Augmentation of Transient Donor Cell Chimerism and Alloantigen-Specific Regulation of Lung Transplants in Miniature Swine.

Donor alloantigen infusion induces T cell regulation and transplant tolerance in small animals. Here, we study donor splenocyte infusion in a large animal model of pulmonary transplantation. Major histocompatibility complex-mismatched single lung transplantation was performed in 28 minipigs followed by a 28-day course of methylprednisolone and tacrolimus. Some animals received a perioperative donor or third party splenocyte infusion, with or without low-dose irradiation (IRR) before surgery. Graft survival was significantly prolonged in animals receiving both donor splenocytes and IRR compared with controls with either donor splenocytes or IRR only. In animals with donor splenocytes and IRR, increased donor cell chimerism and CD4(+) CD25(high+) T cell frequencies were detected in peripheral blood associated with decreased interferon-γ production of leukocytes. Secondary third-party kidney transplants more than 2 years after pulmonary transplantation were acutely rejected despite maintained tolerance of the lung allografts. As a cellular control, additional animals received third-party splenocytes or donor splenocyte protein extracts. While animals treated with third-party splenocytes showed significant graft survival prolongation, the subcellular antigen infusion showed no such effect. In conclusion, minipigs conditioned with preoperative IRR and donor, or third-party, splenocyte infusions may develop long-term donor-specific pulmonary allograft survival in the presence of high levels of circulating regulatory T cells.

Breast cancer patients with metastatic spinal cord compression. Number of extraspinal organs involved by metastases influences survival.

BACKGROUND AND PURPOSE: The goal of the present work was to investigate the predictive value of the number of extraspinal organs involved by metastases for the survival of patients with metastatic spinal cord compression (MSCC) from breast cancer. PATIENTS AND METHODS: Data of 145 breast cancer patients who received 10 fractions of 3 Gy of radiotherapy (RT) alone for MSCC were retrospectively analyzed. Seven potential prognostic factors were investigated including age, Eastern Cooperative Oncology Group (ECOG) performance score, number of involved vertebrae, interval from breast cancer diagnosis to RT of MSCC, ambulatory status prior to RT, time to developing motor deficits, and the number of involved extraspinal organs. RESULTS: The 1-year survival rates for involvement of 0, 1, 2, and ≥ 3 extraspinal organs were 86, 73, 36, and 16 % (p < 0.001). In the multivariate analysis, the number of involved extraspinal organs remained significant (risk ratio 2.19; 95 % confidence interval 1.61-3.00; p < 0.001). ECOG performance score (p < 0.001), ambulatory status prior to RT (p = 0.003), and the time to developing motor deficits (p < 0.001) were also significantly associated with survival in the multivariate analysis. CONCLUSION: The number of extraspinal organs involved by metastases is an independent prognostic factor of survival in patients with MSCC from breast cancer.

A new prognostic factor for the survival of patients with renal cell carcinoma developing metastatic spinal cord compression.

BACKGROUND AND PURPOSE: This study aimed to identify a potential association of the number of involved extraspinal organs with the survival of patients with metastatic spinal cord compression (MSCC) from renal cell carcinoma. PATIENTS AND METHODS: Data of 69 patients irradiated for MSCC from renal cell carcinoma were retrospectively evaluated for survival. The prognostic value of the number of involved extraspinal organs and eight additional factors were investigated. These additional factors included age, gender, performance status, number of involved vertebrae, interval from cancer diagnosis to radiotherapy (RT) of MSCC, ambulatory status prior to RT, time developing motor deficits, and the fractionation regimen (30 Gy in 10 fractions vs. higher doses). RESULTS: The 6-month survival rates for involvement of 0, 1, and ≥ 2 extraspinal organs were 93, 57, and 21%, respectively (p < 0.001). In the multivariate analysis, the number of involved extraspinal organs maintained significance (risk ratio 2.65; 95% confidence interval 1.64-4.52; p < 0.001). The interval from cancer diagnosis to RT of MSCC (p = 0.013) and ambulatory status prior to RT (p = 0.002) were also independent predictors of survival. CONCLUSION: The number of involved extraspinal organs is a new prognostic factor of survival in patients with MSCC from renal cell carcinoma and should be considered in future clinical trials.

