Yoshinobu Hattori

Comprehensive screening for antigens overexpressed on carcinomas via isolation of human mAbs that may be therapeutic

Although several murine mAbs that have been humanized became useful therapeutic agents against a few malignancies, therapeutic Abs are not yet available for the majority of the human cancers because of our lack of knowledge of which antigens (Ags) can become useful targets. In the present study we established a procedure for comprehensive identification of such Ags through the extensive isolation of human mAbs that may become therapeutic. Using the phage-display Ab library we isolated a large number of human mAbs that bind to the surface of tumor cells. They were individually screened by immunostaining, and clones that preferentially and strongly stained the malignant cells were chosen. The Ags recognized by those clones were isolated by immunoprecipitation and identified by MS. We isolated 2,114 mAbs with unique sequences and identified 21 distinct Ags highly expressed on several carcinomas. Of those 2,114 mAbs 356 bound specifically to one of the 21 Ags. After preparing complete IgG1 Abs the in vitro assay for Ab-dependent cell-mediated cytotoxicity (ADCC) and the in vivo assay in cancer-bearing athymic mice were performed to examine antitumor activity. The mAbs converted to IgG1 revealed effective ADCC as well as antitumor activity in vivo. Because half of the 21 Ags showed distinct tumor-specific expression pattern and the mAbs isolated showed various characteristics with strong affinity to the Ag, it is likely that some of the Ags detected will become useful targets for the corresponding carcinoma therapy and that several mAbs will become therapeutic agents.

Does repeated surgery improve the prognosis of colorectal liver metastases

Hepatic resection for colorectal metastases was performed for 188 patients. Overall survival rates after the first hepatectomy are 41.4% and 32.7% for 5 and 10 years, respectively. The survival rate of 116 cases with unilobar hepatic metastases (H1) is significantly higher than those of 48 cases with two to four bilobar metastases (H2) and 24 cases with more than four (H3), respectively. However, the differences between the survival rates from H1 with multiple metastases, H2, and H3 are not significant, even though the H3 group has no 10-year survivors. The 5-year survival rates after the second hepatectomy (30 patients) and the resection of the lung (26 patients) are 30.3% and 35.2%, respectively, in this series. In those patients, the 5-year survival rates from the first metastasectomy are 43.4% and 50.3%, respectively. There are 14 5-year survivors with multiple metastases and 8 of those patients underwent multiple surgeries. There are 13 patients with three or more repeat resections of the liver and/or lung. The 5-year survival rates of the patients from the first and third metastasectomy are 53.9% and 22.5%, respectively. Repeat operations for the liver and the lung contribute to the improving prognosis.

Single-Port Thymectomy Through an Infrasternal Approach

We report a surgical procedure in which a port and devices designed for single-incision endoscopic surgery are employed for thymectomy through an infrasternal approach. As this single-port thymectomy procedure can be performed through a single 3.5-cm incision in the abdominal region usually concealed under clothes, it is esthetically excellent and is among the least invasive thymectomy procedures because no sternal incision is applied and no intercostal nerve is injured. Investigation of the safety of this procedure and long-term therapeutic outcomes for myasthenia gravis and anterior mediastinal tumors is necessary.

Single-Incision Subxiphoid Approach for Bilateral Metastasectomy

We report a case of single-incision bilateral partial lung resection using the subxiphoid approach. This approach requires a 3-cm incision in the abdomen, making it aesthetically favorable. In addition, it does not cause postoperative intercostal neuropathy, and postoperative pain is minimal because the intercostal space is bypassed. Moreover, this technique enables exposure to both lungs through a single incision and has potential for widespread use if maneuverability can be increased by improving the instruments used.

Selection and analysis of anti-cancer antibodies for cancer therapy obtained from antibody phage library

The search for effective antibodies (Ab) for curable cancer immunotherapy has been a quest of many research groups in order to find an effective target that exists on the cancer cell surface. So far there have been no conclusive answers to shed light on the search. This study therefore aimed to bridge the gap of cancer therapy. Screening against 49 kinds of cell lines belonging to 11 kinds of solids cancers was performed. Isolation and characterization for approximately 4200 monoclonal antibodies (mAb) was also performed thereafter. Of those mAb 488 clones that turned out to bind to 29 tumor‐associated antigens (TAA) were subjected to immunohistochemical (IHC) analyses. Selection of target antigens (Ag) and a potential antibody for cancer therapy was conducted prior to clinical examinations. In order to find predictably effective targets for therapeutic Ab against solid cancers, expression of the Ag on the surface of cancer and normal cells was extensively examined by IHC analyses using fresh cancer specimens resected from patients. In this study, the tendencies of all staining patterns and distribution of the Ab are reported. While all of the TAA appeared to be involved in tumorigenesis, their expression was not restricted to some specific tumor types but rather randomly distributed among various cancers. Some kinds of Ab including anti‐epidermal growth factor receptor (EGFR) and anti‐human epidermal growth factor receptor 2 (HER2) indicated the frequency of expression in normal cells was generally low. We concluded that identification of 488 mAb and the accumulated results of IHC analyses in this study could be the key for further therapeutic Ab against cancers. The targets that showed cancer‐specific expression are expected to be better for therapeutic Ab than the other Ab. Moreover, further investigation into the growth of cancer cell lines using full human IgG form of Ab shows available efficacy in specific cases. (Cancer Sci 2011; 102: 175–181)

Frequent overexpression of CADM1/IGSF4 in lung adenocarcinoma.

