Search

Besides being a predictive biomarker of response to immunotherapy in lung cancer in general, programmed death-ligand 1 (PD-L1) is not so well correlated with treatment outcomes of lung adenocarcinoma (ADC) harbouring epidermal growth factor receptor (EGFR) mutations, as reported studies are inconclusive and seldom addressed the issues of response to treatment and resistance. The primary objective is to evaluate the association of PD-L1 and EGFR tyrosine kinase inhibitor (TKI) efficacy, resistance, and relevant clinical outcomes. The secondary objective is to further explore the tumour microenvironments of EGFR mutant tumours with different PD-L1 expression.Using immunohistochemical (IHC) staining, we retrospectively tested PD-L1 expression (Dako 22C3) in the pre-treatment tumours from advanced EGFR mutant lung ADC patients, of whom all were treated with TKIs. Multiplex IHC assay was applied for exploring immune cells in tumour microenvironments.A total of 153 Taiwanese patients were enrolled in our study, of whom a majority of cases were female (58.9%) and non-smokers (75.8%). The objective response rate (ORR) to EGFR TKI and progression-free survival (PFS) were better in patients with PD-L1 expression50% (ORR/PFS in PD-L1 0% versus 1-49% versus ≥50%: 65.6%/12.5 months versus 56.4%/12.8 months versus 38.9%/5.9 months, P 0.05). The multivariate analysis showed that PD-L150% was an independent prognostic factor for longer PFS (hazard ratio (HR) 0.433, 95% confidence interval (CI) 0.250-0.751, P = 0.003). Furthermore, tumours with higher PD-L1 expression were less likely to develop a secondary T790M mutation (T790M+ in PD-L1 0% versus 1-49% versus ≥50%: 53.7% versus 35.7% versus 10%, P = 0.024). Multiplex IHC tests were applied in 15 cases and revealed a potential correlation between PD-L1, immune cells, and EGFR TKI responses.Lower pre-treatment PD-L1 is associated with better ORR, PFS, and higher frequency of T790M resistance in EGFR TKI-treated lung ADC patients.

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

This study aims to assess whether geranylgeranylacetone (GGA) could reduce ototoxicity induced by cisplatin through upregulation of not only heat shock protein(HSP)-70, but also HSP-27 and HSP-40, and to study if GGA would reduce cisplatin-induced increase in oxidative stress. 48 guinea pigs were used in this study and treated with the following regimen: 0.5% CMC (sodium carboxymethyl cellulose) control for 7days, GGA (600mg/kg/d) for 7days, a combination of GGA (600mg/kg) for 7days and then one dose of 10mg/kg cisplatin (GGA+Cis), and a combination of CMC for 7days and then 10mg/kg cisplatin (cisplatin group). Auditory brainstem response (ABR) measurement was performed in each animal at time before treatment and 7days after the last dose. Additionally, HSPs, nitric oxide (NO), and lipid peroxidation (LPO) levels in cochlear membranous tissues were assessed. The mean ABR thresholds in the cisplatin group were significantly (p

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

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

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

Introduction Tumor tissue is often not obtainable or suitable for molecular-based epidermal growth factor receptor ( EGFR ) mutational analysis in advanced non–small-cell lung cancer (NSCLC). This retrospective and single-institution study was conducted to evaluate the role of effusion immunocytochemistry using two EGFR mutant-specific antibodies for the detection of relevant EGFR mutations in NSCLC, along with the selection of candidates for first-line therapy with EGFR tyrosine kinase inhibitors (TKIs). Methods Immunocytochemistry using two antibodies binding specifically to the major forms of mutant EGFR, L858R, and E746-A750 deletion (delE746-A750), was performed on cell blocks of malignant pleural effusion (MPE) from 78 patients with lung adenocarcinoma, who received first-line EGFR TKIs. The yield of EGFR -mutation detection and prediction of response rate and progression-free survival to TKI treatment by immunocytochemistry were compared with those by clinical characteristics and EGFR sequencing using cell-derived RNA from MPEs. Results Of the 78 MPE samples, direct sequencing using cell-derived RNA identified L858R mutation in 42 cases, deletions in exon 19 in 12 cases (delE746-A750 in eight cases), other types of mutations in three cases, and wild-type EGFR in 21 cases. Effusion immunocytochemistry with these two mutant-specific antibodies exhibited a sensitivity of 71% and 88% and a specificity of 86% and 96% for identifying predefined L858R and delE746-A750 mutations, respectively. Effusion immunocytochemistry provided a superior prediction of tumor response and progression-free survival to first-line EGFR TKIs than did clinical characteristics like sex and smoking status. Patients whose effusion immunocytochemistry showed a reaction to either of the two antibodies had a comparable TKI response rate (67% versus 72%) to those with EGFR mutations assessed by direct sequencing from cell-derived RNA. Conclusions Effusion immunocytochemistry could be introduced into clinical practice to identify more NSCLC patients likely to have benefit from first-line TKI treatment, especially for those without adequate tissue for molecular-based EGFR analysis.

