Characteristics and timing of recurrence during postoperative surveillance after curative resection for lung adenocarcinoma.

PURPOSE: To establish the most effective methods of postoperative surveillance to detect early recurrence of lung adenocarcinoma. METHODS: The subjects of this retrospective study were 485 patients with p-stage I-III lung adenocarcinoma, who underwent postoperative surveillance. We examined the sites and detection modes of recurrence and calculated the recurrence-free probabilities. Patients with stage I disease were divided into low- and high-risk recurrence groups using a risk score calculated by assigning points proportional to risk factor regression coefficients. RESULTS: Of the 112 patients with recurrence, 86 had intrathoracic recurrence. Routine computed tomography (CT) revealed recurrence in 60 patients. The recurrence-free probability curves showed that 95% of recurrences were identified within the first 4 years after resection in patients with stage II/III disease. In patients with stage I disease, the predictors of recurrence included male sex, positive pleural lavage cytology, moderate-to-poor differentiation, and visceral pleural invasion. Postoperative recurrences were detected throughout the follow-up period in the high-risk group. CONCLUSIONS: Routine chest CT plays an important role in the postoperative surveillance of lung adenocarcinoma. We recommend intensive follow-up during the early post-resection period for patients with advanced stage disease and long-term follow-up for high-risk patients with stage I disease.

[Simultaneous pulmonary resection and endovascular repair for patients with coexisting primary lung cancer and aneurysm].

The surgical strategy for coexisting lung cancer and aneurysm is controversial owing to the risk of aneurysm rupture during the perioperative period of pulmonary resection. We performed simultaneous pulmonary resection and endovascular repair in 2 patients with coexisting lung cancer and aneurysm. Case 1:A 74-year-old man presented at our hospital with cT2aN0M0 lung cancer and a 5.0 cm abdominal aortic aneurysm. Because computed tomography indicated the possibility of advanced lung cancer, we decided to perform simultaneous surgery for lung cancer and the aneurysm. Under general anesthesia, endovascular aneurysm repair was performed before right lower lobectomy with lymphadenectomy. The postoperative course was uneventful, and the patient was discharged on postoperative day 12. Case 2:A 72-year-old man presented at our hospital with cT2aN1M0 lung cancer, a 5.0 cm left internal iliac artery aneurysm, and right renal cell carcinoma( RCC). Because the lung cancer was advanced and the patients needed following surgical treatment for RCC, we decided to perform simultaneous surgery for lung cancer and the aneurysm. Under general anesthesia, endovascular aneurysm repair was performed before right upper lobectomy with lymphadenectomy. The postoperative course was uneventful, and the patient was discharged on postoperative day 11.

[Detection of the communication site by dye injection method at the surgery for pleuroperitoneal communication].

A 65-year-old male with end stage renal failure due to IgA nephritis commenced continuous ambulatory peritoneal dialysis (CAPD). Three weeks after initiation of CAPD, right hydrothorax developed. Then, we strongly assumed pleuroperitoneal communication( PPC) although the pleural effusion did not show high concentration of glucose. He underwent thoracoscopic surgery for PPC. On the inner, central tendons part of the diaphragm, there were a few blebs. One hour after 3 l of peritoneal dialysis solution containing 15 ml indigocarmine was instilled into the abdomen through a CAPD catheter, the blebs were tense and colored blue by the dye solution. The blebs were directly sutured and diaphragm was covered by polyglycolic acid sheet and fibrin glue all over. Since then, he resumed CAPD, without recurrence of hydrothorax. Then we investigated the treatment outcome of video-assisted thoracic surgery (VATS) for PPC in Japan. The outcome was poorer in cases in which communication was not detected intraoperatively. These patients should be given sufficient consideration for surgical procedure.

Pembrolizumab Therapy Leading to Complete Remission for Recurrence of Pulmonary Metastases after their Resection and Radical Cystectomy following Gemcitabine and Cisplatin Therapy.

