The extent of irradiation-induced long-term visceral organ damage depends on cranial/brain exposure.

In case of high-dose radiation exposure, mechanisms controlling late visceral organ damage are still not completely understood and may involve the central nervous system. To investigate the influence of cranial/brain irradiation on late visceral organ damage in case of high-dose exposure, Wistar rats were irradiated at 12 Gy, with either the head and fore limbs or the two hind limbs protected behind a lead wall (head- and hind limbs-protected respectively), which allows long-term survival thanks to bone marrow protection. Although hind limbs- and head-protected irradiated rats exhibited similar hematopoietic and spleen reconstitution, a late body weight loss was observed in hind limbs-protected rats only. Histological analysis performed at this time revealed that late damages to liver, kidney and ileum were attenuated in rats with head exposed when compared to animals whose head was protected. Plasma measurements of inflammation biomarkers (haptoglobin and the chemokine CXCL1) suggest that the attenuated organ damage in hind limbs-protected rats may be in part related to reduced acute and chronic inflammation. Altogether our results demonstrate the influence of cranial/brain exposure in the onset of organ damage.

Half-body irradiation with tomotherapy for pain palliation in metastatic breast cancer.

CONTEXT: Half-body irradiation (HBI) is the fastest and most effective tool against uncontrolled pain from widespread bone metastases but is somewhat toxic. OBJECTIVES: To assess the feasibility of lower HBI with helical tomotherapy in patients with metastatic breast cancer in terms of acute toxicity and delay in chemotherapy administration. METHODS: Thirteen breast cancer patients with multiple painful bone metastases to the lower half of the body were enrolled in this prospective trial. Eight patients were receiving chemotherapy. Target volume included all bones from the L3-L4 interface to the femoral shafts. Radiation consisted of 8 Gy in one fraction, delivered with helical tomotherapy. Patients were premedicated only with oral steroids. Pain intensity was scored using the Numeric Rating Scale from 0 to 10. Toxicity was scored using the Common Terminology Criteria for Adverse Events, version 3.0. Quality of life was scored with the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30, before and 21 days after the radiation course. This trial was approved by the local review board. RESULTS: Median follow-up was at seven months (range 2-12 months). All but two patients had pain relief in the radiated field. Six patients stopped their analgesic drug consumption. Toxicity was acceptable: two Grade 3 hematologic toxicities were registered (anemia and leukopenia). Grade 1-2 toxicities were hematologic = 13, fever = 3, nausea = 2, and diarrhea = 1. Three of the eight patients had a delay in chemotherapy administration because of leukopenia or anemia. Twelve patients answered to European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30, and an improved quality of life was documented in eight cases. CONCLUSION: Lower HBI delivered with helical tomotherapy resulted in a well-tolerated regimen, without significant delay in chemotherapy schedule.

Partial depletion of regulatory T cells does not influence the inflammation caused by high dose hemi-body irradiation.

There is clinical interest in the modulation of regulatory T cells for cancer therapy. The safety of these therapies in combination with conventional anti-cancer therapies, including radiation therapy, can be studied in animal models. The effects of partial depletion of regulatory T (Treg) cells with an anti-CD25 antibody in conjunction with ionizing radiation on inflammation and tissue injury were analyzed in C57BL/6 mice. An anti-CD25 antibody (PC61) was administered 3 days prior to 13 Gy lower-half hemi-body irradiation (HBI). The blood, spleen, mesenteric lymph nodes (mLNs) and inguinal lymph nodes (iLNs) were harvested at various times thereafter. Alterations in the proportion of leukocyte subsets including CD4(+) T cells, CD8(+) T cells, Treg cells, B cells, NK cells, NK1.1(+) T cells, macrophages and granulocytes were analyzed by FACS. The lungs, liver, pancreas, stomach, jejunum, duodenum, ileum, colon and kidney were harvested and studied by H&E staining. Expression of inflammatory mediators in plasma and tissue were investigated by ELISA. HBI significantly decreased the leukocyte pool though the various leukocyte subsets had different sensitivities to HBI. The administration of PC61 significantly decreased the proportion of Treg cells in spleen, iLN, mLN and blood (reduction of approximately 60%). Irradiation significantly increased the proportion of Treg cells in the spleen, iLN and mLN. HBI induced a systemic inflammatory reaction as demonstrated by increased plasma levels of IL-6, KC/CXCL1 and circulating granulocytes in the blood. Neutrophils also infiltrated the small bowel. The same general patterns were observed whether or not Treg cells were partially depleted with PC61 prior to HBI. These data demonstrate that partial depletion of Treg cells in these mice does not influence HBI-induced inflammatory response and tissue injury, and that combining anti-CD25 therapy with radiation may be safe and well tolerated in a clinical setting.

