Pulmonary Metastasectomy after Radiofrequency Ablation of Hepatocellular Carcinoma.

Introduction: Single distant metastases after radiofrequency ablation (RFA) of hepatocellular carcinoma (HCC) are rare. There are no guidelines for treating patients without liver tumors after resecting lung metastases. Case Presentation: Here, we report a patient with HCC recurring as a single lung metastasis 14 months after RFA. A 76-year-old woman with primary biliary cholangitis without hepatitis B virus or hepatitis C virus infection had been treated by RFA for a single 16-mm-sized HCC lesion in liver S8. Fourteen months thereafter, despite lack of intrahepatic recurrence, a single new 26-mm-sized mass was found in S10 of the right lung. The patient underwent right lower lobectomy. The histopathological diagnosis was HCC metastasis. Because no residual disease could be found, she was followed up without any additional treatment after surgery. She remains alive with no signs of recurrence 3 years later. Conclusion: HCC patients who relapse with lung metastases but without intrahepatic recurrence after RFA are extremely rare, especially when RFA is used to treat HCC lesions <30 mm. However, it should be noted that, although rare, HCC may recur in the form of extrahepatic metastases after RFA. Furthermore, it is suggested that, as in the presently-described case, at least some patients without intrahepatic recurrence whose lung metastases are completely resected have a good prognosis even without additional treatment for HCC.

Case report: Postoperative abdominal recurrence of pulmonary pleomorphic carcinoma showed a dramatic response to S-1 after pembrolizumab.

The patient was an 80-year-old woman with combined pulmonary fibrosis and emphysema. She was diagnosed with pulmonary pleomorphic carcinoma in the right upper lobe, which relapsed 18 months after the operation. Computed tomography showed a mass in contact with the posterior wall of the lower part of the stomach. The patient was treated with two cycles of pembrolizumab, but the disease progressed. She was treated with S-1 as second-line therapy, resulting in tumor-shrinking after two cycles. Progression was not observed over the next twelve months. We report a rare case involving S-1 after immune checkpoint inhibitor treatment.

CD40 Expression in Human Esophageal Squamous Cell Carcinoma Is Associated with Tumor Progression and Lymph Node Metastasis.

BACKGROUND: The co-stimulatory molecule cluster of differentiation 40 (CD40) is widely expressed in various types of malignant tumors, but its role remains unclear. The purpose of this study was to investigate the relationship between CD40 expression and clinicopathological variables in patients with esophageal squamous cell carcinoma (ESCC), as well as the function of CD40 expressed on ESCC tumor cells in vitro. MATERIALS AND METHODS: Tumor specimens of patients who underwent surgical resection for ESCC were immunohistochemically analyzed for CD40 expression. RESULTS: Of the 122 specimens, 45 (37%) were positive for CD40. Significant positive correlation was found between CD40 expression and p-stage (p=0.0011), histopathological grade (p=0.0143), pT-classification (p=0.0011), and pN-classification (p=0.0007). Survival of patients with stage III and IV disease with positive CD40 expression was significantly shorter than that of those with negative expression (log-rank test, p=0.0422). In in vitro analysis, while the addition of recombinant human CD154 did not inhibit growth, it did induce a significant increase in interleukin 6 production in ESCC cell lines. CONCLUSION: These results suggest that functional expression of CD40 on tumor cells might play an important role in tumor progression and lymph node metastasis in ESCC.

A case of Castleman's disease with myasthenia gravis.

A rare case of Castleman's disease with myasthenia gravis is reported. A 55-year-old woman with bilateral ptosis, speech impairment, and severe dyspnea had been previously diagnosed with myasthenia gravis. Computed tomography showed a 5 cm × 3 cm paratracheal mass in the mediastinum, thought to be an ectopic thymoma. Two days after surgical resection, the patient suddenly developed dyspnea. Postoperative myasthenic crisis was diagnosed, and plasmapheresis was performed. Her general condition improved, and her subsequent course was uneventful. The final pathological diagnosis was mediastinal solitary Castleman's disease, hyaline vascular type. Castleman's disease with myasthenia gravis is especially rare. One of the serious complications is postoperative myasthenic crisis. For patients with myasthenia gravis, the rate of postoperative myasthenic crisis seems significantly higher in Castleman's disease patients than in patients with thymic epithelial tumors. Castleman's disease with myasthenia gravis is discussed along with a review of the literature.

