Intraoperative radiotherapy with low-energy x-rays after neurosurgical resection of brain metastases-an Augsburg University Medical Center experience.

PURPOSE: External-beam radiotherapy (EBRT) is the predominant method for localized brain radiotherapy (LBRT) after resection of brain metastases (BM). Intraoperative radiotherapy (IORT) with 50-kV x­rays is an alternative way to focally irradiate the resection cavity after BM surgery, with the option of shortening the overall treatment time and limiting normal tissue irradiation. METHODS: We retrospectively analyzed the outcomes of all patients who underwent neurosurgical resection of BM and 50-kV x­ray IORT between 2013 and 2020 at Augsburg University Medical Center. RESULTS: We identified 40 patients with 44 resected BM treated with 50-kV x­ray IORT. Median diameter of the resected metastases was 2.8 cm (range 1.5-5.9 cm). Median applied dose was 20 Gy. All patients received standardized follow-up (FU) including 3­monthly MRI of the brain. Mean FU was 14.4 months, with a median MRI FU for alive patients of 12.2 months. Median overall survival (OS) of all treated patients was 26.4 months (estimated 1­year OS 61.6%). The observed local control (LC) rate of the resection cavity was 88.6% (estimated 1­year LC 84.3%). Distant brain control (DC) was 47.5% (estimated 1­year DC 33.5%). Only 25% of all patients needed WBI in the further course of disease. The observed radionecrosis rate was 2.5%. CONCLUSION: IORT with 50-kV x­rays is a safe and appealing way to apply LBRT after neurosurgical resection of BM, with low toxicity and excellent LC. Close MRI FU is paramount to detect distant brain failure (DBF) early.

Oncostatin M-mediated regulation of KIT-ligand-induced extracellular signal-regulated kinase signaling maintains hematopoietic repopulating activity of Lin-CD34+CD133+ cord blood cells.

We investigated whether KIT signaling was sufficient to maintain human hematopoietic stem cells in culture or whether, as with murine stem cells, signaling through glycoprotein 130 (gp130) is additionally required. Sorted CD34(+)CD133(+)(CD33/CD38/CD71)(-) cells from human umbilical cord blood (UCB) were cultured in the presence of combinations of KIT-ligand (KL) and the gp130 stimulating molecule oncostatin M (OSM). We found that OSM increased KL-induced proliferation, which was accompanied by an expansion in numbers of mature progenitors colony-forming cells (CFC, CAFCw2). More primitive progenitors, CAFCw6 and long-term culture-CFC, were not maintained by KL as a single factor. Although addition of OSM did not improve survival, the KL/OSM combination showed improved maintenance of immature progenitors as well as higher CD34 expression. Similarly, both KL and OSM were required to maintain NOD/SCID-repopulating activity. In experiments to investigate the underlying mechanism, we found that extracellular signal-regulated kinase (ERK) and its downstream target p90 ribosomal S6 kinase were activated by KL and downregulated by the inclusion of OSM during stimulation. The p38 mitogen-activated protein kinase (p38 MAPK) was not modulated by either KL or OSM. Indeed, many of the effects of OSM (increased cell division, maintenance of CFC, and maintenance of high CD34 expression) could be mimicked by using the mitogen-activated protein kinase kinase inhibitor U0126. More importantly, NOD/SCID-repopulating activity was preserved in the KL/U0126-stimulated cells, but not in cells stimulated with a combination of KL and the p38 MAPK inhibitor SB203580. Our results show that the loss of repopulating activity during KL stimulation is counteracted by OSM through the downregulation of ERK pathway signaling. Disclosure of potential conflicts of interest is found at the end of this article.

Comparison of three different mediastinal radiotherapy techniques in female patients: Impact on heart sparing and dose to the breasts.