Initial evaluation of safety of wide-field irradiation in the treatment of hematopoietic neoplasia in the cat.

Localized radiation therapy is well tolerated in cats with confined tumors; however, the use of wide-field radiation therapy to treat disseminated neoplasia has not been evaluated systematically in this species. Wide-field external beam radiation therapy, which we define as irradiation of cranial or caudal halves of the body either individually or sequentially, was undertaken as an experimental option to treat cats with either chemotherapy-refractory or naive hematopoietic neoplasia considered to have a poor prognosis. Fifteen cats with hematopoietic malignancies received wide-field external beam radiation therapy between 2003 and 2006. Cats received 8 Gy delivered in 4 Gy fractions with 60Co photons. Treatment-related toxicity was scored according to criteria established by the Veterinary Cooperative Oncology Group. Animals without preexisting abnormalities on hemograms exhibited no or mild (Grade 1 or 2) hematopoietic toxicity. Although most cats (14 of 15) had preexisting gastrointestinal (GI) signs, these signs were stable (29%) or improved (42%) following irradiation. Worsening GI signs following irradiation occurred transiently in two cats and in association with progressive disease in two others. No pulmonary, renal, hepatic, or dermatologic toxicities were detected. In summary, wide-field external beam radiation therapy can be administered safely to, and may provide therapeutic benefit for, cats with disseminated hematopoietic neoplasia.

Densities of glutamatergic and GABAergic presynaptic terminals are altered in experimental cortical dysplasia.

PURPOSE: Cortical dysplasia (CD) is a major cause of epilepsy in children and adults, but underlying mechanisms of epileptogenesis in this disorder are poorly understood. We have utilized the irradiated rat model to study an injury-based form of diffuse CD in rats. Prior studies in this model have shown reduced numbers of γ-aminobutyric acid (GABA)ergic interneurons and reduced inhibitory synaptic currents in pyramidal cells in CD. We analyzed the number of excitatory and inhibitory presynaptic terminals in the neocortex of irradiated rats to better characterize altered connectivity in experimental CD. METHODS: Antibodies to vesicular glutamate transporter 1 (VGLUT1), vesicular glutamate transporter 2 (VGLUT2), vesicular GABA transporter (VGAT), and parvalbumin (PV) were used to quantify glutamatergic and GABAergic presynaptic terminals in control and dysplastic cortex. RESULTS: We found that the density of VGLUT1 terminals was increased in CD in comparison to layers IV, V, and VI in control cortex. VGLUT2 terminals were increased in CD compared to layers IV and VI. VGAT terminals were reduced in CD compared to layers II/III, IV, and V in controls as were PV-immunoreactive somata and terminals. DISCUSSION: These findings suggest an overall increase in excitatory synaptic connectivity and decrease in inhibitory synaptic connectivity in CD in irradiated rat. We propose that these changes contribute to hyperexcitability in these animals and may contribute to epileptogenicity in some forms of human CD.

Half-body irradiation: a safe and acceptable treatment.

BACKGROUND: The aim of this study was an evaluation of the acute toxicity of single-fraction half-body irradiation (HBI). MATERIAL/METHODS: The material comprised 92 patients. Upper, lower, and middle HBI (UHBI, LHBI, MHBI) were performed in 34, 49, and 9 cases, respectively, with 6 Gy delivered for UHBI, 8 Gy for LHBI, and 6 or 8 Gy for MHBI. The patients' weights were measured on the HBI day. Two weeks later their weights and blood parameters were checked and diarrhea, skin toxicity (scale: 0-4), and nausea and vomiting intensity (scale: 0-3) were evaluated using WHO Toxicity Criteria. Items of all the evaluated symptoms were summarized and the means of the sums were calculated. RESULTS: Mean weight loss after HBI was 0.7 kg. One patient had grade 4 toxicity (thrombopenia). Grade 3 toxicity appeared in 9 cases (nausea and vomiting in 5, leukopenia in 1, and thrombopenia in 3). None had radiation pneumonitis. The means of the summarized items were 1.9 for UHBI than 1.4 for LHBI. The means of the summarized items were 1.6 for 8 Gy and 1.8 for 6 Gy. UHBI provoked a higher incidence and intensity of nausea and vomiting and LHBI caused a higher incidence and intensity of diarrhea. The remaining evaluated symptoms of toxicity were similar for irradiations of both halves of the body. CONCLUSIONS: From these results one can conclude that single-dose (6-8 Gy) HBI is a safe treatment, causing a low percentage of low-level, patient-acceptable adverse radiation sequels.

