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Oncogenic EGFR is essential for the development and growth of non–small cell lung cancer (NSCLC), but the precise roles of EGFR in lung cancer metabolism remain unclear. Here, we show that EGFR mutation-mediated enhancement of glycolysis is critical for EGFR stability. EGFR knockdown significantly decreased levels of glycolytic pathway intermediates via transcriptional regulation of glycolytic genes. EGFR mutation-enhanced glycolysis was required for fueling the tricarboxylic acid cycle, a critical component of EGFR stability. Nonsustained ATP production enhanced reactive oxygen species accumulation and subsequent JNK-mediated activation of autophagy, which in turn induced EGFR degradation. Our data show that EGFR-mutant NSCLCs require EGFR mutation-enhanced glycolysis to maintain EGFR stability. This pathway may serve as an attractive therapeutic target for EGFR-mutant NSCLCs.Significance: Enhanced glycolysis by EGFR mutation is required for maintaining EGFR levels via inhibition of JNK-induced autophagy. This provides a promising rationale for use of JNK activators in patients with EGFR-mutated NSCLC. Cancer Res; 78(16); 4482–96. ©2018 AACR.

Supplementary information contains 8 supplementary figures. Supplementary Figure 1. EGFR knockdown decreases glycolytic gene expression at the transcription level. Supplementary Figure 2. Glucose deprivation renders EGFR-mutant NSCLCs more sensitive to cell growth and death. Supplementary Figure 3. EGFR-mediated enhanced glycolysis is an important TCA cycle fuel source. Supplementary Figure 4. Mitochondrial ATP production is necessary for EGFR stability. Supplementary Figure 5. Anisomycin treatment inhibits the EGFR signaling pathway and activates apoptosis via JNK activation in vivo. Supplementary Figure 6. JNK is a downstream target of ROS. Supplementary Figure 7. Activated autophagy induces apoptotic cell death in EGFR-mutant NSCLCs. Supplementary Figure 8. Glucose deprivation has minimal effect on the growth of EGFR-TKIs-resistant cell lines without EGFR dependency.

Background Epidermal growth factor receptor (EGFR) mutations in non-small cell lung cancers have emerged as key predictive biomarkers in EGFR tyrosine kinase inhibitor (TKI) treatment. However, a few patients with wild-type EGFR also respond to EGFR TKIs. This study investigated the factors predicting successful EGFR TKI treatment in lung adenocarcinoma patients with wild-type EGFR. Methods We examined 66 patients diagnosed with lung adenocarcinoma carrying wide-type EGFR who were treated with EGFR TKIs. The EGFR gene copy number was assessed by silver in situ hybridization (SISH). We evaluated the clinical factors and EGFR gene copy numbers that are associated with a favorable clinical response to EGFR TKIs. Results The objective response rate was 12.1%, while the disease control rate was 40.9%. EGFR SISH analysis was feasible in 23 cases. Twelve patients tested EGFR SISH-positive, and 11 were EGFR SISH-negative, with no significant difference in tumor response and survival between EGFR SISH-positive and -negative patients. The overall median progression-free survival (PFS) and overall survival (OS) of 66 patients were 2.1 months and 9.7 months, respectively. Female sex and Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0–1 were independent predictors of PFS. ECOG PS 0–1 and a low tumor burden of extrathoracic metastasis were independent predictors of good OS. Conclusion Factors such as good PS, female sex, and low tumor burden may predict favorable outcomes following EGFR TKI therapy in patients with EGFR wild-type lung adenocarcinoma. However, EGFR gene copy number was not predictive of survival.

Simple Summary Pediatric osteosarcoma is one of the most aggressive cancers, and predictions of metastasis and chemotherapy response have a significant impact on pediatric patient survival. Radiogenomics, as methods of analyzing gene expression or image texture features, have previously been used for the diagnosis of chemotherapy responses and metastasis and can reveal the current state of cancer. In this study, we aimed to generate a predictive model using gene expression and 18F-FDG PET/CT image texture features in pediatric osteosarcoma in relation to metastasis and chemotherapy response. A predictive model using radiogenomics technology that incorporates both imaging features and gene expression can accurately predict metastasis and chemotherapy responses to improve patient outcomes. Abstract Chemotherapy response and metastasis prediction play important roles in the treatment of pediatric osteosarcoma, which is prone to metastasis and has a high mortality rate. This study aimed to estimate the prediction model using gene expression and image texture features. 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) images of 52 pediatric osteosarcoma patients were used to estimate the machine learning algorithm. An appropriate algorithm was selected by estimating the machine learning accuracy. 18F-FDG PET/CT images of 21 patients were selected for prediction model development based on simultaneous KI67 and EZRIN expression. The prediction model for chemotherapy response and metastasis was estimated using area under the curve (AUC) maximum image texture features (AUC_max) and gene expression. The machine learning algorithm with the highest test accuracy in chemotherapy response and metastasis was selected using the random forest algorithm. The chemotherapy response and metastasis test accuracy with image texture features was 0.83 and 0.76, respectively. The highest test accuracy and AUC of chemotherapy response with AUC_max, KI67, and EZRIN were estimated to be 0.85 and 0.89, respectively. The highest test accuracy and AUC of metastasis with AUC_max, KI67, and EZRIN were estimated to be 0.85 and 0.8, respectively. The metastasis prediction accuracy increased by 10% using radiogenomics data.

Background: It is difficult to distinguish parathyroid lesions (PLs) from thyroid lesions using fine needle aspiration cytology (FNAC) because of their proximity and their similar cytomorphological features. Methods: FNAC smears of 46 patients with pathologically proven PLs that were histologically diagnosed as parathyroid adenoma (PA, n = 35), parathyroid hyperplasia (PH, n = 3), atypical parathyroid adenoma (APA, n = 1), and parathyroid carcinoma (PC, n = 7) were retrospectively reviewed and analyzed. Results: Our initial cytological diagnoses indicated correct diagnoses in 31 of 46 PL patients (67%). The 15 erroneous diagnoses were 5 patients with non-specific benign disease (11%), 4 with nodular hyperplasia of the thyroid (9%), 5 with atypical cells (11%), and 1 with a metastatic papillary thyroid carcinoma (2%). Follicular pattern, papillary structures, colloid-like material, and macrophages, which often suggest thyroid lesions, were also present in some PLs. We found that branching capillaries along the papillary structures, stippled nuclear chromatin, and frequent occurrence of naked nuclei were useful for determining a parathyroid origin. Conclusions: It is important to be aware that PLs are frequently mistaken for thyroid lesions based on FNAC. The specific and unique characteristics of PLs identified here may be helpful in diagnosis.

