Yujiro Yokoyama

Mutational analysis of multiple lung cancers: Discrimination between primary and metastatic lung cancers by genomic profile

In cases of multiple lung cancers, individual tumors may represent either a primary lung cancer or both primary and metastatic lung cancers. Treatment selection varies depending on such features, and this discrimination is critically important in predicting prognosis. The present study was undertaken to determine the efficacy and validity of mutation analysis as a means of determining whether multiple lung cancers are primary or metastatic in nature. The study involved 12 patients who underwent surgery in our department for multiple lung cancers between July 2014 and March 2016. Tumor cells were collected from formalin-fixed paraffin-embedded tissues of the primary lesions by using laser capture microdissection, and targeted sequencing of 53 lung cancer-related genes was performed. In surgically treated patients with multiple lung cancers, the driver mutation profile differed among the individual tumors. Meanwhile, in a case of a solitary lung tumor that appeared after surgery for double primary lung cancers, gene mutation analysis using a bronchoscopic biopsy sample revealed a gene mutation profile consistent with the surgically resected specimen, thus demonstrating that the tumor in this case was metastatic. In cases of multiple lung cancers, the comparison of driver mutation profiles clarifies the clonal origin of the tumors and enables discrimination between primary and metastatic tumors.

New therapeutic targets for pulmonary sarcomatoid carcinomas based on their genomic and phylogenetic profiles

Objectives Pulmonary sarcomatoid carcinomas are rare and generally aggressive tumors composed of carcinomatous and sarcomatous components; however, the evolution of sarcomatoid cancer has not been elucidated. Here, we aimed to evaluate the mutational profiles and phylogeny of sarcomatoid carcinomas using next generation sequencing and in-silico analysis to facilitate the development of novel therapies. Methods Four patients who underwent surgery for sarcomatoid cancer were enrolled. Cancer cells were collected from carcinomatous and sarcomatous components in each tumor by laser capture microdissection. Next-generation sequencing was performed in each component, and the mutation profiles were compared. For further inference of phylogenies, phylogenetic and PyClone analyses were performed. Mismatch repair disturbance and programmed death ligand-1 (PD-L1) expression were also evaluated. Results Comparative genetic analysis of different histological areas revealed that the separate components shared several common mutations, which showed relatively high cellular prevalence in the PyClone statistical inference. Phylogenetic analysis showed that the sarcomatous component had ramified from the carcinomatous component in the early phase of the evolution process and accumulated a number of mutations that were different from those of the carcinomatous component. Moreover, microsatellite instability was detected in a case of sarcomatoid cancer and PD-L1 was strongly positive (≥ 50%) in all sarcomatoid cancers. Conclusions Our data suggest that sarcomatoid carcinoma evolves from a common ancestral clone, and its phylogenetic features may reflect high-grade malignancy in pulmonary sarcomatoid carcinoma. High tumor mutation burden and strong PD-L1 staining may provide a rationale for the use of targeted immunotherapies in pulmonary sarcomatoid carcinomas.

Distribution of circulating tumor DNA in lung cancer: analysis of the primary lung and bone marrow along with the pulmonary venous and peripheral blood

Circulating tumor DNA (ctDNA), extracted from plasma, is a non-invasive surrogate biomarker. However, the distribution of ctDNA in the body still remains to be elucidated. In this study, resected lung tumors, with simultaneous blood and bone marrow samples, were analyzed to elucidate the distribution of ctDNA. Rib bone marrow, pulmonary venous blood (Pul.V) and peripheral blood (Peri.B) were obtained from 30 patients. The liquid samples were divided into cell pellets and supernatant by centrifugation; a total of 212 DNA samples were subjected to massively parallel sequencing. ctDNA was detected in 5 patients. Given that the frequency of mutations in the primary tumor was considered to be 100%, those in the other specimens were as follows; Pul.V plasma 20%, Peri.B plasma 11%, and the other samples 0%. Furthermore, ctDNA reflected the predominant mutations in the primary lesion. Clinically, the presence of ctDNA was associated with significantly poorer survival. These results suggest ctDNA “spill over” into an immediate outflow tract (Pul.V), and from there is disseminated to the entire body. Thus, it can be inferred that ctDNA reflects the cancer progression and could function as a prognostic marker.