BACKGROUND AND PURPOSE: To study different radiotherapy techniques for female patients with mediastinal target volumes. Especially in highly curable diseases such as lymphoma, long-term survivors might develop late cardiac damage and radiation-induced second cancer. PATIENTS AND METHODS: Planning CT scans were obtained in eight cases. We contoured the clinical target volume (three different scenarios with or without lower mediastinum and hili) and organs at risk and compared standard 6MV ap-pa opposed fields to a 3D conformal 4-field technique and a 7-field step-and-shoot IMRT technique and evaluated DVHs for each structure. The planning system was BrainSCAN 5.21 (BrainLAB, Heimstetten, Germany). RESULTS: Target volume coverage did not improve significantly with 4-field or IMRT techniques. However, IMRT resulted in better dose reduction to the heart than the other techniques. The median heart dose (intermediately sized target volume) was 98% (95-100) with ap-pa fields, 56% (52-79) with the 4-field technique, and 39% (36-65) with IMRT, for example (p<0.05). Better heart sparing was achieved at all dose levels down to the 15% isodose. The median maximum dose to the breasts was lowest with IMRT. The breast volume receiving low doses (15% or less), however, was highest with IMRT. There was also a disadvantage in mean lung dose. CONCLUSIONS: IMRT might result in a reduced cardiac complication risk. In younger females, however, this advantage might be offset by the risk of breast cancer. The best technique for a given patient depends on age, comorbidity, and the individual risk estimates for breast cancer and cardiac morbidity, respectively.

Detrimental effects of an antibody directed against tumor necrosis factor alpha in experimental kidney irradiation.

Antibodies directed against tumor necrosis factor (TNF)-alpha are clinically used for Crohn's disease, rheumatoid arthritis and psoriasis. TNF-alpha is also an important cytokine in radiotherapy because it mediates inflammatory responses in normal tissues. To study the influence of TNF-alpha inhibition on radiation toxicity, we used a well-established mouse model of kidney irradiation, where the portal also includes parts of the intestine. Mice were treated with single-fraction radiotherapy to the right kidney with doses of 8 or 10 Gy with or without the monoclonal TNF-alpha antibody infliximab injected i.v. in three doses. The kidney function was assessed by means of repeated 99mTc-dimercaptosuccinate scans during a maximum follow-up of 49 weeks. Treatment with infliximab significantly exacerbated radiation nephropathy at all time points, both in the 8 Gy and 10 Gy groups. The drug itself is not known to cause renal impairment. In the control group irradiated with 10 Gy, one mouse died from delayed radiation-induced intestinal toxicity. Skin reactions and general performance status were also similar across the groups. These data suggest that administration of infliximab concomitant to radiotherapy causes profound alterations in the development of kidney dysfunction. Importantly, other radiation-related toxicities were similar across all groups.

Evaluation of insulin-like growth factor-1 in a mouse model of long-term abdominal radiation toxicity.

The purpose of these experiments was to test whether a brief course of insulin-like growth factor-1 (IGF-1) injection (escalating doses) concomitant to irradiation ameliorates radiation-induced kidney dysfunction and lethal bowel toxicity in a mouse model of unilateral high-dose irradiation of the kidney and adjacent bowel. The kidney function was assessed by means of repeated 99mTc-dimercaptosuccinate scans (every six weeks) during a maximum follow-up of 49 weeks. The experiments with single fractions of 12 Gy and 15 Gy revealed only minor differences in the severity of kidney dysfunction and no reduction in lethal bowel toxicity from IGF-1 treatment In the absence of any significant radioprotective effect, other strategies of response modification need to be developed.

Preclinical evaluation of erythropoietin administration in a model of radiation-induced kidney dysfunction.

PURPOSE: To test whether the clinically available growth factor erythropoietin (EPO) influences radiation-induced normal-tissue damage in a model of kidney dysfunction. METHODS: Animal experiments were conducted to test the role of EPO administration in a C3H mouse model of unilateral kidney irradiation with 6, 8, and 10 Gy and to assess the effects of 2 different dose levels of EPO. The kidney function was assessed before radiotherapy, as well as 19, 25, 31, and 37 weeks thereafter by means of (99m)Tc-dimercaptosuccinat scans (static scintigraphy). RESULTS: Concomitant EPO administration significantly increased the degree of radiation-induced kidney dysfunction. A dose of 2,000 IU/kg body weight per injection tended to cause more damage than the lower dose of 500 IU/kg. CONCLUSION: Administration of growth factors concomitant to radiotherapy might modify the development of kidney dysfunction. Although insulin-like growth factor-1 has previously been shown to protect the kidney, such an effect could not be demonstrated for EPO. The latter agent even increased the development of nephropathy.

