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Background: Among the histologic types of lung cancer, adenocarcinoma is the most common. Moreover, lung adenocarcinoma with neuroendocrine differentiation (LANED) is a rare histologic character. So far, the clinical significance remains unclear. Material and methods: We searched for the patients diagnosed with LANED from the electronic pathology database between January 2000 and June 2020 in a tertiary hospital. The tumor specimens were reviewed by a pathologist to confirm the diagnosis. EGFR mutation, ALK translocation, as well as programmed death ligand 1 (PD-L1) and rearranged during transfection (RET) expression were tested in the specimens of LANED. The clinical data were also collected and analyzed. Results: A total of 10 patients diagnosed with LANED were included. Most were male (80%) and ever smokers (70%). The median age was 71.5 years old. At diagnosis, most had tumors harboring no EGFR mutation (70%), negative ALK translocation (88.9%), and without PD-L1 expression (90%). All specimens tested by immunohistochemical staining for RET expression (n = 9) showed positive results. Among the 10 patients, five underwent operation (stage I, n = 4; stage II, n = 1). The patient with stage II disease had recurrence 11 months later. For patients with advanced stages (stage III, n = 1; stage IV, n = 4), the treatment modalities varied and the overall survival ranged from 11.0 to 46.7 months. Conclusion: LANED might be associated with a high proportion of RET expression, whereas EGFR mutation, ALK alteration, and PD-L1 expression were uncommon. Further large-scale prospective studies on molecular testing profile and clinical significance of LANED are warranted.

Abstract Background Front‐line platinum‐base chemotherapy for advanced thymoma and thymic carcinoma (TC) improves resectability and prolongs patients' overall survival (OS). In this study, we evaluated patients' outcomes given different front‐line regimens: cisplatin, doxorubicin, and cyclophosphamide (CAP); cisplatin and etoposide (EP); or cisplatin and paclitaxel (TP). Materials and Methods We retrospectively evaluated the medical records of patients with advanced thymoma and TC who were treated at our medical center between 2005 and 2015. We investigated objective response rates (ORRs), progression‐free survival (PFS), and OS after undergoing different front‐line regimens. Results Among the 108 enrolled patients, 37 (34%) had thymoma and 71 (66%) had TC; 45 received CAP, 36 received EP, and 27 received TP regimens. The ORRs of patients receiving CAP, EP, and TP were 51%, 50%, and 41%, respectively. For patients with stage III and IVA disease, the median PFS after CAP, EP, and TP were 34.5, 26.4, and 18.0 months (p = 0.424), respectively, and the 5‐year OS rates were 84.9%, 70.6%, and 60.0% (p = 0.509). In patients with stage IVB disease, the median PFS were 9.4, 8.2, and 11.6 months after undergoing CAP, EP, and TP (p = 0.173), respectively, and the 5‐year OS rates were 41.1%, 39.1%, and 14.3% (p = 0.788). TC pathology subtype and liver metastasis were associated with poor OS. Three patients with stage IVB TC had an OS of more than 5 years. Conclusion Different front‐line chemotherapy regimens may provide similar long‐term PFS and OS in patients with advanced thymoma and TC. In addition to TC and liver metastasis were associated with poor OS, other potential prognostic factors are warranted for studying.

Abstract 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

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.

Abstract 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.

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.

Targeting metabolic reprogramming is an emerging strategy in cancer therapy. However, clinical attempts to target metabolic reprogramming have been proved to be challenging, with metabolic heterogeneity of cancer being one of many reasons that causes treatment failure. Here, we stratified non-small cell lung cancer (NSCLC) cells, mainly lung adenocarcinoma, based on their metabolic phenotypes and demonstrated that the aerobic glycolysis-preference NSCLC cell subtype was resistant to the OXPHOS-targeting inhibitors. We identified that monocarboxylate transporter 4 (MCT4), a lactate transporter, was highly expressed in the aerobic glycolysis-preference subtype with function supporting the proliferation of these cells. Glucose could induce the expression of MCT4 in these cells through a ΔNp63α and Sp1-dependent pathway. Next, we showed that knockdown of MCT4 increased intracellular lactate concentration and induced a reactive oxygen species (ROS)-dependent cellular apoptosis in the aerobic glycolysis-preference NSCLC cell subtype. By scanning a panel of monoclonal antibodies with MCT4 neutralizing activity, we further identified a MCT4 immunoglobulin M (IgM) monoclonal antibody showing capable anti-proliferation efficacy on the aerobic glycolysis-preference NSCLC cell subtype. Our findings indicate that the metabolic heterogeneity is a critical factor for NSCLC therapy and manipulating the expression or function of MCT4 can be an effective strategy in targeting the aerobic glycolysis-preference NSCLC cell subtype.

