Introduction: Post-transplant lymphoproliferative disorder (PTLD) is the most frequent malignant complication of organ transplantation in children. PTLD often arises in the setting of prior Epstein-Barr virus (EBV) infection and therapeutic immunosuppression (IS) for prevention of allograft rejection. Treatment strategies with IS reduction, anti-CD20 antibody (rituximab) and chemotherapy (CTX) have continue to improve survival outcomes. We present a large, single-institutional experience of pediatric patients from the University of Florida. Methods: A retrospective analysis of pediatric patients (<18 years) diagnosed with PTLD after solid organ or allogeneic stem cell transplant (HSCT) was performed through a review of individual electronic medical records. Results: Of 138 PTLD cases diagnosed between 1994 and 2017, 49 pediatric patients (47% liver, 22% heart, 22% kidney, 6% lung, and 2% HSCT) were identified and analyzed for secondary outcomes. Median age at transplant and PTLD diagnosis were 19 months and 7 years, respectively. Fifty-three percent (n = 26) were males. The median interval from transplant to PTLD was 35 months. Pathology included early lesions (12%, n = 6), polymorphic (27%, n = 13), monomorphic (53%, n = 26), Hodgkin-like (4%, n = 2), EBV+ by EBER PCR (67%, n = 33) and CD-20+ (67%, n = 33). Extra-nodal site involvement was identified in 53% (n = 26), the most common site being the GI tract. Ann Arbor stage III/IV was present in 47% (n = 23). Initial PTLD management was IS reduction alone in 37% (n = 18), rituximab (R) in 18% (n = 9) and CTX with or without (R) in 39% (n = 19). The most common CTX regimen was R + cyclophosphamide 27% (N = 13). After first-line therapy, 55% patients had complete remission (CR), 25% partial remission (PR) or stable disease (SD) and 6% progressive disease (PD). A 2nd line treatment was required in 39% (n = 19) and 8% (n = 4) required 3rd line treatment. During PTLD treatment 25% (n = 12) experienced acute organ rejection, with 4% (n = 2) developing allograft failure. Final analysis showed 84% (n = 41) achieved CR, 8% (n = 4) had PD, 78% (n = 38) patients were alive and 76% (n = 37) are alive without PTLD. Conclusions: Despite nearly 50% of patients having stage III/IV disease and extranodal involvement, our transplant center reports encouraging outcomes in survival and allograft function. We identified multiple prognostic indices (performance status, IPI score, graft rejection, malignancy history and recipient EBV status), which in the future could help generate a prognostic scoring system for this population. While these outcomes are promising, 25% of patients did not achieve long-term PTLD remission with modern treatment modalities. This illustrates the need for novel therapies for pediatric patients with PTLD to achieve cure rates above 90%, which are attainable in other childhood lymphomas. Keywords: Epstein-Barr virus (EBV); non-Hodgkin lymphoma (NHL); post-transplant lymphoproliferative disorders (PTLDs)

Introduction Amiodarone is often used in the suppression of tachyarrhythmias. One of the more serious adverse effects includes amiodarone pulmonary toxicity (APT). Several pulmonary diseases can manifest including interstitial pneumonitis, organizing pneumonia, acute respiratory distress syndrome, diffuse alveolar hemorrhage, pulmonary nodules or masses, and pleural effusion. Incidence of APT varies from 5–15% and is correlated to dosage, age of the patient, and preexisting lung disease. Description A 56-year-old male with a past medical history of coronary artery disease and chronic obstructive pulmonary disease was admitted for a coronary artery bypass graft. Post-operatively, the patient was admitted to the ICU for ventilator management and continued to receive his home dose of amiodarone 400 mg orally twice daily, which he had been taking for the past 3 months. The patient was found to be hypoxemic with a PaO2 52 mmHg and bilateral infiltrates on chest x-ray. Patient also complained of new onset dyspnea. Physical exam found bilateral rhonchi with bibasilar crackles and subcutaneous emphysema along the left anterior chest wall. Daily chest x-rays showed worsening of bilateral interstitial infiltrates and pleural effusions. A chest high-resolution computed tomography on post-operative day 3 showed extensive and severe bilateral ground glass opacities. APT was suspected and amiodarone was discontinued. A course of oral prednisone without antibiotics was initiated, and after one week of treatment the chest film cleared, the PaO2 value normalized and dyspnea resolved. Discussion APT occurs via cytotoxic T cells and indirectly by immunological reaction. Typically the lungs manifest a diffuse interstitial pneumonitis with varying degrees of fibrosis. Infiltrates with a ‘ground-glass’ appearance appreciated on HRCT are more definitive than chest x-ray. Pulmonary nodules can be seen, frequently in the upper lobes. These are postulated to be accumulations of amiodarone in areas of previous inflammation. Those undergoing major cardiothoracic surgery are known to be predisposed to APT. Some elements require consideration: a baseline pulmonary function test (PFT) did not exist prior. APT would manifest a restrictive pattern of PFTs. In APT diffusing capacity (DLCO) is generally >20 percent from baseline. A DLCO was not done in this patient. Therefore, not every type of interstitial lung disease could be ruled out. Key features support a clinical diagnosis: (1) new dyspnea, (2) exclusion of lung infection, (3) exclusion of heart failure, (4) new radiographic features, (5) improvement with withdrawal of amiodarone. Our case illustrates consideration of APT in patients who have extensive use of amiodarone and new onset dyspnea.