A 64-year-old man was diagnosed with invasive bladder and right lower ureteral urothelial cancer with right pelvic lymph node and lung metastases. He received four courses of gemcitabine and cisplatin therapy. He underwent lung metastasectomy and radical cystoprostatectomy, with not only primary lesions but also metastatic lesions showing a complete response. New multiple lung metastases were revealed five months after adjuvant chemotherapy. On starting pembrolizumab therapy, the metastatic lesions are notably reduced in size. He is currently receiving pembrolizumab therapy, and no recurrence has been observed for over one year.

Primary lung cancer treatable with radical resection after complete remission with pembrolizumab therapy following gemcitabine and carboplatin chemotherapy for multiple metastases of bladder cancer.

Introduction: We report a patient with the complete remission of multiple metastases and primary bladder lesions of bladder cancer who developed primary lung cancer requiring radical resection. Case presentation: A 68-year-old man diagnosed with invasive bladder cancer, right hydroureteronephrosis, and multiple metastases were administered six courses of gemcitabine and carboplatin chemotherapy and thereafter has been receiving pembrolizumab therapy. Bladder cancer and multiple metastases decreased in size, whereas a ground-glass opacity lesion in the lung gradually increased in size. Fluorodeoxyglucose-positron emission tomography revealed the accumulation of fluorodeoxyglucose in the ground-glass opacity lesion only. The patient was diagnosed with primary lung cancer and underwent a thoracoscopic lobectomy. Histopathological findings showed ALK-negative, EGFR L858R mutation-positive invasive adenocarcinoma with a programmed death-ligand 1 tumor proportion score of less than 1%. Conclusion: This is the first case report of patients with the complete remission of multiple metastases of bladder cancer who developed primary lung cancer requiring radical resection.

The predominant expression of hepatocyte nuclear factor 4α (HNF4α) in thyroid transcription factor-1 (TTF-1)-negative pulmonary adenocarcinoma.

AIMS: To investigate TTF-1-negative pulmonary adenocarcinoma, focusing upon mucin production and the expression of hepatocyte nuclear factor-4α (HNF4α). MATERIALS AND METHODS: Two hundred and sixty-two cases of pulmonary adenocarcinoma were examined histologically and immunohistochemically; TTF-1 was expressed in 222 cases (84.7%), and 40 cases (15.3%) were negative. Among TTF-1-negative cases there were 31 mucinous-type tumours, and HNF4α, MUC5AC and MUC2 were expressed in 34 cases (85%), 29 cases (72.5%) and four cases (10%), respectively. In contrast, their expression was rare in TTF-1-positive tumours. A statistically inverse correlation was confirmed between the expression of TTF-1 and that of HNF4α and MUC5AC. CONCLUSION: Most TTF-1-negative pulmonary adenocarcinomas are mucinous lesions with the predominant expression of HNF4α and MUC5AC.

Predictive advantage of a cell type classification for pulmonary adenocarcinoma coupled with data for p53, K-ras and EGFR alterations.

We analyzed relationships between histological subtypes of pulmonary adenocarcinomas and three gene alterations (p53, K-ras, and epidermal growth factor receptor gene), or thyroid transcription factor-1 (TTF-1) expression, and also studied prognoses by the subtypes, with or without combined multiple gene mutation status. Our purpose was to clearly determine pathogenesis, along with the best predictive value for biology and therapy-related traits. A total of 223 consecutively resected pulmonary adenocarcinomas were sub-classified using either the World Health Organization (WHO) or our five-cell type (FCT) classification system (hobnail, columnar/cuboidal, mixed, polygonal/oval, and goblet cell types). DNAs extracted from frozen samples of the adenocarcinomas were examined for gene alterations, and TTF-1 expressions were determined using immunohistochemistry. Next, relationships among the various data and clinicopathological factors were analyzed. The most striking result was: while almost 70% of adenocarcinomas were sub-classified as a mixed subtype by WHO, the FCT classified many of them as other cell subtypes. The FCT closely reflected differences in etiological factors, cellular lineages, and frequencies of gene mutations; and whether the data from combined gene mutations were used or not, differences among the cell types in postoperative survivals appeared. In contrast, subtypes of WHO did not show any association with the gene alteration or prognosis, and the FCT more suitably indicated sensitivity to gefitinib therapy than did WHO. The FCT combined with multiple gene mutation status appears to be useful in indicating pathogenesis and predicting the biological nature of pulmonary adenocarcinomas, and it could facilitate development of new therapies for each subtype.