A validated scoring system to identify long-term survivors after radiotherapy for metastatic spinal cord compression.

PURPOSE: This study aimed to develop and validate a scoring system to identify long-term survivors after conventional radiotherapy (RT) for metastatic spinal cord compression (MSCC). PATIENTS AND METHODS: Data from 1,125 patients who had received long-course RT for MSCC were included in this study. Of these patients, 344 survived for over 12 months and 781 died within a year following RT. Based on differences between the distributions of patient characteristics in the two groups, a scoring system was developed. Scores ranged from 0 to 18 points and 15 points was selected as the cutoff for identifying long-term survivors. Data from the 1,125 long-course RT patients (test group) were compared to data from 773 patients receiving short-course RT (validation group). RESULTS: A score of ≥ 15 points was associated with a 94 % proportion of long-term survivors. The 15-point cutoff resulted in a specificity of 98 % and a positive predictive value of 94 % for identification of long-term surviving patients. The proportions of long-term survivors for each scoring point in the validation group were very similar to those in the test group. CONCLUSION: This new scoring system enabled identification of long-term survivors after RT for MSCC with very high specificity and positive predictive value. The score proved to be valid and reproducible.

Postoperative periclavicular radiotherapy in breast cancer patients with 1-3 positive axillary lymph nodes. Outcome and morbidity.

PURPOSE: The goal of this work was to examine the possible influence of periclavicular irradiation on outcome of breast cancer patients with 1-3 positive lymph nodes with special emphasis on late toxicity rates. PATIENTS AND METHODS: Between 1997 and 2000, 235 breast cancer patients (T1-2, 1-3 involved lymph nodes) were treated at our department following breast conservative surgery: 139 patients (59.1%) had one, 62 patients (26.4%) two, and 34 patients (14.5%) three positive lymph nodes. Extracapsular spread (ECS) was described in 72 patients (30.6%). There were 67 patients (28.5%) who received additional radiotherapy to the ipsilateral periclavicular lymph nodes (PCLNI), while 168 patients did not (noPCLNI). Patients were re-examined or contacted by phone with regard to treatment-related late effects. RESULTS: After a median follow-up of 78 months (range 7-107 months), 22 patients (9.4%) developed local, 9 (3.8%) axillary, 4 periclavicular (1.7%), and 41 distant failure (17.4%). The actuarial 8-year locoregional recurrence-free (LRRFS), disease-free (DFS), and overall survival rates (OS) were 83%, 67%, and 74%, respectively. Survival data for the PCLNI vs. noPCLNI group were 72% vs. 89% (p = 0.3), 56% vs. 73% (p = 0.4), and 86% vs. 70% (p = 0.3), respectively. No higher toxicity rates were reported in the PCLNI group compared to the noPCLNI group. CONCLUSION: We could not demonstrate any difference in outcome in breast cancer patients with 1-3 positive axillary lymph node metastases with or without periclavicular lymph node irradiation. In addition, patients with PCLNI did not complain about higher rates of late toxicities. However, patients with ECS, which may predict for locoregional failure, may benefit from adjuvant periclavicular irradiation.

HDR brachytherapy: an option for preventing nonmalignant obstruction in patients after lung transplantation.