Background To propose a personalized therapeutic approach in osteosarcoma treatment, we assessed whether sequential [18F]FDG PET/CT (PET/CT) could predict the outcome of patients with osteosarcoma of the extremities after one cycle and two cycles of neoadjuvant chemotherapy. Methods A total of 73 patients with AJCC stage II extremity osteosarcoma treated with 2 cycles of neoadjuvant chemotherapy, surgery, and adjuvant chemotherapy were retrospectively analyzed in this study. All patients underwent PET/CT before (PET0), after 1 cycle (PET1), and after the completion of neoadjuvant chemotherapy (PET2), respectively. Maximum standardized uptake value (SUVmax) (corrected for body weight) and the % changes of SUVmax were calculated, and histological responses were evaluated after surgery. Receiver-operating characteristic (ROC) curve analyses and the Cox proportional hazards models were used to analyze whether imaging and clinicopathologic parameters could predict event-free survival (EFS). Results A total of 36 patients (49.3%) exhibited a poor histologic response and 17 patients (23.3%) showed events (metastasis in 15 and local recurrence in 2). SUVmax on PET2 (SUV2), the percentage change of SUVmax between PET0 and PET1 (Δ%SUV01), and between PET0 and PET2 (Δ%SUV02) most accurately predicted events using the ROC curve analysis. SUV2 (relative risk, 8.86; 95% CI, 2.25–34.93), Δ%SUV01 (relative risk, 5.97; 95% CI, 1.47–24.25), and Δ%SUV02 (relative risk, 6.00; 95% CI, 1.16–30.91) were independent predicting factors for EFS with multivariate analysis. Patients with SUV2 over 5.9 or Δ%SUV01 over − 39.8% or Δ%SUV02 over − 54.1% showed worse EFS rates than others (p < 0.05). Conclusions PET evaluation after 1 cycle of presurgical chemotherapy can predict the clinical outcome of extremity osteosarcoma. [18F]FDG PET, which shows a potential role in the early evaluation of the modification of timing of local control, can be a useful modality for early response monitoring of neoadjuvant chemotherapy.

Oncogenic EGFR is essential for the development and growth of non–small cell lung cancer (NSCLC), but the precise roles of EGFR in lung cancer metabolism remain unclear. Here, we show that EGFR mutation-mediated enhancement of glycolysis is critical for EGFR stability. EGFR knockdown significantly decreased levels of glycolytic pathway intermediates via transcriptional regulation of glycolytic genes. EGFR mutation-enhanced glycolysis was required for fueling the tricarboxylic acid cycle, a critical component of EGFR stability. Nonsustained ATP production enhanced reactive oxygen species accumulation and subsequent JNK-mediated activation of autophagy, which in turn induced EGFR degradation. Our data show that EGFR-mutant NSCLCs require EGFR mutation-enhanced glycolysis to maintain EGFR stability. This pathway may serve as an attractive therapeutic target for EGFR-mutant NSCLCs. Significance: Enhanced glycolysis by EGFR mutation is required for maintaining EGFR levels via inhibition of JNK-induced autophagy. This provides a promising rationale for use of JNK activators in patients with EGFR-mutated NSCLC. Cancer Res; 78(16); 4482–96. ©2018 AACR.

BACKGROUND Trophoblast antigen 2 (TROP2) is a human trophoblast cell-surface glycoprotein that is overexpressed in several types of epithelial cancers, and is suggested to be associated with an unfavorable prognosis. BRAF mutations are the most common genetic alteration in papillary thyroid carcinoma (PTC). We evaluated the correlation between TROP2 expression and BRAF mutation in PTC. METHODS First, we carried out pyrosequencing for BRAF mutations and immunohistochemistry for TROP2 expression with a tissue microarray consisting of 52 PTC cases. Membranous staining in at least 5% of tumor cells was designated as positive staining and we analyzed the relationship between TROP2 expression and diverse clinicopathological factors, including BRAF mutation. Second, we tested TROP2 mRNA expression in three thyroid cancer cell lines with BRAF mutations (BCPAP, SNU790, and 8505C) and a normal thyroid cell line. Additionally, we checked TROP2 protein levels in a normal thyroid cell line after introduction of the BRAF V600E mutation. RESULTS In this study, 21 of 26 cases with BRAF mutation showed TROP2 immunoreactivity, whereas all 26 cases without BRAF mutation showed no immunoreactivity for TROP2 with a statistically significant difference (p

Background It is difficult to correctly diagnose follicular neoplasms (FNs) on fine-needle aspiration cytology (FNAC) because it shares many cytological features with other mimicking lesions. The aim of this study was to identify the cytological features that differentiate FNs from mimicking lesions. Methods We included the cytological slides from 116 cases of thyroid FN diagnosed on FNAC, and included their subsequent histological diagnoses. We evaluated the cytological architectural pattern and nuclear features of the lesions according to their histological groups. Results The final histological diagnoses of the 116 cases varied, and included 51 FNs (44%), 47 papillary thyroid carcinomas (40%) including follicular variant, and seventeen cellular nodular hyperplasias (15%). Regardless of the final histological diagnosis, microfollicular pattern was observed in most cases. On the other hand, trabecular pattern was identified in 34% of FNs, but not in any other lesions. Additionally, elongated nuclei and ground glass chromatin were found in only some papillary thyroid carcinomas. Conclusions This study shows that the trabecular pattern is a representative cytological feature of FNs that can be used to distinguish FNs from mimicking lesions. In addition, nuclear shape and chromatin pattern can be used to further confirm the diagnosis of FNs from mimicking lesions through FNAC.

Background Trophoblast antigen 2 (TROP2) is a human trophoblast cell-surface glycoprotein that is overexpressed in several types of epithelial cancers, and is suggested to be associated with an unfavorable prognosis. BRAF mutations are the most common genetic alteration in papillary thyroid carcinoma (PTC). We evaluated the correlation between TROP2 expression and BRAF mutation in PTC. Methods First, we carried out pyrosequencing for BRAF mutations and immunohistochemistry for TROP2 expression with a tissue microarray consisting of 52 PTC cases. Membranous staining in at least 5% of tumor cells was designated as positive staining and we analyzed the relationship between TROP2 expression and diverse clinicopathological factors, including BRAF mutation. Second, we tested TROP2 mRNA expression in three thyroid cancer cell lines with BRAF mutations (BCPAP, SNU790, and 8505C) and a normal thyroid cell line. Additionally, we checked TROP2 protein levels in a normal thyroid cell line after introduction of the BRAF V600E mutation. Results In this study, 21 of 26 cases with BRAF mutation showed TROP2 immunoreactivity, whereas all 26 cases without BRAF mutation showed no immunoreactivity for TROP2 with a statistically significant difference (p

Tumor implantation of lung cancer at the wire localization site has not been reported previously while there have been several reported cases of chest wall implantation after percutaneous core needle biopsy and chest tube insertion for malignant pleural effusion. We report the case of a 64-year-old-man with lung cancer (squamous cell carcinoma). The patient had lung cancer implantation in the chest wall 8 months after computed tomography-guided wire localization and subsequent anterior segmentectomy of right upper lobe with mediastinal lymph node dissection.

