Aki Ishikawa

A Phase I Study of α-Galactosylceramide (KRN7000)–Pulsed Dendritic Cells in Patients with Advanced and Recurrent Non–Small Cell Lung Cancer

Purpose: Human Vα24 natural killer T (NKT) cells bearing an invariant Vα24JαQ antigen receptor, the counterpart of murine Vα14 NKT cells, are activated by a specific ligand, α-galactosylceramide (αGalCer, KRN7000), in a CD1d-dependent manner. I.v. administration of αGalCer-pulsed dendritic cells (DC) induces significant activation and expansion of Vα14 NKT cells in the lung and resulting potent antitumor activities in mouse tumor metastatic models. We did a phase I dose escalation study with αGalCer-pulsed DCs in lung cancer patients. Experimental Design: Patients with advanced non–small cell lung cancer or recurrent lung cancer received i.v. injections of αGalCer-pulsed DCs (level 1: 5 × 107/m2; level 2: 2.5 × 108/m2; and level 3: 1 × 109/m2) to test the safety, feasibility, and clinical response. Immunomonitoring was also done in all completed cases. Results: Eleven patients were enrolled in this study. No severe adverse events were observed during this study in any patient. After the first and second injection of αGalCer-pulsed DCs, dramatic increase in peripheral blood Vα24 NKT cells was observed in one case and significant responses were seen in two cases receiving the level 3 dose. No patient was found to meet the criteria for partial or complete responses, whereas two cases in the level 3 group remained unchanged for more than a year with good quality of life. Conclusions: In this clinical trial, αGalCer-pulsed DC administration was well tolerated and could be safely done even in patients with advanced disease.

A Phase I Study of In vitro Expanded Natural Killer T Cells in Patients with Advanced and Recurrent Non–Small Cell Lung Cancer

Purpose: Human Vα24 natural killer T (Vα24 NKT) cells bearing an invariant Vα24JαQ antigen receptor are activated by a glicolipid ligand α-galactosylceramide (αGalCer; KRN7000) in a CD1d-dependent manner. The human Vα24 NKT cells activated with αGalCer and interleukin-2 have been shown to produce large amounts of cytokines, such as IFN-γ, and also exerting a potent killing activity against various tumor cell lines. We did a phase I study with autologous activated Vα24 NKT cell therapy. Experimental Design: Patients with advanced or recurrent non–small cell lung cancer received i.v. injections of activated Vα24 NKT cells (level 1: 1 × 107/m2 and level 2: 5 × 107/m2) to test the safety, feasibility, and clinical response of this therapeutic strategy. Immunomonitoring was also done in all cases. Results: Six patients were enrolled in this study. No severe adverse events were observed during this study in any patients. After the first and second injection of activated Vα24 NKT cells, an increased number of peripheral blood Vα24 NKT cells was observed in two of three cases receiving a level 2 dose of activated Vα24 NKT cells. The number of IFN-γ-producing cells in peripheral blood mononuclear cells increased after the administration of activated Vα24 NKT cells in all three cases receiving the level 2 dose. No patient was found to meet the criteria for either a partial or a complete response. Conclusions: The clinical trial with activated Vα24 NKT cell administration was well tolerated and carried out safely with minor adverse events even in patients with advanced diseases.

Latest treatments for spontaneous pneumothorax

ObjectiveCurrently, the treatment of pneumothorax varies among hospitals. Three factors account for the differences. First, pneumothorax expresses the state of disease instead of the disease itself. Some pneumothoraces heal on their own but patients with pneumothorax due to chronic diseases may need further intervention. The decision for the choice of treatment is up to the physician. Second, it is insufficient to treat pneumothorax with current treatment guidelines. Third, prognosis and follow-up after pneumothorax treatment is not well documented. Therefore, verification/assessment of treatment and its effect is insufficient.MethodsTo prevent postoperative bulla neogenesis, the “covering technique” is most effective. Chemical pleurodesis has shown a great number of recurrences and has led to inconveniences, such as various results among individuals. Therefore, it should not be the recommended therapy.Results and conclusionIntractable pneumothorax in elderly patients has been increasing year after year. Interventional treatments such as endobronchial Watanabe spigot embolization and the thoracographic fibrin glue sealing method are expected to become more common in the future, keeping some patients from undergoing surgery. Causes are still unknown for certain pneumothoraces in women, and there are still numerous cases of postoperative recurrence among young males. Further studies in this field are expected in future.