Endobronchial closure of a bronchopleural fistula using a fibrin glue-coated collagen patch and fibrin glue.

Bronchopleural fistulas associated with empyema can occur as life-threatening sequelae after pulmonary resection, occurring most frequently after pneumonectomy. Three bronchopleural fistulas, 5-6 mm in diameter, were successfully treated using a fibrin glue-coated collagen patch (FGCCP) and fibrin glue (FG) at the site of a bronchopleural fistula. Through the clinical experiences, we introduce the methodology to perform the endobronchial closure of bronchopleural fistulas.Data were collected by reviewing the clinical charts of patients diagnosed with post-lobectomy bronchopleural fistula at Sapporo Minami-Sanjo Hospital from June 2004 to December 2010. Bronchopleural fistula was diagnosed by means of endoscopic visualization. Three cases of post-lobectomy and one case of post-pneumonectomy bronchopleural fistula were collected.A FGCCP fragment was packed within the fistula, and the fragment grasped with the forceps was kept in this position for approximately a minute, a time during which a FGCCP becomes adhesive, and the patch fragment was released. After releasing the patch fragment, the FG was applied directly on the FGCCP using a two-channel catheter.There have been few reports of the bronchoscopic closure of bronchopleural fistulas using a FGCCP and FG. Closure of small bronchopleural fistulas with the application of a FGCCP and FG may offer a valuable therapeutic alternative.

Reduced port video-assisted thoracoscopic surgery using a needle scope for lung and mediastinal lesions.

OBJECTIVES: There are many recent and minimally invasive surgical innovations, yet there has been little evaluation of the limitations of such techniques, particularly those related to video-assisted thoracoscopic surgery. The aims of this study were to determine the usefulness and limitations of video-assisted thoracoscopic surgery using one-port access and needle scope and to evaluate the feasibility of this procedure based on our institutional experience. METHODS: This retrospective study involved 127 patients who underwent video-assisted thoracoscopic surgery using the one-window and puncture method at our institute from 1997 to 2011. One hundred patients underwent surgical treatment and 27 underwent diagnostic procedures. If there was one lesion present with only mild adhesion that did not require lymph node dissection, we decided to opt for the one-direction approach that provisionally indicates the one-window and puncture method. We compared the conversion and success groups for factors like age, sex, laterality of surgery, objective of surgery, target organ and surgery location. RESULTS: Of 127 cases, 115 (91%) successfully underwent the one-window and puncture procedure. Twelve cases (9%) were converted to the two-window method or thoracotomy. Compared with those targeting the lung, patients with mediastinal lesions demonstrated a higher tendency for conversion (P<0.05). However, age (P=0.89), sex (P=0.46), laterality of surgery (P=0.34) and purpose of surgery (P=0.68) did not show any significant differences between the groups. CONCLUSIONS: For lung and mediastinal diseases, video-assisted thoracoscopic surgery with the one-window and puncture method can be performed at any location (upper, middle and lower lobe of lung and anterior, middle and posterior of the mediastinum) under limited indications that include the possibility of one-way resection, mild adhesion and no requirement of lymph node dissection. Under provisional criteria, the procedure may be feasible.

Method for the validation of immunohistochemical staining using SCID mouse xenografts: expression of CD40 and CD154 in human non-small cell lung cancer.

This report proposes a concept for the standardization of immunohistochemical evaluation. Immunohistochemical staining has several problems associated with the sensitivity of the technical process and standardization of the assessment of potent staining. We provided data focusing on this concept through immunostaining for CD154 in non-small cell lung cancer (NSCLC). We used two types of anti-CD154 antibody as primary antibodies in immunohistochemical staining, as previously reported. Western blot analysis confirmed strong CD154 expression in the cultured cell line PC10, but not in LK2. We also assessed CD154 expression in SCID mouse xenografts of these cell lines. SCID xenograft data on western blot analysis were consistent with those of cultured cell lines. These xenografts could thus be used as positive or negative tissue controls for CD154 immunostaining. Primary antibodies should therefore be confirmed as recognizing target lesions, while control tissue specimens should be objectively confirmed as having target products using another experimental method. Our method would allow results to be unified at more than one laboratory and could act as an objective control assessment method in immunohistochemistry.