Mediastinal seminomas are uncommon primary mediastinal neoplasms, and most are solid in appearance. Cystic mediastinal seminoma is an unusual type of extragonadal germ cell tumor that has rarely been reported in the literature. Here we describe a 36-year-old man with a 7.5-cm cystic mediastinal seminoma. The tumor was excised successfully by video-assisted thoracoscopic surgery. No recurrence was noted during 28 months of follow-up.

Autogenic bone graft is the first choice for managing bone defects. However, donor site-associated morbidity and limited bone volume are constraints in clinical applications. Allografts can provide sufficient amounts for bone defects but have a high risk of infection. Bone substitute composed of hydroxyapatite (HA) is an alternative material for avoiding the aforementioned risks. Sintered bovine bone is a naturally occurring HA that has been proved to have excellent bioactivity for inducing osteoblastic expression and new bone formation in animal studies. The objective of this study was to evaluate the interactions between the tissue and the bone substitute composed of HA (sintered from bovine bone) in the human body.From 2003 to 2005, a total of 33 patients were enrolled to receive the sintered bovine HA as a bone substitute. Inclusion criteria were fractures with bony defects, benign bone tumors with a cavity, and spinal fusions. Bone healing was monitored by a series of radiographs, and bone microstructure was checked by scanning electron microscopy (SEM) and von Kossa staining.In 81.8% (27/33) of cases, significant fusion mass formation was visible in the radiographs after 6-12 months. New bone formation on the surface of the sintered bovine HA was seen under microscopic observation. Tight bonding between the interface of the bone and the sintered bovine HA was shown with SEM/energy-dispersive spectroscopy and von Kossa staining.Sintered bovine HA is a suitable material as a bone substitute to provide bone growth and promote bone healing.

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

Objectives According to our previous study, the concurrent detection of p53 and epidermal growth factor receptor mutations significantly improves the clonality assessment and impact management of patients with multiple primary lung cancer. Nevertheless, the treatment, outcome, and safety of patients with this complex disease remain controversial. This series of cases detail our experiences with surgical resections in 92 patients during the past 16 years. Methods A database of 1651 patients was evaluated for unilateral and bilateral synchronous multiple primary lung cancers. The relationships among the location of tumors, number of tumors, tumor size, tumor histology, vascular invasion, regional lymph node metastasis, extranodal extension, type of surgery, mortality, and survival were analyzed. Results The 5-year survival for all synchronous multiple primary lung cancers was 35.3%. The overall surgical mortality was 1.1%. Notably, lymph node metastasis, extranodal extension, vascular invasion, tumors with adenosquamous carcinoma or different histology, and poor survival were observed. Multivariate analysis showed that only the occurrence of lymph node metastasis remained a statistically significant prognostic factor. The 5-year survivals were 52.5% and 15.5% for patients with and without lymph node metastasis, respectively ( P Conclusion An aggressive surgical approach is safe and justified in patients with synchronous multiple primary lung cancers and node-negative diseases. The status of this particular form of non–small cell lung cancers might be considered in the conventional TNM staging system for more accurate prediction of patient prognosis.

