Search

Targeted therapies against human epidermal growth factor receptor 2 (HER2) are associated with increased interstitial lung disease (ILD). Trastuzumab, lapatinib, pertuzumab, and trastuzumab emtansine have markedly extended HER2 breast cancer survival but current knowledge on how these HER2-targeted agents induce interstitial lung disease is still poorly defined due to limited cases in the literature. Physicians mostly managed this complication by dose interruption, dose de-escalation, or discontinuation with success. In 2019, the FDA had granted accelerated approval on trastuzumab deruxtecan (T-Dxd) in HER2 breast cancer in the late line setting. Severe ILD incidence rate was over ten percent and led to fatal outcomes in 2.2% of patients in the T-Dxd trial. Searching for biomarkers to detect ILD incidence before it becomes clinically fulminant or for treatment response monitoring is of high clinical value. A Case of life-threatening trastuzumab-induced ILD was encountered in our facility. The ILD was confirmed to be antineutrophil cytoplasmic antibody (ANCA) pulmonary capillaritis. The biomarker of neutrophil extracellular traps (NETs), serum MPO-DNA complex, showed a good correlation with the clinical severity. Soon after B cell depleting agent rituximab usage, the serum MPO-DNA outperformed ANCA autoantibody and maintained its correlation with clinical severity. In addition to the trastuzumab-induced ILD case, a prospective cohort in our facility also confirmed the usefulness of MPO-DNA in monitoring vasculitis activity. We postulated that upfront testing with biomarkers of vasculitis during HER2 targeted treatment with high ILD incidence may be beneficial in the future., Graphical abstract Interaction Between Anti-HER2 Antibody and ANCA-Associated Vasculitis and Neutrophil In lung tissues, only bronchial epithelial cells express human epidermal growth factor 2 (HER2) protein in the cell surfaces. Once trastuzumab binds to the HER2 protein, trastuzumab acts as a stimulus to activate neutrophils to express autoantigen, including leukocyte proteinase 3 (PR3) and myeloperoxidase (MPO). The neutrophils could also directly release PR3 and MPO with cell-free DNA and histone through exocytosis to form a neutrophil extracellular trap (NETs). NETs containing PR3 and MPO could further trigger autoreactive B cells to produce ANCA antibodies, resulting in more neutrophil activation and alveolar-capillary endothelial as well as alveolar epithelial damage, although alveolar epithelial cells do not express HER2. A two-step mechanism explains how all previously reported cases that we identified manifests late with a median time of onset two months after the first trastuzumab exposure.Image 1, Highlights • Drug-induced Interstitial lung disease (DIILD) induced by HER2-targeted therapies, is a well-known adverse drug reaction, but the mechanism is ill-defined and no effective strategy for monitoring and prevention were reported. • We report a Case of trastuzumab-related interstitial lung disease induced by anti-neutrophil cytoplasmic antibody, which was never reported in previous literature. • As neutrophils dominate the inflammatory infiltrate in vasculitis, serum MPO-DNA, a biomarker of neutrophil activity, was performed in this Case and within a prospective vasculitis cohort in our facility and showed promising clinical severity correlation. • Monitoring with vasculitis-related autoantibodies and serum MPO-DNA may be helpful in future HER2-targeted agents since high rates of DIILD were reported due to this group of HER2-targeted agents.

Here, we demonstrated that the multikinase framework including ERK/AKT and CDK2 promotes the proliferation and invasion of lung adenocarcinoma cell lines through activating DRP1. Our results further uncovered the prognostic significance of DRP1 in early‐stage lung adenocarcinoma, showing that the expression and activation of DRP1 are both significantly associated with an increased risk of postoperative recurrence., Recent studies revealed the role of dynamin‐related protein 1 (DRP1), encoded by the DNM1L gene, in regulating the growth of cancer cells of various origins. However, the regulation, function, and clinical significance of DRP1 remain undetermined in lung adenocarcinoma. Our study shows that the expression and activation of DRP1 are significantly correlated with proliferation and disease extent, as well as an increased risk of postoperative recurrence in stage I to stage IIIA lung adenocarcinoma. Loss of DRP1 in lung adenocarcinoma cell lines leads to an altered mitochondrial morphology, fewer copies of mitochondrial DNA, decreased respiratory complexes, and impaired oxidative phosphorylation. Additionally, the proliferation and invasion are both suppressed in DRP1‐depleted lung adenocarcinoma cell lines. Our data further revealed that DRP1 activation through serine 616 phosphorylation is regulated by ERK/AKT and CDK2 in lung adenocarcinoma cell lines. Collectively, we propose the multikinase framework in activating DRP1 in lung adenocarcinoma to promote the malignant properties. Biomarkers related to mitochondrial reprogramming, such as DRP1, can be used to evaluate the risk of postoperative recurrence in early‐stage lung adenocarcinoma.

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.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.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 expression50% (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-L150% 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.Lower pre-treatment PD-L1 is associated with better ORR, PFS, and higher frequency of T790M resistance in EGFR TKI-treated lung ADC patients.

This study investigated the diagnostic accuracy and affecting factors of ultrasound (US)-guided core-needle biopsy (CNB) in patients with treated head and neck squamous cell carcinoma (HNSCC). We retrospectively reviewed patients with treated HNSCC who received US-guided CNB from January 2011 to December 2018 with corresponding imaging. Pathological necrosis and fibrosis of targeted lymph nodes (LNs) were evaluated. We analyzed the correlation between CNB accuracy and clinical and pathological characteristics. In total, 260 patients were included. The overall sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy of CNB for nodal recurrence were 84.47%, 100%, 100%, 54.67%, and 86.92%, respectively. CNB of fibrotic LNs had significantly worse sensitivity, NPV, and accuracy than that of non-fibrotic LNs. Similarly, CNB of necrotic LNs had significantly worse sensitivity, NPV, and accuracy than non-necrotic LNs. Multivariate regression revealed that fibrotic LN was the only independent factor for a true positive rate, whereas both necrotic LN and fibrotic LN were independent factors for a false negative rate. The diagnostic accuracy of CNB in treated HNSCC patients is affected by LN necrosis and fibrosis. Therefore, CNB results, particularly for necrotic or fibrotic LNs, should be interpreted carefully.

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 p p 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.

Although induction chemotherapy improves the resectability of thymic neoplasms, it is unclear whether surgery after induction chemotherapy can improve outcomes. We compared long-term outcomes of surgery with and without induction chemotherapy in patients with thymic neoplasms.We retrospectively investigated the clinical information of patients with thymic neoplasms at the National Taiwan University Hospital between 2005 and 2013.Of 204 patients, 119 underwent direct surgery (group 1), 45 underwent surgery after induction chemotherapy (group 2), and 40 underwent no surgery (group 3). The 5-year overall survival rates of groups 1, 2, and 3 were as follows: for 204 patients, 96.3%, 76.4%, and 35.5% (P .001); for 119 thymoma patients, 96.6%, 88.9%, and 100.0% (P = .835); for 85 thymic carcinoma patients, 94.7%, 69.7%, and 17.7% (P .001); for 36 American Joint Committee on Cancer (AJCC) stage III-IVA thymoma patients, 92.9%, 83.3%, and 100% (P = .833); and for 28 stage III-IVA thymic carcinoma patients, 75.0%, 76.2%, and 62.5%, (P = .160). Univariate analysis showed that for group 2 (P = .0208) and group 3 (P .0001), thymic carcinoma pathology type (P = .0010) and stage IVB disease (P .0001) were poor prognostic factors. Multivariate analysis found thymic carcinoma (P = .0026) and stage IVB disease (P = .0449) to be poor prognostic factors.Up-front surgery leads to best overall survival, and induction chemotherapy followed by surgery may improve resectability and outcomes. Only thymic carcinoma and stage IVB disease were poor prognostic factors in multivariate analysis.