BACKGROUND:Malignant pleural mesothelioma (MPM) is an aggressive neoplasm arising from mesothelial lining of pleura. CD26 molecules preferentially expressed on epithelioid type of MPM. This study investigates the molecular mechanisms of CD26 regulating MPM cells in vitro and in vivo.METHODS:Biochemical and cell biological approaches were used for identifying a novel molecular target of MPM. Its contribution to tumour expansion has been also assessed using animal models. The clinical samples of MPM were also assessed for its expression.RESULTS:We identify that cytostatic effects in MPM are mediated by somatostatin (SST) receptor 4 (SSTR4), being inhibited by the interaction of CD26 molecules. We also indicates that SSTR4-mediated cytostatic effects are regulated by SHP-2 PTP, and that this inhibitory effect by SST agonist is enhanced via lipid raft clustering of associated molecules following crosslinking of anti-CD26 antibody. Finally, using an in vivo xenograft model, we demonstrate that the anti-tumour effect of anti-CD26 mAb is enhanced when combined with SSTR4 agonist treatment, and that SSTR4 is highly coexpressed with CD26 on epithelioid or biphasic types of MPM tissues obtained from patients' surgical specimens.CONCLUSIONS:Combination therapy with humanised anti-CD26 mAb and SSTR4 agonist may therefore potentiate anti-tumour effect on MPM.

Purpose/Objective(s)To describe the early outcomes of patients with Hodgkin lymphoma (HL) involving the mediastinum treated with consolidative involved-node proton therapy (INPT) on a prospective study.Materials/MethodsBetween September 2009 and March 2012, 16 patients with de novo HL consented to treatment with double-scatter INPT on an IRB-approved protocol after completing chemotherapy. The cohort included 4 males and 12 females; the median age was 22 years (range, 7-57 years). Stage distribution included favorable early-stage (IIA, n = 2), unfavorable early-stage (B symptoms and/or bulky disease, n = 12), and advanced-stage (IIIA bulky, n = 2) disease. Six patients were treated per pediatric protocols with 4 cycles of ABVE-PC or VAMP chemotherapy and 15 to 25.5 CGE of INPT. Ten patients were treated with 3 to 6 cycles of ABVD followed by INPT to between 30.6 and 36 CGE after a complete response(CR) by positron emission tomography (PET) to ABVD (n = 8) or 39.6 CGE after a partial response (PR) by PET (PR; n = 2). Patients were evaluated for toxicity weekly via Common Terminology Criteria for Adverse Events, v3.0, during treatment, then every 3 months for the first 2 years, and then every 6 months for the subsequent 3 years. Basic blood work and computed tomography (CT) and/or PET scans were performed every 6 to 12 months after treatment. Progression-free (PFS) and event-free (EFS) survival rates were calculated by the Kaplan-Meier method from the time of diagnosis.ResultsThe median follow-up was 32 months (range, 5-47 months). Two events have occurred during follow-up, including 1 relapse (in a pediatric patient with stage IIB bulky disease with PET-confirmed CR and CT-confirmed PR after ABVE-PC x 4) inside and outside (peripheral lung) the targeted field at 4 months after INPT, and 1 transformation into a primary mediastinal large B cell lymphoma (stage IIB bulky disease with a CT-confirmed and PET-confirmed PR after ABVDx6) within the INPT field at 5 months after treatment. The 2-year PFS rate was 93% and the 2-year EFS rate was 85%. No acute or late grade 3 nonhematologic toxicities were observed. Acute grade 2 toxicities included 3 patients with esophagitis and 3 others with dyspepsia. Late toxicities included 1 patient with dyspepsia requiring medication.ConclusionsPT following chemotherapy in patients with HL is well-tolerated with results similar to conventional photon therapy. Longer follow-up will be needed to realize the likely benefit of proton therapy in reducing the risk of radiation-induced cardiovascular late effects and second malignancies. Purpose/Objective(s)To describe the early outcomes of patients with Hodgkin lymphoma (HL) involving the mediastinum treated with consolidative involved-node proton therapy (INPT) on a prospective study. To describe the early outcomes of patients with Hodgkin lymphoma (HL) involving the mediastinum treated with consolidative involved-node proton therapy (INPT) on a prospective study. Materials/MethodsBetween September 2009 and March 2012, 16 patients with de novo HL consented to treatment with double-scatter INPT on an IRB-approved protocol after completing chemotherapy. The cohort included 