Stereotactic hypofractionated radiation therapy for stage I non-small cell lung cancer.

We reviewed our initial institutional experience with the use of stereotactic hypofractionated radiation therapy (SFRT) in patients with stage I non-small cell lung cancer (NSCLC). Thirty patients with inoperable stage I non-small cell lung cancer due to a severe chronic obstructive pulmonary disease (COPD) and/or chronic heart disease (Eastern Cooperative Oncology Group (ECOG) performance status of 0-2) were treated between December 2000 and October 2003 with SFRT in curative intent. Infiltration of locoregional lymph nodes and distant metastases were ruled out by computerized tomography (CT) scan of the brain, thorax, and abdomen, and by whole body FDG-positron emission tomography scan in all patients. Total RT doses ranged from 24.0 to 37.5 Gy, given in 3-5 fractions to the 60% isodose encompassing the planning target volume. Immobilization was carried out by a vacuum couch and a low-pressure foil. The clinical target volume was the tumor as it appeared in lung windowing on lung CT scan. Organ movements (caused by breathing; range, 6-22 mm) and reproducibility of patient positioning in the couch (range, 3-12 mm) were calculated by sequential CT and orthogonal films. The individual values were taken into account as a safety margin for the definition of the planning target volume (PTV). The median follow-up of living patients is 18 months (range, 6-38 months). As maximum response, there were 10 (33%) complete responses (CRs) and 14 (47%) partial responses (PRs), resulting in a total response rate of 80%. Stable disease was observed in 6 (20%) patients, while no patient experienced progressive disease. During follow-up, 2 (7%) local recurrences were observed (after 17 and 18 months, respectively). Of 5 (17%) patients who developed distant metastasis, 1 patient developed it in liver (3 months), another one in brain (6 months), and another one in the lung (36 months), while 2 patients developed it in mediastinal lymph nodes (after 8, and 11 months, respectively) only. Of 9 (30%) patients who have died, only 3 (10%) died of cancer, while 6 (20%) died of cancer-unrelated or unknown causes. Acute side effects were mild and affected 9 (33%) patients during the RT course (fatigue being the most frequent one in 6 patients). There were 22 acute events occurring in 19 (63%) patients during the first 3 months post-SFRT, the most frequent one being pneumonitis observed in 14 (46%) patients. However, there was only one (3%) grade 3 acute toxicity and no patient experienced greater than grade 3 toxicity during this study. One (3%) patient experienced rib fracture as the late event. SFRT is a feasible and safe treatment method in inoperable patients with stage I NSCLC having reduced lung capacity. Longer follow-up is necessary to get robust data on late toxicity as well as survival.

The prognostic value of irradiated lung volumes on the prediction of intra-/ post-operative mortality in patients after neoadjuvant radiochemotherapy for esophageal cancer. A retrospective multicenter study.

