[Clinical Efficacy of Monotherapy with Immune Checkpoint Inhibitors for Advanced Non-Small Cell Lung Cancer].

OBJECTIVE: To retrospectively assess data on immune checkpoint inhibitors(ICIs)in an actual clinical setting, examine the factors that contribute to response and survival using real-world data, and compare the effectiveness of the 3 types of ICIs for patients with non-small cell lung cancer(NSCLC). METHODS: A retrospective analysis of 127 patients with NSCLC treated with ICIs at our hospital was conducted. RESULTS: Nivolumab(56 patients)showed a 3-year survival rate of 21.6% and a disease control rate of 57.1%. These results are consistent with the clinical trials of Nivolumab. Pembrolizumab(36 patients) showed a 2-year survival rate of 60.3%, a response rate of 50.0%, and a disease control rate of 63.9%. Atezolizumab(35 patients)displayed a particularly low response rate with a 1-year survival rate of 58.4%, response rate of 8.6%, and disease control rate of 25.7%. The treatment results for recurrence after surgery for lung cancer were comparable to those for unresectable lung cancer. CONCLUSION: Anti-PD-1 antibody displayed better therapeutic results than anti-PD-L1 antibody. The efficacy of ICI administration for postoperative recurrent lung cancer was also shown in this study.

Clinical outcome of posterior fixation surgery in patients with vertebral metastasis of lung cancer.

Vertebral metastasis of non-small-cell lung cancer (NSCLC) often leads to neurological paralysis, with deterioration of the patients' activities of daily living (ADL). Surgical treatments for the symptoms are unlikely to be recommended due to the poor prognosis of patients with advanced NSCLC. The aim of the present study was to retrospectively evaluate the clinical outcome of posterior spinal fixation surgery in patients with neurological paralysis resulting from vertebral metastasis of NSCLC. Between April, 2007 and March, 2012, 4 patients (3 men and 1 woman; median age, 56.5 years) underwent fixation surgery at the Shiga University of Medical Science Hospital (Otsu, Japan). The mean preoperative Tokuhashi and Tomita scores of the patients were high (8.25 and 7.0, respectively). However, the Frankel grade functional score and performance status of the patients improved following fixation surgery, after which all patients received chemoradiotherapy. Postoperatively, the median paralysis-free time was 41 months (range, 17-42 months) and the median survival time was 42.5 months (range, 22-43 months). According to the functional scores, the patients had a poor prognosis, which may have been a contraindication for fixation surgery. In these cases, however, surgical treatment improved the patients' ADL and increased the likelihood of receiving anticancer therapy, contributing to the prolongation of survival. Therefore, fixation surgery may be beneficial for patients with neurological paralysis following vertebral metastasis of advanced NSCLC.

Predictive biomarkers and effectiveness of MUC1-targeted dendritic-cell-based vaccine in patients with refractory non-small cell lung cancer.

BACKGROUND: The dendritic cell (DC)-based vaccine targeting the highly immunogenic tumor antigen, MUC1, has been promising for a cancer immunotherapy; however, predictive biomarkers for beneficial clinical responses of the vaccine remain to be determined. METHODS: DCs loaded with MUC1-derived peptide were subcutaneously administered to patients with MUC1-positive non-small cell lung cancer (NSCLC) that was refractory to standard anticancer therapies, every 2 weeks. The effectiveness and tolerability of the vaccine were evaluated, and predictive biomarkers of clinical responses were explored. RESULTS: Between August 2005 and May 2015, 40 patients received the vaccines. The median survival time (MST) after the initial vaccination was 7.4 months, and the 1-year survival rate was 25.0%. The MST for patients who received more than six vaccinations was 9.5 months, and the 1-year survival rate was 39.3%. In this cohort, patients who experienced immune-related adverse events, including skin reactions at the vaccination site and fever, had significantly longer survival times compared with patients without those immune-related adverse events (12.6 versus 6.7 months, p = 0.042). Longer survival times were also observed in patients whose peripheral white blood cells contained >20.0% lymphocytes (12.6 versus 4.5 months; p = 0.014). MUC1-specific cytotoxic immune responses were achieved in all of seven patients analyzed who received six vaccinations. CONCLUSION: The MUC1-targeted DC-based vaccine induced an antitumor immune response that promoted prolonged survival of patients with refractory NSCLC. The occurrence of immune-related adverse events and having a higher percentage of peripheral lymphocytes were predictive biomarkers of a beneficial clinical response during cancer immunotherapy for NSCLC.

