Seshiru Nakazawa

Linear ubiquitination is involved in the pathogenesis of optineurin-associated amyotrophic lateral sclerosis

Optineurin (OPTN) mutations cause neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and glaucoma. Although the ALS-associated E478G mutation in the UBAN domain of OPTN reportedly abolishes its NF-κB suppressive activity, the precise molecular basis in ALS pathogenesis still remains unclear. Here we report that the OPTN-UBAN domain is crucial for NF-κB suppression. Our crystal structure analysis reveals that OPTN-UBAN binds linear ubiquitin with homology to NEMO. TNF-α-mediated NF-κB activation is enhanced in OPTN-knockout cells, through increased ubiquitination and association of TNF receptor (TNFR) complex I components. Furthermore, OPTN binds caspase 8, and OPTN deficiency accelerates TNF-α-induced apoptosis by enhancing complex II formation. Immunohistochemical analyses of motor neurons from OPTN-associated ALS patients reveal that linear ubiquitin and activated NF-κB are partially co-localized with cytoplasmic inclusions, and that activation of caspases is elevated. Taken together, OPTN regulates both NF-κB activation and apoptosis via linear ubiquitin binding, and the loss of this ability may lead to ALS.

Three-dimensional computed tomography for analyzing the vascular anatomy in laparoscopic surgery for right-sided colon cancer.

Background: The mesenteric vessels have many branching patterns. This study clarified the anatomic relationship between the superior mesenteric vein (SMV), the right colic artery (RCA), and the ileocolic artery (ICA) using 3-dimensional computed tomography (3D-CT). The relationship between the RCA and the right colic vein (RCV) was also examined. Methods: Between April 2006 and July 2011, all patients with colorectal cancer underwent multidetector computed tomography (MDCT) before laparoscopic surgery. The 100 most recent consecutive cases were analyzed. 3D-CT images were made by combining arterial angiography, venous angiography, colonography, tumor, lymph node, and duodenal images. Results: The RCA branched from the SMA in 37 cases (37%); of these, 21 had an ICA that crossed anterior to the SMV and 16 had an ICA that crossed posterior. When the ICA crossed anterior to the SMV, all had an RCA that crossed anterior to the SMV, and no posterior RCA was seen. Furthermore, the RCV joined the SMV in 10 cases (27%) and the gastrocolic trunk in 27 cases (73%). Conclusions: Our study clarified the anatomic variety of the vessels in right-sided colon cancer. Preoperative 3D-CT is useful for understanding the anatomy to ensure a safe, precise operation.

Analysis of variation in bronchovascular pattern of the right middle and lower lobes of the lung using three-dimensional CT angiography and bronchography

ObjectivesGeneral thoracic surgeons must be familiar with anatomical variation in the pulmonary vessels and bronchi. Here, we analyzed the bronchovascular pattern of the right middle lobe (RML) and right lower lobe (RLL) of the lung using three-dimensional CT angiography and bronchography (3DCTAB).MethodsWe reviewed the anatomical patterns of the pulmonary vessels and bronchi in 270 patients using 3DCTAB images.ResultsThe branching patterns of vessels and bronchi of RML and S6 were classified according to the number of stems. The single-stem type was the most common, except in the artery of the RML, for which the two-stem type was the most common. The artery and bronchus of S*, which is an independent segment between S6 and S10, were observed in 20.4% of cases. The branching pattern of A7 (B7) was classified into four types. The A7a (B7a) type was observed in 74.8% of cases, and was the most common. The branching pattern of the artery and bronchus of S8−10 was classified into five and three types, respectively. The A8 and A9 + A10 type, and the B8 and B9 + B10 type, were observed in 68.1 and 80.4% of cases, respectively, and were the most common types. The branching pattern of V8−10 was more complex than that of A8−10 and B8−10.ConclusionWe explored the bronchovascular patterns of RML and RLL and their frequencies using a large number of 3DCTAB images. Our data can be used by thoracic surgeons to perform safe and precise lung resections.

VATS segmentectomy: past, present, and future

Video-assisted thoracoscopic surgery (VATS) has gradually been implemented in thoracic surgery, and the VATS approach has now been extended to technically challenging procedures, such as segmentectomy. The definition of VATS segmentectomy is changing over time, and the repertoire of segmentectomy is getting wider with increasing reports on atypical segmentectomy. VATS segmentectomy bears surgical, oncological, and technical advantages; however, there are still areas of controversy, particularly regarding oncological outcomes. The indication of VATS segmentectomy is diverse and is used for treating lung cancer, metastatic lung tumors, or a variety of nonmalignant diseases. It is particularly valuable for the lung-sparing resection of deeply located small nodules or repeated surgery for multiple lung lesions. VATS segmentectomy requires a thorough analysis of segmental anatomy and a tailored preoperative planning with the assessment of surgical margins. Technical challenges include intraoperative navigation, methods to identify and dissect the intersegmental plane, and the prevention of air leakage. This review will discuss the present state of VATS segmentectomy, with a focus on past studies, current indications and techniques, and future view.