Optimal predictive value of preoperative serum carcinoembryonic antigen for surgical outcomes in stage I non-small cell lung cancer: differences according to histology and smoking status.

BACKGROUND: The cutoff value of preoperative serum carcinoembryonic antigen (CEA) levels has not been investigated using appropriate subgroup analyses for non-small cell lung carcinoma (NSCLC). This study was undertaken to determine whether the most predictive preoperative CEA level for risk of recurrence differs according to histological type, and how smoking status influences predictive values in Stage I NSCLC. METHODS: Subjects comprised Stage I NSCLC patients [141 patients with adenocarcinoma (ADC) and 36 with squamous cell carcinoma (SCC)]. RESULTS: In patients with Stage I ADC, recurrence-free survival (RFS) differed most significantly at a preoperative CEA level of 2.5 ng/ml, regardless of smoking status. Cases with preoperative CEA >2.5 ng/ml correlated with male sex, high maximum standard uptake value on (18) F-fluorodeoxyglucose positron emission tomography, poorer histopathological grade, lymphatic invasion, and smoking status. Importantly, preoperative CEA >2.5 ng/ml was identified as an independent risk factor for recurrence (P = 0.0015). Conversely, in patients with SCC, a preoperative CEA level of 3.0 ng/ml was the most predictive threshold. CONCLUSIONS: Thresholds of preoperative CEA should be considered when predicting risk of relapse, even if these levels are within normal limits, as optimal cutoff levels may vary according to histological type.

[Indication of video-assisted thoracic surgery for mediastinal mass lesions].

BACKGROUND: Most of mediastinal tumors are benign cysts and neoplasms. Resection is indicated for cystic lesions because of possibility of malignancy, compression symptom and possible rupture in future. However careful observation might be appropriate for asymptomatic tumors without risk of malignancy. Although video-assisted thoracoscopic surgery (VATS) is increasingly performed, its indication is still controversial. PATIENTS AND RESULTS: Among 37 mediastinal cystic lesions with confirmed pathological diagnosis, 17 were neoplasms. All of 20 non-neoplastic lesions have cyst wall thinner than 5 mm. Five cases( 29%) of neoplastic lesions have cyst wall thinner than 5 mm. Three of them underwent preoperative fluorodeoxyglucose-positron emission tomography( FDG-PET) or PET-computed tomography( CT). All 3 neoplastic lesions with thin wall showed accumulation of FDG. None of non-neoplastic cyst had FDG accumulation. Ninety-seven patients underwent surgical resection for mediastinal tumors. Out of 51 VATS, 2 were converted to open thoracotomy. One patient with thymoma had ipsilateral pleural recurrence after VATS. Tumor sizes of those 3 patients were larger than 7 cm. CONCLUSIONS: Cystic mediastinal tumor with wall thickness less than 5 mm and no FDG accumulation might be observed without resection because it is very unlikely to be a neoplasm. Mediastinal tumor larger than 7 cm might not be suitable for VATS.

Angiolymphatic invasion exerts a strong impact on surgical outcomes for stage I lung adenocarcinoma, but not non-adenocarcinoma.

Angiolymphatic invasion (ALI), representing lymphatic invasion (Ly) and intratumoral vascular invasion (V), is considered to be a useful prognostic factor for pathological stage I non-small cell lung carcinoma (NSCLC). However, the types of tumor for which prognoses are most influenced by ALI positivity have not previously been discussed, nor has the question of whether these findings should influence postoperative therapeutic decision-making after complete resection. The present study investigated 195 cases of stage I NSCLC treated by potentially curative surgical resection of the primary tumor and systematic lymphadenectomy. ALI-positive (ALI(+)) results were found in 31.8% of tumors, and 5.1% exhibited both Ly(+) and V(+). Five-year recurrence-free survival was significantly lower in ALI(+) cases (50.6%) than in ALI(-) cases (85.9%; p<0.0001, log-rank test). In particular, 5-year recurrence-free survival rate was only 10.0% for Ly(+)V(+) cases. ALI(+) correlated with high age, male sex, tumor size (>2.0 cm), elevated preoperative serum carcinoembryonic antigen level (≥5.0 ng/mL), high maximum standard uptake value (SUVmax) on (18)F-fluorodeoxyglucose positron emission tomography (FDG-PET) (≥5.0), pleural invasion, and histological classification of non-adenocarcinoma (ADC). According to histopathological subset analyses, ALI(+) was associated with shorter recurrence-free survival than ALI(-) only among ADC patients (p<0.0001, log-rank test), and not among non-ADC patients (p=0.7710). High preoperative serum CEA level, high SUVmax on FDG-PET, pleural invasion, Ly(+), and V(+) were significant risk factors for recurrence in univariate Cox survival analysis among stage I ADC patients. Importantly, Ly(+) and V(+) were identified as independent risk factors for recurrence by multivariate analysis. Histopathological detection of ALI as a risk factor for recurrence should be considered for inclusion in the staging criteria and as additional information for determining postoperative adjuvant treatment of stage I NSCLC, particularly among ADC patients, but not among non-ADC patients.

