ZBTB2 links p53 deficiency to HIF-1-mediated hypoxia signaling to promote cancer aggressiveness.

Aberrant activation of the hypoxia-inducible transcription factor HIF-1 and dysfunction of the tumor suppressor p53 have been reported to induce malignant phenotypes and therapy resistance of cancers. However, their mechanistic and functional relationship remains largely unknown. Here, we reveal a mechanism by which p53 deficiency triggers the activation of HIF-1-dependent hypoxia signaling and identify zinc finger and BTB domain-containing protein 2 (ZBTB2) as an important mediator. ZBTB2 forms homodimers via its N-terminus region and increases the transactivation activity of HIF-1 only when functional p53 is absent. The ZBTB2 homodimer facilitates invasion, distant metastasis, and growth of p53-deficient, but not p53-proficient, cancers. The intratumoral expression levels of ZBTB2 are associated with poor prognosis in lung cancer patients. ZBTB2 N-terminus-mimetic polypeptides competitively inhibit ZBTB2 homodimerization and significantly suppress the ZBTB2-HIF-1 axis, leading to antitumor effects. Our data reveal an important link between aberrant activation of hypoxia signaling and loss of a tumor suppressor and provide a rationale for targeting a key mediator, ZBTB2, to suppress cancer aggressiveness.

A Deep Learning-Based Assay for Programmed Death Ligand 1 Immunohistochemistry Scoring in Non-Small Cell Lung Carcinoma: Does it Help Pathologists Score?

Several studies have developed various artificial intelligence (AI) models for immunohistochemical analysis of programmed death ligand 1 (PD-L1) in patients with non-small cell lung carcinoma; however, none have focused on specific ways by which AI-assisted systems could help pathologists determine the tumor proportion score (TPS). In this study, we developed an AI model to calculate the TPS of the PD-L1 22C3 assay and evaluated whether and how this AI-assisted system could help pathologists determine the TPS and analyze how AI-assisted systems could affect pathologists' assessment accuracy. We assessed the 4 methods of the AI-assisted system: (1 and 2) pathologists first assessed and then referred to automated AI scoring results (1, positive tumor cell percentage; 2, positive tumor cell percentage and visualized overlay image) for final confirmation, and (3 and 4) pathologists referred to the automated AI scoring results (3, positive tumor cell percentage; 4, positive tumor cell percentage and visualized overlay image) while determining TPS. Mixed-model analysis was used to calculate the odds ratios (ORs) with 95% CI for AI-assisted TPS methods 1 to 4 compared with pathologists' scoring. For all 584 samples of the tissue microarray, the OR for AI-assisted TPS methods 1 to 4 was 0.94 to 1.07 and not statistically significant. Of them, we found 332 discordant cases, on which the pathologists' judgments were inconsistent; the ORs for AI-assisted TPS methods 1, 2, 3, and 4 were 1.28 (1.06-1.54; P = .012), 1.29 (1.06-1.55; P = .010), 1.28 (1.06-1.54; P = .012), and 1.29 (1.06-1.55; P = .010), respectively, which were statistically significant. For discordant cases, the OR for each AI-assisted TPS method compared with the others was 0.99 to 1.01 and not statistically significant. This study emphasized the usefulness of the AI-assisted system for cases in which pathologists had difficulty determining the PD-L1 TPS.

Thoracoscopic precision excision technique for small lung lesions using radiofrequency identification marking.

With the introduction of multi-detector computed tomography (CT), the number of incidentally detected small lung nodules has dramatically increased. Determination of lung nodule malignancy is crucial, and an early diagnosis of these indeterminate lesions can lead to subsequent potentially curative treatment. However, there are some limitations to excising these nodules with sublobar resection in a minimally invasive thoracoscopic setting. Under thoracoscopy, although stapler-based wedge resection seems to be the preferred technique, particularly in patients whose lesions are located far from the edge of the lobe, the stapler can unexpectedly sacrifice normal pulmonary parenchyma. To overcome this issue, we have developed a wireless excision precision technique using cone-beam CT-guided electromagnetic navigation bronchoscopy in a minimally invasive thoracoscopic setting. Our technique is implemented in a hybrid operating room, and small tumors can be removed using a radiofrequency identification microchip without intraoperative fluoroscopy and do not require lung palpation under thoracoscopy.

Impact of perioperative airway pathogens on living-donor lobar lung transplantation outcomes.