Simultaneous resection of pulmonary tumor following cardiovascular surgery.

BACKGROUND: A pulmonary tumor is occasionally detected on a chest computed tomography (CT) scan before cardiovascular surgery. PURPOSE: In this study, we examined clinical courses of patients who had undergone the simultaneous resection of a pulmonary tumor following cardiovascular surgery. METHODS: From 2008 to 2013, 18 patients (13 men and 5 women) with a median age of 69.8 years underwent the wedge pulmonary resection for a lung tumor through a median thoracotomy following cardiovascular surgery in our hospital. Cardiovascular surgeries consisted of off-pump coronary artery bypass grafting (CABG) in six patients, aortic valve replacement and/or mitral valve plasty in 10 patients, total arch replacement in 10 patients and descending aorta replacement in 10 patients. RESULTS: No complications associated with pulmonary resections were observed. Pathological examination revealed that 15 patients (83.3%) were diagnosed with lung cancers including 13 adenocarcinomas and two squamous cell carcinomas, with the clinical stages of 1A in 13 patients, 2A in one patient and 2B in one patient. Among them, five patients received the radical pulmonary resection subsequently, whereas 10 patients were unable to receive it due to their poor cardiopulmonary function. Kaplan-Meier analysis of patients with lung cancer revealed that the 5-year survival rate and progression-free survival (PFS) rate after 3 years from the surgery were 46.2% and 73.8%, respectively. CONCLUSION: The simultaneous resection of pulmonary tumor following cardiovascular surgery is safely performed, and is useful for the pathological diagnosis of the tumor. Further studies are warranted, however, this procedure may contribute to controlling the progression of lung cancer in patients with cardiovascular disease with comorbidities.

Cancer-associated fibroblast-targeted strategy enhances antitumor immune responses in dendritic cell-based vaccine.

Given the close interaction between tumor cells and stromal cells in the tumor microenvironment (TME), TME-targeted strategies would be promising for developing integrated cancer immunotherapy. Cancer-associated fibroblasts (CAFs) are the dominant stromal component, playing critical roles in generation of the pro-tumorigenic TME. We focused on the immunosuppressive trait of CAFs, and systematically explored the alteration of tumor-associated immune responses by CAF-targeted therapy. C57BL/6 mice s.c. bearing syngeneic E.G7 lymphoma, LLC1 Lewis lung cancer, or B16F1 melanoma were treated with an anti-fibrotic agent, tranilast, to inhibit CAF function. The infiltration of immune suppressor cell types, including regulatory T cells and myeloid-derived suppressor cells, in the TME was effectively decreased through reduction of stromal cell-derived factor-1, prostaglandin E2 , and transforming growth factor-ß. In tumor-draining lymph nodes, these immune suppressor cell types were significantly decreased, leading to activation of tumor-associated antigen-specific CD8(+) T cells. In addition, CAF-targeted therapy synergistically enhanced multiple types of systemic antitumor immune responses such as the cytotoxic CD8(+) T cell response, natural killer activity, and antitumor humoral immunity in combination with dendritic cell-based vaccines; however, the suppressive effect on tumor growth was not observed in tumor-bearing SCID mice. These data indicate that systemic antitumor immune responses by various immunologic cell types are required to bring out the efficacy of CAF-targeted therapy, and these effects are enhanced when combined with effector-stimulatory immunotherapy such as dendritic cell-based vaccines. Our mouse model provides a novel rationale with TME-targeted strategy for the development of cell-based cancer immunotherapy.