4 males and 12 females; the median age was 22 years (range, 7-57 years). Stage distribution included favorable early-stage (IIA, n = 2), unfavorable early-stage (B symptoms and/or bulky disease, n = 12), and advanced-stage (IIIA bulky, n = 2) disease. Six patients were treated per pediatric protocols with 4 cycles of ABVE-PC or VAMP chemotherapy and 15 to 25.5 CGE of INPT. Ten patients were treated with 3 to 6 cycles of ABVD followed by INPT to between 30.6 and 36 CGE after a complete response(CR) by positron emission tomography (PET) to ABVD (n = 8) or 39.6 CGE after a partial response (PR) by PET (PR; n = 2). Patients were evaluated for toxicity weekly via Common Terminology Criteria for Adverse Events, v3.0, during treatment, then every 3 months for the first 2 years, and then every 6 months for the subsequent 3 years. Basic blood work and computed tomography (CT) and/or PET scans were performed every 6 to 12 months after treatment. Progression-free (PFS) and event-free (EFS) survival rates were calculated by the Kaplan-Meier method from the time of diagnosis. Between September 2009 and March 2012, 16 patients with de novo HL consented to treatment with double-scatter INPT on an IRB-approved protocol after completing chemotherapy. The cohort included 4 males and 12 females; the median age was 22 years (range, 7-57 years). Stage distribution included favorable early-stage (IIA, n = 2), unfavorable early-stage (B symptoms and/or bulky disease, n = 12), and advanced-stage (IIIA bulky, n = 2) disease. Six patients were treated per pediatric protocols with 4 cycles of ABVE-PC or VAMP chemotherapy and 15 to 25.5 CGE of INPT. Ten patients were treated with 3 to 6 cycles of ABVD followed by INPT to between 30.6 and 36 CGE after a complete response(CR) by positron emission tomography (PET) to ABVD (n = 8) or 39.6 CGE after a partial response (PR) by PET (PR; n = 2). Patients were evaluated for toxicity weekly via Common Terminology Criteria for Adverse Events, v3.0, during treatment, then every 3 months for the first 2 years, and then every 6 months for the subsequent 3 years. Basic blood work and computed tomography (CT) and/or PET scans were performed every 6 to 12 months after treatment. Progression-free (PFS) and event-free (EFS) survival rates were calculated by the Kaplan-Meier method from the time of diagnosis. ResultsThe median follow-up was 32 months (range, 5-47 months). Two events have occurred during follow-up, including 1 relapse (in a pediatric patient with stage IIB bulky disease with PET-confirmed CR and CT-confirmed PR after ABVE-PC x 4) inside and outside (peripheral lung) the targeted field at 4 months after INPT, and 1 transformation into a primary mediastinal large B cell lymphoma (stage IIB bulky disease with a CT-confirmed and PET-confirmed PR after ABVDx6) within the INPT field at 5 months after treatment. The 2-year PFS rate was 93% and the 2-year EFS rate was 85%. No acute or late grade 3 nonhematologic toxicities were observed. Acute grade 2 toxicities included 3 patients with esophagitis and 3 others with dyspepsia. Late toxicities included 1 patient with dyspepsia requiring medication. The median follow-up was 32 months (range, 5-47 months). Two events have occurred during follow-up, including 1 relapse (in a pediatric patient with stage IIB bulky disease with PET-confirmed CR and CT-confirmed PR after ABVE-PC x 4) inside and outside (peripheral lung) the targeted field at 4 months after INPT, and 1 transformation into a primary mediastinal large B cell lymphoma (stage IIB bulky disease with a CT-confirmed and PET-confirmed PR after ABVDx6) within the INPT field at 5 months after treatment. The 2-year PFS rate was 93% and the 2-year EFS rate was 85%. No acute or late grade 3 nonhematologic toxicities were observed. Acute grade 2 toxicities included 3 patients with esophagitis and 3 others with dyspepsia. Late toxicities included 1 patient with dyspepsia requiring medication. ConclusionsPT following chemotherapy in patients with HL is well-tolerated with results similar to conventional photon therapy. Longer follow-up will be needed to realize the likely benefit of proton therapy in reducing the risk of radiation-induced cardiovascular late effects and second malignancies. PT following chemotherapy in patients with HL is well-tolerated with results similar to conventional photon therapy. Longer follow-up will be needed to realize the likely benefit of proton therapy in reducing the risk of radiation-induced cardiovascular late effects and second malignancies.