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

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

Pemphigus is an autoantibody-mediated blistering disease. In addition to conventional pemphigus vulgaris and pemphigus foliaceus, several other types have been reported. Among them, IgG/IgA pemphigus is less well defined and seldom reported. To characterize the clinical, histopathologic, and immunohistochemical presentation of IgG/IgA pemphigus, we retrospectively identified 22 patients with the disease at a referral center in Taiwan. These patients showed two types of skin lesion: annular or arciform erythemas with blisters or erosions (45.5%) and discrete erosions or blisters such as those in conventional pemphigus (54.5%). Mucosal involvement was found in 40.9%. Histopathologic analysis identified acantholysis (77.3%) and intra-epidermal aggregates of neutrophils (40.9%) and eosinophils (31.8%). Direct immunofluorescence studies showed IgG/IgA (100%) and C3 (81.8%) depositions in the intercellular space of the epidermis. In immunohistochemical staining, patients with IgG/IgA pemphigus demonstrated significantly higher levels of epidermal expression of interleukin-8 and matrix metalloproteinase-9 than those with conventional pemphigus (p < 0.05). In conclusion, although IgG/IgA pemphigus is heterogeneous in presentation, it shows characteristic features that are different from other forms of pemphigus and should be considered a distinct type of pemphigus.

Abstract Adenocarcinoma (ADC) is the most common form of lung cancer; however, some other types of lung cancer can sometimes mimic ADC. It then takes experienced pathologists and special stains to make the correct diagnosis. Here, we present a patient with pulmonary pleomorphic carcinoma who was misdiagnosed with ADC, and was treated with pembrolizumab for 13 months. The diagnosis and treatment (including immunotherapy) are also reviewed.

Current National Comprehensive Cancer Network (NCCN) guidelines suggest plasma‐based testing (liquid biopsy) for T790M in epidermal growth factor receptor (EGFR)‐mutated non‐small cell lung carcinoma (NSCLC) with acquired resistance to first‐/second‐generation EGFR tyrosine kinase inhibitors (TKIs). Positivity for resistant mutation on liquid biopsy may obviate the need for invasive tissue biopsy. We report a rare case of primary resistance to osimertinib, although liquid biopsy revealed EGFR T790M positivity. A 63‐year‐old male, never smoker, was diagnosed with stage IV lung adenocarcinoma with EGFR exon 19 deletion. Treatment started with erlotinib and was continued for 15 months until disease progression. Osimertinib was initiated when liquid biopsy showed EGFR T790M positivity. However, primary resistance to osimertinib was noted on follow‐up imaging. Re‐biopsy revealed small cell lung cancer. Detection of T790M via liquid biopsy among NSCLC patients with acquired resistance to EGFR‐TKI might miss other possible resistant mechanisms. Tissue biopsy should be considered to exclude small cell lung carcinoma (SCLC) transformation.

Abstract 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.

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.

Abstract 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

Hypoxia and epithelial-to-mesenchymal transition promotes cancer metastasis. Here the authors show that Daxx inhibits hypoxia-induced lung cancer metastasis by attenuating Slug-mediated transcriptional repression of epithelial-like markers that in turn cause cells to exhibit low invasiveness.

Abstract 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

Patients aged ≤50 years are rarely diagnosed with nonsmall cell lung cancer. We conducted a retrospective cohort study to understand the mutation status of EGFR and the efficacy of epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) treatment in young Asian patients with lung adenocarcinoma. We collected tumour specimens and malignant pleural effusions from lung adenocarcinoma patients from June 2005 to April 2014, recorded their clinical demographic data, and analysed EGFR mutations by reverse transcriptase PCR. EGFR mutation data were collected from 1039 lung adenocarcinoma patients, including 161 patients aged ≤50 years and 878 patients aged >50 years. Fewer patients aged ≤50 years had EGFR mutations than older patients (p=0.043), but they showed a higher rate of uncommon EGFR mutations (p=0.035). A total of 524 patients with EGFR mutations received EGFR-TKI treatment, including 81 patients aged ≤50 years. Younger patients had a lower response rate than older patients (p=0.038) and had the shortest progression-free survival compared with other predefined age categories (p=0.033). Multivariate analysis of overall survival revealed age ≤50 years as a poor prognostic factor. In conclusion, fewer Asian patients aged ≤50 years had EGFR mutations, but the EGFR mutation types were more uncommon. Age ≤50 years is associated with poorer efficacy of EGFR-TKI treatment.