Half body irradiation of patients with multiple bone metastases: a phase II trial.

AIM OF STUDY: The primary aim of this study was to evaluate the effect of half-body irradiation (HBI) on pain and quality of life in cancer patients with multiple bone metastases. The secondary aim was to evaluate side effects of the treatment. PATIENTS AND METHODS: A total of 44 patients received lower (n = 37), upper (n = 5), or sequential HBI (n = 2). The dose for lower HBI was 8 Gy in one fraction and for upper HBI 7 Gy in one fraction, with reduction of the lung dose to 6 Gy in one fraction by partial shielding. The majority of patients (n = 41) were males with prostate cancers (93%). Outcome and side effects were measured by the EORTC Quality of Life Questionnaire C30 (QLQ-C30), and by the doctors' toxicity scores in the medical record. Pain relief was defined as a reduction of more than 10 points on the QLQ-C30 scale. Evaluations were performed before and 2, 4, 8, 16, and 24 weeks after treatment. RESULTS: Relief of pain was observed in 76% of the patients receiving HBI with 8.8% of the patients experiencing complete pain relief with no residual pain in the treated field. For most patients, the pain relief was lasting throughout the follow-up period. About one third of the patients were able to reduce their intake of analgesics. Grade 1-2 diarrhoea was the most common side effect observed in 49% of the patients two weeks after treatment. Mild pulmonary symptoms (grade 1-2) were observed in four of seven patients receiving upper HBI. No clear effect was observed on the patients' global quality of life. CONCLUSION: Single fraction HBI is safe and effective providing long lasting pain reduction in 76% of patients with multiple bone metastases.

Use of a modified hemi-body irradiation technique for metastatic carcinoma of the prostate: report of a 10-year experience.

AIMS: To determine whether patients receiving hemi-body irradiation required further treatment to painful bone sites out with the radiation field (skull or lower leg), whether patients required further treatment to areas within the treated radiation field for pain or new skeletal events, and whether the treatment outcome was successful in terms of pain control. Toxicities, the need for transfusions and survival were also analysed. MATERIALS AND METHODS: In our retrospective review, 103 men aged 50-87 years, with skeletal metastases from prostate cancer, received modified hemi-body irradiation (HBI) during a consecutive 10-year period, using the same radiotherapy technique and dose. The upper HBI field excluded the region above the ramus of the mandible and the lower HBI field excluded the lower limb below the knee. A successful outcome was determined by assessing the pain response in combination with a change in analgesic intake. RESULTS: Twenty patients received upper HBI; 17/20 (85%) had a successful outcome at the 6-week review, sustained in 94.1% at the final follow-up with no need for radiotherapy to the skull. Thirty-eight patients received lower HBI; 26/38 (68.4%) had a successful outcome at the 6-week review, sustained in 80.8% at the final follow-up with no need for radiotherapy to the lower leg. Forty-five patients received sequential HBI; 33/45 (73.3%) had a successful outcome at the 6-week review, sustained in 87.9% at the final follow-up, with three patients requiring further radiotherapy to the skull (2/45) or lower leg (1/45). Only 5/103 patients (4.8%) developed new skeletal events in the treated area. Toxicity and transfusion requirements were minimal. CONCLUSIONS: Modifying the field size for single-fraction HBI does not have a significant effect on the final outcome of treatment, namely pain control and a need for additional radiotherapy. In our experience, modified HBI should be considered in patients with multiple bone pain sites, especially if they will probably require several visits for localised radiotherapy to single painful bone sites within a short period of time.

Drug-dependent requirement of hippocampal neurogenesis in a model of depression and of antidepressant reversal.