PURPOSE: To elucidate the clinical impact of pathogenic organism (PO) positivity early after transplantation, we evaluated the impact of perioperative airway POs on outcomes after living-donor lobar lung transplantation (LDLLT), where the graft airway is supposed to be sterile from a healthy donor. METHOD: A retrospective review of 67 adult LDLLT procedures involving 132 living donors was performed. Presence of POs in the recipients' airways was evaluated preoperatively and postoperatively in intensive-care units. RESULTS: POs were detected preoperatively in 13 (19.4%) recipients. No POs were isolated from the donor airways at transplantation. POs were detected in 39 (58.2%) recipients postoperatively; most were different from the POs isolated preoperatively. Postoperative PO isolation was not associated with short-term outcomes other than prolonged postoperative ventilation. The 5-year overall survival was significantly better in the PO-negative group than in the PO-positive group (89.1% vs. 63.7%, P = 0.014). In the multivariate analysis, advanced age (hazard ratio [HR]: 1.041 per 1-year increase, P = 0.033) and posttransplant PO positivity in the airway (HR: 3.684, P = 0.019) significantly affected the survival. CONCLUSIONS: The airways of the living-donor grafts were microbiologically sterile. PO positivity in the airway early after transplantation negatively impacted long-term outcomes.

M2-like tumor-associated macrophages promote epithelial-mesenchymal transition through the transforming growth factor ß/Smad/zinc finger e-box binding homeobox pathway with increased metastatic potential and tumor cell proliferation in lung squamous cell carcinoma.

Epithelial-mesenchymal transition (EMT) promotes primary tumor progression toward a metastatic state. The role of tumor-associated macrophages (TAMs) in inducing EMT in lung squamous cell carcinoma (LUSC) remains unclear. We aimed to clarify the significance of TAMs in relation to EMT in LUSC. We collected 221 LUSC specimens from patients who had undergone surgery. Immunohistochemistry was performed to evaluate M1-like and M2-like TAM distribution and EMT by E-cadherin and vimentin staining. Human LUSC cell lines (H226 and EBC-1) and a human monocyte cell line (THP-1) were used for in vitro experiments. M2-like polarization of TAMs and EMT marker expression in LUSC cells were evaluated by western blotting. The biological behavior of LUSC cells was evaluated by migration, invasion, and cell proliferation assays. Immunohistochemical analysis showed that 166 (75.1%) tumors were E-cadherin-positive and 44 (19.9%) were vimentin-positive. M2-like TAM density in the tumor stroma was significantly associated with vimentin positivity and worse overall survival. Western blotting demonstrated higher levels of CD163, CD206, vascular endothelial growth factor, and transforming growth factor beta 1 (TGF-ß1) in TAMs versus unstimulated macrophages. Furthermore, increased TGF-ß1 secretion from TAMs was confirmed by ELISA. TAM-co-cultured H226 and EBC-1 cells exhibited EMT (decreased E-cadherin, increased vimentin). Regarding EMT-activating transcriptional factors, phosphorylated Smad3 and ZEB-family proteins were higher in TAM-co-cultured LUSC cells than in parental cells. TAM-co-cultured H226 and EBC-1 cells demonstrated enhanced migration and invasion capabilities and improved proliferation. Overall, the present study suggests that TAMs can induce EMT with increased metastatic potential and tumor cell proliferation in LUSC.

Deep Learning for Predicting Effect of Neoadjuvant Therapies in Non-Small Cell Lung Carcinomas With Histologic Images.

Neoadjuvant therapies are used for locally advanced non-small cell lung carcinomas, whereby pathologists histologically evaluate the effect using resected specimens. Major pathological response (MPR) has recently been used for treatment evaluation and as an economical survival surrogate; however, interobserver variability and poor reproducibility are often noted. The aim of this study was to develop a deep learning (DL) model to predict MPR from hematoxylin and eosin-stained tissue images and to validate its utility for clinical use. We collected data on 125 primary non-small cell lung carcinoma cases that were resected after neoadjuvant therapy. The cases were randomly divided into 55 for training/validation and 70 for testing. A total of 261 hematoxylin and eosin-stained slides were obtained from the maximum tumor beds, and whole slide images were prepared. We used a multiscale patch model that can adaptively weight multiple convolutional neural networks trained with different field-of-view images. We performed 3-fold cross-validation to evaluate the model. During testing, we compared the percentages of viable tumor evaluated by annotator pathologists (reviewed data), those evaluated by nonannotator pathologists (primary data), and those predicted by the DL-based model using 2-class confusion matrices and receiver operating characteristic curves and performed a survival analysis between MPR-achieved and non-MPR cases. In cross-validation, accuracy and mean F1 score were 0.859 and 0.805, respectively. During testing, accuracy and mean F1 score with reviewed data and those with primary data were 0.986, 0.985, 0.943, and 0.943, respectively. The areas under the receiver operating characteristic curve with reviewed and primary data were 0.999 and 0.978, respectively. The disease-free survival of MPR-achieved cases with reviewed and primary data was significantly better than that of the non-MPR cases (P<.001 and P=.001), and that predicted by the DL-based model was almost identical (P=.005). The DL model may support pathologist evaluations and can offer accurate determinations of MPR in patients.