A novel technique for chest drain removal using a two layer method with triclosan-coated sutures

In thoracic surgery, a thoracic drain is always inserted after the surgical procedure. Repair of the wound after removal of the thoracic tube is performed postoperatively, but no universally standard methods currently exists for this tube removal. Here we report a technique using triclosan-coated sutures that is used in thoracic surgery in our hospital. There are several advantages of this technique. First, there is no need for stitches removal on follow-up. Second, it prevents the leakage of pleural exudate because of the tight two-layer sutures. In addition, it was observed to be superior in terms of both wound healing and cosmetic aspects, due to the layer-to-layer sutures. The use of triclosan-coated sutures helps prevent infection and empyema is quite unlikely to occur as the result of the tight ligating of the muscular layer using these sutures. We applied this method in 168 patients over a period of 24 months. There were no complications on removal of the chest tube such as infection, fluid leakage or opening of the surgical wound.

Lymph node cancer of the mediastinum with a putative necrotic primary lesion in the lung: a case report

BackgroundAlthough mediastinal lymph node cancer is presumed to originate in the lung, the primary site is usually unidentified, so the pathological course remains unclear. We recently encountered a case of mediastinal lymph node cancer having a putative primary lesion remaining in the lung as a necrotic focus.Case presentationThe patient was a 56-year-old man who visited our department because computed tomography screening had revealed a nodular shadow in the lingular segment. However, on positron emission tomography, fluorine-18 deoxyglucose accumulation was detected in a subcarinal lymph node and not in the nodule in the lingular segment. Biopsy of the lung tumor and the lymph node was performed via minimal thoracotomy. Intraoperative pathologic examination showed necrosis alone and no malignant findings in the lung tumor. By contrast, carcinoma was detected in the lymph node. Additional subcarinal lymph node dissection was performed. Results of postoperative histopathologic examination indicated poorly differentiated adenocarcinoma of the subcarinal lymph node. Meanwhile, the nodule in the lingular segment was speculated to be a spontaneously resolved primary focus of lung cancer.ConclusionsIn this case, the primary lung cancer focus resolved spontaneously after lymph node metastasis, explaining the pathogenesis underlying mediastinal lymph node cancer of unknown primary site. For similar cases of malignancy, aggressive treatment, including surgery, is effective.

Lingular segmentectomy and left lower lobectomy via unique bronchial dissection

In general, bronchoplasty is a procedure performed on tumors located near the hilar area to achieve radical resection while preserving pulmonary function by avoiding pneumonectomy (1-5). Bronchoplasty requires a rather complicated technique that involves bronchial sutures after division of the bronchus and is associated with the risk of serious postoperative complications, including dehiscence of the bronchial sutures (6). We recently encountered a case of adhesion of the interlobar lymph node to the bronchus, which made conventional left lower lobectomy unfeasible. To avoid bronchoplasty, we successfully performed lingular segmentectomy and left lower lobectomy by devising a unique dissection line.

Debulking surgery for venous hemangioma arising from the epicardium: report of a case

BackgroundCardiac hemangiomas are rare benign vascular tumors that can occur in any cardiac layer: endocardium, myocardium, or epicardium. Histologically, cardiac hemangiomas may be classified as capillary, cavernous, or arteriovenous; venous hemangiomas are extremely rare.Case presentationA 46-year-old man reported experiencing precordial discomfort. Computed tomography revealed a massive tumor adjacent to the right ventricle. The right coronary artery was found to be located at the center of the tumor. Cardiovascular angiography showed that the artery was completely encased by the tumor without any obstruction and that the right ventricular lumen was compressed by the tumor. Surgical debulking of the tumor was performed under cardiopulmonary bypass, and the frozen section led to a diagnosis of benign hemangioma. The tumor was debulked as much as possible until the right coronary artery appeared. For decompression of the heart, the pericardium was left open to the thoracic cavity and unsutured. Histopathologic examination revealed a diagnosis of epicardial venous hemangioma.ConclusionsCardiac hemangioma should be included in the differential diagnosis of mediastinal tumor in reference to the location and flow of the coronary artery. Surgical resection, or at least tumor debulking, is required to confirm the diagnosis and prevent further complications and has a favorable clinical outcome.