Objectives Dysplastic changes at the surgical margin of oral squamous cell carcinoma (OSCC) could be encountered frequently. However, the impact of a dysplastic surgical margin on patients with OSCC remains unclear. Materials and methods Retrospectively, we reviewed patients with OSCC who were diagnosed and treated at the National Taiwan University Hospital between January 2010 and December 2015. Patients were divided into four groups: clear (≥5 mm), close ( Results Of 1642 patients, 596 had clear margin, 169 had positive margin, 707 had close margin, and 170 had dysplastic margin. The mean age at diagnosis was 55 ± 11 years (range, 16-97 years). Dysplastic margins were frequently present in patients with primary T1/T2 OSCC (odds ratio [OR] = 1.7, p = 0.009), tumor without perineural invasion (OR = 1.48, p = 0.04), and tumor thickness ≤10 mm (OR = 1.94, p = 0.001). In patients with clear, close, positive, and dysplastic margins, the 5-year disease-free survival rates were 63.1%, 51%, 37.2%, and 54.7%, respectively; overall survival (OS) rates were 71.1%, 61.9%, 49%, and 72%, respectively. Disease-free and overall survival were not significantly different in patients with dysplastic and clear margins (p = 0.37 and p = 0.38, respectively). Adjuvant radiotherapy had no significant benefit for patients with dysplastic margins. Finally, a multivariate analysis showed that the presence of a dysplastic margin was not an independent risk factor for disease-free (p = 0.43) and overall survival (p = 0.71). Conclusions The survival rates of the patients with OSCC who had dysplastic margin were significantly better than those with positive margin.

Purpose To compare the locations of recurrences and survival outcomes in esophageal squamous cell carcinoma (ESCC) patients with pathological complete response (pCR) after neoadjuvant concurrent chemoradiotherapy (CCRT) with or without preceding induction chemotherapy (IC) followed by esophagectomy. Methods Among 276 patients with locally advanced ESCC undergoing trimodality treatment during 2004–2014, 94 (34.1%) with pCR were eligible. The cohort included 26 patients undergoing IC before CCRT (IC group), and 68 patients who did not receive IC (non-IC group). Results At a median follow-up of 51.4 months (95% confidence interval; 42.9–62.1), 19 patients experienced recurrences. There was a trend toward fewer distant failures in the IC group (0% vs.14.7%, p = 0.057), while locoregional recurrence was similar (7.7% vs. 7.4%). IC was associated with significantly improved survivals with the 5-year RFS and OS rates for the IC group of 85.1% and 90.5%, respectively, compared to of 46.2% and 48.1% for the non-IC group (p = 0.008 for RFS, and p = 0.015 for OS). By multivariable analyses, IC remained the only significant factor associated with survivals (HR:0.18 for RFS, p = 0.020 and HR:0.18 for OS, p = 0.025). The effect of IC in the whole cohort, irrespective of pathological response, was also assessed. Patients with non-pCR in the IC group had a trend toward worse survivals compared to the non-IC group Conclusions In ESCC patients with pCR after trimodality treatment, IC was associated with favorable survivals. The benefits of IC might be a hypothesis generation for adjuvant treatment for patients with pCR.

Background: The incidence of HPV positive oropharyngeal cancer is increasing in Taiwan. Given this, it is critical to understand the prevalence of oral HPV infection since this cancer is potentially preventable. A community-based study was conducted to evaluate the prevalence of oral HPV infection and sexual behavior changes. Methods: Between January and December 2016, 100 subjects between 20 and 70 years-old with current/ever betel nut chewing or current cigarette smoking visited the Department of Health, New Taipei City. Subjects with cancer history or known HIV/AIDS were excluded. Sexual behavior information was collected through a questionnaire. Oral rinse samples and oropharyngeal swabs were obtained for HPV genotyping using the EasyChip HPV genotyping array (King-Car, Taiwan). Results: 92 men and 8 women were recruited. The prevalence of oral HPV infection was 3%, present between 60 and 70 (11%) and between 30 and 40 years old (4%). The prevalence of the first sexual contact at younger than 20 years old were 71.4%, 53.6%, 15.4% and 44% in

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).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.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).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.

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.

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.

Summary Background Osimertinib is approved for the treatment of non-small-cell lung cancer in patients who develop the EGFR Thr790Met mutation after treatment with epidermal growth factor receptor (EGFR) tyrosine-kinase inhibitors (TKIs). We assessed outcomes in patients with non-small-cell lung cancer and the EGFR Thr790Met mutation who were treated with osimertinib, a third-generation EGFR TKI, after previous treatment failure with one or more other EGFR TKIs. Methods Eligible patients had been enrolled at one centre in the AURA study, had shown resistance to a previous EGFR TKI, and had EGFR -activating mutations and acquired Thr790Met mutation detectable in tumour tissue or plasma. Patients took 20–240 mg osimertinib per day until disease progression or development of intolerable side-effects. Plasma samples were collected every 6 weeks and tumour tissue biopsy was done at study entry and was optional after disease progression. We tested samples for resistance mechanisms, including EGFR -activating, Thr790Met, and Cys797Ser mutations, and assessed associations with overall survival, progression-free survival, and survival after disease progression. Findings Of 71 patients enrolled in AURA, 53 were eligible for this analysis. Median progression-free survival was 11·1 months (95% CI 8·4–13·9) and overall survival was 16·9 months (11·7–29·1). 47 patients had disease progression. Median overall survival after osimertinib progression was 5·4 months (95% CI 4·1–10·0). Plasma samples were available for 40 patients after disease progression. 12 (30%) of these had the Thr790Met mutation (four of whom also had Cys797Ser mutations). Patients without detectable EGFR -activating mutations in plasma before treatment had the best overall and post-progression survival (22·4 months, 95% CI 15·6–not reached, and 10·8 months, 7·2–not reached, respectively). Loss of the Thr790Met mutation but presence of EGFR -activating mutations in plasma were associated with the shortest progression-free survival (median 2·6 months, 95% CI 1·3–not reached). In 22 post-progression tumour samples, we found one squamous cell and two small-cell transformations. We detected Thr790Met in nine (50%) of 18 samples, Cys797Ser in two (17%) of 12, cMET amplification in five (50%) of ten, BRAF mutation in one (8%) of 13, and KRAS mutation in one (8%) of 13. Interpretation Heterogeneous resistance mechanisms developed in patients receiving osimertinib. Differences in resistance mechanisms might dictate future development strategies for osimertinib in clinical trials. Funding AstraZeneca, Taiwan Ministry of Science and Technology.

