Isao Nozaki

Expression of minor histocompatibility antigen, HA-1, in solid tumor cells.

Background. Minor histocompatibility antigen (mHag) induces and mounts graft-versus-host disease after allogeneic hematopoietic stem cell transplantation. Among several mHags, HA-1 is one that acts alone and is the most studied. It is suggested that HA-1 may be one of the immunodominant antigens inducing not only graft-versus-host disease but also graft-versus-malignancy effects. There are some reports that mHag HA-1–specific cytotoxic T lymphocytes generated from an HA-1–negative donor can lyse HA-1–positive leukemic cells. However, the tissue distribution of HA-1 has been described as restricted to the cells of the hematopoietic lineage. Methods. We examined the HA-1 expression in peripheral blood mononuclear cells (PBMNC), leukemia/lymphoma cell lines, solid tumor cell lines, and paired samples of tumor and normal tissues from individual cancer patients by quantitative reverse-transcription polymerase chain reaction. Results. We found that mRNA of HA-1 is expressed in all leukemia/lymphoma cell lines and PBMNC. Most of the leukemia/lymphoma cell lines have the same levels of HA-1 expression as a leukemia/lymphoma cell line, Raji. The expression levels of human PBMNC were 14- to 19-fold higher than those of Raji. Among 32 solid tumor cell lines, 7 showed >50% expression levels compared with Raji. Conclusions. HA-1 expression in the mRNA level is higher in cells of hematopoietic origin, but this tissue distribution is not strictly restricted. Some solid tumor cells and tissues express HA-1 gene equal to hematopoietic cells.

Long-term outcome after laparoscopic wedge resection for early gastric cancer

BackgroundLaparoscopic wedge resection (LWR) can be applied for the management of early gastric cancer without the risk of lymph node metastasis. Although LWR for early gastric cancer is one of the minimally invasive procedures, its radicality in cancer therapy is controversial. This study aimed to evaluate the long-term outcomes after LWR.MethodsData on 43 consecutive cases of LWR performed for preoperatively diagnosed mucosal gastric cancer were analyzed retrospectively in terms of long-term outcomes.ResultsNo postoperative deaths occurred after LWR. Histologically, resected specimens showed submucosal invasion in 11 cases (26%) and positive surgical margins for cancer in 4 cases (9%). Three patients (7%) showed local recurrence near the staple line, and one patient (2%) died due to the local recurrence, but no lesional lymph node or distant recurrence occurred. The overall 5-year survival rate was 88%. The gastric remnant after LWR developed metachronous multiple gastric cancer in five cases (12%).ConclusionsThe findings show a relatively high incidence of positive surgical margin, local recurrence, and gastric remnant cancer after LWR. Although LWR can be performed for properly selected patients, periodic postoperative endoscopic examination is necessary to detect metachronous multiple gastric cancer and local recurrences.

The Prevalence of Overall and Initial Lymph Node Metastases in Clinical T1N0 Thoracic Esophageal Cancer: From the Results of JCOG0502, a Prospective Multicenter Study.

Objective: To evaluate the sites and frequencies of overall and initial lymph node (LN) metastases (LNMs) of clinical T1N0 esophageal cancer. Background: The sites and frequencies of initial LNMs and sentinel LNs (SLNs) of esophageal cancer remain unclear. Methods: The Japan Clinical Oncology Group JCOG0502 trial was a 4-arm prospective study that compared esophagectomy with chemoradiotherapy for clinical T1N0 esophageal cancer in both randomized and patient-preference arms. The preoperative diagnostic accuracy was evaluated for patients assigned to the surgery arm. Patients who withdrew consent and who were not treated were excluded. All patients underwent esophagectomy with D2 or greater LN dissection. From the pathologic findings, sites and frequencies of LNMs and SLNs were assessed and the frequency of skip LNMs was calculated. Results: In total, 211 patients underwent LNM and SLN analysis. Regarding N-factor accuracy, 57 (27.0%) of 211 clinical N0 cases had pathologic LNMs. The upper mediastinal and mediastinal/abdominal regions were frequent sites of LNMs in upper and lower thoracic cases, respectively. However, in middle thoracic cases, LNMs were observed in the neck, mediastinal, and abdominal regions, and pathologic SLN spread to all 3 fields. The frequency of skip LNMs was 36.7%. Conclusions: A clinical diagnosis of T1N0 is not sufficiently accurate, and therefore, it is unacceptable to omit LN dissection or minimize the prophylactic radiation field. SLNs, which are not location restricted, should be surveyed in all 3 fields.