BACKGROUND: Depression and anxiety disorders have been linked to dysfunction of the hypothalamo-pituitary-adrenal (HPA) axis and structural changes within the hippocampus. Unpredictable chronic mild stress (UCMS) can recapitulate these effects in a mouse model, and UCMS-induced changes, including downregulation of hippocampal neurogenesis, can be reversed by antidepressant (AD) treatment. We investigated causality between changes in hippocampal neurogenesis and the effects of both chronic stress and chronic ADs. METHODS: Mice were treated with either a sham procedure or focal hippocampal irradiation to disrupt cell proliferation before being confronted with 5 weeks of UCMS. From the third week onward, we administered monoaminergic ADs (imipramine, fluoxetine), the corticotropin-releasing factor 1 (CRF(1)) antagonist SSR125543, or the vasopressin 1b (V(1b)) antagonist SSR149415 daily. The effects of UCMS regimen, AD treatments, and irradiation were assessed by physical measures (coat state, weight), behavioral testing (Splash test, Novelty-Suppressed feeding test, locomotor activity), and hippocampal BrdU labeling. RESULTS: Our results show that elimination of hippocampal neurogenesis has no effect on animals' sensitivity to UCMS in several behavioral assays, suggesting that reduced neurogenesis is not a cause of stress-related behavioral deficits. Second, we present evidence for both neurogenesis-dependent and -independent mechanisms for the reversal of stress-induced behaviors by AD drugs. Specifically, loss of neurogenesis completely blocked the effects of monoaminergic ADs (imipramine, fluoxetine) but did not prevent most effects of the CRF(1) and the V(1b) antagonists. CONCLUSIONS: Hippocampal neurogenesis might thus be used by the monoaminergic ADs to counteract the effects of stress, whereas similar effects could be achieved by directly targeting the HPA axis and related neuropeptides.

A toxicity study of low-dose rate half-body irradiation and chemotherapy in dogs with lymphoma.

Thirteen dogs with previously untreated multicentric lymphoma were enrolled in a prospective study investigating the effects of low-dose rate total body irradiation (TBI) and chemotherapy. Dogs received either 6 or 8 Gy TBI in half-body fractions, 2 weeks apart. Toxicity consisted of mild to moderate haematological and gastrointestinal (GI) signs. One dog died from treatment complications. Anorexia was noted independent of dose. Haematological toxicity was more common and more severe after 8 Gy treatment. GI toxicity was more likely postcaudal half-body irradiation with 8 Gy. Other than leukotrichia, late effects from radiation were not observed. Results indicated that haematological and nonhaematological toxicity was dose dependent. However, the protocol was well tolerated and treatment intensification using a 2-week inter-radiation interval was possible in all dogs treated with 6 Gy. Preliminary survival data for these dogs were very encouraging, providing a strong rationale to analyse the efficacy of low-dose rate irradiation (LDRI) in canine lymphoma.

Risk factors for enlargement of cardiac silhouette on chest radiography after radiotherapy for esophageal cancer.

PURPOSE: To evaluate the incidence and risk factors of enlargement of cardiac silhouette on chest radiographs after radiotherapy for esophageal cancer. MATERIALS AND METHODS: We analyzed 67 patients with esophageal cancer who received external beam radiation therapy with a total dose of >or=50 Gy and were followed for >or=6 months. Sixteen patients received radiation alone, and the remaining 51 received chemoradiotherapy. The difference between the cardiothoracic ratio (CTR) on the pretreatment chest radiograph and that on the posttreatment radiograph with maximum cardiac silhouette for each patient was used for the analysis. RESULTS: The average maximum increase in CTR for the entire group was 4.5%, which was statistically significant. Only the area of the cardiac silhouette in the initial radiation field was a significant risk factor for enlargement of the cardiac silhouette. Pericardial effusions were observed in all patients who underwent computed tomography with severe enlargement of the cardiac silhouette. CONCLUSION: The CTR value significantly increased after radiotherapy for esophageal cancer. Radiation-induced pericardial effusion may be the main cause of enlargement of the cardiac silhouette. The irradiated cardiac area was the only significant risk factor for enlargement of the cardiac silhouette; the use of chemotherapy was not.