Studies surveying melanomas associated with melanocytic nevi in Asia are rare. In this study, we examined whether nevus-associated melanomas differ from de novo melanomas in terms of their associations with clinical factors, histologic characteristics, and patient survival in Taiwan. Using data on cancer cases obtained from the Department of Pathology archives and the Cancer Registry of National Taiwan University Hospital, we conducted a retrospective analysis of 103 consecutive melanoma patients who were diagnosed between 2010 and 2015 and received follow-up through November 2016. Approximately 17.5% of the melanomas in question were associated with a nevus. In patients under 65 years of age, non-acral lentiginous melanomas were significantly associated with a higher percentage of nevus-associated melanomas. The superficial spreading subtype, younger patient age, thinner tumor, intermittent solar exposure, and early stage were significant predictors of a melanoma being histologically associated with a nevus. The appearance of a nevus associated with a melanoma predicted better recurrence-free survival compared with de novo melanomas. Although acral lentiginous melanomas (70.9%) constituted the most common histologic subtype, only 9.6% of the acral lentiginous melanomas were associated with a nevus. Furthermore, there was no statistically significant difference between the nevus-associated and de novo acral lentiginous melanomas with regard to clinicopathological factors and survival. In conclusion, nevus-associated melanomas were uncommon among acral lentiginous melanomas. Relatedly, because over half of all melanomas in Asians are acral lentiginous melanomas, Asians are less likely than Caucasians to have nevus-associated melanomas.

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.

OBJECTIVES:To investigate the effect of radiotherapy (RT) on ultrasound-guided fine needle aspiration (USgFNA) and sonographic characteristics in the assessment of cervical lymph nodes (LNs) in oral squamous cell carcinoma (OSCC) patients after primary treatment. MATERIALS AND METHODS:88 treated OSCC patients underwent 111 USgFNAs of the neck LNs after US evaluation. Among them, 48 USgFNAs were performed on 40 patients following RT and 63 USgFNAs on 48 patients without previous RT. The results of USgFNA and the US characteristics were compared between these two groups. RESULTS:USgFNA had a sensitivity of 88.0%, specificity of 91.4%, positive predictive value (PPV) of 88.0%, negative predictive value (NPV) of 91.4% and accuracy of 90.0% in patients without previous RT, and a sensitivity of 97.1%, specificity of 83.3%, PPV of 94.3%, NPV of 90.9% and accuracy of 93.5% in those with previous neck RT. The ranges of the short-axis and long-axis length were 13.3 ± 8.0 mm (mean ± SD) versus 17.8 ± 9.1 mm, and 18.6 ± 9.0 mm versus 24.4 ± 10.9 mm for recurrent LNs from patients with, versus without, previous RT (both ps < 0.05), respectively. 76.5% (26/34) of the recurrent nodes after RT and 48% (12/25) of the recurrent nodes without previous RT exhibited an irregular margin (p < 0.05). Additionally, irradiated recurrent LNs had a significantly decreased percentage of discernable calcification compared with non-irradiated recurrent nodes (48% versus 20.6%, p < 0.05). CONCLUSIONS:RT had influence on sonographic characteristics but no influence on USgFNA in diagnosing recurrent LNs in treated OSCC patients.

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.

Developing a robust, novel method for performing multiple reactions in a single tube is not only time- and cost-saving but also critical for future high-throughput whole-slide in situ techniques on diseased tissues. In this study, we introduce the use of perfluorocarbons and compound-coated magnetic particles to create pseudochambers in a single tube, allowing different reactions to be performed in different phases. Perfluorocarbons also serve as cell lysis buffer and polymerase chain reaction (PCR) buffer owing to their highly penetrating, repellent and emulsifiable properties. Using this method, nucleic acids can be isolated and purified from various sample types and sizes, followed by PCR, real-time PCR, or multiplex PCR in the same tube. No incubation or enzyme digesting time is needed and the risk of cross-contamination is reduced. Tests can be performed in microemulsions (water-in-oil droplets) containing sequence-specific captures and probes for further high-throughput detection. We present a simple, quick, and robust procedure as a prerequisite step to future high-throughput in situ techniques.