PURPOSE: To assess the association between dosimetric factors of the lung and incidence of intra- and postoperative mortality among esophageal cancer (EC) patients treated with neoadjuvant radiochemotherapy (N-RCT) followed by surgery (S). METHODS AND MATERIALS: Inclusion criteria were: age < 85 years, no distant metastases at the time of diagnosis, no induction chemotherapy, conformal radiotherapy, total dose ≤ 50.4 Gy, and available dose volume histogram (DVH) data. One-hundred thirty-five patients met our inclusion criteria. Median age was 62 years. N-RCT consisted of 36 - 50.4 Gy (median 45 Gy), 1.8 - 2 Gy per fraction. Concomitant chemotherapy consisted of 5-Fluoruracil (5-FU) and cisplatin in 113 patients and cisplatin and taxan-derivates in 15 patients. Seven patients received a single cytotoxic agent. In 130 patients an abdominothoracal and in 5 patients a transhiatal resection was performed. The following dosimetric parameters were generated from the total lung DVH: mean dose, V5, V10, V15, V20, V30, V40, V45 and V50. The primary endpoint was the rate of intra- and postoperative mortality (from the start of N-RCT to 60 days after surgical resection). RESULTS: A total of ten postoperative deaths (7%) were observed: 3 within 30 days (2%) and 7 between 30 and 60 days after surgical intervention (5%); no patient died during the operation. In the univariate analysis, weight loss (≥10% in 6 months prior to diagnosis, risk ratio: 1.60, 95%CI: 0.856-2.992, p=0.043), Eastern Cooperative Oncology Group-performance status (ECOG 2 vs. 1, risk ratio: 1.931, 95%CI: 0.898-4.150, p=0.018) and postoperative pulmonary plus non-pulmonary complications (risk ratio: 2.533, 95%CI: 0.978-6.563, p=0.004) were significantly associated with postoperative mortality. There was no significant association between postoperative mortality and irradiated lung volumes. Lung V45 was the only variable which was significantly associated with higher incidence of postoperative pulmonary plus non-pulmonary complications (Exp(B): 1.285, 95%CI 1.029-1.606, p=0.027), but not with the postoperative pulmonary complications (Exp(B): 1.249, 95%CI 0.999-1.561, p=0.051). CONCLUSIONS: Irradiated lung volumes did not show relevant associations with intra- and postoperative mortality of patients treated with moderate dose (36 - 50.4 Gy) conventionally fractionated conformal radiotherapy combined with widely used radiosensitizers. Postoperative mortality was significantly associated with greater weight loss, poor performance status and development of postoperative complications, but not with treatment-related factors. Limiting the volume of lung receiving higher radiation doses appears prudent because of the observed association with risk of postoperative complications.

Late residual gamma-H2AX foci in murine spinal cord might facilitate development of response-modifying strategies: a research hypothesis.

The central nervous system (CNS) is among the critical late-responding normal tissues which influence radiation treatment planning and dose prescription. Both mouse and rat spinal cord are established radiobiological models. As late reactions in rodents develop many months after irradiation, long-term follow-up is necessary. Development of radioprotective strategies and refinement of optimum dose and administration schedules are therefore quite complicated and time consuming. Obviously, surrogate endpoints that allow for screening of radioprotective agents and optimisation of dosing with shorter follow-up would speed up and facilitate this type of radiobiological research. Such surrogate endpoints should be analyzable during the clinically asymptomatic latent period, ideally as early as possible. As unrepaired cellular damage is a prerequisite for overt side-effects of radiotherapy, detection of residual damage might predict for radiation myelopathy. Immunohistochemical evaluation of irradiated mouse spinal cord with phosphorylated histone H2AX (γ-H2AX) was performed. Preliminary data suggest that residual damage can be detected in mouse spinal cord and that such foci continue to be detectable over a long time period, which clearly extends into the phase where development of late reactions starts. Our initial findings justify further research which attempts to correlate γ-H2AX foci with the primary endpoint, i.e. radiation myelopathy. It can then be explored whether a given radioprotective agent reduces the number of foci and whether this translates into reduced incidence of radiation myelopathy. A rapid and reliable animal model would allow for screening of a large number of candidate drugs that might modify the radiation response of the spinal cord.

Stereotactic radiotherapy of histologically proven inoperable stage I non-small cell lung cancer: patterns of failure.