PURPOSE: Interventional bronchoscopy is the main treatment modality in managing benign airway obstructions following lung transplantation. We analyzed the effect of intraluminal brachytherapy on preventing recurrence of hyperplastic tissue. PATIENTS AND METHODS: From September 2002 to September 2004, a total of 24 intraluminal brachytherapy applications were carried out on 12 lung transplant patients in 15 different locations. A single dose of 3 Gy was calculated at a 5-mm distance from the catheter surface; the target volume included a stenosis plus safety interval of 0.5-1.0 cm. RESULTS: All patients had a mean 10.6 local interventions (Argon plasma coagulation, balloon dilatations, stenting) over 4.4 months before the first application of endobronchial brachytherapy, with a mean amount of 2.4 applications per month. The mean forced expiratory volume in 1 s (FEV1) was 2,219 ml in the 3 months before application of brachytherapy. After endobronchial brachytherapy, all patients experienced improvement in clinical status and respiratory function. The mean level of FEV1 in the 3 months after application was 2,435 ml (p = 0.02), and the number of invasive interventions dropped to a mean rate of 5.2 interventions in the 5.1 months after the first intervention, with an amount of 1 application per month. No treatment-related complications were seen. Four patients were treated twice, 1 patient three times, and 1 patient four times at the same localization. CONCLUSIONS: Recurrent symptomatic benign airway obstruction from hyperplastic tissue in the bronchus after lung transplantation can be successfully treated with intraluminal high-dose-rate brachytherapy with a dose of 3 Gy at a 5-mm distance from the catheter surface and a longitudinal safety margin of 1 cm.

Do elderly patients benefit from surgery in addition to radiotherapy for treatment of metastatic spinal cord compression?

BACKGROUND: Treatment of elderly cancer patients has gained importance. One question regarding the treatment of metastatic spinal cord compression (MSCC) is whether elderly patients benefit from surgery in addition to radiotherapy? In attempting to answer this question, we performed a matched-pair analysis comparing surgery followed by radiotherapy to radiotherapy alone. PATIENTS AND METHODS: Data from 42 elderly (age > 65 years) patients receiving surgery plus radiotherapy (S + RT) were matched to 84 patients (1:2) receiving radiotherapy alone (RT). Groups were matched for ten potential prognostic factors and compared regarding motor function, local control, and survival. Additional matched-pair analyses were performed for the subgroups of patients receiving direct decompressive surgery plus stabilization of involved vertebrae (DDSS, n = 81) and receiving laminectomy (LE, n = 45). RESULTS: Improvement of motor function occurred in 21% after S + RT and 24% after RT (p = 0.39). The 1-year local control rates were 81% and 91% (p = 0.44), while the 1-year survival rates were 46% and 39% (p = 0.71). In the matched-pair analysis of patients receiving DDSS, improvement of motor function occurred in 22% after DDSS + RT and 24% after RT alone (p = 0.92). The 1-year local control rates were 95% and 89% (p = 0.62), and the 1-year survival rates were 54% and 43% (p = 0.30). In the matched-pair analysis of patients receiving LE, improvement of motor function occurred in 20% after LE + RT and 23% after RT alone (p = 0.06). The 1-year local control rates were 50% and 92% (p = 0.33). The 1-year survival rates were 32% and 32% (p = 0.55). CONCLUSION: Elderly patients with MSCC did not benefit from surgery in addition to radiotherapy regarding functional outcome, local control of MSCC, or survival.

Impact of zoledronic acid on control of metastatic spinal cord compression.

BACKGROUND: Zoledronic acid was demonstrated to reduce the rate of skeletal-related events, a hypernym including various outcomes, in patients with bone metastases. In contrast to other studies, this matched-pair analysis focused solely on the impact of zoledronic acid on metastatic spinal cord compression (MSCC). PATIENTS AND METHODS: Data from 98 patients with MSCC receiving radiotherapy plus zoledronic acid were matched 1:2 to 196 patients receiving radiotherapy alone for ten potential prognostic factors. Both groups were compared for local control of MSCC within the irradiated region, overall control of MSCC (local and distant MSCC control), and survival. RESULTS: The 1-year local control rates were 90% after radiotherapy plus zoledronic acid and 81%, after radiotherapy alone (p = 0.042). The 1-year overall control rates were 87% and 75%, respectively (p = 0.016), and the 1-year survival rates were 60% and 52%, respectively (p = 0.17). Results were significant in the Cox proportional hazards model regarding local control (p = 0.024) and overall control (p = 0.008). CONCLUSION: According to the results of this study, zoledronic acid was associated with improved control of MSCC in irradiated patients.