Introduction: Wollongong Hospital is a regional tertiary referral hospital that performs 1600 coronary angiography and interventions via femoral approach annually. Radial approach was commenced in March 2010. When compared to the femoral approach complications including bleeding are significantly lower. Despite the benefits of radial approach, operator uptake has been consistently low worldwide. Our aim is to show that experienced femoral operators can successfully implement radial angiography and show demonstrable improvement. Methods: Data was collected from the radial angiography database maintained in the cardiac catheterisation laboratory from March 2010 to December 2010. The first 50 patients were compared to the second 50 patients using the variables of; fluoroscopy time, catheter type, contrast volume, procedural success rate and complications. Results: Between March and December 2010, 100 patients underwent angiogram via radial approach.Tabled 1First 50Second 50Sheath size5F6FCatheter typeTIGJudkinsDrug cocktails73%26% Open table in a new tab Tabled 1AverageFirst 50Second 50Fluoroscopy (mins)17.822.511.8Contrast volume (ml)102103101Procedural success84%82%86%Major complication3%6%0% Open table in a new tab Most common reason for failure was vasospasm. Major complication included stroke (2%) and dissection (1%). No major bleeding was observed however there was one instance of minor bleeding. Conclusion: Wollongong Hospital successfully introduced diagnostic radial angiography with minimal complications and demonstrable improvement. Plans include expanding our scope to percutaneous coronary intervention via the radial approach. The steep curve to mastering radial angiography should not be a barrier for experienced femoral operators.

Wollongong Hospital is a regional tertiary referral hospital which commenced an in hours primary percutaneous coronary intervention program for STEMI patients in 2008. This was expanded to an after hours service in 2010. Performing PCI without onsite surgical backup is a controversial area. We aim to show it can be performed successfully and safely. Methods: Procedural data for 2008–2010 was retrospectively collected from Wollongong's PCI database and medical records. Patient follow-up was obtained with telephone interviews. Ethics approval was obtained from local HREC. Results: During the study a cohort of 112 consecutive patients underwent primary PCI with 147 lesions treated. Seventy-nine percent were males, with a mean age of 62.3. The overall success rate was 100%. Six patients required transfer for semi urgent bypass grafting based on coronary anatomy after establishing TIMI 3 flow. All patients received aspirin and clopidogel except one who received prasugrel. Glycoprotein IIb/IIIa inhibitors were used in 83%. The commonest vessel intervened was the right coronary artery. Bare metal and drug-eluting stents were used in 55% and 45% respectively. Average D2B time was 95 minutes. Thrombectomy catheter was used in 44%. No acute or subacute stent thrombosis was noted. Major bleeding complications occurred in 0.8%. Follow-up of this cohort is ongoing to confirm low TVF, TLR, and late stent thrombosis rate. Conclusion: Primary PCI's for STEMI can be safely performed in a regional institution without on-site surgical back-up with acceptable D2B time and low TVR, TLR and stent thrombosis rates.