Dendritic cell maturation by CD11c− T cells and Vα24+ natural killer T‐cell activation by α‐Galactosylceramide

Human invariant Vα24+ natural killer T (NKT) cells display potent antitumor activity upon stimulation. Activation of endogenous Vα24+ NKT cells would be one strategy for the treatment of cancer patients. For example, dendritic cells (DCs) loaded with a glycolipid NKT cell ligand, α‐galactosylceramide (αGalCer, KRN7000), are a possible tool for the activation and expansion of functional Vα24+ NKT cells in vivo. In this report, we demonstrate that the levels of expansion and the ability to produce IFN‐γ of Vα24+ NKT cells induced by αGalCer‐loaded whole PBMCs cultured with IL‐2 and GM‐CSF (IL‐2/GM‐CSF‐cultured PBMCs) were superior to those of cells induced by monocyte‐derived CD11c+ DCs (moDCs) developed with IL‐4 and GM‐CSF. Interestingly, CD11c+ cells in the IL‐2/GM‐CSF‐cultured PBMCs showed a mature phenotype without further stimulation and exerted potent stimulatory activity on Vα24+ NKT cells to enable them to produce IFN‐γ preferentially at an extent equivalent to mature moDCs induced by stimulation with LPS or a cytokine cocktail. Cocultivation with CD11c− cells in the IL‐2/GM‐CSF‐cultured PBMCs induced maturation of moDCs. In particular, CD11c−CD3+ T cells appeared to play important roles in DC maturation. In addition, TNF‐α was preferentially produced by CD11c−CD3+ T cells in IL‐2/GM‐CSF‐cultured PBMCs and was involved in the maturation of moDCs. Thus, the maturation of DCs induced by CD11c− T cells through TNF‐α production appears to result in the efficient expansion and activation of Vα24+ NKT cells to produce IFN‐γ preferentially.

Successful resection of schwannoma from an intercostal nerve causing bloody pleural effusion: Report of a case

We report a case of schwannoma arising from the 9th intercostal nerve, which caused a bloodstained pleural effusion. The patient, a 37-year-old woman, presented with left-sided back pain. A chest X-ray showed left pleural effusion, which was subsequently found to be bloodstained but without malignant cells. Chest magnetic resonance imaging showed a 76-mm tumor arising from the 9th intercostal nerve. The tumor and intercostal nerve were successfully resected. Histological examination revealed that the tumor comprised spindle cells with both Antoni types A and B patterns. There were necrotic changes and cystic degeneration, but no atypical or mitotic cells. Based on these findings, benign schwannoma was diagnosed. Schwannoma is rarely accompanied by bloody pleural effusion, which we assume was caused by partial tumor rupture. Magnetic resonance imaging proved very useful in localizing and characterizing the tumor in this case.

Endobronchial Ultrasonography in a Patient With a Mediastinal Thoracic Duct Cyst

Mediastinal thoracic duct cysts are rare clinical findings. We report the case of a symptomatic 58-year-old woman in whom a thoracic duct cyst was successfully treated with surgical resection. Preoperative endobronchial ultrasonography revealed an oval-shaped hypoechoic area with a distinct, thick pedicle, gradual intermittent flux of the fluid content within the lesion, and endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) revealed lymphocyte predominant serous fluid without malignancy, which is consistent with features of a mediastinal thoracic duct cyst. We postulate that EBUS-TBNA can be used as a preoperative diagnostic tool for patients with possible mediastinal thoracic duct cysts.