Mucinous bronchioloalveolar carcinoma with K-ras mutation arising in type 1 congenital cystic adenomatoid malformation: a case report with review of the literature.

Congenital cystic adenomatoid malformation (CCAM) of the lung is a rare hamartomatous cystic lesion, characterized by the presence of large cysts, which are histopathologically lined by pseudostratified ciliated cells. It has been recognized that rare cases of type 1 CCAM show malignant transformation, usually bronchioloalveolar carcinoma (BAC) or adenocarcinoma. Herein, we describe a case of BAC arising in type 1 CCAM with K-ras mutation. A 9-year-old Japanese girl presented with fever. Computed tomography demonstrated large cystic lesions in her right lower lung. Histopathological study of the resected specimen revealed multiple cysts, which were lined by pseudostratified ciliated cells, and occasionally interspersed with mucous cells without atypia. A small focus of proliferation of columnar cells showing lepidic growth pattern was present. These columnar cells had abundant mucin in the cytoplasm and mildly to moderately enlarged nuclei. Accordingly, a diagnosis of BAC arising in type 1 CCAM was made. Polymerase chain reaction analysis revealed K-ras mutation at codon 12 in the BAC component. The presence of mucous cell/goblet cell hyperplasia and atypical adenomatous hyperplasia is a well known phenomenon in type 1 CCAM. A recent study clearly demonstrated K-ras mutation in these lesions, which are thought to be precursors of BAC. Therefore, the concept of malignant transformation in the sequence from type 1 CCAM to mucous cell hyperplasia to atypical adenomatous hyperplasia to BAC and invasive adenocarcinoma due to K-ras mutation has been proposed. Careful histopathological analysis is important for evaluation of malignant lesions in type 1 CCAM.

A phase II study of docetaxel plus nedaplatin in patients with metastatic non-small-cell lung cancer.

PURPOSE: Nedaplatin is a cisplatin derivative, which has similar activity to cisplatin in non-small-cell lung cancer (NSCLC) when combined with vindesine, and causes less nausea/vomiting and nephrotoxicity compared with cisplatin. The aim of this study was to evaluate the efficacy and safety of combination chemotherapy with docetaxel plus nedaplatin in patients with metastatic NSCLC. METHODS: Patients with metastatic stage IIIB excluding locally advanced diseases or stage IV NSCLC were enrolled between March 2004 and March 2006. They were treated with docetaxel (60 mg/m(2)) and nedaplatin (80 mg/m(2)) on day 1 every 3-4 weeks until progression or intolerable toxicity for up to 4 cycles. RESULTS: Forty-four patients (mean age, 65 years; range, 40-79 years) received a total of 140 treatment cycles. Responses could be assessed in all patients (complete response, 0; partial response, 22; stable disease, 11; and progressive disease, 11). Response rate was 50.0 % (95 % confidence interval [CI], 35.2-64.8 %) with a disease control rate of 75.0 % (95 % CI, 62.2-87.8 %). A high response rate was achieved in patients with squamous cell carcinoma (66.7 %) compared with that in patients with adenocarcinoma (41.4 %). Median survival time from the start of the combination chemotherapy was 13.0 months, and the progression-free survival time was 7.4 months. Grade 3 or 4 hematologic toxicities included leukopenia (28.6 %) and neutropenia (61.4 %). Nonhematologic toxicities were mild. CONCLUSION: The combination of docetaxel plus nedaplatin was well tolerated and demonstrated potent activity in patients with metastatic NSCLC, particularly squamous cell carcinoma of the lung.

Thymic papillo-tubular adenocarcinoma containing a cyst: report of a case.