Postoperative tegafur-uracil for stage I lung adenocarcinoma: first real-world data with an exploratory subgroup analysis.

PURPOSE: The effect of postoperative tegafur-uracil on overall survival (OS) after resection of stage I adenocarcinoma has been shown in clinical trials. The purpose of this study was to investigate whether findings from randomized trials of adjuvant tegafur-uracil are reproducible in a real-world setting. METHODS: A retrospective cohort study was performed using a multi-institutional database that included all patients who underwent complete resection of pathological stage I adenocarcinoma between 2014 and 2016. Survival outcomes for patients managed with and without tegafur-uracil were analyzed using the Kaplan-Meier method and a Cox proportional hazards model for the whole patient cohort and in a selected cohort based on eligibility criteria of a previous randomized trial. Propensity score matching was used to adjust for confounding effects. RESULTS: After propensity score matching, the hazard ratios for OS were 0.57 (95% confidence interval (CI) 0.29-1.14, P = 0.11) in the whole cohort and 0.69 (95% CI 0.32-1.50, P = 0.35) in the selected cohort. CONCLUSIONS: The effects of tegafur-uracil in this retrospective study appear to be consistent with those found in randomized clinical trials. These effects may be maximized in patients aged from 45 to 75 years.

High programmed death ligand 1 expression in carcinomatous components predicts a poor prognosis in pulmonary pleomorphic carcinoma.

PURPOSE: This study reviewed the clinicopathological characteristics and programmed death ligand 1 (PD-L1) expression of 46 patients with pulmonary pleomorphic carcinoma to better understand its clinical behavior and factors affecting the survival. METHODS: Data of patients with pulmonary pleomorphic carcinomas resected in our institution were retrospectively reviewed. The tumors were classified as carcinomatous or sarcomatous according to the tissue components. Pathological characteristics were evaluated on hematoxylin and eosin-stained sections. The percentages of tumor cells with membrane staining for PD-L1 in carcinomatous and sarcomatous components were determined. RESULTS: We reviewed data of 46 patients (41 males, 5 females; median age 70.5 years old, range 36-83 years old). Most patients with pulmonary pleomorphic carcinoma expressed PD-L1 (80.4%), and the proportion of PD-L1 expression in tumor cells was significantly higher in sarcomatous components than in carcinomatous components. In univariable analyses, high p-stage (III), necrosis on pathological findings, and high PD-L1 expression in carcinomatous components (≥ 50%) were poor prognostic factors for the overall survival. In multivariable analyses, high PD-L1 expression in carcinomatous components was significantly associated with a poor prognosis after surgery. CONCLUSIONS: High PD-L1 expression in carcinomatous components was significantly associated with a poor prognosis after surgery.

Electromagnetic navigation bronchoscopy versus virtual bronchoscopy navigation for improving the diagnosis of peripheral lung lesions: analysis of the predictors of successful diagnosis.