Overexpression of CDC20 predicts poor prognosis in primary non-small cell lung cancer patients.

BACKGROUND: This study examined the expression of CDC20 in human non-small cell lung cancer (NSCLC), explored its clinicopathological significance, and evaluated as a potential prognostic marker. METHODS: A total of 362 cases of NSCLCs were analyzed immunohistochemically on tissue microarrays (TMAs). Additionally, the immunoreactivity of mitotic arrest defective protein 2 (MAD2) was also studied. The clinicopathological implications of these molecules were analyzed statistically. RESULTS: High-level CDC20 protein expression (CDC20-H) was detected in 71 cases (19.6%). Additionally, CDC20-H was correlated with male sex, pT status, pleural invasion, and non-adenocarcinoma (non-ADC) histology. Significant correlation between CDC20 and MAD2 expression was found. NSCLC patients with tumor exhibiting CDC20-H showed significantly shorter 5-year overall survival (P=0.0007). According to subset analyses, CDC20-H was associated with shorter survival than CDC20-L only among ADC patients (P=0.0008), and not among squamous cell carcinoma (SCC) patients (P=0.5100). Importantly, CDC20-H was also identified as an independent prognostic factor in multivariate analysis (P=0.0065). CONCLUSIONS: CDC20 was a negative prognostic marker with significance in patients with resected NSCLC, particularly those with ADC histology. These results provide additional information for determining postoperative adjuvant treatment.

Spontaneous pneumothorax in a patient with dendriform pulmonary ossification: report of a case.

We report herein the rare case of a patient with dendriform pulmonary ossification (DPO) who developed spontaneous pneumothorax. A 33-year-old male with a history of bronchial asthma presented with pneumothorax of the left lung. An intraoperative inspection revealed no findings of bullae in the entire left lung, but inflammatory pleural changes were identified on the interlobular surface of the left lower lobe. In addition, hard, twig-like configurations were clearly palpable in the subpleural parenchyma and were resected. A histological examination showed acicular bone formations containing myeloid tissue and marrow fat in the lung. DPO was thus diagnosed, and the bony spines were considered to have caused a rupture of the elastic fiber layer of the visceral pleura. DPO may thus have been directly responsible for the pneumothorax in this case.

Overexpression of KIAA0101 predicts poor prognosis in primary lung cancer patients.

High expression of KIAA0101 (p15(PAF)/OEATC-1) which contains a proliferating cell nuclear antigen (PCNA)-binding motif, a key factor in DNA repair and/or apoptosis and cell cycle regulation, has been observed in a variety of human malignancies. The aim of this study was to observe the expression of KIAA0101 in human non-small-cell lung cancer (NSCLC), explore its clinicopathological significance and evaluate KIAA0101 expression as a potential prognostic marker. KIAA0101 transcript was found to be overexpressed in the great majority of lung cancers by semi-quantitative RT-PCR. A total of 357 NSCLCs were analyzed immunohistochemically on tissue microarrays. High-level KIAA0101 expression was observed in 33.9% (121 of 357 cases), and correlated with male gender (P<0.0001), tumor progression (pT status) (P=0.0008), lymph node metastasis (pN status) (P=0.0003), non-adenocarcinoma histological classification (P<0.0001), and smoking history (P<0.0001), but not with patient age or pleural invasion. Patients with tumors displaying high-level KIAA0101 expression showed significantly shorter survival (P<0.0001, log-rank test). Similarly, gender, pT status, pN status, pleural invasion, histological classification, and smoking history were significant prognostic markers in univariate Cox survival analysis. Importantly, high-level KIAA0101 expression was also identified as an independent prognostic factor by multivariate analysis (P=0.0320). These results provide additional information for determining postoperative adjuvant treatment of NSCLC.