We report a case of thymic papillo-tubular adenocarcinoma in a 55-year-old man, who had no symptoms. Sternotomy revealed a tumor in the anterior mediastinum, tightly adhered to the pericardium. It was resected completely. Interestingly, the tumor contained a unilocular cyst filled with mucinous fluid, suggesting that it originated from a pre-existing thymic cyst. Pathological examination of the tumor revealed a primary thymic papillo-tubular adenocarcinoma resembling a tumor of gut origin. Thymic adenocarcinomas, particularly of the tubular subtype, are extremely rare.

Tracheo-brachiocephalic artery fistula after tracheostomy associated with thoracic deformity: a case report.

INTRODUCTION: Tracheo-brachiocephalic artery fistulae are critical long-term complications after tracheostomy, reported in 0.6% of patients within three to four weeks after the procedure. In 30% to 50% of cases there is some bleeding prior to onset. Since the onset involves sudden massive bleeding, the prognosis is poor; the reported survival rate is 10% to 30%. The direct cause of bleeding is the formation of a fistula with the trachea subsequent to arterial injury by the tracheostomy tube. Endo-tracheal factors are movement of the tracheostomy tube due to body movement and seizures, pressure exerted by the cuff of the tracheostomy tube, tracheostomy at lower levels, and the fragility of blood vessels and the trachea due to steroid or radiation therapy, and malnutrition. Extra-tracheal factors include prior surgery and deformity and shifting of the trachea and major blood vessels due to congenital kyphoscoliosis or thoracic deformity. There has been no report of the usefulness of contrast-enhanced computed tomography studies to identify the anatomical relationship between the trachea and brachiocephalic artery. CASE PRESENTATION: A 27-year-old Mongolian woman with congenital muscular dystrophy who underwent tracheal intubation for airway management due to pneumonia and granulation development developed a tracheo-brachiocephalic artery fistula during the placement of the tracheostomy tube. It was diagnosed by contrast-enhanced chest computed tomography and repaired. About a month later she developed massive airway bleeding during replacement of the tracheostomy tube. Temporary hemostasis was achieved by compression via cuff inflation. A contrast-enhanced chest computed tomography scan demonstrated a narrowed brachiocephalic artery running along and ventral to the tube and a tracheo-brachiocephalic artery fistula was suspected. She underwent brachiocephalic artery resection and aorta, right common carotid artery, and subclavian artery bypass surgery with an innominate vein, tracheoplasty, and partial sternectomy. We noted marked thoracic deformity; the brachiocephalic artery was compressed by the trachea and chest wall resulting in localized wall necrosis and the development of a tracheo-brachiocephalic artery fistula, a fatal complication whose prevention is important. CONCLUSIONS: We suggest that before tracheostomy, the anatomic relationship between the trachea and brachiocephalic artery must be confirmed by contrast-enhanced chest computed tomography scan.

Inhibition of transforming growth factor-beta-mediated immunosuppression in tumor-draining lymph nodes augments antitumor responses by various immunologic cell types.

Tumor-draining lymph nodes (DLN) are the most important priming sites for generation of antitumor immune responses. They are also the location where an immunosuppressive cytokine, transforming growth factor-beta (TGF-beta), plays a critical role in suppressing these antitumor immune responses. We focused on TGF-beta-mediated immunosuppression in DLNs and examined whether local inhibition of TGF-beta augmented antitumor immune responses systemically in tumor-bearing mice models. For inhibition of TGF-beta-mediated immunosuppression in DLNs, C57BL/6 mice subcutaneously bearing E.G7 tumors were administered plasmid DNA encoding the extracellular domain of TGF-beta type II receptor fused to the human IgG heavy chain (TGFR DNA) i.m. near the established tumor. In DLNs, inhibition of TGF-beta suppressed the proliferation of regulatory T cells and increased the number of tumor antigen-specific CD4(+) or CD8(+) cells producing IFN-gamma. Enhancement of antitumor immune responses in DLNs were associated with augmented tumor antigen-specific cytotoxic and natural killer activity in spleen as well as elevated levels of tumor-specific antibody in sera. The growth of the established metastatic as well as primary tumors was effectively suppressed via augmented antitumor immune responses. Inhibition of TGF-beta-mediated immunosuppression in DLNs is significantly associated with augmented antitumor responses by various immunocompetent cell types. This animal model provides a novel rationale for molecular cancer therapeutics targeting TGF-beta.