Osteosarcoma (OS) is a malignant tumor of the bone derived from primitive transformed cells of the mesenchymal origin. Local low-linear energy transfer (LET) radiotherapy has limited benefits on OS owing to its radioresistance. Thus, this study aimed to investigate the effects of high-LET radiation on human OS. Therefore, the human OS cell lines, U2O2 and KHOS/NP, were examined invitro, or an orthotopic mouse xenograft model was studied invivo after treatment with low-LET (gamma-ray) and high-LET (neutron) radiation. Notably, OS cells were significantly more sensitive to high-LET radiation invitro and in the orthotopic xenograft tumor model. Specifically, neutron radiation treatment increased the relative percentage of apoptotic sub-G1 phase cells via caspase-3/9 activation; increased intracellular reactive oxygen species, autophagy, and DNA damage; and decreased invasion and migration. Similarly, the mean size of gamma-irradiated (8Gy) orthotopic KHOS/NP OS was 195mm3 at 6weeks after gamma-irradiation (8Gy), but it was only 150mm3 in mice treated with high-LET neutron radiotherapy. Significantly, our results provide a rationale for the use of high-LET radiotherapy to treat patients with OS.

BACKGROUND: The aim of this study was to investigate the association between epidermal growth factor receptor (EGFR) mutation and thyroid cancer in female patients with nonsmall-cell lung cancer (NSCLC). METHODS: In a retrospective study, we examined 835 female patients who were diagnosed with NSCLC and underwent an EGFR mutation test between June 2003 and August 2013. The associations of EGFR mutation with thyroid cancer and a family history of thyroid cancer were evaluated using logistic regression models. RESULTS: EGFR mutation was found in 378 of 835 patients. In addition to adenocarcinoma (P < 0.001), EGFR mutations were positively associated with a personal history of thyroid cancer (5.8% versus 2.6%; P = 0.020), while showing a trend toward inverse association with a personal history of nonthyroid cancer (5.8% vs. 9.0%; P = 0.086). Likewise, the incidence of EGFR mutations was associated with a family history of thyroid cancer (2.9% vs. 0.9%; P = 0.028), while showing a trend toward inverse association with a family history of nonthyroid cancer (27.8% vs. 33.7%; P = 0.066). Multivariate logistic regression showed that the incidence of EGFR mutations was different in women with thyroid or nonthyroid cancer (P = 0.035) and in women with a family history of thyroid or nonthyroid cancer (P = 0.023). CONCLUSIONS: Our data suggest that thyroid cancer and a family history of thyroid cancer are associated with EGFR-mutated NSCLC in female patients. The differences in the incidence of thyroid cancer and a family history of thyroid cancer by EGFR mutational status provide new insight into pathogenesis of this genetic change.

Introduction: Micro-computed tomography with nanoparticle contrast agents may be a suitable tool for monitoring the time course of the development and progression of tumors. Here, we suggest a practical and convenient experimental method for generating and longitudinally imaging murine liver cancer models. Methods: Liver cancer was induced in 6 experimental mice by injecting clustered regularly interspaced short palindromic repeats/clustered regularly interspaced short palindromic repeats-associated protein 9 plasmids causing mutations in genes expressed by hepatocytes. Nanoparticle agents are captured by Kupffer cells and detected by micro-computed tomography, thereby enabling longitudinal imaging. A total of 9 mice were used for the experiment. Six mice were injected with both plasmids and contrast, 2 injected with contrast alone, and one not injected with either agent. Micro-computed tomography images were acquired every 2- up to 14-weeks after cancer induction. Results: Liver cancer was first detected by micro-computed tomography at 8 weeks. The mean value of hepatic parenchymal attenuation remained almost unchanged over time, although the standard deviation of attenuation, reflecting heterogeneous contrast enhancement of the hepatic parenchyma, increased slowly over time in all mice. Histopathologically, heterogeneous distribution and aggregation of Kupffer cells was more prominent in the experimental group than in the control group. Heterogeneous enhancement of hepatic parenchyma, which could cause image quality deterioration and image misinterpretation, was observed and could be due to variation in Kupffer cells distribution. Conclusion: Micro-computed tomography with nanoparticle contrast is useful in evaluating the induction and characteristics of liver cancer, determining appropriate size of liver cancer for testing, and confirming therapeutic response.

Aims The Notch signaling pathway is involved in normal development as well as tumorigenesis. However, it is unclear whether Notch activation is related to diverse clinicopathological factors in papillary thyroid carcinoma (PTC). Methods and Results We examined the relationship between clinicopathological factors and the expression of activated Notch1 and Hey1, which are indicators of Notch signaling pathway activation, in 109 PTC cases. Activated Notch1 showed strong, moderate, and weak expression in 23, 48, and 36 cases, respectively. Its expression was significantly related to histopathological variants (p=0.007), lymph node metastasis (p = 0.016), BRAF mutation (p = 0.036) and extent of surgery (p=0.014). Hey1 immunostaining could be divided into two groups: positive and negative, with 26 and 83 cases, respectively. Its expression was significantly related to histopathological variants (p=0.026), extrathyroidal extension (p = .005), BRAF mutation (p = .048), and recurrence or soft tissue metastasis (p = .000). Multivariate analysis revealed that tumor size (greater than 1 cm), Hey1 immunoreactivity, and the presence of lymph node metastasis were significantly associated with recurrence or soft tissue metastasis (OR = 7.38, 4.28, and 12.00, respectively). Conclusions Thus, we found that activation of Notch signaling was significantly correlated with clinicopathological parameters. Therefore, Notch signaling could be a useful prognostic marker in patients with PTC. This article is protected by copyright. All rights reserved.

// Eun Ho Kim 1 , Mi-Sook Kim 2, * , Kyung-Hee Lee 3 , Jae-Soo Koh 4 , Won-Gyun Jung 1 , Chang-Bae Kong 3, * 1 Division of Heavy Ion Clinical Research, Korea Institute of Radiological and Medical Sciences, Seoul 139-706, South Korea 2 Department of Radiation Oncology, Korea Institute of Radiological and Medical Sciences, Seoul 139-706, South Korea 3 Department of Orthopaedic Surgery, Korea Institute of Radiological and Medical Sciences, Seoul 139-706, South Korea 4 Department of Pathology, Korea Institute of Radiological and Medical Sciences, Seoul 139-706, South Korea * These authors have contributed equally to this work Correspondence to: Mi-Sook Kim, email: mskim@kirams.re.kr Chang-Bae Kong, email: cbkongmd@gmail.com Keywords: zoledronic acid, radiosensitivity, osteosarcoma cells, apoptosis, DNA damage Received: December 30, 2015 Accepted: September 12, 2016 Published: September 27, 2016 ABSTRACT To overcome radioresistance in the treatment of osteosarcoma, a primary malignant tumor of the bone, radiotherapy is generally combined with radiosensitizers. The purpose of this study was to investigate a third-generation bisphosphonate, zoledronic acid (ZOL), as a radiosensitizer for osteosarcoma. We found that exposure of KHOS/NP osteosarcoma cells to 20 μM ZOL decreased the γ-radiation dose needed to kill 90% of cells. This radiosensitizing effect of ZOL was mediated through decreased mitochondrial membrane potential, increased levels of reactive oxygen species, increased DNA damage (as assessed by counting γ-H2AX foci), decreased abundance of proteins involved in DNA repair pathways (ATR, Rad52, and DNA-PKcs), and decreased phosphorylation of PI3K-Akt and MAPK pathway proteins (Raf1, MEK1/2, ERK1/2, and Akt), as compared to γ-irradiation alone. Cells treated with ZOL plus γ-irradiation showed impaired cell migration and invasion and reduced expression of epithelial-mesenchymal transition markers (vimentin, MMP9, and Slug). In Balb/c nude mice, the mean size of orthotopic osteosarcoma tumors 2 weeks post-inoculation was 195 mm 3 following γ-irradiation (8 Gy), while it was 150 mm 3 after γ-irradiation plus ZOL treatment (0.1 mg/kg twice weekly for 2 weeks). These results provide a rationale for combining ZOL with radiotherapy to treat osteosarcoma.