[Surgical treatment for metachronous lung cancer].

We performed a retrospective review of 45 consecutive patients with metachronous multiple primary lung cancer who underwent resection between 1990 and 2009. Surgical treatment of the 1st tumor consisted of 39 lobectomies and 3 segmentectomies, and 3 wedge resections. The 2nd tumor was removed by means of a lobectomy in 9 patients, a segmentectomy in 17 patients, a wedge resection in 19 patients. No postoperative mortality was observed. Histologic classification was similar in 86.4% of patients and different in 13.6%. Postoperative stage of the 2nd tumor was IA in 31 patients, IB in 7, IIA in 1, IIIA in 3, IIIB in 3. Median follow-up was 48.4 months after 2nd operation. The 5-year survival rate was 90.8% after 1st operation and 85.6% after 2nd operation. The 5-year survival rate in patients with p-stage IA was 96.4%. Patients with metachronous lung cancer could have a favorable outcome. Thus we need careful follow-up of the patients after treatment on the 1st lung cancer, and moreover an aggressive surgical treatment is recommended as long as their performance state or residual pulmonary function allows.

Salvage surgery to treat tumor regrowth after stereotactic body radiotherapy in primary non-small cell lung cancer.

BACKGROUND: Stereotactic body radiotherapy (SBRT) is considered to be an effective and safe treatment in patients with primary lung cancer. If local recurrence is confirmed following SBRT, surgical treatment is a possibility. The present study aimed to clarify the safety and survival outcomes of salvage surgery in primary lung cancer patients with local recurrence following SBRT. METHODS: All subjects were patients with primary lung cancer who underwent surgical treatment for local recurrence following SBRT during the period from July 2005 to July 2015. We evaluated the reason for SBRT selection, the surgical procedure, postoperative complications, and prognosis. RESULTS: Of 932 patients underwent SBRT as treatment for primary lung cancer, 48 patients (5.2%) had local recurrence alone and 19 patients (2.0%) underwent salvage surgery. SBRT was selected in eight medically operable patients who refused surgery, and in 11 patients considered medically inoperable by their pulmonologist. Lobectomy was performed in 15 patients. Postoperative complications were documented in 4 patients (21.1%). Incomplete resection was performed in 2 patients. Stage progression was confirmed in 7 patients (36.8%). The 5-year overall survival (OS) was 72.5% and the 5-year disease-free survival (DFS) was 65.2%. CONCLUSIONS: We evaluated patients who underwent salvage surgery due to local recurrence of lung cancer following SBRT. We found that salvage surgery could be performed safely without affecting SBRT outcomes. We further infer that cases of complete resection are likely to be associated with good prognosis, and that SBRT should be selected only after careful consideration because complete resection is not possible in all cases.

Expression of 5-fluorouracil-related enzymes in lung cancer: ELISA characterizes enzyme activity and messenger RNA expression.

The enzymes thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD) and orotate phosphoribosyl transferase (OPRT) are involved in the metabolism of the anticancer drug 5-fluorouracil (FU). Expression of TS, DPD and OPRT in cancer tissue has been reported to be associated with sensitivity and/or resistance to 5-FU therapy. However, the role of TS, DPD and OPRT expression in lung cancer has not been fully established. Furthermore, among several measuring methods, it is not clear which method effectively predicts the response to 5-FU therapy. The aim of this study was to analyze the expression of 5-FU-related enzymes using enzyme-linked immunosorbent assay (ELISA) and to examine the correlation of ELISA and the results obtained using different measuring methods such as reverse transcript polymerase chain reaction (RT-PCR), immunohistochemistry, and enzymatic activity. Lung cancer specimens were obtained from 134 patients who underwent curative resection for lung cancer. As a pilot study, enzyme expression of 11 samples was measured using 4 different methods for DPD: RT-PCR, immunohistochemistry, enzymatic activity and ELISA. The relationships between pairs of results were compared, and then enzyme protein expression was measured using ELISA in 119 patients with adenocarcinoma. Of the 4 independent methods, the highest correlation was observed between protein expression measured by ELISA and enzyme activity. The correlation of gene expression and ELISA was also significant. The protein level in stage I adenocarcinoma measured using ELISA was 13.0+/-24.8 ng/mg protein for TS, 362.2+/-264.3 ng/mg protein for DPD and 4.5+/-2.0 ng/mg protein for OPRT. The predictive value of the enzymes for prognosis and the effectiveness of 5-FU was not determined as few recurrences were observed during the short follow-up period. In conclusion, ELISA is a simple and reliable method to measure key enzymes related to 5-FU therapy.