BACKGROUND AND PURPOSE: To report patterns of failure of stereotactic body radiation therapy (SBRT) in inoperable patients with histologically confirmed stage I NSCLC. MATERIALS AND METHODS: Ninety-two inoperable patients (median age: 75 years) with clinically staged, histologically proven T1 (n=31) or T2 (n=61), N0, M0 non-small cell lung cancer (NSCLC) were included in this study. Treatment consisted of 3-5 fractions with 7-15 Gy per fraction prescribed to the 60% isodose. RESULTS: Freedom from local recurrence at 1, 3 and 5 years was 89%, 83% and 83%, respectively. All 10 local failures were observed in patients with T2 tumors. Isolated regional recurrence was observed in 7.6%. The crude rate of distant progression was 20.7%. Overall survival at 1, 3, and 5 years was 79%, 38% and 17% with a median survival of 29 months. Disease specific survival at 1, 3, and 5 years was 93%, 64% and 48%. Karnofsky performance status, T stage, gross tumor volume and tumor location had no significant impact on overall and disease specific survival. SBRT was generally well tolerated and all patients completed therapy as planned. CONCLUSION: SBRT for stage I lung cancer is very well tolerated in this patient cohort with significant cardiopulmonal comorbidity and results in excellent local control rates, although a considerable portion develops regional and distant metastases.

Influence of different treatment techniques on radiation dose to the LAD coronary artery.

BACKGROUND: The purpose of this proof-of-principle study was to test the ability of an intensity-modulated radiotherapy (IMRT) technique to reduce the radiation dose to the heart plus the left ventricle and a coronary artery. Radiation-induced heart disease might be a serious complication in long-term cancer survivors. METHODS: Planning CT scans from 6 female patients were available. They were part of a previous study of mediastinal IMRT for target volumes used in lymphoma treatment that included 8 patients and represent all cases where the left anterior descending coronary artery (LAD) could be contoured. We compared 6 MV AP/PA opposed fields to a 3D conformal 4-field technique and an optimised 7-field step-and-shoot IMRT technique and evaluated DVH's for several structures. The planning system was BrainSCAN 5.21 (BrainLAB, Heimstetten, Germany). RESULTS: IMRT maintained target volume coverage but resulted in better dose reduction to the heart, left ventricle and LAD than the other techniques. Selective dose reduction could be accomplished, although not to the degree initially attempted. The median LAD dose was approximately 50% lower with IMRT. In 5 out of 6 patients, IMRT was the best technique with regard to heart sparing. CONCLUSION: IMRT techniques are able to reduce the radiation dose to the heart. In addition to dose reduction to whole heart, individualised dose distributions can be created, which spare, e.g., one ventricle plus one of the coronary arteries. Certain patients with well-defined vessel pathology might profit from an approach of general heart sparing with further selective dose reduction, accounting for the individual aspects of pre-existing damage.

Stereotactic hypofractionated radiotherapy in stage I (T1-2 N0 M0) non-small-cell lung cancer (NSCLC).

Stereotactic Radiotherapy has the potential to produce high local control rates with low risk of severe lung toxicity. From December 2000 to January 2006, 68 inoperable patients (median age 76 years) with stage I NSCLC received definitive hSRT. A mean total dose of 37.5 Gy (24-40 Gy; 60%-isodose) in 3-5 fractions was applied. Immobilisation was carried out by means of a vacuum couch and low pressure foil (Medical Intelligence, Schwab München, Germany). Staging procedures were thoracic and abdominal CT-scan, FDG-PET and CT or MRI of the brain in all patients. Clinical target volume was the tumor as seen in lung windowing of CT and in FDG-PET. Organ movements (6-22 mm) and patient positioning in the couch (3-12 mm) were added as safety margin for the definition of the planning target volume (PTV), that was enclosed by the 60%-isodose. We observed four (6%) local tumor recurrences, resulting in an actuarial local tumor control rate of 96%, 88% and 88% after 1, 2 and 3 year follow-up. Nineteen patients died, with eight patients due to cancer (12%), two to local tumor progression alone. Cancer-specific survival is 96%, 82% and 73% at 1, 2 and 3 years. Eleven patients died from comorbidities, making a 53% overall 3-year survival. Fifty five percent of the patients were affected by mild acute and subacute side effects, with only 3% experiencing pneumonitis III degrees . Late effects were pneumonitis III degrees in 1%, rib fractures in 3%, and benign pleural effusion in 2 patients. Hypofractionated SRT is safe even in elderly patients with stage I NSCLC and significantly reduced lung capacity. It leads to high local control rates and should be offered to patients not amenable for curative resection.