PURPOSE The Notch signaling pathway is widely expressed in normal, reactive, and neoplastic tissues; however, its role in thyroid tissues has not been fully elucidated. Therefore, this study was conducted to characterize the expression of the Notch signaling pathway in papillary thyroid cancer (PTC) cells and anaplastic thyroid cancer (ATC) cells. MATERIALS AND METHODS Expression of activated Notch1 in ATC and PTC paraffin-embedded tissues was determined by immunohistochemistry. The small interfering RNA techniquewas employed to knock down Notch1 expression in ATC and PTC cell lines. RESULTS The expression of activated Notch1 was higher in ATC cases than in PTC cases. Inhibition of Notch1 significantly reduced proliferation and migration of ATC cells, but not PTC cells. In addition, inhibition of Notch1 in ATC cells significantly reduced the expression of key markers of epithelial-mesenchymal transition and cancer stem cells. Conversely, changes in the expression of these proteins were not observed in PTC cells. CONCLUSION The results of this study suggest that Notch1 expression plays different roles in tumor progression in ATC and PTC cells. We also found that Notch1 expression was significantly related to the highly invasive or proliferative activity of ATC cells.

We compared the usefulness of 99mTc-methyl diphosphonate (99mTc-MDP) bone scintigraphy and 18F-fluorodeoxyglucose (FDG) for positron emission tomography/computed tomography (PET/CT) in predicting histologic response in patients with osteosarcoma receiving neoadjuvant chemotherapy (NAC). We retrospectively reviewed 62 patients with high-grade osteosarcoma who had received 2 cycles of NAC and surgery. All patients underwent 99mTc-MDP bone scintigraphy and 18F-FDG PET/CT before and after NAC. 99mTc-MDP uptake in the primary tumor was measured quantitatively as the maximum tumor-to-nontumor ratio (T/NTmax) and 18F-FDG uptake was measured as the maximum standardized uptake value (SUVmax), before and after NAC. The percent changes of T/NTmax (percent changes of the maximum tumor-to-nontumor ratio [Δ%T/NTmax]) and SUVmax (percent changes of the maximum standardized uptake value [Δ%SUVmax]) after NAC were calculated and the correlations between these parameters were evaluated. After surgery, the effects of NAC were graded histopathologically (good vs poor) and the optimum cut-off values of Δ%T/NTmax and Δ%SUVmax for predicting histologic response were assessed using the receiver operating characteristic (ROC) curve analysis. Δ%T/NTmax and Δ%SUVmax were positively correlated with each other (r = 0.494, P

Background Epidermal growth factor receptor (EGFR) mutations in non-small cell lung cancers have emerged as key predictive biomarkers in EGFR tyrosine kinase inhibitor (TKI) treatment. However, a few patients with wild-type EGFR also respond to EGFR TKIs. This study investigated the factors predicting successful EGFR TKI treatment in lung adenocarcinoma patients with wild-type EGFR. Methods We examined 66 patients diagnosed with lung adenocarcinoma carrying wide-type EGFR who were treated with EGFR TKIs. The EGFR gene copy number was assessed by silver in situ hybridization (SISH). We evaluated the clinical factors and EGFR gene copy numbers that are associated with a favorable clinical response to EGFR TKIs. Results The objective response rate was 12.1%, while the disease control rate was 40.9%. EGFR SISH analysis was feasible in 23 cases. Twelve patients tested EGFR SISH-positive, and 11 were EGFR SISH-negative, with no significant difference in tumor response and survival between EGFR SISH-positive and -negative patients. The overall median progression-free survival (PFS) and overall survival (OS) of 66 patients were 2.1 months and 9.7 months, respectively. Female sex and Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0–1 were independent predictors of PFS. ECOG PS 0–1 and a low tumor burden of extrathoracic metastasis were independent predictors of good OS. Conclusion Factors such as good PS, female sex, and low tumor burden may predict favorable outcomes following EGFR TKI therapy in patients with EGFR wild-type lung adenocarcinoma. However, EGFR gene copy number was not predictive of survival.

We evaluated the ability of dual-phase (18)F-FDG PET/CT to predict the histological response after neoadjuvant chemotherapy (NAC) in osteosarcoma.Thirty-one patients with osteosarcoma treated with NAC and surgery were prospectively enrolled. After injection of (18)F-FDG, both early (~60 min) and delayed (~150 min) PET were acquired before and after the completion of NAC. SUVmax, early/delayed SUVmax change (RImax), and early/delayed SUVmean change (RImean) of tumour were measured before (SUV1, RImax1, and RImean1) and after NAC (SUV2, RImax2, and RImean2). Then, we calculated the percentage changes between SUV1 and SUV2 (%SUV).Twelve patients (39%) exhibited good histological response after NAC. SUVmax, RImax, and RImean significantly decreased after NAC. Before NAC, only RImean1 predicted good histological response with the optimal criterion of10%, sensitivity of 92%, specificity of 57%, and accuracy of 71%. After NAC, %SUV, SUV2, and RImax2 predicted histological response. By using combined criterion of %SUV and RImax2 or SUV2 and RImean1 or SUV2 and RImax2, accuracies were 81%, 77%, and 77%, respectively.The histological response after NAC could be predicted by using RImean1 before the initiation of NAC in osteosarcoma. The combined use of SUV and RI values may provide a better prediction.• Pretreatment dual-phase FDG-PET was useful to predict histological response in osteosarcoma. • A combination of early and delayed PET may increase the predictive value. • Early/delayed SUV change of tumours significantly decreased after neoadjuvant chemotherapy.