PURPOSE: To investigate if electromagnetic navigation bronchoscopy (ENB) improves the diagnostic yield for peripheral lung lesions from that achieved by virtual bronchoscopy navigation (VBN). METHODS: This retrospective study compared the results of 100 ENB-transbronchial lung biopsies (TBLBs) with those of 50 VBN-TBLBs at a single institution. RESULTS: ENB improved the diagnostic yield significantly compared with VBN (64.0% for 19.4 ± 9.0 mm tumors vs. 46.0% for 27.6 ± 8.9 mm tumors; p < 0.0001). Irrespective of the bronchus sign, ENB was more favorable than VBN, with 81.0% (47/58) achieved by ENB vs. 60.0% (21/35) achieved by VBN in the presence of the positive bronchus sign (p = 0.0283), and 40.5% (17/42) achieved by ENB vs. 13.3% (2/15) achieved by VBN in the absence of the bronchus sign (p = 0.0431). Univariate analysis identified tumor size (p = 0.0048), amount of intravenous sedation (p = 0.0182), registration time (p = 0.0111), minimum distance to target (p = 0.0244), and the bronchus sign (p < 0.0001) as factors that affected the yield significantly for ENB. Multivariate analysis identified the bronchus sign (odds ratio 6.74; 95% CI 1.84-24.7) and the registration time (OR 1.01; 95% CI 1.00-1.02) as significant factors. CONCLUSIONS: Despite the bronchus sign being a significant factor, ENB improved the diagnostic yield of smaller lesions significantly, compared with VBN, regardless of the bronchus sign.

Discohesive growth pattern (Disco-p) as an unfavorable prognostic factor in lung adenocarcinoma: an analysis of 1062 Japanese patients with resected lung adenocarcinoma.

Discohesive growth pattern (Disco-p) is often observed in lung adenocarcinoma (ADC) and mimics tumor budding (TB), stromal invasive-type micropapillary pattern (SMPP), and complex glandular pattern. However, the clinical impact of Disco-p in lung ADC has not been well studied. To investigate the prognostic significance of Disco-p, we analyzed 1062 Japanese patients with resected lung ADC. Disco-p was defined as an invasive growth pattern composed of single tumor cells, or trabeculae or small nests of tumor cells associated with desmoplastic fibrous stroma. We recorded the percentage of Disco-p in 5% increments independent of the major histologic pattern and investigated its correlation with different clinicopathological factors. We also analyzed the overall survival (OS) and disease-free survival (DFS). Disco-p was observed in 203 tumors (19.1%). Disco-p was significantly associated with male sex, smoking, lymph node metastasis, large tumor size, high TNM stage, lymphovascular and pleural invasion, spread through air spaces, and TB (all, p < 0.001). Of the total cases, only eight cases exhibited a dubious pattern between SMPP and Disco-p. Disco-p was also associated with wild-type EGFR (p < 0.001) and ALK fusion (p = 0.008). Patients harboring tumors with Disco-p had significantly worse prognoses (OS and DFS (both, p < 0.001)) compared with those without Disco-p. On multivariate analysis, Disco-p was an independent prognostic factor of worse OS (hazard ratio (HR), 2.572; 95% confidence interval (CI), 1.789-3.680; p < 0.001), and DFS (HR, 3.413; 95% CI, 2.482-4.683; p < 0.001), whereas TB was not an independent unfavorable prognostic factor. Disco-p was an independent unfavorable prognostic factor in patients with resected lung ADC, although a careful evaluation is necessary to distinguish it from similar patterns. We proposed that Disco-p should be recognized as a new invasive pattern and accurately recorded for the better management of patients with lung ADCs.

Diagnostic yield of endobronchial ultrasound-guided transbronchial needle aspiration to assess tumor-programmed cell death ligand-1 expression in mediastinal lymph nodes metastasized from non-small cell lung cancer.

PURPOSE: We investigated the utility of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) to evaluate programmed cell death ligand-1 (PD-L1) expression in patients with advanced non-small cell lung cancer (NSCLC). METHODS: A retrospective chart review of patients who underwent EBUS-TBNA between April 2017 and April 2019 was conducted. Among patients diagnosed with NSCLC, we investigated the rate of successful evaluation of tumor PD-L1 expression, compared the relevant factors between patients with evaluable and those with unevaluable PD-L1 expression, and examined the response to immune checkpoint inhibitors (ICIs) after EBUS-TBNA. RESULTS: Of the 40 patients assessed, 32 (80%) had evaluable PD-L1 expression. Patients with evaluable PD-L1 expression were older than those with unevaluable PD-L1 expression (p = 0.017), and we noted a tendency for a larger diameter of the biopsied lymph node (p = 0.12). The response rate to ICIs was 100% in patients with a tumor proportion score (TPS) ≥ 50%, 33% in those with a TPS 1-49%, and 0% in those with a TPS < 1%. CONCLUSION: The diagnostic yield of EBUS-TBNA to evaluate PD-L1 expression in advanced NSCLC appeared acceptable in association with relevant clinical outcomes after treatment with ICIs. A further prospective study with a larger sample size is required to confirm our findings.