High frequency and allele-specific differences of BRCA1 founder mutations in breast cancer and ovarian cancer patients from Belarus.

Breast cancer and ovarian cancer are common malignancies in Belarus accounting for about 3500 and 800 new cases per year, respectively. For breast cancer, the rates and age of onset appear to vary significantly in regions differentially affected by the Chernobyl accident. We assessed the frequency and distribution of three BRCA1 founder mutations 5382insC, 4153delA and Cys61Gly in two hospital-based series of 1945 unselected breast cancer patients and of 201 unselected ovarian cancer patients from Belarus as well as in 1019 healthy control females from the same population. Any of these mutations were identified in 4.4% of the breast cancer patients, 26.4% of the ovarian cancer patients and 0.5% of the controls. In the breast cancer patients, BRCA1 mutations were strongly associated with earlier age at diagnosis, with oestrogen receptor (ER) negative tumours and with a first-degree family history of breast cancer, although only 35% of the identified BRCA1 mutation carriers had such a family history. There were no marked differences in the regional distribution of BRCA1 mutations, so that the significant differences in age at diagnosis and family history of breast cancer patients from areas afflicted by the Chernobyl accident could not be explained by BRCA1. We next observed a higher impact and a shifted mutational spectrum of BRCA1 in the series of Byelorussian ovarian cancer patients where the three founder mutations accounted for 26.4% (53/201). While the Cys61Gly mutation appeared underrepresented in ovarian cancer as compared with breast cancer cases from the same population (p = 0.01), the 4153delA mutation made a higher contribution to ovarian cancer than to breast cancer (p < 0.01). BRCA1 mutations were significantly enriched among ovarian cancer cases with a first-degree family history of breast or ovarian cancer, whereas the median age at ovarian cancer diagnosis was not different between mutation carriers and non-carriers. Taken together, these results identify three BRCA1 founder mutations as key components of inherited breast and ovarian cancer susceptibility in Belarus and might have implications for cancer prevention, treatment and genetic counselling in this population.

Spectrum of ATM gene mutations in a hospital-based series of unselected breast cancer patients.

Blood relatives of patients with the inherited disease ataxia telangiectasia (A-T) have an increased susceptibility for breast cancer. We therefore looked for sequence alterations of the ATM gene in a large hospital-based series of unselected breast cancer patients. The whole ATM coding sequence was analyzed in genomic DNA samples from a core group of 192 consecutive breast cancer cases to define the spectrum of ATM gene mutations. Common sequence alterations were then screened in the whole series of 1000 breast cancer patients and in 500 random individuals. In the core group, 21 distinct sequence alterations were identified throughout the ATM coding region, and 1 common splicing mutation was uncovered in intron 10. Almost half of the breast cancer patients (46%) were heterozygotes for 1 of 16 different amino acid substitutions, and three patients (1.6%) carried a truncating mutation. These data indicate that approximately 1 in 50 German breast cancer patients is heterozygous for an A-T-causing mutation. In our extended series, the most common A-T mutation 1066-6T-->G was disclosed in 7 of 1000 (0.7%) breast cancer patients. Transcript analyses indicated that the loss of exon 11 in the ATM mRNA was the pathogenic consequence of this splicing mutation, which produced a <10% of full-length ATM mRNA and ATM protein in a homozygous A-T patient. We also found an excess of rare missense substitutions in the breast cancer cohort compared with random individuals (7.9% versus 5.3% of alleles; odds ratio = 1.6; P < 0.01). One missense substitution, S707P in exon 15, was two times more frequent in breast cancer patients (odds ratio = 2.4; 95% confidence interval, 1.0-5.8) and five times more frequent in patients with bilateral disease than in random individuals (P < 0.001). We conclude that a large variety of distinct ATM mutations and variants exist among breast cancer patients, some of which can contribute to the etiology and progression of the malignancy. Screening for frequent A-T mutations such as the 1066-6-->G splice site substitution can be effective to prospectively identify A-T heterozygotes in an unselected cancer patient population.