Small solitary pulmonary metastasis detected before primary sigmoid colon cancer: report of a case.

We report the case of a 60-year-old woman referred to us after chest X-ray and mobile computed tomography screening detected an 8-mm nodule in right S2. Transbronchial aspiration cytology suggested a pulmonary metastasis from colorectal cancer. Therefore, we performed a colonoscopy and found a polypoid lesion, 2 cm in diameter, in the sigmoid colon. An analysis of a biopsy specimen from this polypoid lesion confirmed adenocarcinoma. Surgical resection of the primary sigmoid colon cancer was subsequently performed, followed 4 weeks later by a right S2 segmentectomy to remove the lung metastasis. The patient is currently well without any clinical signs of recurrence, 44 months after her operation.

A new sterilization technique with balloon-tube thoracostomy for thoracic empyema

OBJECTIVE Failure or prolongation of treatment for refractory thoracic empyema by the current chest-tube drainage technique is often due to sterilization difficulties. Insufficient sterilization prolongs hospitalization, and is often associated with life-threatening complications and/or additional invasive surgical procedures. A new chest-tube sterilization technique aimed at making it less invasive and shortening the therapy is proposed. METHODS Following pretreatment for complications including loculation, bronchopleural fistula, or corticated lung, a double-lumen trocar catheter was introduced at the bottom of the empyemic cavity through the lateral chest wall. Then, a Foley balloon urethra-catheter was inserted and attached just inside the anterior chest wall at the top of the cavity for the evacuation of intrathoracic air. After irrigation of the cavity with distilled water once or twice, the cavity was completely filled with a bactericidal solution which was left in place for 30-60 minutes, followed by an antibiotic solution for more than 20 hours. RESULTS Among the five treated post-lobectomy or pneumonectomy cases, sterilization was obtained after only one treatment in four cases and after two courses in the other. Catheterization duration from the initial treatment was 2-13 days. Neither recurrence nor treatment-related major complications were observed. CONCLUSIONS This balloon-tube thoracostomy technique is simple, minimally invasive and cost-effective, due to shortening of the treatment time with minimal manpower and equipment requirements. It is thus a promising therapeutic approach to thoracic empyema and has the potential for application to other intrathoracic disorders.

Eradication of intractable malignant ascites by abdominocentesis, reinfusion of concentrated ascites, and adoptive immunotherapy with dendritic cells and activated killer cells in a patient with recurrent lung cancer: a case report

IntroductionMalignant ascites is often a sign of a terminal stage in several malignant diseases. To control ascites, drainage and intra-abdominal chemotherapy are often used in those patients but eradication of ascites is difficult and prognosis is poor.Case presentationA 55-year-old woman was admitted to our hospital on 26 January 2007 with dyspnea, abdominal distention and oliguria. Abdominocentesis revealed peritoneal carcinomatosis resulting from abdominal recurrence from lung cancer. To alleviate the dyspnea and abdominal distention, we drained the ascites aseptically and infused them intravenously back into the patient after removal of tumor cells by centrifugation, and then concentration by apheresis. After the drainage of ascites, we intraperitoneally infused activated killer cells and dendritic cells from the patients tumor-draining lymph nodes, together with 4.5 × 105U interleukin-2 in 50 ml saline by 2.1 ml/hour infuser balloon.Drastic decreases in the tumor cell count and in ascite retention were observed after several courses of ascites drainage, intravenous infusion and intraperitoneal immunotherapy. The plasma protein level was maintained during the treatment notwithstanding the repeated drainage of ascites. Cell surface marker analysis, cytotoxic activities against autologous tumor cells and interferon-gamma examination of ascites suggested the possibility that these effects were mediated by immunological responses of activated killer cells and dendritic cells infused intraperitoneally.ConclusionCombination of local administration of immune cells and infusion of concentrated cell free ascites may be applicable for patients afflicted with refractory ascites.