Introduction Low-grade osteosarcoma encompasses parosteal osteosarcoma (POS) and low-grade central osteosarcoma (LCOS), with LCOS more rare than POS. LCOS is also more likely to be misdiagnosed and inappropriately treated with an intralesional procedure, due to its misleading radiological features and the overlap of its pathological characteristics with those of benign bone tumors. Therefore, as a diagnostic adjunct for LCOS, immunohistochemical assay with murine double-minute type 2 (MDM2) and cyclin-dependent kinase 4 (CDK4) have been tried with controversial results. We investigated (1) the clinical course and surgical outcome of LCOS, and (2) the diagnostic role of immune-histochemical markers (CDK4, MDM2) and their correlation with clinico-radiologic findings. Materials and methods We retrospectively reviewed 16 LCOS patients with regard to age, gender, tumor location, plain radiographic pattern, tumor volume, extraosseous extension, initial diagnosis, initial treatment, definitive diagnosis, definitive treatment, surgical margins, histochemical markers, and oncological outcome. Results Final survival status was continuous disease-free in 14, alive with disease in 1, and remaining 1 patient died of other cancer. Except for 1 patient who had not undergone excision of their primary lesion, no patients developed a local recurrence. Eight tumors (50 %) showed diffuse immunostaining for CDK4. Three of 8 tumors labeled for CDK4 were also positive for MDM2. Six (75 %) of 8 CDK4-positive tumors displayed lytic lesions on a plain radiograph; in contrast, 2 (33 %) of 6 tumors showing a sclerotic pattern on a plain radiograph were positive for CDK4. Conclusions The diagnosis of LCOS is challenging; however, if it is properly diagnosed, there is a high chance of a cure with wide excision alone. Positive immunostaining for CDK4 or MDM2 may be used as a diagnostic adjunct,although negative immunostaining cannot rule out this tumor. The clinical, radiological, and typical pathological findings are vital in raising the suspicion of this rare tumor.

BACKGROUND Although histological diagnosis of pilomatricoma is not difficult because of its unique histological features, cytological diagnosis through fine-needle aspiration cytology (FNAC) is often problematic due to misdiagnoses as malignancy. METHODS We reviewed the cytological features of 14 cases of histologically-proven pilomatricoma from Korea Cancer Center Hospital, with a discussion on the diagnostic pitfalls of FNAC. RESULTS Among 14 cases of pilomatricoma, 10 (71.4%) were correctly diagnosed through FNAC, and two (14.3%) were misdiagnosed as carcinoma. Cytologically, all cases had easily recognizable clusters of basaloid cells and foreign body-type multinucleated cells. Although ghost cells were also found in all cases, some were inconspicuous and hardly recognizable due to their small numbers. CONCLUSIONS An accurate diagnosis of pilomatricoma in FNAC is feasible with consideration of clinical information and close examination of ghost cells.

Osteosarcoma (OS) is a malignant tumor of the bone derived from primitive transformed cells of the mesenchymal origin. Local low-linear energy transfer (LET) radiotherapy has limited benefits on OS owing to its radioresistance. Thus, this study aimed to investigate the effects of high-LET radiation on human OS. Therefore, the human OS cell lines, U2O2 and KHOS/NP, were examined in vitro, or an orthotopic mouse xenograft model was studied in vivo after treatment with low-LET (gamma-ray) and high-LET (neutron) radiation. Notably, OS cells were significantly more sensitive to high-LET radiation in vitro and in the orthotopic xenograft tumor model. Specifically, neutron radiation treatment increased the relative percentage of apoptotic sub-G1 phase cells via caspase-3/9 activation; increased intracellular reactive oxygen species, autophagy, and DNA damage; and decreased invasion and migration. Similarly, the mean size of gamma-irradiated (8 Gy) orthotopic KHOS/NP OS was 195 mm3 at 6 weeks after gamma-irradiation (8 Gy), but it was only 150 mm3 in mice treated with high-LET neutron radiotherapy. Significantly, our results provide a rationale for the use of high-LET radiotherapy to treat patients with OS.

This research aims to investigate the potential of (18)F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET) to predict pathologic response after neoadjuvant chemotherapy (NAC) and overall survival (OS) of patients with synovial sarcoma in Korea.Twenty patients with synovial sarcoma from January 2001 to December 2011 were reviewed retrospectively. All patients underwent pre-treatment FDG PET and tumor removal. Patients were classified with the maximum SUV (SUVmax), metabolic tumor volume (MTV), total lesion glycolysis (TLG), age, sex, histologic subtype, tumor size, NAC, resection margin, and metastasis at diagnosis. Pathologic response was assessed using the French Federation of Cancer Centers system. Statistical analyses were analyzed using the Kaplan-Meier method, log-rank test, Cox proportional hazards regression model, and Mann-Whitney test.Nine patients (45 %) showed pathologic response, and ten patients survived. Higher SUVmax, higher MTV, higher TLG, monophasic epithelial type, and metastasis at diagnosis were significantly related to poorer OS (p = 0.047, 0.016, 0.016, 0.045, and 0.018, respectively). By multivariate analysis, metastasis at diagnosis was significantly related to poorer OS (p = 0.012/HR = 5.9, 95 % CI 1.47 to 24.1). The SUVmax, MTV, and TLG of the non-responder group were significantly higher than those of the responder group (p = 0.020, 0.020, and 0.020, respectively). There was no significant difference in size between the two groups (p = 0.062).A higher SUVmax on the pre-treatment scan, monophasic epithelial type, and metastasis at diagnosis were significantly associated with a poorer OS, and pathologic responders showed a higher SUVmax before NAC. The PET parameters can be used to predict OS and pathologic response in patients with synovial sarcomas before NAC.

We evaluated the potential of sequential fluorine-18 fluorodeoxyglucose (18 F-FDG) positron emission tomography (PET)/computed tomography (CT) and MRI (PET/MRI) after one cycle of neoadjuvant chemotherapy to predict a poor histologic response in osteosarcoma. A prospective study was conducted on 30 patients with osteosarcoma treated with two cycles of neoadjuvant chemotherapy and surgery. All patients underwent PET/MRI before, after one cycle, and after the completion of neoadjuvant chemotherapy, respectively. Imaging parameters [maximum standardized uptake value (SUVmax), metabolic tumor volume (MTV), total lesion glycolysis (TLG), and tumor volume based on magnetic resonance (MR) images (MRV)] and their % changes were calculated on each PET/MRI data set, and histological responses were evaluated on the postsurgical specimen. A total of 17 patients (57 %) exhibited a poor histologic response after two cycles of chemotherapy. Unlike the little volumetric change in MRI, PET parameters significantly decreased after one and two cycles of chemotherapy, respectively. After one cycle of chemotherapy, SUVmax, MTV, and TLG predicted the poor responders. Among these parameters, either MTV ≥ 47 mL or TLG ≥ 190 g after one cycle of chemotherapy was significantly associated with a poor histologic response on multivariate logistic regression analysis (OR 8.98, p = 0.039). The sensitivity, specificity, and accuracy of these parameters were 71 %, 85 % and 77 %; and 71 %, 85 % and 77 %, respectively. The histologic response to neoadjuvant chemotherapy in osteosarcoma can be predicted accurately by FDG PET after one course of chemotherapy. Among PET parameters, MTV and TLG were independent predictors of the histologic response.