Pulmonary infarction associated with bronchogenic carcinoma.

Computed tomography findings of pathologically proven pulmonary infarction associated with bronchogenic carcinoma are reported for two patients. In one case, the infarction was demonstrated as a well-defined pleura-based large nodule in the peripheral portion of the same lobe of the tumor. The nodule had a smooth, convex border and a linear strand from the apex of the lesion toward the hilum. The obstruction of the subsegmental pulmonary artery due to tumor invasion was considered the cause of pulmonary infarction. In the second case, the infarction was demonstrated as a rapidly appeared, pleura-based consolidation in the same lobe of the tumor with a blurred border. Obstruction of the pulmonary vein by a tumor might have played an important role in the development of the pulmonary infarction in association with a large pulmonary artery obstruction. We conclude that pulmonary infarction should be considered as a differential diagnosis when peripheral pulmonary nodules or masses are located in the same lobe as the primary cancer.

Ultra-low-dose computed tomography system with a flat panel detector: assessment of radiation dose reduction and spatial and low contrast resolution.

PURPOSE: The aim of this study was to introduce a prototype cone-beam computed tomography system equipped with a flat panel detector (FPD-CT system) and measure its radiation dose and spatial and lowcontrast resolution. MATERIALS AND METHODS: A patient was rotated in a sitting position, and cone beam data were acquired with the flat panel detector from a fixed X-ray tube. Absorbed dose, spatial and low-contrast resolution, and variation in the CT attenuation value were assessed quantitatively in the acrylic phantom. The visibility of normal blood vessels in clinical images of seven patients was analyzed qualitatively by five board-certified radiologists. These quantitative and qualitative data were compared between the FPD-CT system and multidetector row CT (MDCT). RESULTS: Minimal low-contrast sensitivity and a moderate spatial resolution were demonstrated in images of central lung fields acquired by FPD-CT. The absorbed dose in the FPD-CT system decreased to approximately 2.5% of the dose in the MDCT system. CONCLUSION: Considering crossover structures in normal blood vessels and bronchi in the central areas of lung fields, this result implies that fairly acceptable spatial resolution can be realized with FPD-CT for detection and frequent follow-up of pulmonary abnormalities in the central lung fields.

HER1-4 expression status correlates with the efficacy of gefitinib treatment and tumor cell proliferative activity in non-small cell lung cancer.

The expression of human epidermal growth factor receptor (HER) family proteins was examined in specimens of 52 non-small cell lung cancers to evaluate their significance in tumor cell proliferation and their response to gefitinib. Epidermal growth factor receptor (EGFR; HER1) protein was expressed most frequently (43/52 cases). HER2 and HER3 were detected in 13 and 18 cases, respectively. HER4 was detected in only one case of squamous cell carcinoma. HER3 was expressed preferentially in adenocarcinomas of the papillary type. In most HER3-positive cases with or without other HER family proteins, the Ki-67 labelling index (18.2%) was significantly lower than in HER3-negative cases (30.6%) (P<0.05). Adenocarcinomas co-expressing EGFR, HER2 and HER3 frequently showed both a good response to gefitinib (6/7 cases) and a mutation of EGFR (4/6 cases). However, cases with a favourable response to gefitinib did not always express EGFR. Gefitinib appears to suppress growth signal pathways other than EGFR-tyrosine kinase activation in non-small cell lung cancers.

Good syndrome coexisting with leukopenia.

A 61-year-old man was admitted to our hospital for further examinations of a mediastinal mass. He had underwent an extended thymothymectomy, and had a tumor that was diagnosed as a type B1 thymoma, according to the World Health Organization. One year after surgery he was admitted again for recurrent diarrhea and pneumonia. Laboratory data revealed severe hypogammaglobulinemia with leukopenia. He was diagnosed with Good syndrome with leukopenia. Regular gamma globulin and figrastim injections were successful in keeping the patient symptom free. The prognosis of patients with Good syndrome and leukopenia is very poor; therefore, immediate diagnosis is important. The development of infectious diseases in a patient with thymoma or after the resection of thymoma mandates early and comprehensive immunologic investigation.