Prospective comparison of short- and long-term effects of pelvic floor exercise/biofeedback training in patients with fecal incontinence after surgery plus irradiation versus surgery alone for colorectal cancer: clinical, functional and endoscopic/endosonographic findings.

OBJECTIVE: The influence of irradiation on the clinical severity of incontinence, sphincter function, morphologic features and short/long-term treatment effects of sphincter training therapy is still insufficiently understood in irradiated patients with fecal incontinence after surgery for colorectal cancer. These parameters were compared in irradiated and non-irradiated patients and followed prospectively with regard to short- and long-term training effects. MATERIAL AND METHODS: Forty-one patients having been irradiated after surgery (50.0+/-5.0 Gy) and 54 non-irradiated patients with fecal incontinence participated in this prospective, non-randomized trial. Baseline evaluation included a semiquantitative severity assessment score of fecal incontinence (modified Cleveland Incontinence Score (MCIS)), rectal manometry and endoscopy. After 3 weeks (short term) of intensive in-hospital pelvic floor exercise combined with biofeedback training, a second evaluation was made. In addition, anal endosonography (EUS) was performed in cases of treatment failure. After one year (long term) a third evaluation was made clinically (MCIS score). RESULTS: Irradiated patients presented with a significantly higher degree of fecal incontinence (lower MCIS) compared to non-irradiated patients: 7.4+/-2.2 versus 8.7+/-2.7 points (p<0.001). Rectosigmoidal inflammation was more frequent in irradiated than non-irradiated patients (26.9% versus 9.3%) (p<0.03). Sphincter pressure, sensation/pain threshold and the rectoanal inhibitory reflex were similar in both groups. A significant short-term training effect was observed in both groups following sphincter training therapy in terms of an increase in MCIS from 7.4+/-2.2 to 9.4+/-2.7 points in the irradiated group and from 8.7+/-2.7 to 11.4+/-2.5 points in the non-irradiated group (p<0.0001). After one year the scores were 8.2+/-3.8 and 10.7+/-4.4 points, respectively (p<0.0001). There was a significant correlation (p<0.001) between baseline MCIS and the short- and long-term MCIS. In patients with short-term treatment failure (16.6%) anal EUS revealed structural defects of the external sphincter in four patients. There was no association of sphincter diameter with sphincter pressure, sensation/pain threshold and short/long-term MCIS. CONCLUSIONS: The main result of this study is that irradiated patients show short- and long-term training effects comparable with those of non-irradiated patients despite the higher degree of incontinence at baseline. The correlation between the initial MCIS and short- and long-term treatment effects may be regarded as an important clinical predictor for treatment outcome. Functional and morphologic features are less suitable for this purpose.

Increased expression of pro-inflammatory cytokines as a cause of lung toxicity after combined treatment with gemcitabine and thoracic irradiation.

BACKGROUND AND PURPOSE: Preclinical evidence suggesting gemcitabine potentiates the anti-tumor effects of irradiation has resulted in clinical trials to evaluate the treatment efficacy of gemcitabine and concurrent thoracic irradiation in non-small-cell lung cancer (NSCLC). Although these studies demonstrated favorable tumor response, this combined treatment modality was accompanied by severe treatment-related toxicities predominantly of the lung. In an attempt to elucidate the determinants of lung toxicity for gemcitabine, we analyzed the expression of the pro-inflammatory cytokines TNF-alpha, IL-1alpha and IL-6 in the lung tissue of mice treated with gemcitabine and concurrent thoracic irradiation. MATERIALS AND METHODS: Four study groups were defined: C57BL/6J mice that received neither irradiation nor gemcitabine (NT-group), those that received gemcitabine (120 mg/kg intraperitoneal, i.p.) but no irradiation (GEM-group), those that underwent thoracic irradiation (12 Gy) without gemcitabine (XRT-group), and those that received both gemcitabine (120 mg/kg i.p., 2 h before irradiation) and thoracic irradiation (GEM/XRT-group). The mice were sacrificed at 1 h, 1 and 3 days, 1, 2 and 4 weeks post-treatment (p.t.). The mRNA expression of TNF-alpha, IL-1alpha and IL-6 in the lung tissue was quantified by competitive RT-PCR. The cellular origin of the cytokine expression was identified by immunohistochemistry. The cytokine expression was correlated with histopathological alterations. RESULTS: The TNF-alpha, IL-1alpha and IL-6 expression in the lung tissue of the GEM/XRT mice was clearly higher at all assessment time points compared to the NT mice (statistically significant at 1 h, 1 and 3 days, 1, 2 and 4 weeks p.t.), XRT mice (statistically significant at 1 week p.t.) or GEM mice (statistically significant at 1 h, 1 and 2 weeks p.t.). Maximal treatment-induced cytokine expression in the lung tissue of the GEM/XRT mice occurred already at 1 week p.t. (TNF-alpha: 30.9 +/- 5.3/IL-1alpha: 28.3 +/- 5.0/IL-6: 4.9 +/- 0.1 times basal level), and coincides with pathohistologically discernable interstitial pneumonitis. The elevated levels of TNF-alpha and IL-1alpha have been found to correlate with immunohistochemical staining of the bronchiolar epithelium and predominantly of inflammatory cells. CONCLUSIONS: Our data provide evidence that the increased expression of pro-inflammatory cytokines and the induction of a cytokine-triggered inflammatory response may be a determinant of the observed elevated lung toxicity after concurrent treatment with gemcitabine and thoracic irradiation.