We reported comprehensive screening for antigens (Ags) overexpressed on various carcinomas via isolation of human monoclonal antibodies (mAbs) that may be therapeutic in a previous paper (Proc. Natl. Acad. Sci. USA 105, 7287-7292, 2008). Twenty-one distinct Ags highly expressed on several carcinomas were identified and 356 mAbs with unique sequences turned out to bind to one of the 21 Ags. Among them CADM1/IGSF4 which had been originally referred to as tumor suppressor lung cancer 1 (TSLC1) was included. Therefore we examined the expression of CADM1 in lung cancers in this study. Eight different anti CADM1 mAbs were used for immunohistochemical analysis of 29 fresh lung cancer specimens. Staining patterns were categorized to six groups based on the extent of positive staining and the localization of stained portions. While overexpression of CADM1 was observed on the cell surface of adenocarcinomas at a high frequency, around 60%, positive stainings were rarely observed on that of other lung carcinomas including squamous cell carcinomas. Moreover, some clones among the eight mAbs gave different staining patterns from those by the other clones against the same fresh specimen, suggesting presence of variant forms of CADM1 differentiated by mAbs.

Rapidly Growing Primary Cardiac Leiomyosarcoma : Report of a Case

Abstract Primary cardiac leiomyosarcomas are very rare. A 19-year-old man was admitted to a local hospital with dyspnea and hemoptysis. He was later transferred to our hospital because of his worsening dyspnea. An enhanced chest computed tomography scan demonstrated a large mass in the left atrium. A transthoracic echocardiogram showed a large mobile mass in the left atrium. The tumor was totally resected. The pathohistological examination showed leiomyosarcoma. The tumor rapidly recurred, and a second and third operation were performed. After the third operation, the patient was treated with radiotherapy. There was no local recurrence but multiple distant metastases were found 2 months after completion of radiation therapy.

Esophageal duplication cyst continuously extending into the peritoneal cavity on the proximal portion of the stomach

Although bronchogenic or esophageal duplication cysts are foregut-derived developmental anomalies most commonly encountered in the mediastinum and rarely in the abdomen, a cyst continuously extending into the abdomen via the esophageal hiatus has not been reported previously. We report a case of esophageal duplication cyst that occurred in the distal esophagus and extended continuously into the proximal portion of the stomach via the esophageal hiatus. A 62-year-old Japanese man was admitted to a local hospital complaining of dysphagia and upper abdominal pain. Abdominal ultrasound and CT scan revealed a cystic mass dorsal to the lateral segment of the liver that extended continuously into the mediastinum via the hiatus. The upper gastrointestinal series and endoscopic examination revealed extramural compression of the distal esophagus without mucosal lesions. Resection of the cystic lesion was performed by thoracotomy followed by laparotomy. The upper part of the cyst originated in the submucosal layer, extending into the muscularis propria of the distal esophagus. Histology of the resected specimen indicated that the cystic wall was composed of two smooth muscle layers and that the inner cystic wall was lined with pseudostratified columnar ciliated and/or squamous epithelium associated without cartilage or respiratory gland, indicating esophageal differentiation. These histological characteristics indicated that the cyst was an esophageal duplication cyst, rather than a bronchogenic cyst. This is the first case of a large esophageal duplication cyst of the distal esophagus continuously extending into the abdomen via the esophageal hiatus. The atypical location of this esophageal duplication cyst provides an insight into the pathogenesis of esophageal duplication cysts.

Primary Cardiac Sarcoma

Two case reports of primary cardiac sarcoma, which is uncommon, are presented. The first case, a 38-year-old male, complained of chest tightness. Chest roentgenograms showed enlargement of the cardiac shadow and left pleural effusion. Transthoracic echocardiography and chest magnetic resonance imaging showed a tumor in the right atrium, and pericardial effusion. The tumor involved the right atrial wall and interatrial septum, and was partially resected. Pathohistological examination revealed angiosarcoma. He died 1 month later. The second case, a 19-year-old male complained of dyspnea and orthopnea. Chest roentgenograms showed pulmonary congestion. Transthoracic echocardiography showed a large mobile mass in the left atrium. An emergency operation was performed and the tumor was totally resected. Pathohistological examination demonstrated leiomyosarcoma. The postoperative course was uneventful, but the tumor rapidly recurred. Second and third operations were performed at intervals of 2 months. After the third operation, he was treated with radiotherapy. Local recurrence was not found but multiple distant metastases were found 2 months after completion of radiation therapy.

Frozen-Section Diagnosis of Small Adenocarcinoma of the Lung for Intentional Limited Surgery

PurposeTo determine if Noguchis classification can be evaluated accurately by frozen-section diagnosis before limited surgery.MethodsWe performed frozen-section diagnosis in 31 of 343 patients who underwent excision of primary lung cancer at our hospital between 1993 and 2004. All 31 patients had pulmonary adenocarcinoma, with a tumor diameter of ≦20 mm. There were 20 men and 11 women, ranging in age from 42 to 79 years (mean, 63.2 years). We assessed the rate of correct Noguchis classification by categorizing all lesions into the following three groups on the basis of tumor diameter: ≤10 mm, 11–15 mm, and 16–20 mm.ResultsThe overall rate of correct frozen-section diagnosis during surgery was 67.7%; being 100%, 41.7%, and 70% in the ≦10 mm, 11–15 mm, and 16–20 mm groups, respectively.ConclusionLimited surgery for primary lung cancer can be performed when the tumor diameter is ≦10 mm, by confirming it as either type A or B according to Noguchis classification, using frozen-section diagnosis. Thus, examination of frozen sections might be an important diagnostic procedure before intentional limited surgery for lung cancer.