Survival outcomes after minimally invasive thymectomy for early-stage thymic carcinoma.

Minimally invasive surgery (MIS) has occasionally been used for selected patients with thymoma, but there is little information on the MIS approach for thymic carcinoma. The aim of this study was to evaluate survival outcomes after MIS for early-stage (Masaoka stage I-II) thymic carcinoma and thymic neuroendocrine carcinoma. A retrospective chart review of the cases recorded in our multi-institutional database was performed to identify patients who underwent resection for thymic carcinoma between 1995 and 2017. MIS thymectomy was performed in 17 cases (VATS, n = 14; RATS, n = 3. male, 41%; median age, 72 years). The median follow-up period was 32.7 (range 7.4-106) months. The five-year overall survival and relapse-free survival rates were 84.4% and 77.8%, respectively. The present study demonstrated encouraging preliminary results regarding MIS for the treatment of early-stage thymic carcinoma and thymic neuroendocrine carcinoma. Further studies with a larger sample size are required to evaluate the indications for this surgery.

GATA6-positive lung adenocarcinomas are associated with invasive mucinous adenocarcinoma morphology, hepatocyte nuclear factor 4α expression, and KRAS mutations.

AIMS: GATA6 is known to play a role in lung development. However, its role in the carcinogenesis of lung cancer is not well studied. The aim of this study was to analyse GATA6 expression in lung adenocarcinomas (LAs) by immunohistochemistry (IHC) in order to define its association with clinicopathological characteristics. METHODS AND RESULTS: IHC analysis of GATA6 was performed with tissue microarray slides containing 348 LAs. The association between GATA6 expression and clinicopathological parameters was evaluated. GATA6 expression in epithelial tumours other than lung cancer was also evaluated. GATA6 expression was found in 47 LAs (13.5%). This occurred more frequently in younger patients (P = 0.005), and was associated with the absence of lymph node metastasis (P =0.024), well-differentiated to moderately differentiated tumours (P < 0.001), the absence of lymphatic invasion (P = 0.020), and the absence of vascular invasion (P = 0.011). GATA6 expression was associated with mucin production (P < 0.001), the invasive mucinous adenocarcinoma subtype (P < 0.001), KRAS mutations (P = 0.026), expression of MUC2 (P < 0.001), CDX2 (P = 0.049), and MUC5AC (P < 0.001), and absence of expression of TTF-1 (P = 0.002). GATA6 expression was also associated with hepatocyte nuclear factor 4α (HNF4α) expression (P < 0.001). GATA6 expression tended to indicate better prognoses, whereas patients with HNF4α expression had significantly worse prognoses (P = 0.033). Of 270 tumours other than lung cancer, 110 expressed GATA6. CONCLUSIONS: These findings suggest that GATA6 might interact with HNF4α and contribute to the development of mucinous-type LAs.

Adjuvant vinorelbine and cisplatin after complete resection of stage II and III non-small cell lung cancer: long-term follow-up of our study of Japanese patients.

PURPOSE: We reported previously a phase II study of adjuvant chemotherapy consisting of four cycles of vinorelbine (25 mg/m2) and cisplatin (40 mg/m2), given on days 1 and 8, every 4 weeks, to Japanese patients with completely resected stage II or III non-small cell lung cancer (NSCLC; UMIN 000005055). However, the follow-up was too short for us to evaluate a definitive 5-year overall survival rate and after-effects. METHODS: Between December 2006 and January 2011, 60 patients were enrolled in this study. We analyzed relapse-free and overall survival, long-lasting adverse effects, the influence of treatment on recurrent tumors, and the development of a second primary cancer, in relation with the regimen. RESULTS: After a median follow-up period of 95.8 months, the 5-year relapse-free and overall survival rates were 51.7 and 76.7%, respectively. Neuralgia developed in one patient and this was the only case of a long-lasting adverse effect. Recurrence developed in 31 patients, 29 of whom received intensive treatment. Although 16 s (or more) primary neoplasms developed among 13 patients, these were common carcinomas in Japan and did not include sarcoma or hematologic malignancies. CONCLUSION: Adjuvant vinorelbine and cisplatin chemotherapy showed encouraging relapse-free and overall survival rates, and long-term safety in Japanese patients with resected NSCLC.

Adipophilin expression in lung adenocarcinoma is associated with apocrine-like features and poor clinical prognosis: an immunohistochemical study of 328 cases.