Introduction: Significant numbers of patients requiring PPM intervention are on anticoagulant medications. Conflicting evidence exists regarding bleeding complications and continuation of anticoagulant medications during PPM insertion. This study examines the relationship between anticoagulation and bleeding post PPM insertion or box change. Method: Between January 2007 and December 2010, 684 patients had PPM intervention at Wollongong Hospital. Data was collected from pacemaker procedure log and medical records. Major bleeding was defined as haematoma requiring exploration or blood transfusion. In this ongoing project, data and results from the first 104 patients are included. We aim to analyse all 684 patients to validate our results. Results: Of the 104 patients, 63.5% (n = 66) were males. Mean age of 79.8 years. The procedures comprised of 23.0% (n = 24) single chamber, 42.3% (n = 44) dual chamber and 34.6% (n = 36) box changes. Anticoagulants used were aspirin 41.3%, clopidogrel 10.5%, Aspirin with Clopidogrel 5.7%, warfarin withheld 9.6%, warfarin with UFH bridging 1.9%, and warfarin with enoxaparin bridging 6.7%. Of these, three had bleeding complication (one haematoma and two minor oozing); none required exploration or evacuation; two of these three were in enoxaparin bridging group. Conclusion: PPM implantation in patients on anticoagulation at our centre had very low incidence of bleeding complication. Our data suggests bridging therapy increases the risk of bleeding. Follow up of this cohort is ongoing to confirm – persistently low incidence of bleeding and Bridging therapy is a predictor of adverse outcome without decreasing cerebro-vascular events.

Purpose/Objective(s)In the dosimetric component of a Phase II prospective study of consolidative involved-node radiotherapy (INRT) in patients with mediastinal Hodgkin lymphoma (HL), proton therapy (PT) reduced doses to the heart, lungs, esophagus, thyroid, and total body compared with either 3-dimensional conformal radiotherapy (3D-CRT), or intensity modulated radiotherapy (IMRT). This study investigates the dosimetric impact of PT to the subunits of the heart.Materials/MethodsFrom June 2009 through December 2010, 13 patients were enrolled on the University of Florida (UF) institutional review board-approved protocol HL01 of consolidative INRT for HL. Three separate treatment plans for each patient were developed prospectively using 3D-CRT, IMRT, and PT. Target constraints included a clinical target volume (CTV) D99% = 100% and a planning target volume (PTV) D95% >95%; organs-at-risk (OAR) constraints included a mean lung dose <18 Gy/CGE, lung V20 <30%, and mean heart dose <20 Gy/CGE. All patients were offered treatment with PT due to the reduction of dose to the OARs. The right atrium (RA), left atrium (LA), right ventricle (RV), left ventricle (LV), aortic valve (AV), mitral valve (MV), tricuspid valve (TV), pulmonic valve (PV), left-anterior descending artery (LAD), left-circumflex artery (LC), and right-circumflex artery (RC) were retrospectively contoured on the 11 patients who had an IV-contrast simulation scan and the doses to these structures were evaluated for all treatment plans. A Wilcoxon paired test was performed to evaluate for statistical significance (p < 0.05) for 3D-CRT and IMRT compared with PT.ResultsThe mean heart doses were 20 Gy, 15 Gy, and 10 CGE with 3D-CRT, IMRT, and PT, respectively. Compared with 3D-CRT, PT significantly reduced the dose to the RV (9 Gy; p < 0.01), LV (10 Gy; p < 0.01), LA (19 Gy; p < 0.01), RA (12 Gy; p < 0.01), AV (14 Gy; p < 0.01), MV (21 Gy; p < 0.01), TV (13 Gy; p = 0.02), LAD (6 Gy; p = 0.03), LC (14 Gy; p < 0.01), and RC(7.2 Gy; p = 0.02). PT also reduced the dose to the PV (5 Gy; p = 0.08). Compared with IMRT, PT significantly reduced doses to the RV (3 Gy; p < 0.01), LV (5 Gy; p < 0.01), LA (9 Gy; p < 0.01), RA (5 Gy; p < 0.01), MV (7 Gy; p < 0.01), TV (9 Gy; p < 0.01), and LC (6 Gy, p < 0.01). Additionally, PT reduced doses to the AV (5 Gy; p = 0.21), LAD (3 Gy; p = 0.06), and RC (2 Gy; p = 0.4) compared with IMRT, but had no effect on the PV.ConclusionsCompared with 3D-CRT and IMRT, PT reduced the doses to the major cardiac subunits, including the chambers of the heart, valves, and coronary vessels. Limiting the doses to these structures should translate into lower rates of cardiomyopathy, valvular dysfunction, and coronary artery disease in this cohort of patients at high risk of these complications. Purpose/Objective(s)In the dosimetric component of a Phase II prospective study of consolidative involved-node radiotherapy (INRT) in patients with mediastinal Hodgkin lymphoma (HL), proton therapy (PT) reduced doses to the heart, lungs, esophagus, thyroid, and total body compared with either 3-dimensional conformal radiotherapy (3D-CRT), or intensity modulated radiotherapy (IMRT). This study investigates the dosimetric impact of PT to the subunits of the heart. In the dosimetric component of a Phase II prospective study of