Assessment of diaphragmatic motion after lung resection using magnetic resonance imaging.

PURPOSE: The aim of this study was to assess quantitatively the impairment of diaphragmatic motion after lung resection, with special reference to the location of the resected lobe, duration of the postoperative period, and patient posture. We used magnetic resonance imaging to make the assessments. MATERIALS AND METHODS: In 44 patients (29 men, 15 women; mean age 62.2 years) with lung cancer, diaphragmatic motion was measured during maximum deep, slow breathing using a spoiled gradient-recalled echo sequence before and after lung resection. The study group consisted of 34 patients who were examined using a 1.5-T unit in the supine position and 10 patients using a vertically open 0.5-T unit in both the sitting and supine positions. The influence of surgery site and patient posture on diaphragmatic motion after lung resection was investigated. RESULTS: In all cases after lung resection, diaphragmatic motion on the operated side was significantly decreased (P < 0.001), and that on the nonoperated side was significantly increased (P = 0.045). After left upper lobectomy and right bilobectomy, the diaphragmatic motion on the operated side was significantly decreased (P < 0.001), and that of the other side was significantly increased (P < 0.001). The diaphragmatic motion was not significantly changed after right middle lobectomy. The diaphragmatic motion on the operated side was impaired significantly more (P = 0.035) in the supine position than in the sitting position. CONCLUSION: After lobe resection, diaphragmatic motion was impaired more significantly in the supine than in the sitting position; and it differed according to the location of the resected lobe. The improvement in diaphragmatic function after lobectomy was observed over a period of 3-24 months.

Preparation of fully activated dendritic cells capable of priming tumor-specific cytotoxic T lymphocytes in patients with metastatic cancer using penicillin-killed streptococcus pyogenes (OK432) and anti-CD40 antibody.

In order to achieve sufficient therapeutic potency, it has been proposed that vaccine therapy with dendritic cells needs to be combined with manipulation of immunological checkpoints, such as inhibition of regulatory T cells and blockade of negative signals, and enhancement of T cell trafficking to tumor sites. In the combinatorial cancer immunotherapy, use of matured/activated dendritic cells (DCs) with more potent antigen presenting capacity seems to be essential for eliciting anti-tumor immune responses. We herein established an ex vivo induction strategy for activated DCs capable of eliciting efficient tumor antigen-specific cytotoxic T lymphocytes (CTLs) from patients with metastatic cancer as well as healthy donors. Immature DCs were matured by 48-h culture in the presence of anti-CD40 antibody and penicillin-killed streptococcus pyogenes (OK432). Supplementation with both anti-CD40 and OK432 resulted in induction of activated DCs with higher surface expression of CD80, CD83, CD86 and major histocompatibility complex class II antigens, compared with other mature DCs that were induced by the combination of anti-CD40 with tumor necrosis factor-alpha or lipopolysaccharide. In analysis of the produced cytokine profiles, the activated DCs produced the highest T-helper 1-type cytokines for at least 72 h. Furthermore, the activated DCs, pulsed with tumor-associated antigen peptide, elicited in vitro tumor-specific CTLs, but DCs activated with other combinations did not in cancer patients. Therefore, we suggest that the activated DCs studied here might be used as a basic element for the combinatorial cancer immunotherapy.

Successful tumor eradication was achieved by collaboration of augmented cytotoxic activity and anti-angiogenic effects following therapeutic vaccines containing helper-activating analog-loaded dendritic cells and tumor antigen DNA.