Introduction The efficacy of pemetrexed-based chemotherapy in patients with advanced lung adenocarcinoma with novel ROS proto-oncogene 1, receptor tyrosine kinase gene ( ROS1 ) oncogenic rearrangement is unclear. This study aimed to compare the efficacy of pemetrexed-based chemotherapy in patients with advanced ROS1 -fusion lung adenocarcinoma with its efficacy in those having different driver mutations. Methods We retrospectively identified patients with advanced lung adenocarcinoma who were screened for epidermal growth factor receptor gene ( EGFR ) mutations, echinoderm microtubule associated protein like 4 gene ( EML4 )–anaplastic lymphoma receptor tyrosine kinase gene ( ALK ) translocation, Kirsten rat sarcoma viral oncogene homolog gene ( KRAS ) mutations, and ROS1 fusion by using multiplex reverse-transcriptase polymerase chain reaction. Patients who received pemetrexed-based therapy were enrolled for further analysis. The demographic data, clinical outcomes, and thymidylate synthase immunostaining (H-score) of patients with ROS1 fusion–positive lung adenocarcinomas were compared with those of patients harboring EGFR mutations, EML4-ALK fusion, KRAS mutations, and quadruple negativity. Results A total of 253 patients with advanced lung adenocarcinoma received a pemetrexed-based regimen and were classified on the basis of molecular findings as follows: 102 patients (40.3%) with EGFR mutations, 32 patients (12.6%) with EML4-ALK translocation, three patients (1.2%) with KRAS mutations, 19 patients (7.5%) with ROS1 fusion, and 97 patients (38.3%) with quadruple-negative status. Patients with ROS1 fusion had a better overall response rate (57.9%, p = 0.026), disease control rate (89.5%, p = 0.033), and longer progression-free survival (7.5 months, p = 0.003) compared with patients harboring other driver mutations. However, the H-score of thymidylate synthase was not associated with the response to pemetrexed therapy in patients with different molecular subtypes of lung adenocarcinoma. Conclusions ROS1 fusion positivity is probably a favorable factor of pemetrexed-based therapy for patients with lung adenocarcinoma.

Background The current World Health Organization (WHO) classification of nasopharyngeal carcinoma (NPC) conveys little prognostic information. This study aimed to propose an NPC histopathologic classification that can potentially be used to predict prognosis and treatment response. Methods We initially developed a histopathologic classification based on the morphologic traits and cell differentiation of tumors of 2716 NPC patients who were identified at Sun Yat-sen University Cancer Center (SYSUCC) (training cohort). Then, the proposed classification was applied to 1702 patients (retrospective validation cohort) from hospitals outside SYSUCC and 1613 patients (prospective validation cohort) from SYSUCC. The efficacy of radiochemotherapy and radiotherapy modalities was compared between the proposed subtypes. We used Cox proportional hazards models to estimate hazard ratios (HRs) with 95% confidence intervals (CI) for overall survival (OS). Results The 5-year OS rates for all NPC patients who were diagnosed with epithelial carcinoma (EC; 3708 patients), mixed sarcomatoid-epithelial carcinoma (MSEC; 1247 patients), sarcomatoid carcinoma (SC; 823 patients), and squamous cell carcinoma (SCC; 253 patients) were 79.4%, 70.5%, 59.6%, and 42.6%, respectively (P

Esophageal squamous cell carcinoma (ESCC) is common in hypopharyngeal squamous cell carcinoma (HSCC) patients. This prospective study is to reveal the prevalence of simultaneous ESCC in newly diagnosed HSCC patients by unsedated transnasal esophagogastroduodenoscopy (EGD) and to analyze the clinical predictors for simultaneous esophageal lesions and their survival.248 patients with newly diagnosed HSCC and without previous head and neck cancer between 2007 and 2014 were prospectively evaluated for HSCC and simultaneous esophageal lesions by unsedated transnasal EGD. The clinical factors for simultaneous esophageal lesions were evaluated. Survival analysis of the HSCC patients receiving complete treatment was done.The mean age was 58years. 170 HSCC (68.5%) were classified as T3-T4. The procedures were successfully performed (98.4%), except 4 huge tumors. 174 HSCC (85.7%, out of 203 tumors biopsied) were pathologically proved malignancy by this technique. Regarding esophageal lesions (45.5%), ESCC occurred in 36 patients (14.8%), dysplasia without ESCC occurred in 23 (9.4%) and Lugol voiding lesion without ESCC or dysplasia occurred in 52 (21.3%). Alcohol drinking (adjusted OR: 6.95, p0.05) and N3 classification (adjusted OR: 2.41, p0.05) of HSCC were the independent risk factors for the presence of esophageal lesions. The overall survival of the HSCC patients with ESCC was significantly lower than those without ESCC (p=0.013).Unsedated transnasal EGD is a promising technique for diagnosis of HSCC and simultaneous ESCC. Simultaneous esophageal lesions including ESCC (15%) are common in newly diagnosed HSCC patients, especially with alcohol drinking or N3 disease.

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. 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. 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

Summary Objective The treatment strategies for advanced oral squamous cell carcinoma (OSCC), especially with necrotic changes, are not effective. The programmed death ligand 1 (PD-L1) immune escape may be one of the underlying sources of resistance. Furthermore, anti-PD-L1 directed immunotherapy may be another choice for adjuvant therapy. Therefore, the expression of PD-L1 in advanced OSCC with necrotic changes is very important. Materials and methods A total of 218 eligible patients with advanced stage (stage III/IV) OSCC and neck metastasis were enrolled. The presence of necrosis was reviewed by pretreatment magnetic resonance imaging. Paired paraffin-embedded primary tumor and metastatic lymph nodes (LN) sections were stained with antibodies against hypoxia-inducible factor-1α (HIF-1α) and PD-L1. Moderate-to strong HIF-1α nuclear staining in >10% and cell surface PD-L1 expression in >5% of OSCC cells were recorded as a positive result. Results For advanced OSCC with necrotic changes, there was substantial agreement in primary tumor (kappa value 0.54) and almost perfect agreement in metastatic LN (kappa value 0.86) between HIF-1α and PD-L1 expression. The patients with both necrosis and positive PD-L1 expression in OSCC surrounding necrosis had worse disease control and survival outcomes. After multivariate analysis, metastatic LN necrosis and positive PD-L1 expression were found to be significant independent adverse factors. Conclusion Advanced OSCC patients with both necrosis and positive PD-L1 expression in OSCC surrounding necrosis had worse outcome. The aggressive behavior of advanced OSCC could be partially related to PD-L1 immune escape. These patients may be good candidates for anti-PD-L1 immunotherapy.

Melanoma differentiation-associated gene-9 (MDA-9)/Syntenin is a novel therapeutic target because it plays critical roles in cancer progression and exosome biogenesis. Here we show that Slug, a key epithelial-mesenchymal-transition (EMT) regulator, is a MDA-9/Syntenin downstream target. Mitogen EGF stimulation increases Slug expression and MDA-9/Syntenin nuclear translocation. MDA-9/Syntenin uses its PDZ1 domain to bind with Slug, and this interaction further leads to HDAC1 recruitment, up-regulation of Slug transcriptional repressor activity, enhanced Slug-mediated EMT, and promotion of cancer invasion and metastasis. The PDZ domains and nuclear localization of MDA-9/Syntenin are both required for promoting Slug-mediated cancer invasion. Clinically, patients with high MDA-9/Syntenin and high Slug expressions were associated with poor overall survival compared to those with low expression in lung adenocarcinomas. Our findings provide evidence that MDA-9/Syntenin acts as a pivotal adaptor of Slug and it transcriptionally enhances Slug-mediated EMT to promote cancer invasion and metastasis.