[Preliminary study on alternative half body irradiation in the treatment of hematological malignancies].

OBJECTIVE: To evaluate the curative effect of alternative half body irradiation (AHBI) in the treatment of hematological malignancies. METHODS: Seventeen patients with hematological malignancies in complete remission received a high-dose chemotherapy, followed by a two-step AHBI on day 14 (12 approximately 22), upper (UHBI) and lower half body irradiation (LHBI) were sequentially given with each a single dose of 6 approximately 9 Gy at an interval of 23 (7 approximately 34) days. Fourteen received autologous hematopoietic stem cell transplantation (AHSCT) during the same period were chosen as control. RESULTS: Hematopoiesis recovery was observed in all the AHBI patients. The 3-year disease free survival (DFS) rate and the AHBI-related mortality were (52.38 +/- 13.47)% and 0, respectively. The longest survival time was 1446 days with a median follow-up period of 927 (428 approximately 1446) days. The 3-year DFS for the 11 acute lymphocytic leukemia (ALL) patients was (47.73 +/- 17.55)%. By contrast, the 3-year DFS and the AHSCT-related mortality for the 14 ALL patients in the control AHSCT group were (53.88 +/- 14.08)% and 14%, respectively. There was no significant difference in 3-year DFS between AHBI and AHSCT ALL patients. CONCLUSIONS: AHBI provides a feasible approach for hematological malignancy patients.

[Assessment of hematopoiesis regeneration in patients with solid tumors after radiotherapy]. / Ocena regeneracji ukladu krwiotwórczego u chorych na nowotwory lite leczonych promieniowaniem jonizujacym.

The myelotoxicity is one of the most severe adverse events of radiotherapy. Increase of CD34+ cells level in peripheral blood as result of raised output of granulocyte colony stimulating factor (G-CSF) can be result of hematopoiesis regeneration after radiotherapy. The aim of this study was to determine the hematopoiesis regeneration using analysis of CD34+ cells level in peripheral blood and serum concentration of G-CSF in patients treated with radiotherapy according to irradiated body region and irradiation field size. Two groups of irradiated patients were examined. Group I consisted of 11 patients (mean age 56) with gynecological malignancies (teletherapy dose 40-50 Gy for pelvic area and brachytherapy with Cs). Group II consisted of 10 patients (mean age 58) with head and neck malignancies (teletherapy only 50-70 Gy). Every patient was evaluated 3 times: before radiotherapy, in the day of ending and 14 days after therapy. 3 ml of blood for CD34 and serum for G-CSF estimation were collected. Blood cells were stained with monoclonal antibody specific for CD34 antigen and analysed by flow cytometry. G-CSF level was estimated by ELISA. After radiotherapy in both groups statistically significant leukopenia (p < 0.001) was observed. There was no difference between two groups in levels of CD34+ cells before and in the last day of therapy but there was significant increase of CD34+ cells in group I compared with group II 14 days after treatment (p < 0.01). Decrease of CD34+ cells during radiotherapy and after its ending in all patients was observed but only in group II was statistically significant. Positive correlation between amount of leukocytes and CD34+ cells percentage was stated. There were no statistically significant differences in serum G-CSF concentration within particular groups and between group I and II. Our results indicate that evaluation of CD34+ cells level in peripheral blood is useful in prediction of hematopoiesis regeneration after radiotherapy. G-CSF serum concentration is not prognostic factor in these groups of patients.