Death-associated protein kinase (DAPK) is a calmodulin-regulated serine/threonine kinase and elicits tumor suppression function through inhibiting cell adhesion/migration and promoting apoptosis. Despite these biological functions, the signaling mechanisms through which DAPK is regulated remain largely elusive. Here, we show that the leukocyte common antigen-related (LAR) tyrosine phosphatase dephosphorylates DAPK at pY491/492 to stimulate the catalytic, proapoptotic, and antiadhesion/antimigration activities of DAPK. Conversely, Src phosphorylates DAPK at Y491/492, which induces DAPK intra-/intermolecular interaction and inactivation. Upon EGF stimulation, a rapid Src activation leads to subsequent LAR downregulation, and these two events act in synergism to inactivate DAPK, thereby facilitating tumor cell migration and invasion toward EGF. Finally, DAPK Y491/492 hyperphosphorylation is found in human cancers in which Src activity is aberrantly elevated. These results identify LAR and Src as a DAPK regulator through their reciprocal modification of DAPK Y491/492 residues and establish a functional link of this DAPK-regulatory circuit to tumor progression.

Objective Estrogen receptor expression in lung cancer has been understudied, particularly in light of its potential biologic importance in the epidemic of lung cancer in women. The expression of estrogen receptors was investigated to better understand the possible role of sex hormones in lung cancer. Methods A total of 301 patients with surgically resected non–small cell lung cancers of stages I to III were explored. Sections of paraffin-embedded tumor samples were stained with estrogen receptor α and estrogen receptor β antibodies. Tumors with moderate-to-strong nuclear staining in at least 50% of the tumor cells were scored as positive for overexpression. Results The overall frequency of overexpression for estrogen receptor β was 45.8% (138/301). It was detected most frequently in female patients (in 54.3% of 127 tumors vs 39.7% of 174 tumors in men, P = .012). However, there was no estrogen receptor α nuclear staining detectable in non–small cell lung cancers. Interestingly, a significant correlation between estrogen receptor β expression, stage of disease, grade of differentiation, smoking status, vascular invasion, and survival in patients with stage II and III disease was found. By using multivariate analysis of survival among patients with stage II and III disease, estrogen receptor β overexpression, stage II tumor, well differentiation, nonsmoking status, and lack of vascular invasion were significantly favorable prognostic factors. Conclusions The results presented here show for the first time that immunohistochemical expression of estrogen receptor β can be used as a prognostic indicator in patients with surgically resected stage II and III non–small cell lung cancers. These observations might offer a possibility for hormonal therapy in patients with lung cancer.

Sclerosing hemangioma (SH) of the lung is an uncommon tumor with a predilection for middle-aged women. This special phenomenon prompted us to examine SH for the expression of ERalpha (human estrogen receptor) and ERbeta (a second isoform of estrogen receptor). To investigate the staining pattern of these tumors, we also stained lung tissues from patients with non-small cell lung carcinomas and nonneoplastic type II pneumocytes for comparison. Thirty-seven pulmonary SHs and 301 non-small cell lung cancers specimens were explored. Expression of ERalpha and ERbeta was immunohistochemically measured. The overall frequency of overexpression for ERbeta was 91.9%. It was detected in both female (in 91.4% of 35 cases) and male (in 100.0% of 2 tumors from men) patients. There was ERbeta overexpression in all 9 tumors of solid pattern, 6 of 7 tumors of papillary pattern, all 4 tumors of sclerotic pattern, 12 of 13 tumors of hemorrhagic pattern, and 3 of 4 tumors of mixed pattern. The staining pattern of the neoplastic cells of the SH was similar to that of type II pneumocytes adjacent to the tumor rather than that of non-small cell lung cancers, in which the frequency of ERbeta overexpression was 45.8%. However, there was no ERalpha detectable in these neoplasms. Estrogen receptor beta overexpression is very frequent in pulmonary SHs, which is similar to that of alveolar cells but quite different from non-small cell carcinoma.