Mammary analogue secretory carcinoma (MASC) has a specific ETV6-NTRK3 translocation and morphologically overlaps with acinic cell carcinoma (AciCC). Before the recognition of MASC, in AciCC, four histologic patterns were identified including microcystic, solid, papillary-cystic, and follicular. The aim of this study was to evaluate histologic patterns in these two neoplasms through comprehensive histologic subtyping. Using fluorescence in situ hybridization (FISH), we identified 14 cases of MASC and 21 cases of AciCC. We used comprehensive histologic subtyping to provide a semiquantitive assessment of histologic patterns in each tumor and performed immunohistochemical analyses including S100/vimentin/mammaglobin/DOG1. MASC often presented papillary-cystic patterns without a solid component, previously considered to be one of the four major patterns associated with AciCC. However, in our study, this histologic feature was rarely seen in AciCC and more characteristic of MASC. In aspiration cytology samples, MASC was associated with more cellular atypia. An immunohistochemical panel of S100/mammaglobin/DOG1 was found useful for differential diagnosis. Comprehensive subtyping of histologic patterns is a useful screening method prior to initiation of molecular testing.

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 pathogenesis of melanomas emerging in plantar surfaces remains unclear; however, mechanical stress has been reported to increase the formation of melanomas. In this study, we conducted a multicenter retrospective analysis of 153 acral melanomas diagnosed between 2000 and 2015 in Taiwan. The male-to-female ratio of the patients in question was 1:1.28, and the mean age at diagnosis was 68 years. We examined whether melanomas which developed in different areas of the patients’ soles differed in their associations with various clinicopathological characteristics and survival. Testing by goodness of fit indicated that stress-bearing areas were significantly more conducive to the generation of melanomas than non-stress-bearing areas (P P P

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

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). One hundred and five patients who underwent surgery between 2001 and 2008 for advanced hypopharyngeal SCCs were consecutively enrolled and reviewed. 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 (

The prevalence, demographic features, and clinical outcomes of lung adenocarcinoma patients with novel ROS1 oncogenic rearrangement in East Asian populations are not clear. This study aimed to investigate the clinical and prognostic characteristics of lung adenocarcinoma in patients with ROS1 fusion compared with other driver mutations.Multiplex reverse transcription-polymerase chain reaction was used to detect the ROS1 fusion gene in lung adenocarcinoma cases. Immunohistochemistry was used to confirm the expression of ROS1. The demographic data and clinical outcomes of patients with the ROS1 fusion gene were compared with those of patients without the ROS1 fusion gene, including those with the EGFR mutation, EML4-ALK fusion, KRAS mutation, and quadruple-negative patients.Of 492 patients with lung adenocarcinoma, 12 (2.4%) had the ROS1 fusion gene. Their median age was 45.0 years, significantly younger than that of the ROS1 fusion-negative cohorts (p0.001). Acinar (including cribriform) and solid patterns were the two most common histologic subtypes in the ROS1 fusion tumors (7 of 12, 58.3%) and were predominantly seen in CD74-ROS1 fusion tumors (66.7%). There was no significant survival difference between the ROS1 fusion-positive and ROS1 fusion-negative cohorts in surgical group, but ROS1 fusion-positive patients might have worse outcomes than EGFR-mutant patients in the stage IV group.The ROS1 fusion gene can be successfully detected in East Asian patients with lung adenocarcinoma using multiplex reverse transcription-polymerase chain reaction. These patients tend to be younger and have characteristic histologic subtypes. Due to the small number of ROS1 fusion patients, the prognostic value of ROS1 fusion need further studies to confirm.

Human pulmonary dirofilariasis (HPD) is a rare zoonotic infection caused by Dirofilaria immitis. Dogs are the definite hosts and humans are infected occasionally via a vector, generally a mosquito. Most thoracic neurilemmoma arise in the mediastinum and fewer tumors originate peripherally from the intercostal nerves. Most patients with HPD or thoracic neurilemmoma are asymptomatic and these diseases are often discovered incidentally. We present a 53-year-old female who was found to have a pulmonary nodule and a chest wall nodule during a routine health examination. She underwent a video-assisted thoracoscopic surgery (VATS) with partial lung resection and local excision of the chest wall. The pathological examination revealed a coiled, degenerating Dirofilariasis immitis worm surrounded by granulomatous inflammation with caseous necrosis and a neurilemmoma composed of S-100 protein immunoreactive but smooth muscle actin negative spindle cells. Because these diseases are self-limiting and make further treatment unnecessary, video-assisted thoracoscopic surgery (VATS) is considered preferable and less invasive for definitive diagnosis and management.

Tid1 (DNAJA3), a DnaJ cochaperone, may promote degradation of oncogenic kinases. Tid1 has 2 isoforms, Tid1-L and Tid1-S, that may function differently. In this study, we investigated the role of the Tid1 isoforms in regulating EGF receptor (EGFR) signaling and lung cancer progression. We found that both Tid1-L and Tid1-S expressions were reduced in patients with non–small cell lung cancer compared with normal counterparts. Tid1-L expression correlated inversely with EGFR expression. Low Tid1-L/high EGFR expression predicted poor overall survival in patients with lung adenocarcinoma. Tid1-L overexpression in lung cancer cells attenuated EGFR signaling and inhibited cell proliferation, colony formation, and tumor growth in subcutaneous and orthotropic xenograft models. Conversely, depletion of Tid1 restored EGFR signaling and increased cell proliferation and colony formation. Tid1-L, but not Tid1-S, interacted with EGFR/HSP70/HSP90 through the DnaJ domain, counteracting the EGFR regulatory function of HSP90 by causing EGFR ubiquitinylation and proteasomal degradation. Tid1-L inhibited EGFR signaling even more than the HSP90 inhibitor 17-allylamino-demethoxy geldanamycin. We concluded that Tid1-L acted as a tumor suppressor by inhibiting EGFR signaling through interaction with EGFR/HSP70/HSP90 and enhancing EGFR ubiquitinylation and degradation. Cancer Res; 73(13); 4009–19. ©2013 AACR.

