral cavity cancers or hypopharynx cancers. However, ALDH2 gene was expressed in high (p = 0.03) levels in patients with oropharyngeal cancers or laryngeal cancers. HPV-positive patients were found to have high (p = 0.02) expression levels of ALDH2. SOD2 gene was expressed in high (p = 0.005) levels in patients who had greater mean pack-year of tobacco smoking. Based on log rank test, the group of patients with high expression of ALDH2 showed better (p = 0.002) clinical results than those with low expression of ALDH2. Difference of survival results between ALDH2 high-expressed group and ALDH2 low-expressed group was validated in another cohort (GSE39368, N = 138). CONCLUSIONS: Heavy alcohol drinking downregulates ALDH2 gene expression level. Heavy smoking up-regulates SOD2 gene expression level in patients with head and neck squamous cell carcinoma. The group of patients with low expression levels of ALDH2 showed significantly poorer survival results compared to those with high expression levels of ALDH2.

HIPK2 Overexpression and Its Prognostic Role in Human Papillomavirus-Positive Tonsillar Squamous Cell Carcinoma.

Tonsillar squamous cell carcinomas (TSCCs) are the most common human papillomavirus- (HPV-) associated oropharyngeal cancers with poor prognosis. Homeodomain-interacting protein kinase 2 (HIPK2) is a central regulator of p53, which participates in apoptosis during the DNA damage response. HIPK2 is involved in HPV-associated uterine cervical and cutaneous carcinogenesis through its binding of HPV E6, thereby preventing apoptosis and contributing to tumor progression. However, its clinical and prognostic significance in TSCC remains unclear. HIPK2 mRNA levels were analyzed in 20 normal tonsils and 20 TSCC specimens using real-time reverse transcription polymerase chain reaction. Immunohistochemistry of HIPK2 was performed in 79 resected specimens. HIPK2 was expressed in 57% of the TSCCs, and HIPK2 protein expression and HIPK2 mRNA levels were higher in TSCCs than in normal tonsils. HIPK2 overexpression was associated with poorly differentiated carcinoma and low alcohol consumption and was an independent prognostic factor for overall survival and disease-free survival (DFS) in TSCC and a negative independent prognostic factor for DFS in patients receiving postoperative radiotherapy. HIPK2 overexpression had a significant association with poorer DFS in HPV-positive TSCCs, but not in HPV-negative tumors. HIPK2 overexpression may be a potential prognostic marker for predicting prognoses and a high risk of recurrence, particularly in patients with HPV-positive TSCC.

Comparing Clinical Characteristics and Outcomes of Young-onset and Late-onset Colorectal Cancer: An International Collaborative Study.

BACKGROUND: Compared with the general population, the incidence of young-onset (YO) colorectal cancer (CRC) is increasing. However, a significant knowledge gap exists in the clinical characteristics, treatment patterns, and outcomes for these patients. MATERIALS AND METHODS: Six international tertiary cancer centers conducted a retrospective study. Patients with YO CRC (aged 18-44 years) and LO CRC (aged > 44 years) diagnosed with histologically proven colorectal adenocarcinoma from June 2003 to June 2014 were enrolled. Patients were randomly chosen from each center's database, and the patient demographics and treatment information were collected. The data were then centralized, and the final analysis was performed at a single institution. Cox proportional hazards models were used to estimate the crude and adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) for progression-free survival and mortality, and YO was compared with LO. Site-specific HRs were pooled using a random-effects meta-analysis. RESULTS: Overall, 498 patients, including 224 with YO (129 men; mean age, 37 ± 5.5 years) and 274 with LO (167 men; mean age, 64.8 ± 9.5 years) CRC, were included. At the diagnosis, 137 patients (61.2%) and 122 patients (44.5%) with YO and LO CRC had metastatic disease, respectively. For both cohorts, the 3 most common presenting symptoms were pain, hematochezia, and weight loss. Surgery was performed in 141 YO (63.0%) and 219 LO (79.9%) patients. The longitudinal noncurative treatment patterns were similar, but more biologic therapy was used for these YO patients. The pooled progression-free survival analysis results for first-line noncurative treatment favored LO (HR, 1.96; 95% CI, 1.04-3.68). The mortality analysis showed no significant differences between the 2 groups (YO: HR, 1.53; 95% CI, 0.91-2.58). CONCLUSION: Despite similar treatment patterns and survival outcomes, YO disease might be clinically more aggressive.