18F-FDG uptake in primary lung cancer as a predictor of intratumoral vessel invasion.

OBJECTIVE: This study investigated how fluorodeoxyglucose (FDG) uptake on PET in the primary tumor may predict intratumoral vessel invasion (IVI) in it. METHODS: A total of 512 patients with lung neoplasms determined by a surgical procedure and histopathological diagnosis had undergone FDG-PET scanning. RESULTS: Among the 440 cases confirmed to be malignant, the maximum standardized uptake value (SUV(max)) was significantly lower in IVI-negative cases than IVI-positive cases (P < 0.001). In the substudy on adenocarcinoma (AC), SUV(max) was significantly lower in IVI-negative cases too (P < 0.001), but SUV(max) in squamous cell carcinoma was without significant difference. In addition, IVI was associated with a significantly higher probability of lymph node metastasis (P < 0.001). CONCLUSIONS: This study indicates that a malignant lung tumor with higher SUV(max) has a significantly higher probability of IVI and lymph node metastasis, particularly if the malignancy is an AC.

Pleomorphic carcinoma of the lung arising in a patient with Li-Fraumeni syndrome: report of a case.

We herein report the case of a patient with Li-Fraumeni syndrome (LFS) who developed lung pleomorphic carcinoma. A 28-year-old female patient with a family history of early-onset malignancies was diagnosed with lung carcinoma and treated by surgical resection. Histological examination revealed a heterogeneous tumor with epithelial and mesenchymal components. The final pathological diagnosis was pulmonary pleomorphic carcinoma. In this patient, a constitutional mutation at codon 213 in exon 6 of the p53 gene was identified in the peripheral lymphocytes and the resected tumor, and LFS was suspected. This mutation causes a nonsense mutation (Arg-to-Stop codon) that has been shown to attenuate p53 function. This is the first report of pulmonary pleomorphic carcinoma developing in an LFS patient, and may suggest a relationship between germline p53 mutation and carcinogenesis in pulmonary pleomorphic carcinoma.

Overexpression of MAD2 predicts clinical outcome in primary lung cancer patients.

High-level expression of mitotic arrest defective protein 2 (MAD2), a central component of the spindle assembly checkpoint, has been observed in a variety of human malignancies. Aim of the present study was to observe the expression of MAD2 in human non-small-cell lung cancer (NSCLC) and explore its clinicopathologic significance and evaluate MAD2 expression as a prognostic marker. MAD2 transcript was found to be overexpressed in the great majority of lung cancers by semi-quantitative RT-PCR. A total of 358 NSCLCs were analyzed immunohistochemically on tissue microarrays. High-level MAD2 expression was observed in 26.3% (94 of 358 cases), and correlated with male sex (P=0.0002), tumor progression (pT status) (P=0.0009), visceral or parietal pleural invasion (P=0.0151), non-adenocarcinoma, histological classification (P<0.0001), and smoking history (P=0.0022), but not with patient age or lymph node metastasis (pN status). Patients with tumors displaying high-level MAD2 expression showed significantly shorter survival (P<0.0001, log-rank test). Similarly, gender, pT status, pN status, pleural invasion, histological classification, and smoking history were significant prognostic markers in univariate Cox survival analysis. Importantly, high-level MAD2 expression was also identified as an independent prognostic factor by multivariate analysis (P=0.0076). These results provide additional prognostic information for surgical treatment of NSCLC.

The CD40-CD154 interaction would correlate with proliferation and immune escape in pancreatic ductal adenocarcinoma.