Proteus syndrome is a very rare, sporadic and congenital condition that is characterized by postnatal mosaic overgrowth. This disorder is thought to be caused by a somatic gene mutation, but the exact etiology is unknown. Commonly involved tissues include connective tissue, bone, skin and the central nervous system. Another less common symptom involves pulmonary emphysematous changes. This report documents a 25-year-old man with Proteus syndrome who presented with progressive exertional dyspnea and asymmetric overgrowth of his extremities. He underwent left pneumonectomy and his postoperative course was uneventful. Lung tissue showed emphysematous changes with multiple bulla formation and scattered calcification. We also review recent literature related to pulmonary manifestations and management of Proteus syndrome.

Few studies have examined the surgical outcomes of mediastinal mature teratoma in Taiwan. In the present study, the clinicopathological characteristics of mature teratoma and their impact on surgical outcome were analyzed. Methods: From 1988 to 2005, 57 cases of mediastinal mature teratoma were reviewed. We collected and analyzed data about patient age, sex, symptoms, blood sugar, pulmonary function, diagnosis, tumor size, histopathological features, operative methods, operative time, tumor adhesion, blood loss, ventilator requirement, intensive care unit stay, chest tube requirement, and postoperative hospital stay. Results: There were 18 male and 39 female patients with a median age of 27 years. Forty-three patients received conventional open surgery, whereas 14 received video-assisted thoracoscopic surgery. The patients in the thoracoscopic group had a decreased operative time (106.4 ± 35.7 min vs. 205.4 ± 75.7 min, p = 0.038), fewer ventilator days (0.2 ± 0.4 vs. 0.5 ± 0.8, p = 0.034), and a shorter stay in the intensive care unit (0.6 ± 0.8 days vs. 1.5 ± 1.4 days, p = 0.030). Pancreatic tissue was identified in 21 of 57 tumors (36.8%). The patients with tumors that contained pancreatic tissue had more presenting symptoms and complicated surgery than those whose tumors were without pancreatic tissue (76.2% vs. 33.3%, p = 0.002, and 42.9% vs. 11.1%, p = 0.008). The patients with symptoms had a higher incidence of complicated surgery than those without (39.3% vs. 6.9%, p = 0.004). Conclusion: Mediastinal mature teratoma commonly occurs in young women. Thoracoscopic surgery is a feasible technique for mediastinal mature teratoma resection if no dense adhesions are found during preoperative assessment. The presence of symptoms might be a relative contraindication for thoracoscopic teratoma resection because of its association with surgical complications.

Thyroglossal duct cysts (TDC) are the most common cervical cysts and are usually considered to be a benign embryonic malformation where the thyroglossal duct fails to obliterate. Parathyroid cysts (PTC) are a rare disease and may also result from malformation of the remnants of the third pharyngeal pouch. Although several sporadic cases of concurrent TDC with other head and neck malformations have been reported in the literature, a combination of TDC and PTC has never been reported. Here, we report the first case of a 35-year-old woman with a metachronous TDC and PTC. The embryologic origins of TDCs and inferior PTCs are revealed from the experience of this case.

Paraneoplastic pemphigus (PNP), also called paraneoplastic autoimmune multiorgan syndrome, is a rare disorder associated with underlying neoplasia. The common underlying neoplasms include non-Hodgkin's lymphoma, chronic lymphocytic leukemia, and Castleman's disease. Though B-cell lymphoma is the most common underlying malignancy, only one case associated with splenic B-cell lymphoma has been recognized. The prognosis of PNP is very poor, and PNP-associated bronchiolitis obliterans (BO) is not uncommon. Herein, we report a 44-year-old woman who initially presented with multiple oral ulcers, conjunctivitis, and numerous cutaneous blisters. Serial workup established the diagnosis of PNP and revealed an underlying splenic B-cell lymphoma. Although the mucocutaneous lesions gradually healed after splenectomy and chemotherapy, deteriorating respiratory function developed 7 months later with pathologically proven BO. She finally succumbed to respiratory failure 12 months after presentation despite intensive respiratory care.

