Magnetic resonance imaging and image analysis of post - radiation changes of bone marrow in patients with skeletal metastases.

PURPOSE: To evaluate the post-radiation lesions of the bone marrow with magnetic resonance imaging (MRI) and image analysis in patients with bone metastases undergoing radiation therapy (RT). METHODS: Thirty-five patients with bone metastases were studied from June 2008 to December 2010. All patients had osseous metastases from various primary malignancies and underwent palliative RT. MRI was performed in a Philips Gyroscan Intera 1T scanner at the beginning of RT and 12-18 days later. T1-TSE, T2-TSE and short tau inversion recovery (STIR) sequences were used. All images obtained were evaluated for early post-radiation lesions. Additionally, 1st and 2nd order textural features were extracted from these images and were introduced into a probabilistic neural network (PNN) classifier in order to create an automated classification system for those lesions. RESULTS: Changes of signal intensity in T1-TSE, T2-TSE and STIR sequences were evaluated for the presence of edema, fatty conversion of the bone marrow or areas of hemorrhage within the limits of the irradiated area. The automated classification system showed positive results in correctly discriminating the post-radiation lesions that MRI revealed. The overall classification accuracy for discriminating between pre-radiation and post-radiation lesions was 93.2%. Furthermore, the overall classification accuracy for discriminating between post-radiation lesions was 86.67%. CONCLUSION: It seems that MRI can evaluate the degree of early therapy-induced bone marrow lesions observed during the first 18 days from the beginning of RT. The proposed neural network-based classification system might be used as an assisting tool for the characterization of these lesions.

The dawn of Clinical Oncology education in Greece.

Major advances in cancer research, escalating improvements in cancer management and epidemic increase of cancer incidence drive today Clinical Oncology disciplines into most appealing and challenging medical practices. In reflection, medical schools worldwide consider upgrading their curricula on cancer education. In this article we portray the current situation of undergraduate cancer education and professional training in Clinical Oncology in Greece. In this country the need of systemic education in Oncology was early realized by pioneer oncologists two decades ago and since then it gets steadily improving. Today, intra- and extra-curriculum education activities are intense and offer advanced teaching and training opportunities at both undergraduate and postgraduate levels. Medical and Radiation Oncology are two officially recognized specialties of Medicine in Greece and have both contemporary education curricula which are officially portrayed in the establishment acts. Centers accredited as training centers for Clinical Oncology have regular commitments to teaching and develop structured training programs; however, the burden of service commitments and shortage in senior staff compromise in some cases the educational activities. Finally, generous training and research grants offered by National and European scientific bodies provide now advanced educational opportunities to willing young oncologists.

The management of metastatic bone disease with the combination of bisphosphonates and radiotherapy: from theory to clinical practice.

Bone metastases are common in the event of malignancy and are inevitably associated with serious complications that may deteriorate the quality of life (QOL) of patients and threaten life. Both radiotherapy (RT) and bisphosphonates (BPs) have an established role in the management of metastatic bone disease. Many clinical trials have demonstrated their effectiveness when used as sole treatment modalities, but only a few have evaluated their therapeutic value when applied concomitantly. We herein discuss the pathophysiology of bone metastases and the potential interactions between RT and BPs. Moreover, the results of both animal models and clinical studies are presented in detail. Apart from aspects of normal tissue tolerance, other interactions include spatial cooperation and additive or super-additive effects. The latter brings about a synergistic activity that results in an enhanced reossification, improved bone stability and microarchitecture, and increased mechanical strength, as documented through animal model studies. The results of published clinical studies investigating the effectiveness of concomitant application of RT and BPs are promising, reporting a significant clinical and radiologic response. More specifically, a significant reduction of pain scores and a worth noticing improvement in QOL and performance status (PS) were noted, accompanied by a considerable increase in bone density. Pain relief was accompanied by a marked reduction in analgesic opioid need. The enhanced reossification may be responsible for the improved therapeutic response, since it was shown that the correlation between pain and bone density is negative and strong. Although promising and encouraging, the results of such studies should be corroborated by larger, randomized trials.

Simulation studies on the effect of absorbers on dose distribution in rotational radiotherapy.

The effect of cylindrical protector dimensions, material and distance from the source on the dose distribution in rotational radiotherapy was studied to assess the potential protection possibilities of small-sized radiosensitive structures, such as spinal cord. The dose distributions were evaluated in terms of dose at the protected region and surface dose, ratio of the dose at the protected region to the maximum dose, and dose gradient. High-density materials, such as lead, tungsten, gold and cerrobend, along with new polymer-metal composite ones were used in simulation studies, performed by an in-house developed Monte Carlo Radiotherapy Simulator. To ensure correct modeling of the composite materials, simulated attenuation data were verified against experimentally measured data. The dependence of the dose at the protected region from the protector diameter and the field size was established. Protectors of higher density and larger diameter provide not only lower dose at the protected region, but also steeper dose gradient and lower ratio of the dose at the protected region to the treatment dose. For the protection of small structures, high-density protectors placed further from the source allow thicker protectors to be used. The surface dose increases insignificantly for the studied protector-surface distances. The results have shown that shielding properties of composite materials are close to those of lead.