Background. For early-stage oral squamous cell carcinoma (OSCC) patients, the impact of perineural invasion (PNI) and lymphovascular invasion (LVI) on disease control and survival has not been clarified. Methods. The medical records of all early-stage OSCC patients who underwent curative surgery between 2004 and 2009 were reviewed. Results. A total of 442 early stage patients were included in this study. There were 360 patients in group A (without PNI or LVI) and 82 patients in group B (with PNI and/or LVI). Between groups A and B patients, there were no significant differences in the 5-year disease-free survival (73.8 vs 68.7 %, p = 0.48) and overall survival (90.9 vs 86.1 %, p = 0.25). Between groups A and B patients without postoperative radiotherapy (PORT), there were no significant differences in the 5-year disease-free survival (73.8 vs 70.2 %, p = 0.51) and overall survival (90.9 vs 85.2 %, p = 0.18). Between group B patients with and without PORT, there was no significant difference in either the disease-free survival (61.1 vs 70.2 %, p = 0.98) and overall survival (88.9 vs 85.2 %, p = 0.64). Multivariate analyses revealed that PNI, LVI, and PORT could not provide significant effect on treatment outcome. Conclusions. PNI and LVI were not significant risk factors for the disease control and overall survival for early stage OSCC patients. Furthermore, PORT could not provide an additional benefit for the disease control and overall survival for stages I and II OSCC patients with PNI and/or LVI.

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.The study enrolled 120 patients with pathologically stage 4 hypopharyngeal cancer treated with pharyngolaryngectomy and neck dissection between 2001 and 2007.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).A LN ratio of 0.113 or higher is a strong predictor of disease recurrence and survival for patients with stage 4 hypopharyngeal cancer.

To understand the impact of PIK3CA mutations on clinical characteristics and treatment response to epidermal growth factor tyrosine kinase inhibitors (EGFR TKIs) of lung adenocarcinoma, we examined PIK3CA and EGFR mutations in lung adenocarcinoma patients, and analyzed their clinical outcomes. Surgically excised tumor, bronchoscopy biopsy/brushing specimens and pleural effusions were prospectively collected from 1029 patients. PIK3CA and EGFR mutations were analyzed by RT-PCR and direct sequencing. In EGFR TKI-nave specimens, PIK3CA mutation rate was 1.8% (14/760). Twelve patients had coexisting PIK3CA and EGFR mutations. Among the 344 EGFR TKI-treated EGFR mutant patients, there was no significant difference in treatment response (p = 0.476) and progression-free survival (p = 0.401) of EGFR TKI between PIK3CA mutation-positive and negative patients. The PIK3CA mutation rate in lung adenocarcinoma with acquired resistance to EGFR TKI is not higher than that in EGFR TKI-naïve tissue specimens (2.9% (6/207) vs. 1.8%; p = 0.344). Of the 74 patients with paired specimens (TKI-naïve and acquired resistance to TKIs) only one patient (1.4%) developed acquired PIK3CA (E545K) mutation, and he also had acquired EGFR (T790M) mutation. In conclusion, PIK3CA mutation may not be associated with primary resistance to EGFR TKI among lung adenocarcinoma patients. Acquired PIK3CA mutation related to EGFR TKI treatment is rare.

Hyalinizing clear cell carcinoma (HCCC) is a rare salivary gland tumor with a specific EWSR1-ATF1 fusion gene and can have mucin production. Mucoepidermoid carcinoma (MEC) with a clear cell component is its morphologic mimic. Using MAML2 fluorescence in situ hybridization (FISH), a total of 49 MEC cases were separated into MAML2 fusion-positive (32 cases) and MAML2 fusion-negative groups (17 cases). This study used EWSR1 FISH to investigate MAML2 fusion-negative cases to identify previously unrecognized HCCC. Among 17 MAML2 fusion-negative cases, 3 had rearrangement of the EWSR1 gene and were reclassified as HCCC. Including 5 previously diagnosed HCCC cases, these 8 HCCC cases had a male-to-female ratio of 1:7, and most (7/8) tumors arose from oral minor salivary glands in the oral cavity (tongue base and palate). EWSR1-ATF1 fusion was confirmed by FISH in all 8 HCCC cases. The histologic features between genetically confirmed HCCC and MEC were compared. HCCC was significantly associated with minor salivary gland involvement, a discrepancy between low-grade cytology and intermediate- to high-grade histology using the MEC grading system, and absence of both epidermoid cells with abundant cytoplasm and goblet cells lining cysts or forming clusters. Clear cells and a hyalinized stroma were not specific for HCCC. HCCC may be erroneously classified as MEC because clear cells may be a minor histologic component and mucin production is not uncommon. Previously diagnosed MEC cases should be reevaluated, especially those arising from minor salivary glands or without MAML2 fusion. Careful histologic evaluation with supporting molecular testing can facilitate pathologic diagnoses.

The prognostic implication of BRAF mutant colorectal cancer remains paradoxical. Records of BRAF mutant and wild-type colorectal cancer patients at all stages were reviewed. Clinicopathologic features, including microsatellite instability, CpG islands methylator phenotype, and overall survival, of these patients were analyzed. Between 2005 and 2013, 428 colorectal cancer patients were enrolled in this study. The overall survival between BRAF mutant and wild-type patients with early-stage (stages I and II) colorectal cancer differed nonsignificantly (P = 0.99). By contrast, in late-stage (stages III and IV) patients, the median overall survival of BRAF mutant patients (N = 25) was significantly poorer than that of BRAF wild-type (N = 207) patients (BRAF mutant: 21.3 months (95% confidence interval [CI] 7.1-35.5); BRAF wild-type: 53.5 months (95% CI 37.5-69.5), P < 0.0001). In early-stage patients, we found that BRAF mutation was significantly associated with CpG island methylator phenotype-positive (P < 0.001), and microsatellite instability-high status (P = 0.0013). Conversely, in late-stage patients, BRAF mutation was significantly associated with CpG island methylator phenotype-positive (P = 0.0015) and the right-side colon (P = 0.014). BRAF mutation may have different prognostic implications in early- and late-stage colorectal cancer.

Insulin-like growth factor-II mRNA-binding protein 3 (IMP-3) is an RNA-binding protein expressed in multiple cancers, including melanomas. However, the expression of IMP-3 has not been investigated in acral lentiginous melanoma (ALM). This study sought to elucidate its prognostic value in ALMs. IMP-3 expression was studied in 93 patients diagnosed with ALM via immunohistochemistry. Univariate and multivariate analyses for survival were performed, according to clinical and histologic parameters, using the Cox proportional hazard model. Survival curves were graphed using the Kaplan-Meier method. IMP-3 was over-expressed in 70 out of 93 tumors (75.3%). IMP-3 expression correlated with thick and high-stage tumor and predicted poorer overall, melanoma-specific, recurrence-free and distant metastasis-free survivals (P = 0.002, 0.006, 0.008 and 0.012, respectively). Further analysis showed that patients with tumor thickness ≤ 4.0 mm and positive IMP-3 expression had a significantly worse melanoma-specific survival than those without IMP-3 expression (P = 0.048). IMP-3 (hazard ratio 3.67, 95% confidence intervals 1.35–9.97, P = 0.011) was confirmed to be an independent prognostic factor for melanoma-specific survival in multivariate survival analysis. Positive IMP-3 expression was an important prognostic factor for ALMs.

We report a case of giant cell tumor of the left distal femur with simultaneous bilateral pulmonary metastases. Pathologic examination of the left lung nodule showed a metastatic giant cell tumor with a noncontinuous ossified rim, and the right lung nodules were totally hyalinized or ossified without residual giant cell tumor components. Hyalinization was a consistent finding in both the primary bone lesion and the pulmonary metastases. Because the patient did not receive chemotherapy or radiotherapy before her surgical procedure, we believe that these changes represent spontaneous tumor regression.