BACKGROUND: CD40 and CD154 are associated with lymphocyte signaling pathways and they are also expressed in some malignant neoplasms, but the significance in pancreatic cancer is unknown. METHODS: Eighty pancreatic cancer specimens were stained immunohistochemically, and the results were correlated with the patients' clinicopathologic features. Subsequently, in vitro analysis of CD40-CD154 signaling was performed. RESULT: Immunohistochemical analysis of tumor cells showed that 29 patients (36.3%) were positive for CD40, and 17 patients (21.3%) had very high CD154 expression. The survival of patients who had very high CD154 expression was significantly better than that of others (P = 0.0198). Univariate and multivariate analysis revealed that very high CD154 expression in cancer cells was not an independent, favorable prognostic factor (risk ratio, 0.493; P = 0.0224). On in vitro proliferation assay, the growth of PK-45P and KP-4 cells was blocked by CD40 and CD154 blocking antibodies. Moreover, on in vitro cytokine assay, Th-2 cytokines from PK-45P and SUIT-2 were blocked by CD40 or CD154 blocking antibody. CONCLUSION: These results suggest that the CD40-CD154 interaction would correlate with cell proliferation and secretion of cytokines in PDAC cells, and CD154 overexpression could be a favorable prognostic factor in PDAC patients.

Adenovirus-mediated eukaryotic initiation factor 4E binding protein-1 in combination with rapamycin inhibits tumor growth of pancreatic ductal adenocarcinoma in vivo.

Over-expression of eIF4E indicates a poor prognosis in different tumors. In the present study, we investigated the frequency of eIF4E, 4E-BP1 and phosphorylated 4E-BP1 expression in PDAC cell lines, gastric carcinoma (GC) cell lines and human embryonic pancreatic cells, as well as gene therapy using translation repressor gene 4E-BP1 in combination with the mTOR inhibitor rapamycin. We also assessed the significance of eIF4E expression in 80 PDAC cases. Combination therapy of adenovirus vector-delivered 4E-BP1 gene and rapamycin was administered to determine their growth inhibition effect in vitro and in vivo in mice. Our study revealed that all PDAC cell lines, GC cell lines and human embryonic pancreas-derived cells expressed the 25-kDa eIF4E protein (MIAPaca-2 cells also expressed the 13-kDa protein 4E-BP1). The 80 PDAC specimens showed a heterogeneous pattern of eIF4E staining. No significant correlation between eIF4E expression and TNM classification was found. Adenovirus vectors Ad-4E-BP1 and Ad-GFP efficiently showed transgenic expression with hyperphosphorylation of 4E-BP1; however, insignificant growth inhibition of the PDAC and GC cell lines was observed. Combination therapy with rapamycin significantly inhibited proliferation and tumor growth in vitro as well as in vivo. Therefore, combination of Ad 4E-BP1 and rapamycin may be a more effective adjuvant therapy.

Up-regulation of CD40 with juxtacrine activity in human nonsmall lung cancer cells correlates with poor prognosis.

BACKGROUND: CD40 and its ligand, CD154, play a regulatory role in several signaling pathways among lymphocytes. Recently, it was reported that CD40 is expressed in several malignant tumors. However, the clinical impact of CD40 expression in nonsmall cell lung cancer has not been studied widely. METHODS: One hundred twenty-nine surgical specimens of nonsmall cell lung cancer were assessed immunohistochemically for CD40 and CD154 expression, and that expression was correlated with patients' clinicopathologic parameters and outcome. Subsequently, in vitro analysis of CD40-CD154 signaling was performed. RESULTS: Immunohistochemical staining of tumor cells confirmed that 67 patients (51.9%) were positive for CD40, and 76 patients (58.9%) were positive for CD154. The survival of patients who had tumors that were negative for CD40 was significantly better than the survival of patients who had tumors that were positive for CD40 (P = .0004). Multivariate analysis using a Cox regression model indicated that CD40 expression in cancer cells is an independent, unfavorable prognostic factor (risk ratio, 1.855; P = .0403). By using an in vitro juxtacrine growth factor assay, the growth of LK2 cells (CD40-positive/CD154-negative) was accelerated by CD154-positive cancer cells, such as PC10 cells (CD40-negative/CD154-positive), by a juxtacrine mechanism. CONCLUSIONS: The current results suggested that CD40 expression in tumors is associated with a poor prognosis and that the juxtacrine interaction of CD40-CD154 among cancer cells facilitates the development of malignant potential in nonsmall cell lung cancer.