consolidative involved-node radiotherapy (INRT) in patients with mediastinal Hodgkin lymphoma (HL), proton therapy (PT) reduced doses to the heart, lungs, esophagus, thyroid, and total body compared with either 3-dimensional conformal radiotherapy (3D-CRT), or intensity modulated radiotherapy (IMRT). This study investigates the dosimetric impact of PT to the subunits of the heart. Materials/MethodsFrom June 2009 through December 2010, 13 patients were enrolled on the University of Florida (UF) institutional review board-approved protocol HL01 of consolidative INRT for HL. Three separate treatment plans for each patient were developed prospectively using 3D-CRT, IMRT, and PT. Target constraints included a clinical target volume (CTV) D99% = 100% and a planning target volume (PTV) D95% >95%; organs-at-risk (OAR) constraints included a mean lung dose <18 Gy/CGE, lung V20 <30%, and mean heart dose <20 Gy/CGE. All patients were offered treatment with PT due to the reduction of dose to the OARs. The right atrium (RA), left atrium (LA), right ventricle (RV), left ventricle (LV), aortic valve (AV), mitral valve (MV), tricuspid valve (TV), pulmonic valve (PV), left-anterior descending artery (LAD), left-circumflex artery (LC), and right-circumflex artery (RC) were retrospectively contoured on the 11 patients who had an IV-contrast simulation scan and the doses to these structures were evaluated for all treatment plans. A Wilcoxon paired test was performed to evaluate for statistical significance (p < 0.05) for 3D-CRT and IMRT compared with PT. From June 2009 through December 2010, 13 patients were enrolled on the University of Florida (UF) institutional review board-approved protocol HL01 of consolidative INRT for HL. Three separate treatment plans for each patient were developed prospectively using 3D-CRT, IMRT, and PT. Target constraints included a clinical target volume (CTV) D99% = 100% and a planning target volume (PTV) D95% >95%; organs-at-risk (OAR) constraints included a mean lung dose <18 Gy/CGE, lung V20 <30%, and mean heart dose <20 Gy/CGE. All patients were offered treatment with PT due to the reduction of dose to the OARs. The right atrium (RA), left atrium (LA), right ventricle (RV), left ventricle (LV), aortic valve (AV), mitral valve (MV), tricuspid valve (TV), pulmonic valve (PV), left-anterior descending artery (LAD), left-circumflex artery (LC), and right-circumflex artery (RC) were retrospectively contoured on the 11 patients who had an IV-contrast simulation scan and the doses to these structures were evaluated for all treatment plans. A Wilcoxon paired test was performed to evaluate for statistical significance (p < 0.05) for 3D-CRT and IMRT compared with PT. ResultsThe mean heart doses were 20 Gy, 15 Gy, and 10 CGE with 3D-CRT, IMRT, and PT, respectively. Compared with 3D-CRT, PT significantly reduced the dose to the RV (9 Gy; p < 0.01), LV (10 Gy; p < 0.01), LA (19 Gy; p < 0.01), RA (12 Gy; p < 0.01), AV (14 Gy; p < 0.01), MV (21 Gy; p < 0.01), TV (13 Gy; p = 0.02), LAD (6 Gy; p = 0.03), LC (14 Gy; p < 0.01), and RC(7.2 Gy; p = 0.02). PT also reduced the dose to the PV (5 Gy; p = 0.08). Compared with IMRT, PT significantly reduced doses to the RV (3 Gy; p < 0.01), LV (5 Gy; p < 0.01), LA (9 Gy; p < 0.01), RA (5 Gy; p < 0.01), MV (7 Gy; p < 0.01), TV (9 Gy; p < 0.01), and LC (6 Gy, p < 0.01). Additionally, PT reduced doses to the AV (5 Gy; p = 0.21), LAD (3 Gy; p = 0.06), and RC (2 Gy; p = 0.4) compared with IMRT, but had no effect on the PV. The mean heart doses were 20 Gy, 15 Gy, and 10 CGE with 3D-CRT, IMRT, and PT, respectively. Compared with 3D-CRT, PT significantly reduced the dose to the RV (9 Gy; p < 0.01), LV (10 Gy; p < 0.01), LA (19 Gy; p < 0.01), RA (12 Gy; p < 0.01), AV (14 Gy; p < 0.01), MV (21 Gy; p < 0.01), TV (13 Gy; p = 0.02), LAD (6 Gy; p = 0.03), LC (14 Gy; p < 0.01), and RC(7.2 Gy; p = 0.02). PT also reduced the dose to the PV (5 Gy; p = 0.08). Compared with IMRT, PT significantly reduced doses to the RV (3 Gy; p < 0.01), LV (5 Gy; p < 0.01), LA (9 Gy; p < 0.01), RA (5 Gy; p < 0.01), MV (7 Gy; p < 0.01), TV (9 Gy; p < 0.01), and LC (6 Gy, p < 0.01). Additionally, PT reduced doses to the AV (5 Gy; p = 0.21), LAD (3 Gy; p = 0.06), and RC (2 Gy; p = 0.4) compared with IMRT, but had no effect on the PV. ConclusionsCompared with 3D-CRT and IMRT, PT reduced the doses to the major cardiac subunits, including the chambers of the heart, valves, and coronary vessels. Limiting the doses to these structures should translate into lower rates of cardiomyopathy, valvular dysfunction, and coronary artery disease in this cohort of patients at high risk of these complications. Compared with 3D-CRT and IMRT, PT reduced the doses to the major cardiac subunits, including the chambers of the heart, valves, and coronary vessels. Limiting the doses to these structures should translate into lower rates of cardiomyopathy, valvular dysfunction, and coronary artery disease in this cohort of patients at high risk of these complications.