In order to improve prognostic applications and treatment decisions, we report our experiences of visceral pleural surface invasion (VPSI) in non-small cell lung cancers (NSCLCs) with pleural retraction. A total of 321 NSCLCs with pleural retraction were identified by carefully inspecting surgically resected specimens. The extent of pleural invasion, including the use of elastic stain, was evaluated. Patients with and without VPSI were compared for clinicopathologic parameters and survival. VPSI was identified in 170 (53.0 %) of the stage I–III cases and 98 (43.4 %) of the patients with stage I disease. VPSI was associated with a higher frequency of tumor size greater than 3 cm, moderate/poor differentiation, vascular invasion, mediastinal lymph node metastasis, extranodal involvement, and higher TNM stages. Multivariate analysis revealed VPSI to be a significant independent predictor of unfavorable prognosis. The 5-year survival of patients with and without VPSI was 57.9 and 83.0 %, respectively (P = 0.001), and was 74.3 and 88.5 % (P = 0.005) in stages I–III and stage I disease, respectively. VPSI is an independent factor for poor prognosis in NSCLCs, regardless of lymph node status. Stage IB NSCLCs with PL1 pleural invasion are associated with a survival rate similar to that of stage IA NSCLCs and could be classified as T1 lesions. While surgical treatment is adequate in these patients, stage IB NSCLCs with VPSI have poor prognosis, and these patients should be considered for adjuvant chemotherapy.

Trop-2, a cell surface glycoprotein, contains both extracellular epidermal growth factor-like and thyroglobulin type-1 repeat domains. Low TROP2 expression was observed in lung adenocarcinoma tissues as compared with their normal counterparts. The lack of expression could be due to either the loss of heterozygosity (LOH) or hypermethylation of the CpG island DNA of TROP2 upstream promoter region as confirmed by bisulphite sequencing and methylation-specific (MS) polymerase chain reaction (PCR). 5-Aza-2′-deoxycytidine treatment on lung cancer cell (CL) lines, CL1-5 and A549, reversed the hypermethylation status and elevated both TROP2 mRNA and protein expression levels. Enforced expression of TROP2 in the lung CL line H1299 reduced AKT as well as ERK activation and suppressed cell proliferation and colony formation. Conversely, silencing TROP2 with shRNA transfection in the less efficiently tumour-forming cell line H322M enhanced AKT activation and increased tumour growth. Trop-2 could attenuate IGF-1R signalling-mediated AKT/β-catenin and ERK activation through a direct binding of IGF1. In conclusion, inactivation of TROP2 due to LOH or by DNA methylation may play an important role in lung cancer tumourigenicity through losing its suppressive effect on IGF-1R signalling and tumour growth.

The determining risk factors for patients with squamous cell carcinoma of the hard palate are not well verified.Medical records from our facility of all patients with squamous cell carcinoma of the hard palate receiving curative surgery between March 2003 and May 2009 were reviewed.Seventy-eight patients were enrolled in the study. The 5 year disease-free and overall survival rates were 49.8 and 49.7%, respectively. The 5 year disease-free and overall survival rates were statistically different between positive/close margins and negative margins (24.6% vs. 65.4%, P = 0.02; 20.1% vs. 63.1%, P = 0.001, respectively), with and without soft palate invasion (38.8% vs. 68.9%, P = 0.02; 27.4% vs. 77.5%, P = 0.001, respectively), and soft palate invasion patients with and without perineural invasion (10.4% vs. 52.8%, P = 0.02; 0% vs. 38.1%, P = 0.008, respectively). The rate of positive nodal metastasis for T3 and T4 tumors was 44%. For the tumor with soft palate invasion, the rate of positive nodal metastasis was 29%. After multivariate analyses, soft palate invasion and positive/close margins were the determining risk factors for disease-free and overall survival.Soft palate invasion and positive/close margins were the determining risk factors for disease-free and overall survival in patients with squamous cell carcinoma of the hard palate. Elective neck dissection is suggested for advanced primary tumors (T3 or T4) or tumors with soft palate invasion.

IntroductionThe echinoderm microtubule-associated protein like 4-anaplastic lymphoma kinase (EML4-ALK) fusion represents a novel target in a subset of non-small cell lung cancer, especially adenocarcinoma. EML4-ALK fusion is mutually exclusive with epidermal growth factor receptor (EGFR) mutations. To understand the impact of EML4-ALK on the prognosis of non-small cell lung cancer, we examined EML4-ALK fusion in lung adenocarcinoma from patients with wild-type EGFR and analyzed their clinical treatment outcomes.MethodsLung adenocarcinoma patients with malignant pleural effusions having wild-type EGFR and measurable target lesions were enrolled for EML4-ALK analysis by reverse transcription-polymerase chain reaction and direct sequencing. Demographic data, EML4-ALK status, and survival data were analyzed. We also performed fluorescence in situ hybridization on some available tumor samples to validate the PCR result. In addition, K-ras mutation was analyzed for patients without EML4-ALK fusion genes.ResultsA total of 116 patients with wild-type EGFR sequencing results had complete clinical data for analysis. No patients received ALK inhibitor therapy. There were 39 patients (34%) with the EML4-ALK fusion gene. The concordance rate between reverse transcription-polymerase chain reaction and fluorescence in situ hybridization was 85%. The K-ras mutation rate for patients without EML4-ALK fusion gene was 6.5%. By multivariate analysis, patients who had better performance status (p < 0.001) and EML4-ALK translocation (p = 0.017) had longer overall survival. Comparing patients with tumors harboring variant 1 with those harboring nonvariant 1 EML4-ALK fusion genes, there were no significant differences in clinical factors and survival outcome.ConclusionFor lung adenocarcinoma patients with wild-type EGFR, EML4-ALK translocation is associated with longer overall survival.

Thymidylate synthase (TS) and dihydrofolate reductase (DHFR) are target enzymes of inhibition by pemetrexed, an antifolate for treatment of advanced non-small-cell lung cancer (NSCLC). This study is to evaluate the association of TS and DHFR expressions and the treatment efficacy of pemetrexed in NSCLC patients. From January 2006 to October 2008, patients with advanced NSCLC treated with pemetrexed after prior chemotherapy were included. The TS and DHFR expressions in tumor tissues were examined by immunohistochemistry and evaluated by a semiquantitative histologic score (H-score). The H-score was derived from the degrees of intensity of tumor cells multiplied by the percentage of positive neoplastic cells. The medical records were reviewed and analyzed with respect to patients' characteristics, histology types, treatment responses and survivals. Among 268 NSCLC patients treated with pemetrexed, 49 had tumor specimens available for TS and DHFR evaluation. The TS expression was positively correlated with DHFR expression (r(2)=0.11, p=0.02). Patients with low TS (≤150) expression had a longer median progression-free survival (PFS) than those with high TS (>150) expression (4.8 vs. 3.4 months; p=0.01). Patients with low DHFR expression (≤120) also had a longer median PFS than patients with high DHFR expression (>120), which was not statistically significant (5.8 vs. 3.6 months; p=0.33). In patients with adenocarcinoma, the low TS patient group also had a longer median PFS and a longer median overall survival (OS) as compared with patients with high TS expression (PFS, 4.8 vs. 3.8 months, p=0.03; OS, 21.4 vs. 10.0 months, p=0.03). Nevertheless, the association of DHFR expression level and median PFS as well as OS were not statistically significant. TS expression, rather than DHFR, may be an important predictive factor for treatment efficacy of pemetrexed in NSCLC patients.