Background: Epidermal growth factor receptor (EGFR ) mutations in non-small cell lung cancers have emerged as key predictive biomarkers in EGFR tyrosine kinase inhibitor (TKI) treatment. However, a few patients with wild-type EGFR also respond to EGFR TKIs. This study investigated the factors predicting successful EGFR TKI treatment in lung adenocarcinoma patients with wild-type EGFR . Methods: We examined 66 patients diagnosed with lung adenocarcinoma carrying wide-type EGFR who were treated with EGFR TKIs. The EGFR gene copy number was assessed by silver in situ hybridization (SISH). We evaluated the clinical factors and EGFR gene copy numbers that are associated with a favorable clinical response to EGFR TKIs. Results: The objective response rate was 12.1%, while the disease control rate was 40.9%. EGFR SISH analysis was feasible in 23 cases. Twelve patients tested EGFR SISH-positive, and 11 were EGFR SISH-negative, with no significant difference in tumor response and survival between EGFR SISH-positive and -negative patients. The overall median progression-free survival (PFS) and overall survival (OS) of 66 patients were 2.1 months and 9.7 months, respectively. Female sex and Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0-1 were independent predictors of PFS. ECOG PS 0-1 and a low tumor burden of extrathoracic metastasis were independent predictors of good OS. Conclusion: Factors such as good PS, female sex, and low tumor burden may predict favorable outcomes following EGFR TKI therapy in patients with EGFR wild-type lung adenocarcinoma. However, EGFR gene copy number was not predictive of survival.

We evaluated the ability of metabolic and volumetric parameters measured by pretreatment 18F-FDG PET/CT to predict the survival of patients with osteosarcoma of the extremities. Methods: The records of 83 patients with American Joint Committee on Cancer stage II extremity osteosarcoma treated with surgery and chemotherapy were retrospectively reviewed. Imaging parameters (maximum standardized uptake value, metabolic tumor volume [MTV], total lesion glycolysis, and tumor volume based on MR images) were measured before treatment, and histologic responses to neoadjuvant chemotherapy were assessed by examination of postsurgical specimens. Receiver-operating-characteristic curve analyses and the Cox proportional hazards model were used to analyze whether imaging and clinicopathologic parameters could predict metastasis-free survival. Results: Of the imaging parameters, MTV at the fixed standardized uptake value threshold of 2.0 (MTV(2.0)) most accurately predicted metastasis by receiver-operating-characteristic curve analysis (area under the curve = 0.679, P = 0.011). By multivariate analysis, MTV(2.0) > 105 mL (relative risk, 3.93; 95% confidence interval, 1.55–9.92) and poor response to neoadjuvant chemotherapy (relative risk, 4.83; 95% confidence interval, 1.64–14.21) independently shortened metastasis-free survival (P = 0.004 for both parameters). The stratification of patients by the combined criteria of MTV(2.0) and histologic response predicted outcome in more detail. Conclusion: MTV is an independent predictor of metastasis in patients with osteosarcoma of the extremities. The combination of MTV and histologic response predicts survival more accurately than the chemotherapeutic response alone.

Purpose This study evaluated the usefulness of the maximum standardized uptake value (SUVmax) as a measure of histologic response to neoadjuvant chemotherapy in patients with extremity osteosarcoma. The correlation between [18 F]FDG PET SUVmax values and histologic response to preoperative chemotherapy was also assessed prospectively using PET/MRI.

OBJECTIVE Chordoma is a rare bone tumor of the axial skeleton believed to originate from the remnants of the embryonic notochord. The available tumor cells are characteristically physaliferous and express brachyury, a transcription factor critical for mesoderm specification. Although chordomas are histologically not malignant, treatments remain challenging because they are resistant to radiation therapy and because wide resection is impossible in most cases. Therefore, a better understanding of the biology of chordomas using established cell lines may lead to the advancement of effective treatment strategies. The authors undertook a study to obtain this insight. METHODS Chordoma cells were isolated from the tissue of a patient with dedifferentiated-type chordoma (DTC) that had recurred. Cells were cultured with DMEM/F12 containing 10% fetal bovine serum and antibiotics (penicillin and streptomycin). Cell proliferation rate was measured by MTS assay. Cell-cycle distribution and cell surface expression of proteins were analyzed by fluorescence-activated cell sorting (FACS) analysis. Expression of proteins was analyzed by Western blot and immunocytochemistry. Radiation resistance was measured by clonogenic survival assay. Tumor formation was examined by injection of chordoma cells at hindlimb of nude mice. RESULTS The putative (DTC) cells were polygonal and did not have the conventional physaliferous characteristic seen in the U-CH1 cell line. The DTC cells exhibited similar growth rate and cell-cycle distribution, but they exhibited higher clonogenic activity in soft agar than U-CH1 cells. The DTC cells expressed high levels of platelet-derived growth factor receptor–β and a low level of brachyury and cytokeratins; they showed higher expression of stemness-related and epithelial to mesenchymal transition–related proteins than the U-CH1 cells. Intriguingly, FACS analysis revealed that DTC cells exhibited marginal surface expression of CD24 and CD44 and high surface expression of CXCR4 in comparison to U-CH1 cells. In addition, blockade of CXCR4 with its antagonist AMD3100 effectively suppressed the growth of both cell lines. The DTC cells were more resistant to paclitaxel, cisplatin, etoposide, and ionizing radiation than the U-CH1 cells. Injection of DTC cells into the hindlimb region of nude mice resulted in the efficient formation of tumors, and the histology of xenograft tumors was very similar to that of the original patient tumor. CONCLUSIONS The use of the established DTC cells along with preestablished cell lines of chordoma may help bring about greater understanding of the mechanisms underlying the chordoma that will lead to therapeutic strategies targeting chordomas.

Objective: This study explored the potential association between epidermal growth.factor receptor. (EGFR) mutation status and brain metastasis in patients with nonadenocarcinoma nonsmall cell lung cancer. (NSCLC). Patients and Methods: We analyzed clinical data from 286 patients with nonadenocarcinoma NSCLC, who were tested for EGFR mutations and underwent brain magnetic resonance imaging at diagnosis. We examined the relationship between EGFR mutation and brain metastasis at initial presentation. Results: Of the 286 patients, 20 patients (7.0%) had EGFR mutations. EGFR mutations were more frequent in younger patients (11.1% in patients =64 years vs. 3.3% in patients >64 years: P = 0.01), females (21.4% vs. 3.5% in males: P

PURPOSE: Features of epidermal growth factor receptor (EGFR) expression in osteosarcoma and in vitro efficacies of EGFR inhibitors against osteosarcoma cells were evaluated. MATERIALS AND METHODS: Thirty biopsy samples of osteosarcoma patients were retrospectively analyzed for EGFR protein expression by immunohistochemistry. Relationships between EGFR expression and clinicopathologic characteristics and treatment outcomes were evaluated. Four osteosarcoma cell lines were analyzed for EGFR and p-EGFR expression by western blotting. Efficacies of gefitinib and BIBW2992 on osteosarcoma cells were evaluated using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Tyrosine kinase domains in exons 18 to 21 were sequenced and gene expression analyses of EGFR and PTEN were performed in four osteosarcoma cell lines. RESULTS: EGFR protein was expressed in 27 (90%) samples (6 low, 12 intermediate, 9 high) and in three cell lines. Intermediate or high staining for EGFR was related to a tumor volume

Synovial sarcoma arises in the para-articular tissues, and it can also occur in various unexpected sites. We report a rare case of primary monophasic synovial sarcoma (MSS) arising in the mesentery. A 59-year-old man presented with a palpable abdominal mass. On microscopic examination, the entire tumor comprised a dense proliferation of the spindle cells without epithelial components. The tumor cells were positive for transducin-like enhancer of split 1, bcl-2, epithelial membrane antigen and CD99 but negative for CD34, CD117, alpha-smooth muscle actin, cytokeratin, and calretinin on immunohistochemistry. The reverse transcriptase-polymerase chain reaction revealed a single 151-bp fragment representing the SYT-SSX2 fusion transcript. Because mesenteric MSS is extremely rare and many cases display histologic findings that overlap with those of more frequently involved tumors such as hemangiopericytoma and gastrointestinal stromal tumor, there is a chance of making an incorrect diagnosis that can result in an inappropriate treatment.