Primary extranodal non-Hodgkin’s lymphoma of the common bile duct manifesting as obstructive jaundice: Report of a case

Primary non-Hodgkin’s lymphoma (NHL) of the common bile duct (CBD) manifesting as obstructive jaundice is extremely rare: to our knowledge, only 22 cases of primary NHL arising from the CBD have been reported. The patient in this case report was a 63-year-old man who presented with obstructive jaundice. Abdominal sonography, positron emission tomography, and computed tomography showed a mass with abnormal 18-fluorodeoxyglucose uptake in pancreatic head. Magnetic resonance cholangiopancreatography demonstrated a strictured segment of the CBD with proximal bile duct dilatation. We performed pancreaticoduodenectomy for a presumptive diagnosis of pancreatic head carcinoma or cholangiocarcinoma of the CBD. However, the histological diagnosis was a primary, diffuse, large B-cell lymphoma of the CBD. He received three courses of combination chemotherapy, including rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). The patient remains well, without evidence of tumor recurrence, 8 months after surgery. In summary, primary NHL of the CBD, despite its rarity, should be considered in the differential diagnosis of obstructive jaundice. An accurate histopathologic diagnosis and complete surgical resection, followed by combination chemotherapy plus rituximab may be effective.

Pulmonary angioplastic procedure for lung cancer surgery.

PurposeAlthough bronchoplasty for the treatment of lung cancer is widely accepted as a reliable, safe procedure for the preservation of lung function, there have been only a few reports on pulmonary artery (PA) resection and reconstruction.MethodsRetrospectively, we reviewed our medical records of pulmonary angioplastic procedures and assessed the results.ResultsA total of 25 patients (5 women, 20 men) with a mean age of 68 years (range 44–85 years) underwent a pulmonary angioplastic procedure for lung cancer surgery. Altogether, 13 patients had adenocarcinoma, and 11 had squamous cell carcinoma. The cancers were located in the left lung in 15 cases and in the right lung in 10 cases. The PA reconstructions comprised 4 circumferential resections and anastomoses, 18 wedge resections and end-to-end anastomoses, 2 tangential resections with direct suturing, and 1 wide wedge resection and autologous pericardial patch repair. Six patients underwent concomitant bronchoplasty with pulmonary artery reconstruction. Prior to surgical treatment, seven patients had received neoadjuvant therapy. Although early postoperative complications occurred in eight patients (32%), no operative or in-hospital deaths occurred. All the patients in this series were discharged from hospital and went home. The overall 5-year survival rate was 45%, with a mean 27 months of follow-up.ConclusionMost operative complications after PA reconstruction were controllable despite the high morbidity rate. Pulmonary angioplastic procedures for the surgical treatment of lung cancer are both useful and feasible with good intermediate-term results.

Establishment of a human hepatoma cell line, HLE/2E1, suitable for detection of P450 2E1-related cytotoxicity

Abstract By transfection of an expression vector of human cytochrome P450 2E1 (CYP2E1) into a human hepatoma cell line (HLE), a new cell line (HLE/2E1) that stably expresses activity of CYP2E1 has been established. The HLE/2E1 cell line expressed a higher level of CYP2E1 messenger ribonucleic acid than did the mother HLE cell line. CYP2E1 enzyme activity determined by a p-nitrophenol oxidation assay was also higher in HLE/2E1 cells than in HLE cells. In addition, the enzyme activity of the HLE/2E1 cells was increased by ethanol treatment. Exposure to acetaminophen (APAP) or buthionine sulfoximine (BSO) caused a greater decrease in viability of the HLE/2E1 cells than that of the HLE cells, as determined by the 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide assay. The cytotoxicity of APAP or BSO to HLE/2E1 cells was inhibited by the addition of ethanol or vitamin E. However, the cytotoxicity of both APAP and BSO was enhanced by 24-h preincubation of HLE/2E1 cells with ethanol. These results show that this cell line provides a useful model for studying catalytic properties of CYP2E1 and cytotoxic mechanisms of chemicals metabolized by CYP2E1.

Determination factors of patients' decision between surgery and chemoradiotherapy for stage I esophageal carcinoma: From the results of JCOG0502—A comparative study of the two modalities.

114 Background: Surgery is the standard of care for stage I esophageal squamous cell carcinoma. However, definitive chemoradiothearpy (CRT) is optional treatment which can preserve organ function with cure. The aim of this study was to investigate what factors have influence patients(pts)’ decision on the treatment, surgery or CRT. Methods: JCOG0502 is a randomized controlled trial comparing surgery to CRT. Sufficient information about both treatments was provided for pts before enrollment. Pts who declined to participate in randomized part can choose a preferred treatment and join a non-randomized part of JCOG0502. Between Dec 2006 and Feb 2013, 379 pts were enrolled to JCOG0502 from 37 institutions of Japan Clinical Oncology Group. Among those, 368 pts who enrolled to non-randomized part were analyzed. Clinical baseline data, social data and doctor’s preference which was not mandatory informed to patients were collected on the case report forms and compared between surgery arm and CRT arm. Preference of...

The prevalence of lymph node metastases in clinical T1N0 thoracic esophageal cancer from the results of JCOG0502.

