Hiroyuki Hirahara

Limited Resection for Noninvasive Bronchioloalveolar Carcinoma Diagnosed by Intraoperative Pathologic Examination

BACKGROUND The establishment of limited resection procedures for non-small cell lung cancer is expected. Many groups have suggested noninvasive bronchioloalveolar carcinoma (BAC) to be a potential indication for limited resection. METHODS We designed a prospective phase II study evaluating limited resection for noninvasive BAC diagnosed by intraoperative pathologic examination. From 1999 to 2007, limited resection was the procedure in 46 patients (16 men and 30 women; median age, 69 years; range, 49 to 83) who were diagnosed intraoperatively as having noninvasive BAC. The first end point was the predictive value of the intraoperative pathologic examination for noninvasive BAC diagnosis. The second end point was overall survival, disease-free survival, and cancer-specific survival, calculated using the Kaplan-Meier method. RESULTS We performed wedge resections for 44 patients and segmentectomy for 2 patients. Permanent pathologic examination revealed 3 patients had primary lung adenocarcinomas other than noninvasive BAC. The predictive value of intraoperative pathologic examination for noninvasive BAC diagnosis was 94%. During a median 51-month follow-up, there were only 2 cancer unrelated deaths. The 5-year overall survival rate and the disease-free survival rate were 93%, and the 5-year cancer-specific survival rate was 100%. CONCLUSIONS The results of our prospective phase II study indicate that limited resection, mainly by wedge resection, is a potentially curative surgical procedure and may be an acceptable alternative to lobectomy for patients with noninvasive BAC. Furthermore, an intraoperative pathologic diagnosis of noninvasive BAC is strongly predictive and allows for an intraoperative decision to perform a limited resection in these patients.

Induction of specific unresponsiveness to cardiac allografts by short-term administration of anti-T cell receptor alpha beta antibody.

Organ graft rejection is a T cell-dependent process in which activation of alloreactive T cells via the T cell receptor/CD3 complex is a critical step. Although treatment with anti-CD3 has been shown to prevent and reverse allograft rejection, there is little information available regarding the effects of immunotherapy using anti-TCR alpha beta mAb for rejection. In the present study, short-term preoperative treatment of rats with a mAb against alpha beta TCR (R73) completely prevented the rejection of cardiac allografts. These rats accepted second cardiac allografts from the same donor strain, but not from a third-party strain, without additional treatment. In mixed lymphocyte cultures, T cells from rats that had received cardiac grafts did not respond to donor-strain heart cells, but did respond to donor-strain spleen cells and third-party heart cells. These findings suggest that specific unresponsiveness to cardiac tissue was induced in R73-treated rats. Such unresponsiveness was induced only when rats were pretreated with the mAb and subsequently received a transplant. It is likely that administration of a small dose of R73 induced transient immunomodulation of TCR molecules, resulting in unresponsiveness to a subsequent cardiac allograft. Immunotherapy with mAb against TCR alpha beta is very effective, without apparent side effects, and may provide a new method for preventing graft rejection.

LONG-TERM SURVIVAL OF CARDIAC ALLOGRAFTS IN RATS TREATED BEFORE AND AFTER SURGERY WITH MONOCLONAL ANTIBODY TO CD2

The rejection of a transplanted allograft is dependent on T cell activation, which requires T cell receptor engagement by antigen and costimulatory signals delivered by T cell surface molecules such as CD2. Anti-CD2 mAbs have been shown to suppress cell-mediated immunity. The effects of anti-CD2 mAbs OX34 and OX54 on rejection of BN (RT1n) rat hearts transplanted heterotopically to LEW (RT1l) rats were investigated. Administration of OX34 (7 mg/kg/day i.p.), either for 3 consecutive days immediately before or 8 consecutive days immediately after transplantation induced indefinite allograft survival (median survival time: 7, > 150, and > 150 days for control, preoperative treatment, and postoperative treatment, respectively). In contrast, pre- or postoperative treatment with OX54 (40 mg/kg/day) prolonged median survival time to only 28 and 11 days, respectively. Administration of OX34 or OX54 to naive rats induced a transient depletion of T cells in the peripheral immune organs. In vitro studies revealed that whereas OX54 had no effect on the allogeneic mixed lymphocyte reaction, OX34 partially inhibited both the allogeneic mixed lymphocyte reaction, in an IL-2-reversible manner, and T cell proliferation in response to immobilized mAb to either the T cell receptor or CD3. OX34-treated rats in which the cardiac allograft had survived > 100 days accepted a second heart from the donor strain. Treatment with OX34 induced an alloantigen-unresponsive state in T cells. These results suggest that treatment with an appropriate anti-CD2 mAb, especially postoperatively, may prove an effective approach for preventing cardiac allograft rejection.