We reported previously that pigeon cytochrome c-derived peptides (Pan-IA), which bind broad ranges of MHC class II molecules efficiently, activate T helper (Th) function in mice. In an experimental model, Pan-IA DNA vaccines augmented antitumor immunity in tumor antigen-immunized mice. To elicit more potent antitumor immunity and to eradicate tumors in a therapeutic setting, Pan-IA-loaded dendritic cells (DCs) were inoculated in combination with vaccines including ovalbumin (OVA) antigen DNA in tumor-bearing mice. Seventy percent of the immunized mice survived tumor-free for at least 4 months after treatment. In contrast, mice vaccinated with OVA DNA, either with or without naïve DCs, did not eliminate the tumors and died within 5 weeks. Only in mice vaccinated with OVA DNA and Pan-IA-loaded DCs were both cytotoxic and helper responses specific for OVA induced at the spleen and tumor sites as well as at the vaccination sites. Furthermore, accumulation of OVA-specific CD4(+) and CD8(+) T lymphocytes and interferon-gamma-mediated anti-angiogenesis were observed in the tumors of these mice. Thus, the combined vaccination primed both tumor-specific cytotoxicity and helper immunity resulting in augmented tumor lysis ability and anti-angiogenic effects. This is the first report to show that most established tumors were successfully eradicated by collaboration of potent antitumor immunity and anti-angiogenic effects by vaccination with tumor antigens and helper-activating analogs. This novel vaccination strategy is broadly applicable, regardless of identifying helper epitopes in target molecules, and contributes to the development of therapeutic cancer vaccines.

Bilateral multiple pulmonary sclerosing hemangioma.

We present herein a rare case of bilateral pulmonary sclerosing hemangioma, for which a differential diagnosis was made from metastatic lung tumors. A 32-year-old asymptomatic woman was referred to our hospital for further evaluation of abnormal chest shadows. A chest computed tomogram revealed two round, well-circumscribed masses in both sides of the lungs. Metastatic lung tumors were suspected, however, a primary lesion was not detected by several examinations. Thus, simultaneous video-assisted thoracic surgery for the bilateral tumors was performed. The tumors, measuring 16x13x12 mm in the left lung and 27x24x20 mm in the right lung, were resected, and then pathological examination confirmed the diagnosis of sclerosing hemangioma. Her postoperative course was uneventful and she has been doing well without any sign of recurrence.

Identification of antigenic epitopes recognized by Mac-2 binding protein-specific cytotoxic T lymphocytes in an HLA-A24 restricted manner.

We previously reported that 90K/Mac-2 binding protein (M2BP) is highly expressed in lung cancer and that M2BP-specific immunity was observed in many patients with lung cancer. These findings suggested the possibility of using M2BP as a target antigen in cancer immunotherapy. In this study, we selected 11 peptides derived from M2BP with an HLA-A24 binding motif and analyzed their ability to induce M2BP-specific cytotoxic T lymphocytes (CTL). CTLs were generated with the M2BP-derived peptides from peripheral blood CD8-positive T lymphocytes of HLA-A24-positive healthy donors in multiple in vitro stimulations. Two CTLs, one induced with M2BP(241-250) (GYCASLFAIL) and the other with M2BP(568-576) (GFRTVIRPF), produced interferon-gamma in response to HLA-A24-positive TISI cells pulsed with the same peptide used for the in vitro stimulation. Although the CTLs induced with M2BP(241-250) reacted with both peptide-pulsed TISI cells and BT20 cells expressing both M2BP and HLA-A24, the CTLs induced with M2BP(568-576) did not react with BT20 cells. The cytokine production was blocked by antibodies against HLA class I in CTLs induced using M2BP(241-250), but not in CTLs induced using M2BP(568-576). These findings suggest that M2BP(241-250) is naturally processed from the native M2BP molecule in cancer cells and recognized by M2BP-specific CTLs in an HLA-A24 restriction. An M2BP-derived CTL epitope with an HLA-A24 binding motif was identified for the first time in this study, and it is expected to be useful as a target antigenic epitope in clinical immunotherapy for lung cancer.