10 Background: Recently, a limited operation to avoid needless lymph node (LN) dissection in clinical T1bN0 esophageal cancer (EC) is considered. However, how LN dissection or radiation field should be decided for such cases has not yet been clarified. The information about prevalence of LN metastases (LNMs) would be valuable when the radiation field and extent of LN dissection are considered in the treatment of T1bN0 EC. Methods: JCOG0502 is a randomized controlled trial including a patient preference arm comparing surgery alone to definitive chemoradiotherapy in clinical T1bN0 EC. By using baseline clinical and pathological data of JCOG0502, diagnosis accuracy of LNM was evaluated by comparing clinical and pathologic findings. Then, the sites of pathologic LNMs were determined and the initial sites and the prevalence of LNM were estimated. Results: Between Dec 2006 and Feb 2013, 213 patients (pts) enrolled to the surgery arm in JCOG0502. Pts with multiple lesions or without esophagectomy were excluded a...

Endoscopic Follow-up for the Remnant Stomach After Early Cancer Surgery: Reply

We thank Dr. Katsios [1] for his interest in our article andfor raising some important points. We agree that one has tobalance the cost effectiveness of the intensity of theendoscopic follow-up with the likelihood of events, whichis why, based on our results, we recommend examinationsevery 2–3 years [2]. Furthermore, as we mentioned in ourarticle, the tumors (n = 26) in the remnant stomach werenot recurrent tumors but metachronous secondary gastriccancers. All the tumors were resected curatively by gas-trectomy or endoscopic mucosal resection, and the prog-nosis for these 26 patients was good following theresections [2]. The first choice for the treatment of curablegastric cancer is surgical resection and not chemotherapy.Since symptomatic advanced gastric remnant cancers areassociated with unresectable T4 tumors and poor prognosis[3], periodic postoperative endoscopies are necessary todetect them at an asymptomatic early stage. Typically,secondary metachronous gastric cancer develops within5–10 years after the primary cancer surgery [2, 4]. There-fore, only two to five endoscopic examinations are neededif you follow our recommendations [2]. Moreover, patientswithout any of risk factors may need fewer examinations.Postoperative endoscopic examinations are not onlyfor detecting secondary metachronous gastric cancer orrecurrent tumor but are also for detecting postoperativemorbidities after gastrectomy, such as peptic ulcer and/orbleeding in the remnant stomach, anastomotic stenosis, andgastroesophageal reflux disease. Endoscopic identificationof these morbidities allows patients to be treated withappropriate drugs. Since upper gastrointestinal endoscopycan be performed safely now, we believe our recommen-dations are not extreme and are acceptable.

Abstract 2691: Prognostic significance of heat shock protein 90 expression in patients with advanced gastric cancer

Purpose: Heat shock protein 90 (HSP90) is a chaperone mediating the folding and stabilization of many oncoproteins. Considerable attention has been focused on the role of the HSP90 in the therapeutic strategy of molecular targeting HSP90. Recently it has reported that Trastuzumab, a recombinant monoclonal antibody against HER2, plus chemotherapy improved survival in HER2-positive gastric cancer patients. This study was designed to delineate the clinical implications of Hsp90 and HER2 immunoexpression in advanced gastric cancer. Material and Methods: The study group comprised 47 patients who underwent gastrectomy at Shikoku Cancer Center Hospital excluding patients with stage I. According to the TNM classification, 18 tumors were identified as being stage II, 25 stage III, 4 stage IV. Using immunohistochemical techniques, we analyzed the expressions of HSP90 and HER2 on formalin-fixed paraffin-embedded specimens of surgically removed primary tumors. Immunostaining was graded as follows: low-HSP90 (defined as weaker staining compared with adjacent normal gastric mucosa), moderate-HSP90 (defined as equal), high-HSP90 (defined as stronger). HER2 expression was graded using a 4-point scale according to the criteria of HER2 membranous staining, which have been widely accepted. Chi-square test, Kaplan-Meier and Cox regression analysis were used for statistical analysis. Results: Low-HSP90 expression was found in 13 tumors (28%) and HER2 high-expression (moderate to strong membrane staining in > 10% of tumor cells) in 13 tumors (28%). Low-HSP90 was significantly detected in diffuse type (p = 0.0047) and was associated with clinicopathological parameters involved with tumor progression, including the depth of tumor invasion (p = 0.049) and advanced stage tumor (p = 0.029). Of note, High-HSP90 and HER2 overexpression (3+) were mutually exclusive (P=0.031). Kaplan-Meier survival analysis determined that tumors with low-HSP90 expression were statistically associated with worse disease-free survival (p = 0.036), and tended to detect poor postoperative survival (p = 0.084). Multivariate survival analysis showed that HSP90-negative expression [hazard ratio (HR) 3.05, 95% confidence interval (95% CI) 1.02-9.18; p = 0.046] and lymph node metastasis (HR 5.55; 95% CI 1.68-18.2; p = 0.005) were significant predictors of poor postoperative survival. Conclusions: Our results indicate that low-HSP90 expression correlated with more aggressive disease and poor prognosis, and that HSP90 and HER2 overexpression might separately be molecular targets in gastric cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2691.