Superior vena cava reconstruction via a posterolateral thoracotomy without venous occlusion for locally advanced lung cancer: report of a case.

We performed a right upper lobectomy with prosthetic replacement of the superior vena cava (SVC) through a posterolateral thoracotomy in a 65-year-old man undergoing complete resection of a locally advanced non-small-cell lung cancer with invasion of the SVC. Instead of using a vascular shunt, the right atrium and a right brachiocephalic vein (BCV) were anastomosed using a ringed polytetrafluoroethylene (PTFE) graft. During the anastomosis, vascular flow was maintained through the left BCV. By using this technique, SVC resection and reconstruction during lung cancer surgery can be safely performed through a posterolateral thoracotomy without blood flow interruption.

Etiologic value of p53 mutation spectra and differences with histology in lung cancers.

A total of 297 resected Japanese non-small cell lung cancers (74 squamous cell carcinomas and 223 adenocarcinomas) were analyzed to evaluate the validity of the p53 mutation spectrum as a fingerprint for mutagenic substances as etiological factors. Frequencies of G-->T transversions in smokers were significantly higher than in non-smokers (P = 0.003) and the average incidence of G-->T at hot spot codons of adduct formation was higher than that in other codons in smokers and in the hot spots in non-smokers. Further, the mutation showed a marked strand bias. G-->A transitions at CpG sites (CpG-->CpA) were equally distributed in smokers and non-smokers, and on both strands. A-->G transitions did not show any variation with smoking status in terms of frequency, but exhibited a marked strand bias. Taken together, the G-->T may be a fingerprint of direct mutagenic action of tobacco-related compounds, the A-->G being a new marker for other environmental chemicals, while the CpG-->CpA may be attributable to endogenous spontaneous mutation, for active in lung carcinogenesis.

Absence of gene mutations in KIT-positive thymic epithelial tumors.

BACKGROUND: Overexpression of KIT, a tyrosine kinase receptor protein encoded by the proto-oncogene c-kit, is observed in human neoplasms such as gastrointestinal stromal tumors (GISTs), myeloproliferative disorders, melanoma and seminoma. In patients with GIST, overexpression of mutated KIT within the tumor is predictive of response to molecular targeted therapy using imatinib. However, the role of KIT expression in thymic carcinoma is not fully understood. METHODS: Thymic epithelial tumors from 37 patients (17 thymic carcinomas and 20 thymomas) were examined. Immunohistochemical staining with anti-KIT polyclonal antibody and anti-CD5 was performed. Mutation analyses in the juxtamembrane domains, exons 9 and 11, and in the tyrosine kinase domains, exons 13 and 17, were undertaken using polymerase chain reaction (PCR) and direct DNA sequencing in KIT-positive samples. RESULTS: KIT- and CD5-positive staining was observed only in thymic carcinoma. Percentage of positive staining was 100% in squamous cell carcinoma, with no positive staining in other histologies, including atypical carcinoid. Mutation analysis of the KIT gene was performed in 11 squamous cell carcinomas, 1 adenocarcinoma and 1 adenosquamous cell carcinoma. None of the tested samples showed mutations in any of the four exons. CONCLUSIONS: Squamous cell carcinoma of the thymus frequently expressed KIT and CD5 proteins, whereas other tumors did not. Unlike GIST, overexpression of KIT does not necessarily indicate gene mutation in thymic carcinoma. KIT and CD5 appear useful for evaluating and subtyping thymic epithelial tumors.

Isolated Adrenocorticotropin Deficiency due to Nivolumab-induced Hypophysitis in a Patient with Advanced Lung Adenocarcinoma: A Case Report and Literature Review.