Prognostic significance of the time of developing motor deficits before radiation therapy in metastatic spinal cord compression: one-year results of a prospective trial.

PURPOSE: To investigate prospectively the prognostic value of the time of developing motor deficits before radiation therapy (RT) for post-treatment functional outcome in metastatic spinal cord compression. METHODS AND MATERIALS: From November 1998 until October 1999, 57 patients were included. Two subgroups were formed according to the time of developing motor deficits before RT: 1-14 days (n = 29) and > 14 days (n = 28). Therapeutic effect on motor function was evaluated by an 8-point scale directly, 6, 12, and 24 weeks after RT. Patients with rapid deterioration of motor function within 48 h before RT (n = 14) were evaluated separately. RESULTS: Directly after RT, 26/28 patients (93%) of the group developing motor deficits > 14 days showed improvement of motor function, in comparison to 3/29 patients (10%) of the group 1-14 days (p < 0.001). Deterioration rates were 0% (> 14 days) and 45% (1-14 days). In patients with rapid deterioration of motor function within 48 h before RT, prognosis was poor (improvement 0%, no change 43%, deterioration 57%). Results were comparable 6, 12, and 24 weeks after RT. CONCLUSION: A slower development of motor deficits before RT predicts a better post-treatment functional outcome. In patients with rapid deterioration of motor function within 48 h before RT, prognosis was extraordinarily poor. These results support the findings of our preceding retrospective analysis.

Spondylodiscitis in patients with spinal cord compression: a possible pitfall in radiation oncology.

PURPOSE: In patients presented for spinal irradiation it may be difficult to distinguish between malignant and benign lesions if only plain X-rays and computed tomography (CT)-scans are available. Spinal magnetic resonance imaging (MRI) can be of great diagnostic value. METHODS: From 11/1995 to 05/2000 447 patients were presented for spinal irradiation, 264 beyond regular operating hours. At presentation no spinal MRI was available in 170/447 and 132/264 patients. RESULTS: After spinal MRI, diagnosis was changed from vertebral metastases to spondylodiscitis in 10/170 and 8/132 patients. Six of these patients were already known as cancer patients. CONCLUSION: In patients presented for spinal irradiation spondylodiscitis is not very uncommon. If there is any doubt about metastatic disease as the cause for spinal cord compression a spinal MRI has to be demanded, even beyond regular operating hours.

Application of a new verification technique allowing craniospinal irradiation in supine position.

To minimize anaesthesia related risks during craniospinal irradiation in children, treatment in supine position would be preferable. Verification especially of the cervical three-field junction causes problems, because direct visual control is not possible. We present clinical experiences with a new verification technique with all three fields exposed on one single film.

Therapeutic options for meningeal melanocytoma. Case report.

Meningeal melanocytomas are uncommon lesions. They are generally considered to be benign tumors that derive from leptomeningeal melanocytes. A rare case of a metastatic spinal meningeal melanocytoma is presented. All relevant cases reported in literature since 1972, when the term "meningeal melanocytoma" was first used, were reviewed. Rates of tumor recurrence from 1 to 5 years were calculated for this rare lesion, based on published data and on additional information obtained from personal contact with most of the authors. Recurrency rates of 47 patients suitable for evaluation were correlated with the different therapeutic approaches. Complete tumor resection alone and incomplete resection alone followed by irradiation appeared to be superior to incomplete resection alone in terms of disease-free survival. Statistical significance was achieved for complete tumor resection at follow up between I and 4 years (range p = 0.010-0.050) and for incomplete resection combined with radiotherapy after 2 years (p = 0.034). Complete tumor resection should be considered the best therapeutic option, followed by incomplete resection combined with postoperative radiotherapy.

