Delayed non-myeloablative irradiation to induce long-term allograft acceptance in a large animal lung transplantation model.

We previously induced long-term allograft acceptance in an allogeneic lung transplantation (LTx) model in miniature swine using perioperative non-myeloablative irradiation (IRR) combined with infusion of donor specific alloantigen. In order to improve clinical applicability, we delayed induction with irradiation in this study. Left sided single LTx was performed in minipigs. Group 1 received non-myeloablative irradiation (7Gy thymus and 1.5Gy whole body IRR) before LTx and a perioperative donor specific splenocyte infusion (SpTx). Group 2 received perioperative SpTx but delayed IRR three days after LTx. Group 3 was exposed to delayed IRR without SpTx. Whereas 4 out of 7 animals from the non-delayed group never rejected their grafts and were electively sacrificed on postoperative day (POD) +500, all animals from group 2 rejected their grafts before POD 108. In group 3, 3 out of 8 animals developed long-term allograft acceptance. In all groups, donor leukocyte chimerism peaked up to 20% in peripheral blood one hour after reperfusion of the lung. Group 1 maintained prolonged chimerism beyond POD 7, whereas chimerism levels in groups 2 and 3 decreased continuously thereafter. Delayed irradiation has the potential to improve long-term graft survival, yet not as efficient as a perioperative conditioning protocol.

Splenocyte Infusion and Whole-Body Irradiation for Induction of Peripheral Tolerance in Porcine Lung Transplantation: Modifications of the Preconditioning Regime for Improved Clinical Feasibility.

BACKGROUND: Preoperative low-dose whole-body irradiation (IRR) with 1.5 and 7 Gy thymic IRR of the recipient, combined with a perioperative donor splenocyte infusion lead to reliable donor specific peripheral tolerance in our allogeneic porcine lung transplantation model. To reduce the toxicity of this preconditioning regime, modifications of the IRR protocol and their impact on allograft survival were assessed. METHODS: Left-sided single lung transplantation from major histocompatibility complex and sex mismatched donors was performed in 14 adult female minipigs. Recipient animals were exposed to 3 different protocols of nonmyeloablative IRR within 12 hours before transplantation. All animals were administered a donor splenocyte infusion on the day of lung transplantation. Intravenous pharmacologic immunosuppression was withdrawn after 28 postoperative days. Allograft survival was monitored by chest radiographs and bronchoscopy. RESULTS: IRR prolonged transplant survival in a dose- and field-dependent manner. Shielding of the bone marrow from IRR (total lymphoid IRR at 1.5 and 7 Gy thymic IRR) significantly reduced protocol toxicity defined as thrombocytopenia and consecutive increased bleeding propensity, but had a less effective impact on graft survival. Whole-body IRR at 0.5 and 7 Gy thymic IRR proved to be ineffective for reliable tolerance induction. Eventually, high levels of circulating CD4+CD25high regulatory T cells were present in long-term survivors. CONCLUSIONS: These data show that the infusion of donor-specific alloantigen in combination with IRR is efficient once a threshold dose is exceeded.

Hypofractionated stereotactic radiotherapy of limited brain metastases: a single-centre individualized treatment approach.

BACKGROUND: We retrospectively report treatment results of our single-centre experience with hypofractionated stereotactic radiotherapy (hfSRT) of limited brain metastases in primary and recurrence disease situations. Our aim was to find the most effective and safe dose concept. METHODS: From 04/2006 to 12/2010, 75 patients, with 108 intracranial metastases, were treated with hfSRT. 52 newly diagnosed metastases (48%), without up-front whole brain radiotherapy (WBRT), received hfSRT as a primary treatment. 56 metastases (52%) received a prior WBRT and were treated in this study in a recurrence situation. Main fractionation concepts used for primary hfSRT were 6-7x5 Gy (61.5%) and 5x6 Gy (19.2%), for recurrent hfSRT 7-10x4 Gy (33.9%) and 5-6x5 Gy (33.9%). RESULTS: Median overall survival (OS) of all patients summed up to 9.1 months, actuarial 6-and 12-month-OS was 59% and 35%, respectively. Median local brain control (LC) was 11.9 months, median distant brain control (DC) 3.9 months and intracranial control (IC) 3.4 months, respectively. Variables with significant influence on OS were Gross Tumour Volume (GTV) (p = 0.019), the biological eqivalent dose (calculated on a 2 Gy single dose, EQD2, α/ß = 10) < and ≥ median of 39 Gy (p = 0.012), extracerebral activity of the primary tumour (p < 0.001) and the steroid uptake during hfSRT (p = 0.03). LC was significantly influenced by the EQD2, ≤ and > 35 Gy (p = 0.004) in both uni- and multivariate Cox regression analysis. Median LC was 14.9 months for EQD2 >35 Gy and 3.4 months for doses ≤35 Gy, respectively. Early treatment related side effects were usually mild. Nevertheless, patients with a EQD2 >35 Gy had higher rates of toxicity (31%) than ≤35 Gy (8.3%, p=0.026). CONCLUSION: Comparing different dose concepts in hfSRT, a cumulative EQD2 of ≥35 Gy seems to be the most effective concept in patients with primary or recurrent limited brain metastases. Despite higher rates of only mild toxicity, this concept represents a safe treatment option.

Hypofractionated stereotactic radiotherapy (hfSRT) after tumour resection of a single brain metastasis: report of a single-centre individualized treatment approach.