Synergistic effect of anti-T cell receptor monoclonal antibody and 15-deoxyspergualin on cardiac xenograft survival in a mouse-to-rat model

BACKGROUND Successful xenograft transplantation faces several obstacles including the presence of xenoantibodies, natural killer cell- and macrophage-mediated rejection, and T lymphocyte activation. METHODS A mouse-to-rat cardiac xenograft model was used to examine the synergistic effect of anti-T cell receptor (TCR) monoclonal antibodies (mAb) and 15-deoxyspergualin (DSG) on graft survival. RESULTS Pretransplantation injections (days -5, -3, and -1) of anti-TCR mAb (500 microg/kg/day) combined with continuous i.p. infusion of DSG (5 mg/kg/day) from day -7 to 28 significantly prolonged graft survival compared to untreated controls (3.3+/-0.5 vs. 44.2+/-5.6 days, P<0.001). Postoperative splenectomy combined with discontinuation of all other treatment on day 28 enhanced graft survival in rats treated with anti-TCR mAb and DSG to 71.0+/-2.5 days. Histological examination of grafts showed characteristic signs of vascular rejection: interstitial edema and hemorrhage, and polymorphonuclear cell infiltration. Antimouse antibody titers in recipients were increased upon rejection in each group that received a xenograft. Flow cytometry analysis showed a markedly decreased T cell population and a relatively increased mature B cell population (IgM(bright)/IgD(dull)) in spleens of rats treated with anti-TCR mAb and DSG on day 28. CONCLUSIONS The mechanism of prolonged xenograft survival in this model may include inhibition of antibody production by arrest of B-cell maturation during development from IgM(dull)/IgD(bright) mature B cells to antibody producing cells, and inhibition of T cell activation. The rejection seen in our model may be caused by xenoreactive antibodies and may be associated with T cells, natural killer cells, and macrophages.

Electroporation-mediated transfer of plasmid DNA encoding IL-10 attenuates orthotopic tracheal allograft stenosis in rats.

BACKGROUND Electroporation has been shown to increase the efficacy of intramuscular injection of plasmid DNA, resulting in a higher level of foreign gene expression. Using this technique, we examined the effect of viral IL-10 gene transfer on the prevention of tracheal allograft stenosis in an animal model. METHODS On the day of tracheal transplantation, recipient Lewis rats were intramuscularly injected with either plasmid pCAGGS-LacZ or plasmid pCAGGS-viral IL-10, followed immediately by electroporation. Tracheas from Brown Norway donors were transplanted into the backs of Lewis recipients, and the histology of the grafts were assessed 2 and 4 weeks after transplantation. RESULTS The serum level of IL-10 peaked at 2000 pg/ml one day after injection; the level then slowly decreased, but was maintained above 1000 pg/ml until 8 days after injection. At Day 28, the airway lumina of the tracheal allografts were almost completely obliterated by fibroproliferative tissue in the control pCAGGS-LacZ-treated rats. In rats injected once with pCAGGS-viral IL-10, luminal obliteration was significantly decreased compared with the control pCAGGS-LacZ-treated rats (mean luminal opening 46.8% vs 0% p<0.05). The loss of epithelial cells lining the airway was also decreased in the IL-10-treated group (mean epithelial coverage 42% vs 5% p<0.05). Multiple injections with pCAGGS-viral IL-10 did not further improve the histological changes. CONCLUSION IL-10 gene transfer by intramuscular injection using electroporation attenuated tracheal allograft stenosis associated with mild epithelial injury.

Patch Repair of Left Main Coronary Artery Using Autologous Pericardium in a Young Female

Successful patch repair of the left main coronary artery was performed using fresh autologous pericardium in a 19-year-old female without evidence of aortitis. Early and late postoperative studies revealed good patency of the left main coronary artery, and the patient is free of symptoms. Patch repair may be the best option for isolated left main coronary artery disease, especially in young patients.