Highly sensitive detection of a HER2 12-base pair duplicated insertion mutation in lung cancer using the Eprobe-PCR method

Somatic mutation in human epidermal growth factor receptor-related 2 gene (HER2) is one of the driver mutations in lung cancer. HER2 mutations are found in about 2% of lung adenocarcinomas (ADCs). Previous reports have been based mainly on diagnostic screening by Sanger sequencing or next-generation sequencing (NGS); however, these methods are time-consuming and complicated. We developed a rapid, simple, sensitive mutation detection assay for detecting HER2 12 base pair-duplicated insertion mutation based on the Eprobe-mediated PCR method (Eprobe-PCR) and validated the sensitivity of this assay system for clinical diagnostics. We examined 635 tumor samples and analyzed HER2 mutations using the Eprobe-PCR method, NGS, and Sanger sequencing. In a serial dilution study, the Eprobe-PCR was able to detect mutant plasmid DNA when its concentration was reduced to 0.1% by mixing with wild-type DNA. We also confirmed amplification of the mutated plasmid DNA with only 10 copies per reaction. In ADCs, Eprobe-PCR detected the HER2 mutation in 2.02% (9/446), while Sanger sequencing detected it in 1.57% (7/446). Eprobe-PCR was able to detect the mutation in two samples that were undetectable by Sanger sequencing. All non-ADC samples were wild-type. There were no discrepancies between frozen and formalin-fixed paraffin-embedded tissues in the nine samples. HER2 mutations detected by NGS data validated the high sensitivity of the method. Therefore, this new technique can lead to precise molecular-targeted therapies.

Laparoscopic resection of a paraganglioma located on the border of the thoracic and abdominal cavities using a transabdominal-transdiaphragmatic approach

We treated a 64‐year‐old woman with high blood pressure. Catecholamine metabolite levels were elevated in the blood and urine. CT revealed a densely stained tumor on the right side of the descending aorta dorsal to the inferior vena cava. PET‐CT revealed abnormal accumulation of 18F‐fluorodeoxyglucose, and 123I‐meta‐iodo‐benzylguanidine uptake was apparent on scintigraphy. The tumor was determined to be a paraganglioma located on the border between the thoracic and abdominal cavities, and laparoscopic tumorectomy was performed. The patient was placed in the left lateral position. The right lobe of the liver was turned over, and we cut the diaphragm to expose the front of the tumor. We resected the straight artery flowing in from the aorta and removed the tumor safely. Herein, we describe the removal of a paravertebral paraganglioma located in the border of the thoracic and abdominal cavities with a laparoscopic transabdominal‐transdiaphragmatic approach.

An immunoglobulin G4-related disease mimicking postoperative lung cancer recurrence

A postoperative lung cancer patient presented with lymphadenopathy, pleural thickening, and 18F-fluorodeoxyglucose (FDG) uptake on a positron emission tomography–computed tomography (PET–CT) scan. Lung cancer recurrence was initially suspected, but bilateral submandibular masses with 18F-FDG uptake indicated the possibility of a systemic disease, such as Mikulicz’s disease. High serum immunoglobulin G4 (IgG4) and IgG4-positive plasma cell infiltration in the submandibular glands led to the diagnosis of IgG4-related disease. After systemic steroid therapy, 18F-FDG uptake decreased in both the submandibular glands and the suspected recurrent lesions.

Segmentectomy of the left superior segment (S6) 4 years after segmentectomy of the left dorsobasal segment (S10)

Abstract To date, repeated segmentectomy in the same lobe has not yet been reported. Herein we report the technical details of a left superior segment (S 6 ) segmentectomy 4 years after left dorsobasal segment (S 10 ) segmentectomy.

3D-CT anatomy for VATS segmentectomy

Segmentectomy has become a widely adopted surgical procedure, with recent reports describing the use of video-assisted thoracoscopic surgery (VATS) and robotic surgery. A major feature of segmentectomy is that it requires a three-dimensional (3D) understanding of the patients pulmonary structure and a thorough preoperative analysis of the patients individual anatomy. Here, we present our method for VATS segmentectomy based on 3D-computed tomography (3D-CT), with a review of the literature. We focus on techniques for 3D-CT reconstruction, analyses of the individual anatomy and anomalies, preoperative simulations of the procedure and surgical margin, and intraoperative navigation with 3D-CT images. We also reference the roles of members of our multi-disciplinary surgical team.

Impact of the Bim Deletion Polymorphism on Survival Among Patients With Completely Resected Non–Small-Cell Lung Carcinoma

Purpose A deletion polymorphism of the Bim gene has been reported to be a prognostic factor for patients with non–small-cell lung cancer (NSCLC) treated with epidermal growth factor receptor-tyrosine kinase inhibitors in the Asian population. We investigated the impact of the Bim deletion polymorphism on survival among patients with completely resected NSCLC. Patients and Methods The Bim polymorphism was detected by polymerase chain reaction analysis. We measured overall survival (OS) and recurrence-free survival rates in 411 patients and postrecurrence survival (PRS) in 94 patients who experienced recurrence and received additional anticancer therapy. Results The Bim deletion polymorphism was detected in 61 patients (14.8%). OS rates were significantly lower for patients with the Bim deletion polymorphism than for those with the wild-type sequence. On multivariable analysis, the Bim deletion polymorphism was identified as an independent prognostic factor for OS (hazard ratio, 1.98; 95% CI, 1.17 to 3.36; P = .011). Among the 94 patients who experienced recurrence and were treated with anticancer therapy, patients with the Bim deletion polymorphism showed significantly poorer PRS than those with the wild-type sequence (median, 9.8 months v 26.9 months, respectively; P < .001). Multivariable analysis revealed that the Bim deletion polymorphism was an independent predictor of PRS (hazard ratio, 3.36; 95% CI, 1.75 to 6.47; P < .001). This trend remained apparent in subgroup analyses stratified by EGFR status, histology, and therapeutic modality. Conclusion The Bim deletion polymorphism is a novel indicator of shortened PRS among patients with recurrent NSCLC treated with anticancer therapy in the Asian population.