Bronchogenic cysts (BCs) are usually located in the mediastinum and they occur less commonly in the lung parenchyma. This study investigated the findings from computed tomography (CT) images, clinical presentation and histopathologic findings of intrapulmonary BCs. Methods: From the last 7 years, the CT images of 20 patients (12 females, 8 males; mean age, 38.8 ± 21.7 year; median age, 34 years) with intrapulmonary BC were available. Contrast-enhanced CT findings were characterized and correlated with clinical presentation and histopathologic findings (using Fisher's exact tests). Results: The majority of intrapulmonary BCs were subpleural in location (55%), in the lower lobes (60%), symptomatic (80%), and in adults (90%). Three CT patterns were identified: cyst with content of fluid attenuation (9 patients), cyst with air and fluid content (9 patients), cyst with content of soft tissue attenuation (2 patients). Preoperative diagnosis of intrapulmonary BC was correct in only 20% using the CT criteria of cysts with fluid attenuation and without anomalous blood supply. Cysts with air component were significantly larger than those without air component (p = 0.0452), but cyst size and air component were not correlated with clinical presentation. Surrounding infiltration or thick wall on CT were significantly correlated with the presence of any clinical symptom (p = 0.014) or fever (p = 0.042). CT findings of surrounding consolidation, ground glass opacity or thick wall were significantly correlated with chronic inflammation or pneumonic change on histopathology (p = 0.0008). Conclusion: There is a wide spectrum of intrapulmonary BCs that have CT findings that are correlated with clinical presentations and histopathologic findings. [J Formos Med Assoc 2007;106(1):8-15]

Comparison of protein stability in eukaryotic cells has been achieved by cycloheximide, which is an inhibitor of protein biosynthesis due to its prevention in translational elongation. It is broadly used in cell biology in terms of determining the half-life of a given protein and has gained much popularity in cancer research. Here we present a full cycloheximide chase assay in our laboratory using a lung adenocarcinoma cell line, CL1-5, as a model.

Nature Communications 7: Article number: 13867 (2016); Published 22 December 2016; Updated 7 February 2017 The original version of this Article contained an error in the spelling of the author Yih-Leong Chang, which was incorrectly given as Yi-Liang Chang. This has now been corrected in both the PDFand HTML versions of the Article.

To identify better regimens in currently available chemotherapy would be beneficial to KRAS mutant metastatic colorectal cancer (mCRC) patients because they have fewer treatment options than KRAS wild-type mCRC patients. Clinicopathologic features and overall survival (OS) of KRAS mutant and wild-type mCRC patients who had used oxaliplatin-based, irinotecan-based, bevacizumab-based, as well as cetuximab-based regimens were compared to those who had never-used oxaliplatin-based, irinotecan-based, bevacizumab-based, as well as cetuximab-based regimens respectively. Between 2007 and 2012, a total of 394 mCRC patients, in whom 169 KRAS mutant and 225 KRAS wild-type, were enrolled. In KRAS mutant patients who had used oxaliplatin-based regimens (N = 131), the OS was significantly longer than that in KRAS mutant patients who had never-used oxaliplatin-based regimens (N = 38). The OS was 28.8 months [95% confidence interval (CI): 23.2-34.4] in KRAS mutant patients who had used oxaliplatin-based regimens versus 17.8 months [95% CI: 6.5-29.1] in KRAS mutant patients who had never-used oxaliplatin-based regimens (P = 0.026). Notably, OS in KRAS wild-type mCRC patients who had used oxaliplatin-based regimens (N = 185) was not significantly longer than that in KRAS wild-type mCRC patients who had never-used oxaliplatin-based regimens (N = 40) (P = 0.25). Furthermore, the OS in KRAS mutant patients who had used either irinotecan-based, bevacizumab-based or cetuximab-based regimens was not significantly different than that in KRAS mutant patients who had never-used either irinotecan-based, bevacizumab-based or cetuximab-based regimens respectively. In multivariate analyses, patients who had used oxaliplatin-based regimens remains an independent prognostic factor for longer OS in KRAS mutant mCRC patients. In conclusion, oxaliplatin-based regimens are more beneficial in KRAS mutant than in KRAS wild-type mCRC patients.

The motor protein kinesin superfamily proteins (KIFs) are involved in cancer progression. The depletion of one of the KIFs, KIF14, might delay the metaphase-to-anaphase transition, resulting in a binucleated status, which enhances tumor progression; however, the exact correlation between KIF14 and cancer progression remains ambiguous. In this study, using loss of heterozygosity and array comparative genomic hybridization analyses, we observed a 30% loss in the regions surrounding KIF14 on chromosome 1q in lung adenocarcinomas. In addition, the protein expression levels of KIF14 in 122 lung adenocarcinomas also indicated that approximately 30% of adenocarcinomas showed KIF14 down-regulation compared with the expression in the bronchial epithelial cells of adjacent normal counterparts. In addition, the reduced expression of KIF14 mRNA or proteins was correlated with poor overall survival (P = 0.0158 and