ObjectiveSurgical lung biopsy is considered the final method of diagnostic modality in patients with undiagnosed diffuse pulmonary disease. Nevertheless, the effect of surgical lung biopsy on the diagnosis, treatment, and outcome of the patient still remains controversial. This study reviewed the experiences of surgical lung biopsies in 196 consecutive patients during the past 7 years.MethodsSurgical lung biopsy was performed after achievement of general anesthesia through video-assisted thoracoscopic surgery or a 7-cm minithoracotomy. Biopsy specimens were swabbed for aerobic and anaerobic bacterial, fungal, and mycobacterial cultures. The sections of specimens were routinely stained with hematoxylin and eosin, and acid-fast, Gomori methenamine silver, Gram stain, or other special stains were added if necessary.ResultsThe pathologic diagnosis after surgical lung biopsy included infection (30.6%), interstitial pneumonia or fibrosis (21.9%), diffuse alveolar damage (17.3%), neoplasm (13.3%), autoimmune diseases (8.2%), and others (8.2%). After surgical lung biopsy, 165 (84.2%) patients had changes in their therapy, 124 (63.3%) patients had clinical improvement of their conditions, and 119 (60.7%) patients survived to hospital discharge. Comparison between immunocompromised and immunocompetent patients showed that diagnosis of infection was significantly higher (P < .01) in the former group (41.2% vs 20.2%). In addition, there was no significant difference in the distribution of diagnosis and rate of change in therapy between the respiratory failure and nonrespiratory failure groups. However, the rates of response to therapy and patient survival were significantly lower in the respiratory failure group (51.2% and 41.5%) than in the nonrespiratory failure group (71.9% and 78.1%, P < .05). There was no surgical mortality directly related to the procedure. The surgical morbidity rate was 6.6%.ConclusionSurgical lung biopsy is a safe and accurate diagnostic tool for diffuse pulmonary disease. For a large proportion of the patients, change of therapy and then clinical improvement can be achieved after surgical lung biopsy. Surgical lung biopsy should be considered earlier in patients with undiagnosed diffuse pulmonary disease, especially when the respiratory condition is deteriorating.

Most thin-walled cavities in the lung are benign lesions, but a few cases of lung cancer can have this unusual pattern. All previously reported cases were adenocarcinomas. Here we report a case of lymphoepithelioma-like carcinoma (LELC) of the lung presenting as a thin-walled cavity with a smooth inner surface. LELC is more commonly seen in Southeast Asia, including Taiwan, and its gross picture is usually a solid mass with a round, circumscribed border, which is indistinguishable from other non-small cell lung cancers. Asymmetric thickness of the cystic wall and lymphadenopathy are important features in the diagnosis and the selection of treatment.

Fourteen cases (13 pleural and one intrapulmonary) of solitary fibrous tumors (SFTs) (the so-called fibrous mesothelioma) were studied. The lesions occurred more in females (nine cases) than males (five cases). The age of patients ranged from 44 to 73 years old (median 60 years). The tumors presented as cough with or without blood-tinged sputum, exertional dyspnea, chest pain, nausea, body weight loss, fever, or as asymptomatic masses detected by routine chest radiograph. Two patients with huge (tumor larger than 20 cm) malignant tumors had accompanying pleural effusion and one associated with hypoglycemia. Ten benign tumors measured 2-11 cm (median size 7 cm) while the remaining four histologically malignant ones measured 20-30 cm in size. All of them were well circumscribed and thinly encapsulated. Hemorrhage and necrosis were more frequently seen in the malignant tumors. Histologically, these lesions were characterized by 'patternless pattern' with occasional hemangiopericytic features (three cases). The tumor cells were all immunoreactive for vimentin, CD 34, and focally actin-positive in one case, but not for keratin, desmin, S-100 protein, carcinoembryonic antigen, alpha 1-ACT and F VIII-related antigen, supported a primitive mesenchymal origin. p53 protein was expressed in two of the malignant cases. Proliferating cell nuclear antigen stain was positive with 50 and 80% of the labeling index in the benign and malignant tumors, respectively, but retinoblastoma gene protein was negative in all tumors. This analysis confirmed the relationship between histological malignant SFTs and tumor size, cellularity, mitotic activity, necrosis and tumor suppressor gene expression. However, the clinical behavior was unpredictable. Complete respectability seemed to be the most important indicator of clinical outcome in the less aggressive tumors.

We report an unusual case of gastrointestinal adenocarcinoma arising in a giant posterior mediastinal mature cystic teratoma extending into the retroperitoneum, which was treated by complete excision with a good outcome for more than 2 years. Teratomas with malignant transformation are rare non-germ cell malignant tumors arising from a preexisting mature teratoma. Histological examination revealed that the cyst wall was composed of mature ectodermal, mesodermal, and endodermal elements. Neoplastic glands with a cribriform pattern were found in a small, solid nodule. Strong cytokeratin 20 cytoplasmic immunostaining of the tumor cells supported the diagnosis of gastrointestinal adenocarcinoma. In this report, we describe the potential aggressiveness of a giant mature cystic teratoma with adenocarcinoma and suggest that complete surgical resection without adjuvant chemotherapy be considered as a therapy in the treatment of teratoma with focal malignant transformation.