[Computer tomography for TNM based radiation planning of urological tumours (author's transl]. / Unterstützung einer am TNM-System orientierten Bestrahlungsplanung urologischer Tumoren durch die Computertomographie.

From the extensive statistics concerning treatment results of urological tumours which are available from central tumour registers, a first draft of a treatment plan has been worked out, which is based on tumour spread. Since the extent of tumour invasion is documented by the TNM system of the UICC, one is justified in speaking of TNM orientated treatment planning. For planning it is necessary to consider not only tumour type and depth of infiltration of local tissues, but also the lymph node anatomy, whether the nodes are involved or not. Computer tomography assist significantly in the performance of such TNM orientated treatment planning, particularly in determining the extent of the volume to be irradiated, It must be stressed that computer tomography does not replace the use of simulators, but that it is a valuable addition. In our view, computer tomography has also an undoubted value in treatment planning of urological tumours where palliation only is the aim. It provides the possibility of checking the effect of the chosen treatment by a non-invasive diagnostic method.

[Computer tomography of malignant renal lymphomas]. / Computertomographie renaler maligner Lymphome.

The pre- and postcontrast CT findings of 11 patients with lymphoma involving the kidneys are described. In all cases the renal lesions showed low attenuation values after bolusinjection. In contrary to the literature renal lymphoma might present different attenuation values in the non-contrast enhanced CT scan. The density varies from hypo- to iso- and hyperdens. A bolusinjection of contrast media should be performed to depict even greater nodules.

[Lymphangitis carcinomatosa of the lung in carcinoma of the prostate: frequency, radiological appearances and clinical significance (author's transl)]. / Lymphangiosis carcinomatosa der Lungen beim Prostatakarzinom. Hüfigkeit, röntgenologisches Erscheinungsbild und klinische Bedeutung.

Lung metastases from carcinoma of the prostate usually manifest themselves as radiologically diffuse lymphangitis carcinomatosa. Unlike the pathological findings, a radiological diagnosis is relatively uncommon. We have investigated this retrospectively in 230 patients; in 192, radiographs were available for study. In over 10% lung metastases were found, mostly in the form of lymphangitis carcinomatosa. In view of the bad prognostic significance and therapeutic implications of lymphangitis carcinomatosa, it is important to bear this in mind and to look for it radiologically.

[Detection of bone marrow involvement in breast cancer and malignant lymphoma using immunoscintigraphy of the hematopoietic bone marrow]. / Nachweis des Knochenmarkbefalls beim Mammakarzinom und bei malignen Lymphomen durch Immunszintigraphie des hämatopoetischen Knochenmarks.

Radioimmunoimaging of bone marrow was performed for non-invasive detection of skeletal involvement in 15 patients with carcinoma of the breast and 17 patients with malignant lymphomas. Bone marrow scans were performed by means of a monoclonal 99mTc-labelled antibody, directed against NCA-95 and CEA. The presence and extent of skeletal involvement were controlled by skeletal scintigraphy, plain radiographs and CT; bone marrow biopsies were obtained in 19 patients as well. 20 subjects without suspected malignant disease served as controls. Haematopoietic bone marrow was imaged homogeneously and with high contrast in all controls. 15/15 patients with carcinoma of the breast and 10/17 patients with malignant lymphomas had multifocal bone marrow defects due to skeletal metastases. Bone marrow scans revealed significantly more lesions than skeletal scintigraphy both in carcinoma of the breast (p = 0.027) and malignant lymphomas (p = 0.015). Thus, radioimmunoscintigraphy of bone marrow may provide a new, sensitive approach for non-invasive detection of metastatic spread to the skeletal system.