LCRMP-1, a novel isoform of CRMP-1, can promote cancer cell migration, invasion and associate with poor clinical outcome in patients with non-small-cell lung cancer (NSCLC). However, the underlying regulatory mechanisms of LCRMP-1 in cancer cell invasiveness still remain obscure. Here, we report that GSK3β can phosphorylate LCRMP-1 at Thr-628 in consensus sequences and this phosphorylation is crucial for function of LCRMP-1 to promote filopodia formation, migration and invasion in cancer cells. Impediment of Thr-628 phosphorylation attenuates the stimulatory effects of LCRMP-1 on filopodia forming, migration and invasion abilities in cancer cells; simultaneously, kinase-dead GSK3β diminishes regulation of LCRMP-1 on cancer cell invasion. Furthermore, we also found that patients with low-level Ser-9-phosphorylated GSK3β expression and high-level LCRMP-1 expression have worse overall survival than those with high-level inactive GSK3β expressions and low-level LCRMP-1 expressions (P

Molecular biomarkers to determine the effectiveness of targeted therapies in cancer treatment have been widely adopted in colorectal cancer (CRC), but those to predict chemotherapy sensitivity remain poorly defined. We tested our hypothesis that KRAS mutation may be a predictor of oxaliplatin sensitivity in CRC. KRAS was knocked-down in KRAS-mutant CRC cells (DLD-1(G13D) and SW480(G12V)) by small interfering RNAs (siRNA) and overexpressed in KRAS-wild-type CRC cells (COLO320DM) by KRAS-mutant vectors to generate paired CRC cells. These paired CRC cells were tested by oxaliplatin, irinotecan and 5FU to determine the change in drug sensitivity by MTT assay and flow cytometry. Reasons for sensitivity alteration were further determined by western blot and real-time quantitative reverse transcriptase polymerase chain reaction (qRT -PCR). In KRAS-wild-type CRC cells (COLO320DM), KRAS overexpression by mutant vectors caused excision repair cross-complementation group 1 (ERCC1) downregulation in protein and mRNA levels, and enhanced oxaliplatin sensitivity. In contrast, in KRAS-mutant CRC cells (DLD-1(G13D) and SW480(G12V)), KRAS knocked-down by KRAS-siRNA led to ERCC1 upregulation and increased oxaliplatin resistance. The sensitivity of irinotecan and 5FU had not changed in the paired CRC cells. To validate ERCC1 as a predictor of sensitivity for oxaliplatin, ERCC1 was knocked-down by siRNA in KRAS-wild-type CRC cells, which restored oxaliplatin sensitivity. In contrast, ERCC1 was overexpressed by ERCC1-expressing vectors in KRAS-mutant CRC cells, and caused oxaliplatin resistance. Overall, our findings suggest that KRAS mutation is a predictor of oxaliplatin sensitivity in colon cancer cells by the mechanism of ERCC1 downregulation.

Epidermal growth factor receptor (EGFR) is a novel target for therapy in subsets of non-small cell lung cancer, especially adenocarcinoma. Tumors with EGFR mutations showed good response to EGFR tyrosine kinase inhibitors (TKIs). We aimed to identify the discriminating capacity of immunohistochemical (IHC) scoring to detect L858R and E746-A750 deletion mutation in lung adenocarcinoma patients and predict EGFR TKIs response. Patients with surgically resected lung adenocarcinoma were enrolled. EGFR mutation status was genotyped by PCR and direct sequencing. Mutation-specific antibodies for L858R and E746-A750 deletion were used for IHC staining. Receiver operating characteristic (ROC) curves were used to determine the capacity of IHC, including intensity and/or quickscore (Q score), in differentiating L858R and E746-A750 deletion. We enrolled 143 patients during September 2000 to May 2009. Logistic-regression-model-based scoring containing both L858R Q score and total EGFR expression Q score was able to obtain a maximal area under the curve (AUC: 0.891) to differentiate the patients with L858R. Predictive model based on IHC Q score of E746-A750 deletion and IHC intensity of total EGFR expression reached an AUC of 0.969. The predictive model of L858R had a significantly higher AUC than L858R intensity only (p = 0.036). Of the six patients harboring complex EGFR mutations with classical mutation patterns, five had positive IHC staining. For EGFR TKI treated cancer recurrence patients, those with positive mutation-specific antibody IHC staining had better EGFR TKI response (p = 0.008) and longer progression-free survival (p = 0.012) than those without. In conclusion, total EGFR expression should be included in the IHC interpretation of L858R. After adjusting for total EGFR expression, the scoring method decreased the false positive rate and increased diagnostic power. According to the scoring method, the IHC method is useful to predict the clinical outcome and refine personalized therapy.