Being a first-line treatment for hypersensitivity allergic disease, histamine H1-receptor antagonists possess anti-inflammatory activity in addition to being H1-receptor antagonists. While it is not purely a histamine-related condition, hypersensitivity allergic disease is associated with an increase in the number of T helper type 2 (Th2) cells and Th2 cytokines, and a decrease in the number of Th1 cells and Th1 cytokines. Suppression of Th2-type cytokine production in addition to H1-receptor blockade may therefore represent a successful therapeutic strategy for the treatment of hypersensitivity allergic diseases. H1-receptor antagonists have been reported to modulate immune cascade at various points by acting on T cell-related inflammatory molecules, including adhesion molecules, chemokines and inflammatory cytokines. These effects of H1-receptor antagonists may be optimized for the treatment of allergic diseases. Besides their ability to regulate inflammatory molecules, some H1-receptor antagonists have been reported to down-regulate Th2 cytokine production. In particular, it has been shown that several H1-receptor antagonists specifically inhibit the production of Th2, but not Th1, cytokines. Accumulating evidence indicates a crucial role for Th1/Th2 cytokine imbalance on the development of allergic diseases. Accordingly, the use of H1-receptor antagonist with Th2 cytokine inhibitory activity to modulate Th1/Th2 cytokine imbalance might be a favourable strategy for the treatment of hypersensitivity allergic diseases. Furthermore, the identification of H1-receptor antagonists which possess immunoregulatory activities in addition to their anti-histamine activity will provide an important insight into the development of novel immunoregulatory drugs.

Background: CD26 is a multifunctional membrane-bound glycoprotein that regulates tumour growth in addition to its other activities. Because disease aggressiveness is correlated with CD26 expression in several T-cell malignancies, we decided to investigate the invasiveness of cells expressing different levels of CD26. Methods: To assess CD26 involvement in cell invasion, we performed in vitro invasion assays with human T cell lines expressing different levels of CD26. These included the parental CD26-positive T-lymphoblast cell line HSB-2 and clones infected with a retrovirus expressing siRNA vectors that either targeted CD26 or encoded a missense siRNA, and the parental CD26-negative T-leukaemia cell line Jurkat and clones expressing CD26. CD26 expression in these cell lines was evaluated by flow cytometry and western immunoblotting. CXCR4 expression, phosphorylation of signalling kinases, and MMP-9 secretion were also evaluated by western immunoblotting, whereas MMP-9 activity and the effect of kinase and CD45 inhibitors on activity were measured by zymography of conditioned media. Results: The presence of CD26 enhanced stromal-cell-derived factor-1- α (SDF-1- α )-mediated invasion of T cell lines. This process was regulated in part by the PI-3K and MEK1 pathways, as indicated by increased phosphorylation of p44/42 MAP kinase and Akt in the presence of SDF-1- α and the effect of their respective inhibitors on MMP-9 secretion and in vitro invasion. In addition, CD26-associated enhancement of SDF-1- α -induced invasion was decreased when CD45 was inhibited. Conclusions: Our results indicate that the expression of CD26 in T cell lines leads to increased SDF-1- α -mediated invasion in an in vitro system and that this is controlled in part by the PI-3K and MEK1 pathways. The data also suggest that CD26 enhancement of invasion may be mediated by CD45, however, more studies are required to confirm this involvement.