Purpose Although epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have been proven more effective for patients with lung adenocarcinoma with EGFR-activating mutation rather than wild type, the former group still includes approximately 30% nonresponders. The molecular basis of this substantial response heterogeneity is unknown. Our purpose was to seek molecular aberrations contributing to disease progression at the genome-wide level and identify the prognostic signature unique to patients with EGFR-activating mutation. Patients and Methods We first investigated the molecular differences between tumors with EGFR-activating mutation and wild-type tumors by conducting high-density array comparative genomic hybridization on a collection of 138 adenocarcinoma tissues. We then used an independent group of 114 patients to validate the clinical relevance of copy-number alterations (CNAs) in predicting overall and disease-free survival. Finally, focusing on 23 patients with EGFR mutation receiving EGFR-TKI treatment, we investigated the association between CNAs and response to EGFR-TKIs. Results We identified chromosome regions with differential CNAs between tumors with EGFR-activating mutation and wild-type tumors and found the aberration sites to cluster highly on chromosome 7p. A cluster of six representative chromosome 7p genes predicted overall and disease-free survival for patients with EGFR-activating mutation but not for those with wild type. Importantly, simultaneous presence of more genes with increased CNAs in this cluster correlated with less favorable response to EGFR-TKIs in patients with EGFR-activating mutation. Conclusion Our results shed light on why responses to EGFR-TKIs are heterogeneous among patients with EGFR-activating mutation. They may lead to better patient management in this population.

Malignant pleural effusion (MPE) is a useful specimen allowing for the evaluation of EGFR status in nonsmall cell lung cancer (NSCLC). However, direct sequencing of genomic DNA from MPE samples was found not to be sensitive for EGFR mutation detection. To test whether EGFR analysis from RNA is less prone to interference from nontumour cells that have no or lower EGFR expression, we compared three methods (sequencing from cell-derived RNA versus sequencing and mass-spectrometric analysis from genomic DNA), in parallel, for EGFR mutation detection from MPE samples in 150 lung adenocarcinoma patients receiving first-line tyrosine kinase inhibitors (TKIs). Among these MPE samples, EGFR mutations were much more frequently identified by sequencing using RNA than by sequencing and mass-spectrometric analysis from genomic DNA (for all mutations, 67.3 versus 44.7 and 46.7%; for L858R or exon 19 deletions, 61.3 versus 41.3 and 46.7%, respectively). The better mutation detection yield of sequencing from RNA was coupled with the superior prediction of clinical efficacy of first-line TKIs. In patients with acquired resistance, EGFR sequencing from RNA provided satisfactory detection of T790M (54.2%). These results demonstrated that EGFR sequencing using RNA as template greatly improves sensitivity for EGFR mutation detection from samples of MPE, highlighting RNA as the favourable source for analysing EGFR mutations from heterogeneous MPE specimens in NSCLC.

Objective. Tongue cancer is well known to have a high poten- tial for locoregional metastasis. However, controversy about electively treating the neck in early-stage tongue cancer re- mains. Although many risk factors related to cervical occult nodal metastasis (ONM) have been investigated, the ability of the tumor to spread, a phenomenon that results from the intrinsic property of the tumor and its interaction with the surrounding environment, has seldom been addressed. Study Design. Retrospective case series with chart review. Setting. Tertiary referral hospital of university. Subjects. Patients with early-stage squamous cell carcinoma of the oral tongue. Results. In 71 eligible enrolled patients, ONM was detected in 19 (27%) patients, while the results were negative (ONM(−)) in 52 (73%) patients. The average tumor satellite distance (TSD) in the ONM(+) group was 4.1 ± 4.3 mm, in contrast to that in the ONM(−) group (1.0 ± 1.5 mm; P < .001). When stratified by increased TSD values, the significance of the dif- ference between the 2 groups increased. For clinical applica- tions, the optimal TSD threshold for determining the ONM probability was 3.5 mm. Multivariate analyses demonstrated that TSD was an independent prognosticator. Conclusions. The results indicate that TSD is a feasible pathologi- cal parameter that is useful for determining the status of cervical nodal metastasis. It can be used as an indicator of potential cervi- cal subclinical disease and as a guideline for deciding the necessity and modality of neck treatment.

Erlotinib and gefitinib are tyrosine kinase (TK) inhibitors of epidermal growth factor receptor (EGFR) that are effective in treating non-small cell lung cancer (NSCLC). This study aimed to compare their clinical uses and the influence of EGFR mutation.The usages of erlotinib and gefitinib in advanced NSCLC were analyzed. Clinical data and EGFR mutational status of tumors were collected.Seven hundred and sixteen (716) patients received gefitinib (n=440) or erlotinib (n=276) for stage IIIb or IV NSCLC. Erlotinib was prescribed more frequently than gefitinib in males (58.2% vs. 41.8%, p0.001), smokers (60.5% vs. 39.5%, p0.001), and non-adenocarcinoma (70.6% vs. 29.4%, p0.001). Of the 716 study patients, 327 underwent testing for EGFR mutations (170 with mutant EGFR and 157 with wild-type EGFR). Adenocarcinoma in patients with mutant EGFR and non-smoker status in patients with wild-type EGFR were associated with better overall survival after TK inhibitor treatment. In both patient groups with mutant EGFR or wild-type EGFR, the effectiveness of gefitinib and erlotinib, including drug response or overall survival, were not different.Our study revealed the obvious disparity in drug selection between erlotinib and gefitinib in clinical practice. Type of TK inhibitors did not influence treatment outcomes in patients with EGFR mutation or wild-type EGFR.

Pleomorphic carcinomas of the lung are uncommon malignant tumors composed of carcinomatous and sarcomatous components and are distinguished from other non-small-cell lung carcinomas by a more aggressive clinical course with early distant metastases and far worse survival. Epidermal growth factor receptor (EGFR) and p53 are common genes involved in the pathogenesis of non-small-cell lung carcinomas, but their roles in pleomorphic carcinomas are unclear. The potential clinical activity of EGFR-targeted therapy is also unknown. A total of 42 pleomorphic carcinomas were identified to investigate somatic mutations of EGFR and p53. Genomic DNA was extracted from microdissected cells of paraffin-embedded tumor tissues. Somatic mutations in EGFR (exons 18–21) and p53 (exons 5–8) were examined. EGFR mutations were detected in 10 of 42 cases. Five of these patients had point mutations in exon 21 majorly with L858R; this mutation was found in both adenocarcinomatous and sarcomatous components in 1 case. The other 5 cases harbored 4 deletions and 1 mutation in exon 19. p53 mutations were found in 12 patients. Notably, identical mutation was observed in carcinomatous and sarcomatous components in 3 patients, and this finding strongly supported the theory of monoclonal histogenesis. The occurrence (23.8%) of EGFR mutations, including the exons 19 and 21 mutations observed frequently in our series, suggests that the patients with inoperable pleomorphic carcinomas are likely to benefit from treatment with EGFR tyrosine kinase inhibitors.