AIMS: The lipogenic pathway is up-regulated in proliferating cells. However, the clinical impact of neoplastic steatogenesis in lung cancer is unclear. The aim of the present study was to evaluate the association of intracytoplasmic lipids with the clinicopathological features of lung adenocarcinoma (ADC), by immunohistochemical analysis of adipophilin (ADP), a coating protein found on intracytoplasmic lipid droplets. METHODS AND RESULTS: Tissue microarrays consisting of 328 primary lung ADCs surgically resected at Kyoto University Hospital were immunostained for ADP. Subsequently, correlations between ADP expression and clinical, molecular and survival data were performed. Fifty-one (15.5%) cases were ADP-positive. The presence of vascular invasion (P = 0.003), predominantly solid histology (P < 0.001), poorly differentiated type (P < 0.001), wild-type EGFR (P = 0.002), ALK fusion (P < 0.001), strong/diffuse mitochondrial staining (P < 0.001), a lack of surfactant protein B expression (P = 0.014) and a high Ki67 index (P < 0.001) were significantly correlated with ADP-positive ADC. In contrast, there were no correlations between ADP-positive ADC and sex, age, smoking history, tumour stage, thyroid transcription factor-1 expression, or KRAS mutational status. ADP-positive ADCs had apocrine-like features (P < 0.001). Patients with ADP-positive ADC had worse disease-free and overall survival (P = 0.047 and P = 0.013, respectively) than those with ADP-negative ADC. CONCLUSIONS: ADP was expressed in a small proportion of lung ADCs. ADP-positive lung ADC was significantly associated with apocrine-like features, wild-type EGFR, and poor prognosis, suggesting that ADP-positive lung ADC could be a distinct subtype of lung adenocarcinoma, induced by up-regulation of the lipogenic pathway.

Evaluating the effectiveness of RNA in-situ hybridization for detecting lung adenocarcinoma with anaplastic lymphoma kinase rearrangement.

AIMS: An easy and rapid assay for detecting mRNA in formalin-fixed paraffin-embedded samples [RNA in-situ hybridization (ISH)] has been reported recently. The aim of this study was to investigate the diagnostic accuracy of RNA ISH in detecting lung adenocarcinoma (LA) with anaplastic lymphoma kinase (ALK) gene rearrangement. METHODS AND RESULTS: We tested ALK RNA ISH on 11 resected LAs for which ALK fusion was confirmed by immunohistochemistry (IHC) and/or fluorescence in-situ hybridization (FISH). ALK mRNA expression was detected by RNA ISH in all 11 ALK-positive LAs, with a mean positive cell proportion of 68.4% (median, 75.3%; range, 3-98.8%), by counting 100 tumour cells at 10 different loci; RNA ISH did not detect ALK mRNA expression in the normal surrounding lung cells. Next, we explored the concordance between ALK RNA ISH and IHC/FISH tests by using tissue microarrays (TMAs) containing 294 LAs. In the TMA slides, we found five ALK-positive cases with IHC and/or FISH. The mean proportion of ALK RNA ISH-positive cells in these five cases was 75.6% (median, 82%; range, 40-94%), whereas the proportion of ALK RNA ISH-positive cells in the remaining 289 cases was 0.3% (median 0%; range, 0-15%). When the cutoff value was set at 15%, ALK RNA ISH-positive and ALK RNA ISH-negative cases were distinguishable with 100% sensitivity and specificity relative to the IHC/FISH tests. CONCLUSIONS: Our findings show that RNA ISH is useful for detecting ALK rearrangement with high sensitivity and specificity relative to conventional IHC/FISH tests. Thus, RNA ISH, which is an easy and rapid assay, could be an alternative method to IHC and FISH.

Expression of p16Ink4a in mixed squamous cell and glandular papilloma of the lung.

Mixed squamous cell and glandular papilloma (mixed papilloma) of the lung is an extremely rare neoplasm, with only 21 cases reported in the English literature. Although the expression of p16Ink4a has been analyzed in only two cases of mixed papilloma, they were negative for p16Ink4a . Therefore, the significance of p16Ink4a overexpression in mixed papilloma remains unclear. This is the first case of mixed papilloma with positive p16Ink4a expression in a 72-year-old male smoker. The 20 mm sized tumor was histologically diagnosed as mixed papilloma following right upper lobectomy. Immunohistochemically, cytokeratin 5 and p40 positivity was predominant in basal cells of the glandular component and squamous cells, while thyroid transcription factor-1, p53, and Ki-67 were focally positive. Both glandular and squamous components were diffusely positive for p16Ink4a . This finding could be important to clarify the pathogenesis and biology of mixed papilloma.