PURPOSE: Standard treatment of single brain metastases so far is tumour resection in combination with postoperative whole-brain radiotherapy or stereotactic radiosurgery. Here, we report retrospectively our first experience with postoperative hypofractionated stereotactic radiotherapy (hfSRT) to the resection cavity in order to replace upfront WBRT with respect to treatment efficacy and safety. METHODS: Between March 2006 and October 2011, 33 patients with a single newly diagnosed intracranial metastasis were treated with hfSRT following microsurgical resection. Fractionation concepts were 10 × 4 Gy (n = 22), 7 × 5 Gy (n = 7) and 5 × 6 Gy (n = 4). Planning target volume enclosed the tumour resection cavity with a safety margin of 4 mm. RESULTS: No patient demonstrated toxicity grade 2 or higher. Actuarial median overall survival summed up to 20.2 months, and 12-month survival was 64 %. Actuarial mean local brain control was 30.6 months, median distant brain control 12.4 months and intracranial control 8.8 months, respectively. Actuarial 1-year rates of local, distant brain and intracranial control were 71, 57 and 43 %. Salvage whole-brain radiotherapy due to recurrent brain metastases was performed in 13 patients (39 %). CONCLUSION: Postoperative hfSRT appears to be a feasible treatment option in patients with a single newly diagnosed brain metastasis. Replacing the standard postoperative whole-brain radiotherapy necessitates compliant patients and regular MRI follow-up analysis.

Partial-volume segmentation for dose optimization in whole-breast radiotherapy: a comparative dosimetric and clinical analysis.

PURPOSE: : To analyze the dosimetric and clinical benefit of a forward planned technique to optimize dose distribution in whole-breast irradation (WBI) using additional partial-volume segments (PVSeg). PATIENTS AND METHODS: : In two separate treatment periods, 265 breast cancer patients received tangential-field WBI and were retrospectively analyzed. Between 02/2004 and 03/2006, 96 patients were treated with one to two additional low-weighted PVSeg to reduce dose peaks within the target volume. 169 patients treated between 01/2000 and 12/2001 before implementation of this PVSeg technique served as comparison group. Total dose was 50-50.4 Gy (single dose, 1.8-2 Gy). The planning target volume (PTV) receiving at least 95%, 105% and 110% of the reference dose (V(95-110%)) and frequency of moist skin desquamation during radiotherapy were compared uni- and multivariately with patient- and treatment-related variables. RESULTS: : The mean PTV was 1,144 ml (range, 235-2,365 ml). Moist skin desquamations developed in 16 patients (17%) with PVSeg compared to 30 patients (18%) without PVSeg (p = 0.482). In breast volumes > 1,100 ml, the corresponding figures were 19% versus 29% (p = 0.133). V(105%) was significantly reduced by the use of PVSeg (82 +/- 51 ml vs. 143 +/- 129 ml; p < 0.0001). In univariate analysis, the following variables had significant influence on the development of moist skin desquamation: V(95%) (p < 0.0001), V(105%) (p < 0.001), V(110%) (p = 0.012) adjuvant chemotherapy (p = 0.02), and single dose (p = 0.009). In multivariate analysis, only V(95%) (p = 0.002) remained significant. CONCLUSION: : The use of PVSeg in WBI reduced dose peaks within the PTV while breast volumes > 1,100 ml benefited most. V(95%) was strongly correlated to the risk of developing moist skin desquamations.

Long-term renal toxicity in children following fractionated total-body irradiation (TBI) before allogeneic stem cell transplantation (SCT).

PURPOSE: To retrospectively assess the incidence and time course of renal dysfunction in children (< or = 16 years) following total- body irradiation (TBI) before allogeneic stem cell transplantation (SCT). PATIENTS AND METHODS: Between 1986 and 2003, 92 children (median age, 11 years; range, 3-16 years) underwent TBI before allogeneic SCT. 43 of them had a minimum follow-up of 12 months (median, 51 months; range, 12-186 months) and were included into this analysis. Conditioning regimen included chemotherapy and fractionated TBI with 12 Gy (n = 26) or 11.1 Gy (n = 17). In one patient, renal dose was limited to 10 Gy by customized renal shielding due to known nephropathy prior to SCT. Renal dysfunction was defined as an increase of serum creatinine > 1.25 times the upper limit of age-dependent normal. RESULTS: Twelve children (28%) experienced an episode of renal dysfunction after a median of 2 months (range, 1-10 months) following SCT. In all but one patient renal dysfunction was transient and resolved after a median of 8 months (range, 3-16 months). One single patient developed persistent renal dysfunction with onset at 10 months after SCT. None of these patients required dialysis. The actuarial 3-year freedom from persistent renal toxicity for children surviving > 12 months after SCT was 97.3%. CONCLUSION: The incidence of persistent renal dysfunction after fractionated TBI with total doses < or = 12 Gy was very low in this analysis.

Complete remission of a lymphoma-associated chylothorax by radiotherapy of the celiac trunk and thoracic duct.

BACKGROUND: A chylothorax is a rare complication of mostly advanced malignant lymphomas. A case of a refractory chylothorax unresponsive to chemotherapy and successfully treated with radiotherapy is reported. CASE REPORT: A 45-year-old woman with recurrent stage IV low-grade follicular non-Hodgkin's lymphoma and a progressive chylothorax is described. The CT scans showed bulky lymphadenopathy at the thoracic trunk but no detectable enlargement of mediastinal lymph nodes. After ineffective pretreatment including chemotherapy and chest drainage, fractionated radiotherapy to the celiac trunk (20.4 Gy) and the thoracic duct (15 Gy) was performed. RESULT: Already after 7.5 Gy a rapid decline of chylothorax was noted and the chest drain could be removed. A complete remission of the chylothorax could be achieved after 20.4 Gy. During a follow-up of 16 months no recurrence of chylothorax occurred. CT scans showed nearly complete remission of the lymphadenopathy of the celiac trunk 12 months after radiotherapy. CONCLUSION: Radiotherapy with limited total doses is an effective treatment option for lymphoma-associated chylothorax and should always be taken into consideration, especially in cases unresponsive to chemotherapy.