Introduction: Knowledge about the current status of the epidermal growth factor receptor ( EGFR ) has resulted in an improvement in the treatment of non-small cell lung cancer. In contrast, small cell lung cancer (SCLC) continues to frustrate clinicians with its tendency toward early metastasis and chemotherapy resistance. Recent studies have reported the EGFR mutation and its response to gefitinib treatment in SCLC. We would like to share our experience of EGFR studies on SCLC patients. Methods: Between 2004 and 2009, we prospectively collected 76 specimens from patients with SCLC at the National Taiwan University Hospital, Taiwan. These specimens included 10 computed tomography-guided biopsy specimens, 17 echo-guided aspiration specimens, 37 echo-guided biopsy specimens, 1 surgical lobectomy specimen, and 11 malignant pleural effusion specimens. Molecular genetic analysis of the specimens was conducted to detect the EGFR mutation. Results: Among the 76 SCLC specimens we examined, 2 (2.6%) tested positive for the EGFR mutation and both were deletions in exon 19. One patient was administered gefitinib after several lines of chemotherapy but showed no treatment response. To date, only 11 EGFR mutant-positive SCLC patients, including our 2 patients, have been reported. Most of these patients were never smokers. The SCLC harboring EGFR mutation were more likely to be combined with adenocarcinoma compared with the whole SCLC population. Conclusions: The EGFR mutation is rare in SCLC patients. Despite the presence of the EGFR mutation, gefitinib may not be effective in treating SCLC patients.

p53 and epidermal growth factor receptor (EGFR) are common genes involved in the pathogenesis of lung cancer, but their roles in lymphoepithelioma-like carcinomas (LELC) are unclear. In this study, we investigate the roles of p53 and EGFR in LELC carcinogenesis. Forty-six pulmonary LELCs were identified to evaluate p53 and EGFR aberrations. p53 mutations were identified in three patients, which all occurred in exon 8. EGFR mutations were detected in 8 of 46 cases with a majority of exon 21 mutations but without L858R. The other cases harbored mutations in exons 20 and 18. Only one case gained a deletion in exon 19. Notably, EGFR mutation was more commonly observed in patients with tumor size ≤ 3 cm (P = 0.014). In addition, there was a trend of more common EGFR overexpression in female (22/30) than in male patients (7/16, P = 0.061). However, there was no correlation between p53/EGFR mutations and protein expressions, suggesting the presence of complex mechanisms. p53 and EGFR mutations are uncommon in LELCs, indicating that these genes are not the important events in carcinogenesis for this tumor subtype. The EGFR mutation in 35% patients with LELC tumors

SummaryPulmonary alveolar proteinosis can be secondary to inhaled dust exposure, malignancy, and chronic pulmonary infections. However, pulmonary alveolar proteinosis secondary to extrapulmonary aspergillosis has never been reported. We report herein a case of pulmonary alveolar proteinosis secondary to invasive rhinocerebral aspergillosis. Neither immune modulators nor whole lung lavage was applied during the treatment course. The severe respiratory distress subsided, hypoxia resolved, and radiological infiltrates improved following the successful treatment of invasive rhinocerebral aspergillosis alone.

Fibroblast growth factor (FGF)-9 belongs to the FGF family which modulate cell proliferation, differentiation, and motility. Benzo(a)pyrene is a polycyclic aromatic hydrocarbon (PAH) and ubiquitous environmental carcinogen present in automobile exhaust, cigarette smoke, and foods. The major purposes of this study were to explore the roles of FGF-9 in the benzo(a)pyrene-induced lung cancer invasion in vitro and the metastatic development of lung adenocarcinoma in human. The data of RT-PCR analysis indicated that treatments of human lung adenocarcinoma CL5 cells with benzo(a)pyrene and a PAH mixture motorcycle exhaust particulate (MEP) extracts increased FGF-9 mRNA expression. The increased expression was blocked by cotreatments with a p38 mitogen-activated protein kinase inhibitor SB202190 and an extracellular signal-regulated kinase inhibitor PD98059. The results of immunoblot analysis and Matrigel assay showed that benzo(a)pyrene and MEP extracts produced a concomitant induction of FGF-9 protein and invasive ability of CL5 cells. The benzo(a)pyrene- and MEP-induced invasion was suppressed by FGF-9 neutralizing antibodies. The results of immunohistochemistry analysis of human lung adenocarcinoma specimens showed that FGF-9 protein was detected in the adenocarcinoma cells but not in normal epithelium. FGF-9 staining intensity was positively correlated with status of disease and degree of lymph node metastasis in these lung adenocarcinomas. These present findings suggest that FGF-9 has potential roles in benzo(a)pyrene-induced CL5 cell invasion and human lung adenocarcinoma metastasis.

Collapsin response mediator protein (CRMP) family proteins are cytosolic phosphoproteins involved in semaphorin 3A-mediated neuronal cell growth cone collapse and cancer invasion. We identified a novel human isoform of CRMP family proteins named long form CRMP-1 (LCRMP-1), which was different from the known invasion suppressor, CRMP-1, in its molecular weight and the N-terminal exon-1. This study was aimed to elucidate the clinical significance of LCRMP-1 in non-small cell lung cancer (NSCLC) patients. Full-length human LCRMP-1 was cloned from lung adenocarcinoma based on the Expressed Sequence Tags (EST) database. We generated LCRMP-1 specific antibody and subsequent in vitro and in vivo invasion assays showed positive correlations between LCRMP-1 expression and lung cancer cell invasiveness. We further demonstrated that high LCRMP-1 mRNA expressions were associated with poor overall and disease-free survivals (P=0.004 and 0.006, respectively, log-rank test) in 72 NSCLC patients. The results were confirmed in an independent cohort of 54 NSCLC patients by immunohistochemistry (P=0.032, log-rank test). The metastatic lymph nodes showed higher LCRMP-1 expressions as compared with the paired primary lung tumors (P=0.012, McNemar's test). In conclusion, LCRMP-1 was a cancer invasion enhancer that could be a novel prognostic biomarker in NSCLC.

Objectives/Hypothesis: To report on the clinical profiles and treatment experiences of patients with second primary ear malignancy after treatment of nasopharyngeal carcinoma (NPC). Study Design: Retrospective case series. Methods: A retrospective review of the clinical outcomes and pathology of 11 irradiated NPC patients who subsequently had second primary malignancies of the ear at a single institution. Results: Ten tumors were squamous cell carcinoma and one tumor was chondrosarcoma occurring within the radiation field of previous treatment for NPC. The interval between previous radiotherapy and diagnosis of ear malignancy was 3 to 27 years with a median time of 17 years. Six tumors were located in the external auditory canal, two in the middle ear cavity, two in the periauricular region and one in the mastoid cavity. Four patients underwent surgery, and the other seven patients underwent surgery plus adjuvant radiotherapy. The 3-year disease-free and overall survival rates were 30.3% and 20%, respectively. Conclusions: Postirradiated malignancy of the ear is extremely rare, but is one of the causes of death for NPC long-term survivors despite curative-intended treatment with surgery plus adjuvant radiotherapy is instituted.