Purpose: We did this retrospective study to explore the association between epidermal growth factor receptor (EGFR) mutation and clinical features in postoperative recurrent female non-small-cell lung cancer (NSCLC). Materials and Methods: We reviewed clinical data on 86 female patients who had postoperative recurrent disease between December 1992 and July 2007. The start of tyrosine kinase inhibitor therapy was treated as a censoring event. Corresponding surgical specimens of primary tumors were used to test for EGFR mutations. Results: Thirty patients presented with local recurrence and distant recurrence was identified in 56. Thirty-four of the 86 patients (40%) harbored EGFR mutations. Patients with distant recurrence were more likely to have EGFR mutations than patients with local recurrence (48% versus 23%; P = 0.024). On multivariate analysis, distant recurrence was associated with a high frequency of EGFR mutations (OR, 3.3; P = 0.028). Survival analysis showed poor survival of patients with mutated EGFR (HR, 2.3; P = 0.017) or with non-adenocarcinoma histology (HR, 3.3; P = 0.001). Conclusion: The association between recurrence pattern and EGFR mutation status was suggested in recurrent female NSCLC patients. In addition, our data indicate unfavorable disease process of EGFR mutated tumors. Further studies need to be conducted to validate these findings.

Objective: To evaluate the cytological characteristics of each type of thymoma and introduce an algorithm to classify thymoma using fine needle aspiration biopsy (FNAB). Study Design: We retrospectively reviewed the cytological characteristics of 15 cases of thymoma with three thymic carcinoma (1 type A thymoma, 6 type AB thymomas and 8 type B thymomas), which were confirmed by histology. Three major and one minor cytomorphologic parameter were adopted for classification: (1) number of lymphocytes in the smear background; (2) nuclear characteristics of thymic cells; (3) lymphocytes and crush artifacts in thymic cell clusters, and (4) nuclear arrangement of thymic cells. Results: An abundant lymphocytic smear background indicated type B thymomas in 87.5% of cases, contrary to the few lymphocytes in the remaining thymic tumors excluding type B thymomas (90%). Thymic cells contained no vesicular nuclei and inconspicuous nucleoli in 85.7% of type A thymoma and type AB thymoma cases. Type AB thymomas and type B thymomas showed more prominent crush artifacts in cell clusters than type A thymoma and thymic carcinoma. Thymic cells of type B thymomas and thymic carcinoma were arranged without whirling architecture in clusters. The proposed algorithm demonstrated a predictive rate of 88.8% for thymoma classification. Conclusions: The stepwise classification of thymoma with FNAB may be useful in patients for whom an invasive diagnosis approach is not feasible.

The role of human papillomavirus (HPV) in the development of lung and esophageal cancer remains inconclusive, which is in contrast to the established role HPV plays in the development of uterine cervical cancer. One of the reasons for this is the difference among reported HPV infection rates in these cancers. An analysis of 485 lung and esophageal cancers (176 lung squamous cell carcinoma, 128 lung adenocarcinoma, 181 esophageal carcinoma) in eight institutions in Asia (Tokyo, Kochi, Kagoshima, and Okinawa, Japan; Seoul and Daegu, Korea; Changhua, Republic of China (Taiwan); Singapore, Singapore) was carried out in order to clarify infection rates with HPV. Samples were examined in one laboratory of the Department of Pathology, the University of Tokyo, Japan in order to avoid inter-laboratory variation using a combination of polymerase chain reaction and in situ hybridization (ISH). HPV was found in 6.3%, 7%, and 9.4% of patients with lung squamous cell carcinoma, lung adenocarcinoma, and esophageal cancer, respectively. Among the geographic areas surveyed, Kagoshima exhibited a significantly higher prevalence of HPV infection in cases of esophageal carcinoma (24.1%). There was no geographical difference in the infection rates of HPV in lung carcinomas. Subtype-specific ISH was also performed, which identified the high-risk HPV types 16/18 in the majority (75.7%) of the patients with lung and esophageal cancer positive for HPV.

Intra-uterine growth retardation has been linked to the development of type 2 diabetes in later life. Mitochondrial changes have beensuggested as a link between fetal malnutrition and adult insulin resistance. Taurine has been implicated in this process. We investigatedwhether protein malnutrition in early life alters mitochondria of the pancreatic islets in adulthood, and whether taurine supplementationrestores these changes. Male offspring of rats fed a control diet, a low-protein diet or a low-protein diet supplemented with taurine duringpregnancy and lactation were weaned onto the control diet. In each group, at 20 weeks of age, intravenous glucose tolerance tests, eugly-caemic–hyperinsulinaemic clamp studies, morphometric analysis of the pancreatic islets and ultra-structural analysis of the mitochondria ofthe b-cells were performed. The expressions of cytochrome c oxidase (COX) I and mitochondrial respiratory chain complex II were alsomeasured. Fetal protein-malnourished rats showed decreased pancreatic islet mass and reduced insulin-secretory responses to a glucoseload. These rats also showed reduced mitochondrial DNA-encoded COX I gene expression in the islets. Electron microscopic examinationshowed abnormal mitochondrial shapes in the b-cells of fetal protein-malnourished rats. Taurine supplementation to the low-protein dietrestored all these changes. Our findings indicate that a maternal protein-restriction diet causes long-lasting mitochondrial changes that maycontribute to the development of type 2 diabetes later in life. The lack of taurine may be a key causative factor for these dysfunctionalmitochondrial changes.Key words: Fetal protein malnutrition: Thrifty phenotype: Taurine: Mitochondrial dysfunction

Objective: Controversy exists about the treatment outcomes of the Ewing sarcoma family of tumors among low-incidence populations. We evaluated whether Korean Ewing sarcoma family of tumors patients have poorer outcomes than Euro-American patients. Methods: We retrospectively analyzed the clinicopathologic characteristics and outcomes of patients with localized Ewing sarcoma family of tumors treated at Korea Cancer Center Hospital between 1986 and 2008. Results: Seventy-six patients (48 male, 28 female) of median age 20 years (range: 1–69 years) were evaluated. Tumors were located in central-axial parts of the body in 33 cases (43.4%) and extremity in 43 cases (56.6%). Pelvis and femur were the most frequently involved sites. Histologic response to preoperative chemotherapy was analyzed in 48 cases and there were 32 (66.7%) good responders and 16 (33.3%) poor responders. For a median follow-up of 37.9 months (range: 0.9–260.6 months), 5-year overall survival and event-free survival rates were 58.9+6.1 and 52.6+6.1%, respectively. A poor histologic response to preoperative chemotherapy (P ¼ 0.01) and a tumor location in a central-axial body region (P ¼ 0.008) were found to be related to a poorer event-free survival. Conclusions: Survival of our Ewing sarcoma family of tumors patients was not inferior to those reported for Euro-American cases. Collaborative studies are necessary for further improvements of outcome and we believe that our data provide a basis for future studies targeting Ewing sarcoma family of tumors.