A 63-year-old Japanese woman with advanced lung adenocarcinoma developed isolated adrenocorticotropin deficiency caused by immune checkpoint inhibitor (ICI)-related hypophysitis following 8 months of nivolumab therapy. Prompt corticosteroid replacement therapy effectively relieved her secondary adrenal insufficiency symptoms and allowed her to pursue nivolumab therapy, which had been effective for the control of lung adenocarcinoma. Human leukocyte antigen (HLA) typing revealed the presence of the DRB1*04:05-DQA1*03:03-DQB1*04:01 haplotype, which is associated with susceptibility to autoimmune polyglandular syndrome with pituitary disorder in the Japanese population. This case suggests that genetic factors, such as HLA, contribute to the development of endocrinopathies induced by ICIs.

Lung resection combined with percutaneous coronary intervention using cypher stents: a case report.

Treatment of concomitant severe coronary artery disease and lung cancer is a complicated issue. The present study describes a case of a 65-year-old man with coronary artery disease and primary lung cancer that was successfully treated with lung resection and percutaneous coronary intervention (PCI) using Cypher stents. Prior to lung resection, the patient underwent a PCI for diffuse stenosis of the right coronary artery and the circumflex artery. Cypher stents were deployed for both lesions. Five days after stent implantation, a right lower lobectomy was performed successfully. To the best of our knowledge, this is the first report of lung resection and PCI using Cypher stents.

Cardiac tamponade communicating with a posterior mediastinal chylocele after esophagectomy.

A 75-year-old male received neoadjuvant chemotherapy for locally advanced squamous cell carcinoma of the mid-thoracic esophagus, followed by right transthoracic esophagectomy with extended mediastinal lymphadenectomy. Cardiac tamponade developed on postoperative Days 1 and 13, for which emergency ultrasound-guided drainage was required. Pericardial drainage fluid became chylous after administration of polymeric formula. A computed tomography scan demonstrated the presence of a retrocardiac fluid collection, encompassed by the left pulmonary vein and left atrium, descending aorta and vertebral column. Based on these findings, the diagnosis of chylopericardial tamponade communicating with a posterior mediastinal chylocele was made. The ligation of the thoracic duct was successfully performed via the left-sided thoracoscopic approach on postoperative Day 20 and the clinical course after the second operation was uneventful. The possible mechanisms of this exceptionally rare complication after esophagectomy were discussed.

Resection of a large ectopic parathyroid adenoma: A case report.

INTRODUCTION: Parathyroid adenomas are the most common cause of primary hyperparathyroidism. However, cases of parathyroid adenomas greater than 4cm with osteitis fibrosa cystica are extremely rare. Herein, we report a case of resection of a large ectopic mediastinal parathyroid adenoma. CASE PRESENTATIONS: A 46-year-old female with chief complaints of bone pain and gait disturbance was referred to our hospital. Physical examination revealed many mobile teeth in her oral cavity, distortion of the vertebral body, and bowlegs. Laboratory tests showed hypercalcemia, hypophosphatemia, and elevated serum levels of intact parathyroid hormone. Chest CT revealed a 42-mm well-defined, enhancing mass in front of the left-sided tracheal bifurcation. Her findings were diagnosed as primary hyperparathyroidism due to an ectopic mediastinal parathyroid tumor. We performed a median sternotomy and resected the tumor. The tumor was a solid, yellowish-brown mass measuring 42×42 mm. Pathologically, the tumor consisted mainly of chief cells with some oxyphil cells; there were no necrotic areas or nuclear atypia, and few mitotic figures. We diagnosed the tumor as an ectopic mediastinal parathyroid adenoma. Eight months after the resection, her serum calcium, phosphorus, and intact PTH levels were normal. DISCUSSION AND CONCLUSIONS: Parathyroid adenomas and parathyroid carcinomas have disparate natural histories, but they can be difficult to differentiate on the basis of preoperative clinical characteristics. We believe that long-term follow-up of these cases is required because there have been few reports on the postoperative natural history of large parathyroid adenomas.

A Case of Ectopic ACTH-Producing Pulmonary Carcinoid Arising in an Extralobar Pulmonary Sequestration.