Atrial fibrillation after lung cancer surgery: incidence, severity, and risk factors.

PURPOSE: Atrial fibrillation (Af) is a common post-operative cardiac complication after lung cancer surgery; however, the type of lung cancer surgery being performed has evolved, remarkably, into minimally invasive surgical procedures. The purpose of this study was to quantify the incidence and severity of post-operative Af and to identify the risk factors for Af, using a recent cohort of lung cancer surgery patients. METHODS: We reviewed, retrospectively, the medical records of 593 patients, who underwent lung cancer surgery between 2011 and 2013, for the development of post-operative Af. RESULTS: The overall incidence of post-operative Af in our study was 6.4 % (38/593). Three (8 %) of these 38 patients, subsequently, suffered brain infarction. Multivariate analysis revealed that mediastinal lymph node dissection (OR ND-2/ND-0-1 = 3.06; 95 % CI 1.06-10.9) was associated with the development of post-operative Af. CONCLUSION: Omission of mediastinal lymph dissection for patients with early stage lung cancer and a high risk of Af should be considered to prevent post-operative Af.

Surgical and non-surgical management of repeat pulmonary metastasis from sarcoma following first pulmonary metastasectomy.

PURPOSE: Although repeat pulmonary metastasectomy for sarcoma is not uncommon and associated with a favorable survival in select patients, there is a paucity of data on the demographics and tumor characteristics of patients with repeat pulmonary metastasis following complete resection of pulmonary metastases from osteogenic or soft tissue sarcoma. METHODS: A retrospective chart review was performed to identify patients with isolated repeat pulmonary metastasis after complete resection of pulmonary metastases from sarcoma at Kyoto University Hospital between January 1990 and December 2014. Isolated pulmonary metastasis was defined as limited to presumable pulmonary metastasis according to the follow-up radiologic workup. RESULTS: Thirty-five patients were identified to have repeat pulmonary metastasis. Thirty patients underwent attempted repeat pulmonary metastasectomy (including 21 undergoing documented complete resection and 7 undergoing documented incomplete or aborted resections). Five patients received non-surgical management. The median follow-up period was 16 months (range 1-234) from repeat pulmonary metastasis. The five-year overall survival of the whole patient cohort and those undergoing repeat pulmonary metastasectomy were 37.6 and 41.1 %, respectively, from repeat pulmonary metastasis. CONCLUSIONS: A majority of patients with repeat pulmonary metastasis from sarcoma undergo repeat metastasectomy, which is associated with favorable survival outcomes. However, a greater accumulation of data on non-surgically managed patients is needed as such information is currently limited available.

Gefitinib treatment in patients with postoperative recurrent non-small-cell lung cancer harboring epidermal growth factor receptor gene mutations.

BACKGROUND: The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor gefitinib is an effective treatment for recurrent or advanced lung cancer harboring EGFR gene mutations, and has improved progression-free survival in several clinical trials. However, the effect of gefitinib treatment for recurrent lung cancers with EGFR gene mutations after complete resection and the influence of the timing of such treatment have not been fully elucidated in a practical setting. METHODS: We investigated 64 patients (median age: 68 years; men: 22; women: 42; adenocarcinoma: 61; adenosquamous cell carcinoma: 2; combined large cell neuroendocrine carcinoma: 1) with recurrent lung cancer after complete resection who received gefitinib for the recurrent lesions and in whom the tumors had EGFR gene mutations. Progression-free survival, response rate, and safety were analyzed. RESULTS: Complete response and partial response were achieved in 2 patients and in 42 patients, respectively (objective response rate: 69 %). Stable disease was obtained in 16 patients, the disease control rate was 94 %, and median progression-free survival was 16 months. The timing of gefitinib treatment (first line, second line, or later) and the type of EGFR gene mutation present did not influence progression-free survival. However, a smaller number of recurrent sites at the start of gefitinib treatment was linked to better progression-free survival. Hematologic and nonhematologic toxicities were generally mild, but 1 patient experienced interstitial lung disease. CONCLUSIONS: Our results suggest that gefitinib treatment for recurrent lung cancer with gene EGFR mutations is a useful option in a practical setting, irrespective of the timing of such treatment and the type of EGFR gene mutation present.