Hemithoracic radiation after extrapleural pneumonectomy for malignant pleural mesothelioma.

PURPOSE: The treatment of malignant pleural mesothelioma remains a therapeutic challenge, with median survival rates of about 12 months and local failure rates of up to 80%. Our institution recently published results showing that extrapleural pneumonectomy (EPP) followed by hemithoracic radiation yielded excellent local control. This paper reports our technique for high-dose hemithoracic radiation after EPP. METHODS: Between 1990 and 2001, 35 patients with malignant pleural mesothelioma were treated with EPP followed by hemithoracic radiation therapy (median dose: 54 Gy, range: 45-54 Gy) at Memorial Sloan-Kettering Cancer Center. EPP was defined as en bloc resection of the entire pleura, lung, and diaphragm with or without resection of the pericardium. The radiation therapy target volume was the entire hemithorax, including the pleural folds and the thoracotomy and chest tube incision sites. Patients were treated with a total dose of 5400 cGy delivered in 30 fractions of 180 cGy. Radiation therapy was well tolerated, and toxicity data are described. RESULTS: Of the 35 patients analyzed, 29 patients were male, and 18 had right-sided tumors. Twenty-six had epithelioid histologies. UICC stage was I in 4, II in 11, III in 19, and IV in 1 patient. As shown by axial and sagittal isodose distributions, we were able to deliver adequate doses to the target volume while limiting dose to critical structures such as heart, spinal cord, liver, and stomach. The most common toxicities were RTOG Grades 1 and 2 nausea and vomiting, as well as lung, esophageal, and skin toxicities. CONCLUSION: Extrapleural pneumonectomy followed by high-dose hemithoracic radiation therapy is a feasible treatment regimen that is well tolerated for patients with malignant mesothelioma. We have demonstrated adequate dose distributions, using a combined photon and electron technique with blocking of critical normal structures.

Suitability of FISH painting techniques for the detection of partial-body irradiations for biological dosimetry.

Peripheral blood was irradiated with 2, 3, 4 or 5 Gy of X rays and was mixed with nonirradiated blood at five different dilutions to simulate partial-body irradiations. Analysis by FISH was performed using whole-chromosome painting probes for chromosomes 1, 4 and 11 in combination with a pancentromeric probe. Chromosome aberrations affecting the painted fraction were classified according to the PAINT nomenclature; other unstable aberrations affecting the unpainted material were also recorded. To evaluate the suitability of painting for dose assessment in partial-body irradiations, the ability of the u test and a proposed s test to detect the expected overdispersion and the similarity between the real doses and the doses estimated using Dolphin's approach were considered. For short-term biodosimetry, compared with solid-stained dicentric analyses, the suitability of FISH painting techniques for the detection of partial-body exposures is reduced, because of the decrease in the frequency of aberrations detected by FISH and in the number of cells with two or more aberrations. For reconstruction of past doses, when only complete apparently simple translocations in cells free of unstable aberrations were considered, the detection of the overdispersion and the accuracy of dose estimations were dramatically reduced. In a partial-body exposure, as the original dose increased, the whole-body dose estimated a long time after irradiation would tend to be lower, and the difference from the original dose would tend to be greater.

Fractionated half-body irradiation (HBI) for the rapid palliation of widespread, symptomatic, metastatic bone disease: a randomized Phase III trial of the International Atomic Energy Agency (IAEA).