Ectopic adrenocorticotrophic hormone (ACTH)-producing bronchopulmonary carcinoid arising in a bronchopulmonary sequestration is extremely rare. The case of a 67-year-old woman with a 1.7-cm nodule in the mediastinal side of the left lower lobe is presented. At 52 years of age, she was diagnosed as having ACTH-dependent Cushing's syndrome (CS). However, no ectopic source of ACTH-secretion was detected. Seven years later, she underwent a bilateral adrenalectomy because of aggravation of her health condition. This time, tumor excision was performed by thoracoscopic surgery. The tumor adhered sparsely to the mediastinal pleura and the left lower lobe and was bluntly separated from these tissues. Pathologically, the tumor was a typical carcinoid arising in an extralobar pulmonary sequestration. Immunohistochemical staining confirmed the secretion of ACTH by bronchopulmonary carcinoid tumor cells. After surgery, the serum ACTH level was almost normalized, and the dexamethasone (1 mg) suppression test showed significant suppression of ACTH.

Surgical Outcomes of Lung Cancer Patients with Combined Pulmonary Fibrosis and Emphysema and Those with Idiopathic Pulmonary Fibrosis without Emphysema.

OBJECTIVES: Combined pulmonary fibrosis and emphysema (CPFE) is a unique disorder. The aim of this study was to compare the surgical outcomes of lung cancer patients with CPFE and those with idiopathic pulmonary fibrosis (IPF) without emphysema. METHODS: A total of 1548 patients who underwent surgery for primary lung cancer between January 2001 and December 2012 were retrospectively reviewed. RESULTS: Of the 1548 patients, 55 (3.6%) had CPFE on computed tomography (CT), and 45 (2.9%) had IPF without emphysema. The overall and disease-free 5-year survival rates for patients with CPFE were not significantly worse than those for patients with IPF without emphysema (24.9% vs. 36.8%, p = 0.814; 39.8% vs. 39.3%, p = 0.653, respectively). Overall, 21 (38.1%) patients with CPFE and nine patients (20.0%) with IPF without emphysema developed postoperative cardiopulmonary complications. Patients with CPFE had significantly more postoperative cardiopulmonary complications involving pulmonary air leakage for >6 days, hypoxemia, and arrhythmia than patients with IPF without emphysema (p = 0.048). CONCLUSIONS: There was no significant difference in survival after surgical treatment between CPFE patients and IPF patients without emphysema, but CPFE patients had significantly higher morbidity than IPF patients without emphysema.

Lobectomy and limited resection in small-sized peripheral non-small cell lung cancer.

BACKGROUND: Although lobectomy is the standard surgical procedure for non-small cell lung cancer (NSCLC), recent studies show favorable outcomes after limited resection in patients with small-sized peripheral tumors. We conducted a randomized controlled trial of such patients to estimate postoperative outcomes and pulmonary function following these surgical techniques. METHODS: Between 2005 and 2008, eligible patients with tumors of 2 cm or less were randomly assigned 1:1 to undergo lobectomy or limited resection; 32 and 33 NSCLC patients in each group, respectively, were analyzed. The primary end points were 5-year overall survival (OS) and disease-free survival (DFS), while the secondary end points were postoperative pulmonary function including forced vital capacity (FVC) and forced expiratory volume in 1 second (FEV1). RESULTS: The 5-year OS rates were 93.8% and 90.9% in the lobectomy and limited resection groups, respectively (P=0.921). The 5-year DFS rates were 93.8% and 90.9% in the lobectomy and limited resection groups, respectively (P=0.714). These rates did not differ significantly between the two resection groups. The median postoperative/preoperative FVC ratios were 84.1% and 90.0% in the lobectomy and limited resection groups, respectively, while the median postoperative/preoperative FEV1 ratios were 81.9% and 89.1%, respectively. Both ratios were significantly higher in the limited resection group (P=0.032 and P=0.005 for FVC and FEV1 ratios, respectively). CONCLUSIONS: A similar outcome, with more preserved postoperative pulmonary function, was observed in patients who underwent limited resection compared to those who underwent lobectomy. Ongoing large-scale multi-institutional prospective randomized trials of lobar versus sublobar resection in patients with small peripheral NSCLCs will hopefully provide definitive information about intentional limited resection of small peripheral tumors.