e19509 Background: Three phase III studies (10, 11, 14) have been conducted with Dd, a novel IL-2 receptor-targeted recombinant fusion protein, in subjects with CTCL. Dd is approved for the treatment of persistent/recurrent CD25(+) CTCL and is the most extensively studied agent in CTCL. We retrospectively analyzed the efficacy of two Dd doses in treatment-naïve CD25(+) CTCL subjects to understand the relationship between dose and response to therapy. Methods: Studies 10 and 11 included early or advanced stage CD25(+) subjects (CD25 immunostaining in >20% of malignant cells) while 14 included CD25(-). Subjects received 9 or 18 mcg/kg/day IV for 5 days, repeating every 21 days for up to 8 courses; subjects in study 14 only received the higher dose. Study 11 included a placebo arm. Subject demographics were similar among the three studies and between the 2 dose groups in each. Response confirmation required ≥2 consecutive courses (3 observations) and was adjudicated by an independent Data Endpoint Review Committee in each study, using a weighted severity skin, blood and lymph node count. The primary endpoint was ORR (CR, CCR, PR) and the key secondary endpoint was progression-free survival (PFS). Results: Integrated efficacy results for ORR and PFS are shown in the table for treatment-naïve CD25(+) subjects. In general, the nature and incidence of the adverse events reported in the 3 studies were similar, with studies 11 and 14 proving to be broadly consistent with study 10 in terms of safety. Tolerability of 9 and 18 mcg/kg/d was similar in study 10. In study 11, the only AEs that were more frequent in the high-dose group were vomiting (13.3% vs 34.5%) and dysgeusia (0% vs 10.9%). Conclusions: Overall, there was a trend towards higher efficacy favoring 18 mcg/kg/day in treatment-naïve CD25(+) subjects. The ORR was statistically significant for the higher dose group. [Table: see text]

BACKGROUND Hepatosplenic T-cell lymphoma (HSTCL) is a rare peripheral T-cell lymphoma; treatment with standard anthracycline-containing chemotherapy regimens has been disappointing, and an optimal treatment strategy for this patient population has not yet been determined. METHODS We identified 15 cases of pathologically confirmed HSTCL in the institution's database. Clinical characteristics and treatment results were reviewed. RESULTS Complete responses (CRs) were achieved in 7 of 14 patients who received chemotherapy. Achievement of CR was followed by hematopoietic stem-cell transplantation in three patients. Median duration of CR was 8 months (range 2 to 32+ months) with four patients currently alive and in CR at 5, 8, 12, and 32 months, respectively. Median overall survival (OS) was 11 months (range 2 to 36+ months). Patients who achieved a CR had a median OS of 13 months, compared with 7.5 months in patients who did not achieve a CR. Risk factors associated with worse outcome included male gender, failure to achieve a CR, history of immunocompromise, and absence of a T-cell receptor gene rearrangement in the gamma chain. CONCLUSION A better understanding of the pathophysiology of HSTCL and new therapeutic strategies are needed.

Crk-associated substrate lymphocyte type (Cas-L) is a 105 kDa docking protein with diverse functional properties, including regulation of cell division, proliferation, migration and adhesion. Cas-L is also involved in beta1 integrin- or antigen receptor-mediated signaling in B and T cells. In the present study, we demonstrate that Cas-L potentiates transforming growth factor-beta (TGF-beta) signaling pathway by interacting with Smad6 and Smad7. Immunoprecipitation experiments reveal that single domain deletion of full-length Cas-L completely abolishes its docking function with Smad6 and Smad7, suggesting that the natural structure of Cas-L is necessary for its association with Smad6 and Smad7. On the other hand, both N-terminal and C-terminal deletion mutants of Smad6 and Smad7 still retain their docking ability to Cas-L, suggesting that Smad6 and Smad7 possess several binding motifs to Cas-L. Moreover, Cas-L interaction with Mad-homology (MH)2 domain, but not with MH1 domain of Smad6 or Smad7, ameliorates TGF-beta-induced signaling pathway. Finally, depletion of Cas-L by small-interfering RNA oligo attenuates TGF-beta-induced growth inhibition of Huh-7 cells, with a concomitant reduction in phosphorylation of Smad2 and Smad3. These results strongly suggest that Cas-L is a potential regulator of TGF-beta signaling pathway.