PURPOSE: To find the fastest and most effective/efficient method to economically deliver fractionated half-body irradiation (HBI) for widespread (WS), symptomatic, metastatic bone cancer. METHODS AND MATERIALS: A Phase III trial with 3 HBI arms: (Arm A) Control (15 Gy/5 fractions/5 days); (Arm B) Hyperfractionation (HF) (8 Gy/2 fractions/1 day); (Arm C) Accelerated HF (12 Gy/4 fractions/2 days). Six countries randomized 156 patients (all with WS bone metastases): 51, 56, and 49 patients to Arms A, B, and C, respectively. There were 72 (46%) breast, 50 (32%) prostate, 9 (6%) lung, and 25 (16%) miscellaneous primary tumors. Initial performance status (PS) was 1-2 in 101 (65%) and PS 3-4 in 55 (35%). The lower, upper, and middle halves of the body were treated 79, 68, and 9 times. RESULTS: Pain relief was seen in 91% of patients (45% complete [CR] and 46% partial [PR]) within 3-8 days. Overall (OS), median (MST), and pain-free (PFS) survival was 174, 150, and 122 days. Breast tumors had a higher OS (279 days) than that of other primary tumors, but when analyzed by treatment, was not significantly different than prostate tumors in Arm A. No survival differences were found in patients with PS 1-2 vs. 3-4, CR vs. PR, bone with/without visceral metastases, or by the number of metastases (< or > 15 bone lesions). Quality of life (QOL) assessed by the percent of the remaining life free of pain was 71%; furthermore significant improvements in PS, pain, and narcotic scores were seen after HBI. Toxicity was very acceptable (41% none, 50% mild/moderate, 12% severe but transitory); more was seen with upper HBI. CONCLUSION: In terms of response, time to response, OS, MST, PFS, QOL, and toxicity, schedules for Arms A and C were similar for all but prostate primaries. Schedule for Arm B, which delivered the lowest biologic dose in the shortest time, had significantly worse results in pain relief, OS, MST, PFS, and QOL. Results indicate that, for most primary tumor types (except prostate), delivering two HBI daily doses of 3 Gy in 2 consecutive days is as effective as delivering a daily dose of 3 Gy for 5 consecutive days. Thus, this is a faster and much more convenient HBI schedule for the palliation of pain in widespread cancer.

Tolerance of half-body irradiation as systemic therapy for patients with locally advanced breast cancer.

BACKGROUND: Locally advanced breast cancer (LABC) is one of the main causes of cancer death among women in Bulgaria. In 1988, when this study started, there was still controversy about the role of chemotherapy in controlling systemic disease. There were encouraging results from the Radiation Therapy Oncology Group (RTOG) 82-06 study suggesting that half-body irradiation (HBI) should be used earlier in the disease course to prevent the development of metastases. There were many patients with LABC requiring treatment, but there was a problem with obtaining the drugs needed; they were expensive and not consistently available. PROCEDURE: Taking into account the medical contraindications to chemo-therapy treatment, its toxicity, and the possibility of chemoresistance, we initiated this study to look at the effects of HBI given as two fractions of 4 Gy to the upper and then lower parts of the body, after surgery and before local radiotherapy. RESULTS: The acute tolerance of this regimen in 36 patients with LABC was as good as it was in 4 additional LABC patients with M1 disease, and hematologic recovery was satisfactory. CONCLUSIONS: We conclude that systemic treatment with HBI is tolerable. It therefore may be a convenient and cost-effective treatment for LABC, although better treatments are still needed.

Detection of total- and partial-body irradiation in a monkey model: a comparative study of chromosomal aberration, micronucleus and premature chromosome condensation assays.

PURPOSE: To investigate the efficacy of three cytogenetic methods (dicentrics, micronuclei (MN) and premature chromosome condensation (PCC) analysis) for assessment of the unirradiated fraction and the persistence of damage after total-body (TB) and partial-body (PB) irradiation of rhesus monkeys (Macaca mulatta). MATERIALS AND METHODS: Animals were exposed to X-rays (5 Gy), either TB or PB, with about 6% of marrow cells shielded. Blood samples were collected at different times after exposure, i.e. 1, 3 and 7 days, and cultures were set up for the different cytogenetic endpoints. In addition, blood count analysis was performed before and after irradiation. RESULTS: Blood count analysis was not suitable for discriminating between TB and PB exposure. By using Poisson or overdispersion distribution as the basis, it was not possible to distinguish TB from PB irradiation when dicentric chromosomes and MN were analysed. PCC analysis, in contrast, showed a Poisson distribution after TB exposure and overdispersion after PB exposure. Using the PCC assay, reliable dose estimates could be obtained up to 7 days after irradiation. CONCLUSIONS: For dicentrics and MN, shielding of 6% of bone marrow cells was found to be too small to estimate the unirradiated fraction accurately. The PCC technique was useful for dose assessment and the inhomogeneous exposure of 6% was detected within a short period of time after exposure.