Tenosynovial giant cell tumor of diffuse type (TGCT-D) is a locally aggressive neoplasm that arises in the tendon sheath, bursa, or synovium. It typically involves the appendicular skeleton and rarely involves the axial skeleton. Because there are no specific findings of TGCT-D based on imaging studies or clinical symptoms, TGCT-D can be confused with other primary or metastatic bone tumors. We report findings of TGCT-D involving the T9 vertebra incidentally detected on F-18 FDG PET/CT in a patient with papillary thyroid cancer.

Background Our previous report showed an association between age and outcome in gefitinib-treated female patients with non-small cell lung cancer (NSCLC). Only limited numbers of molecular studies have been performed with respect to the presence of epidermal growth factor receptor ( EGFR ) mutations according to age. This retrospective study was performed to evaluate a possible association between age at the time diagnosis and the presence of EGFR mutations in female patients with NSCLC. Methods Tumor specimens were collected retrospectively from paraffin blocks of 98 female patients with primary NSCLC who underwent surgical resection between January 1992 and December 2002 at the Korea Cancer Center Hospital. To detect EGFR mutations, a Scorpion Amplified Refractory Mutation System was used. Results Most of the study population comprised never smokers (84%) and patients with adenocarcinoma (82%). The age at the time of diagnosis ranged from 34 to 74 years (median, 57 years). When the median age was used as a cutoff value, older patients were more likely to have EGFR mutations than younger patients (70 versus 39%; p = 0.004). After controlling for the effects of histology, smoking history, and stage, age remained a significant predictor for EGFR mutations (odds ratio, 4.03; 95% confidence interval, 1.61–10.09; p = 0.003). Conclusions Our data suggest that age at the time of diagnosis in female patients with NSCLC may be associated with the frequency of EGFR mutations, a strong indicator for favorable outcomes.

Malignant epithelioid hemangioendothelioma (MEHE) is a rare vascular tumor with a biological behavior that lies between those of classical epithelioid hemangioendothelioma and angiosarcoma. Furthermore, MEHE is rarely diagnosed by fine needle aspiration cytology. The authors describe the cytological features of MEHE in a 41-year-old man who presented with increasing dyspnea over a period of 1 month before admission. Computed tomography of the chest showed a 3 cm poorly defined mass in the right lower lobe. Fine needle aspiration cytology demonstrated cellular smears of loosely cohesive clusters of epithelioid cells with numerous intracytoplasmic lumens in a necrotic background. Cellular features included fine chromatin and vesicular or slightly hyperchromatic nuclei with inconspicuous nucleoli and intranuclear inclusions. Nuclear membranes were relatively irregular with indentation. Mean N/C ratio was not increased, presumably due to a moderate amount of cytoplasm. The histologic examination displayed epithelioid and spindle cell proliferation with necrosis accompanying a classical epithelioid hemangioendotheliomatous area. The immunohistochemical evaluation was confirmatory and showed immunoreactivity for vascular markers. The authors also reviewed FNAB findings of epithelioid angiosarcoma, primary adenocarcinoma, and bronchioloalveolar carcinoma of the lung to identify cytomorphologic differences by literature bases. MEHE of the lung is difficult to diagnose cytologically because of its rarity and its cytomorphologic similarities with other malignant epithelial and mesenchymal tumors. However, it may be possible to distinguish it from other entities when the possibility of this unusual vascular neoplasm is suspected and ancillary studies are supportive.

Objective: Due to the low incidence, treatments for Korean soft tissue Ewing sarcoma patients have been heterogeneous, and reported data are limited. In this study, we retrospectively analyzed soft tissue Ewing cases treated at our institution. Methods: We analyzed the clinicopathologic characteristics and treatment outcome of soft tissue Ewing sarcoma patients and compared with those of skeletal cases. Results: Twenty-seven soft tissue Ewing sarcoma cases were evaluated. Patients with soft tissue Ewing sarcoma were older than patients with skeletal tumors (P ¼ 0.03), and tended to have metastasis at diagnosis (P ¼ 0.12). However, sex ratios, pathologies, tumor volumes, and histologic response to preoperative chemotherapy were not different in the two groups. The 5-year overall survival (49.0%) and event-free survival (45.6%) of soft tissue Ewing sarcoma patients were similar to those of skeletal tumor patients (51.8% and 46.0%, respectively). Presence of metastasis at diagnosis and poor histologic response to preoperative chemotherapy were associated with an adverse outcome for both groups. Similar to skeletal tumors, central tumor location, pathology and tumor volume tended to be related to the survival of soft tissue Ewing sarcoma. However, age and the use of a modality other than surgery to achieve local control did not influence the survival of soft tissue Ewing sarcoma patients. Conclusions: Our data could provide a basis to design a collaborative or multinational study targeting Ewing sarcoma family tumors.

We performed this retrospective study to evaluate the association between age at diagnosis and outcome in female patients with non-small-cell lung cancer, who were treated with gefitinib. We analyzed the outcomes for 162 female patients who had received gefitinib monotherapy. Receiver operating characteristic curve analysis was performed to select a cutoff value for age with respect to tumor response. Patients were categorized as older and younger, with a value of 55 years. Most of the study population comprised never-smokers (89%) and patients with adenocarcinoma (82%). The mean age was 58 years and the response rate was 47% (76 patients). Older female patients showed higher response rates than younger patients (57% and 27%, respectively; P0.001), whereas there were no differences between never-smokers and smokers (P=0.824). Patients with adenocarcinoma had better response rates than those with nonadenocarinoma but this difference was not significant (50% and 34%, respectively; P=0.139). In terms of progression-free survival, older age (P=0.005) and adenocarcinoma histology (P=0.008) were favorable factors but never-smoking was not (P=0.316). Multivariate analysis confirmed that age predicted progression-free survival (hazard ratio, 0.60; P=0.008) and overall survival (hazard ratio, 0.60; P=0.014). Our data indicate that age at diagnosis may predict outcomes after gefitinib treatment in female patients with non-small-cell lung cancer. When molecular tests are not feasible, our results might help physician to select a beneficial subgroup in female patients.