Detection of tumor-derived DNA dispersed in the airway improves the diagnostic accuracy of bronchoscopy for lung cancer

The diagnostic accuracy of bronchoscopy for detecting lung cancer, especially peripheral lung cancer with lesions outside the endoscopically visible range, remains unsatisfactory. The aim of this study was to perform next-generation sequencing on bronchoscopic specimens to determine whether this improves the accuracy of bronchoscopy for diagnosing lung cancer and to identify factors influencing sensitivity. The bronchoscopic sensitivity for diagnosing lung cancer was initially evaluated in 191 patients who underwent lobectomy after bronchoscopy at our hospital. Sputum, bronchial wash fluid, and resected lung cancer specimens were subsequently collected from 18 patients with peripheral small cell lung cancer for genomic analysis. DNA was extracted from formalin-fixed, paraffin-embedded surgical tissue specimens and the supernatant and cell fractions of sputum and bronchial wash fluid. Deep sequencing was performed using a lung cancer panel covering all exons of 53 lung cancer-related genes. The bronchoscopic sensitivity for diagnosing lung cancer at our hospital was 60.7%. Multivariate analysis revealed that this was influenced by tumor size and location, but not histological type or lymph node metastasis. The sensitivity was the highest for biopsy followed by curettage and bronchial wash specimens. DNA mutations homologous to those identified in the primary lesions were detected in the bronchial wash fluid of 10 patients (55.6%), while only 2 patients (11.1%) were diagnosed with lung cancer based on conventional cytological examinations. In conclusion, the addition of genomic analysis to routine pathological examinations improves the diagnostic accuracy of bronchoscopy.The diagnostic accuracy of bronchoscopy for detecting lung cancer, especially peripheral lung cancer with lesions outside the endoscopically visible range, remains unsatisfactory. The aim of this study was to perform next-generation sequencing on bronchoscopic specimens to determine whether this improves the accuracy of bronchoscopy for diagnosing lung cancer and to identify factors influencing sensitivity. The bronchoscopic sensitivity for diagnosing lung cancer was initially evaluated in 191 patients who underwent lobectomy after bronchoscopy at our hospital. Sputum, bronchial wash fluid, and resected lung cancer specimens were subsequently collected from 18 patients with peripheral small cell lung cancer for genomic analysis. DNA was extracted from formalin-fixed, paraffin-embedded surgical tissue specimens and the supernatant and cell fractions of sputum and bronchial wash fluid. Deep sequencing was performed using a lung cancer panel covering all exons of 53 lung cancer-related genes. The bronchoscopic sensitivity for diagnosing lung cancer at our hospital was 60.7%. Multivariate analysis revealed that this was influenced by tumor size and location, but not histological type or lymph node metastasis. The sensitivity was the highest for biopsy followed by curettage and bronchial wash specimens. DNA mutations homologous to those identified in the primary lesions were detected in the bronchial wash fluid of 10 patients (55.6%), while only 2 patients (11.1%) were diagnosed with lung cancer based on conventional cytological examinations. In conclusion, the addition of genomic analysis to routine pathological examinations improves the diagnostic accuracy of bronchoscopy.

Combined analgesic treatment of epidural and paravertebral block after thoracic surgery

In pulmonary surgical practice, appropriate pain management after thoracotomy is essential for patient recovery and the prevention of complications. Although epidural analgesia (EPI) has been established for chest surgery, it has some limitations and contraindications. Recently, paravertebral block (PVB) was reported as a good alternative method with fewer side effects. Despite the significant effects of these two treatments, postoperative pain remains among the greatest patient burdens. In our institution, we apply a combination of epidural and PVBs after thoracic surgery to reduce pain more effectively. The purpose of this study was to demonstrate the safety and feasibility of our method. This study included patients who underwent thoracic surgery and analgesic treatment in our institution between November 2014 and December 2016. Per our method of PVB induction, the parietal pleura was peeled off with a metal suction tube and an extrapleural pocket was created. An epidural catheter was inserted into this pocket and used to inject local anesthetics continuously after surgery. The catheters for analgesia were removed on the 4th postoperative day. In total, 368 patients received the combined epidural and PVBs. No severe complication was observed. The rate of rescue medication use in this study was lower than that in the historical control before adoption of this combination method; the incidence of pneumonia and length of hospital stay after surgery were not significantly different in this study from those in the historical control. In conclusion, our study demonstrated the safety and feasibility of the combination method of EPI and PVB. Acute pain after thoracic surgery may be adequately controlled using double analgesic regimens, including EPI and PVBs, suggesting an alternative to conventional modalities of EPI alone or PVB alone.