A randomised phase III trial of adjuvant radio-chemotherapy comparing Irinotecan, 5FU and Leucovorin to 5FU and Leucovorin in patients with rectal cancer: a Hellenic Cooperative Oncology Group Study.

The primary objective was to compare the 3-year survival of rectal cancer patients randomised postoperatively to irinotecan (IRI), Leucovorin (LV) and bolus 5-fluorouracil (5FU) or LV-bolus 5FU with radiotherapy. Secondary objectives included disease-free survival, local relapse and toxicity. The study included 321 eligible patients. The treatment consisted of weekly administration of IRI 80 mg/m(2) intravenously (IV), LV 200 mg/m(2) and 5FU 450 mg/m(2) bolus (arm A) versus LV 200 mg/m(2) and 5FU 450 mg/m(2) IV bolus (arm B). One cycle included four infusions and treatment was continued for a total of six cycles. The first cycle was followed by pelvic irradiation plus 5FU. There were no differences between the arms in 3-year overall, disease-free and local relapse-free survival. Grades 3 and 4 toxicity was similar in both the arms with the exception of leucopaenia, neutropaenia and alopecia, which were higher in the IRI arm. IRI added to adjuvant radiochemotherapy with LV and bolus 5FU was not shown to improve survival, whereas the incidence of severe leucopaenia was significantly higher in the IRI arm.

Nitric oxide and the collagenous protein biosynthesis of irradiated chick chorioallantoic membrane.

PURPOSE: To study the effect of irradiation doses (2 Gy and 5 Gy) on the rate of collagenous protein biosynthesis (CPB) of chick embryo chorioallantoic membrane (CAM) and to investigate the possible role of the nitric oxide (NO) synthase inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME), its inactive enantiomer D-NAME and the NO donor sodium nitroprusside (SNP) in this effect. MATERIALS AND METHODS: The originally established CAM angiogenesis model was used with few modifications described earlier. The CAM areas were irradiated on the 10th or the 14th day of embryo development with a single dose of 2 or 5 Gy and the CPB was determined 6 h later. L-NAME, D-NAME and SNP were added to the CAM after the irradiation. RESULTS: The experiments didn't show any significant differences in almost all of the treatment courses. In the 10-day CAM preparations the irradiation not significantly (NS) inhibited the CAM CPB, whereas L-NAME abolished this effect only in the case of 2 Gy dose (NS). The addition of SNP or D-NAME in the post-irradiated 10-day CAM exerted radiosensitization that was significant only in the case of the combination of D-NAME with the 5 Gy dose. There was no significant effect on the respective treatments of the 14-day CAM. The CPB of the 14-day CAM was significantly lower with regard to the values of the 10-day CAM. CONCLUSION: The biochemical evaluation of the CAM (CPB method) seems to be not suitable for radiobiological studies. Nevertheless, the implication of NO in the X-ray induced antiangiogenicity cannot be excluded.

Expression of HIF-1alpha and iNOS in astrocytic gliomas: a clinicopathological study.

BACKGROUND: Hypoxia-inducible-factor-1 (HIF-1) is present at high levels in human tumors and plays a crucial role in tumor promotion by up-regulating several target genes. HIF-1 stimulates the production of NO through the induction of inducible NO synthase (iNOS). PATIENTS AND METHODS: Sixty-three human astrocytic gliomas were analyzed by immunohistochemistry for HIF-1alpha and iNOS using formalin-fixed paraffin-embedded material. In 39 cases, the results of immunohistochemistry were correlated with the clinical outcomes. RESULTS: HIF-1alpha was detected only in astrocytic gliomas grades III and IV, both in the nucleus and in the cytoplasm. The iNOS expression was increased in astrocytic gliomas grades I, II and III and was statistically significantly decreased in astrocytic gliomas grade IV. iNOS was localized round the capillary vessels as well. Statistical analysis showed that the HIF-1alpha and iNOS expressions did not correlate with patient survival. CONCLUSION: We believe that HIF-1alpha and iNOS expressions merit further investigations in order to understand the biology of astrocytic gliomas. More data are needed from prospective studies.

X-rays affect the expression of genes involved in angiogenesis.

BACKGROUND: We have previously shown, using the chicken embryo chorioallantoic membrane (CAM) model of in vivo angiogenesis, that X-rays act on the extracellular matrix and enhance normal and tumor-induced angiogenesis. In the present work, we studied the effect of X-rays on the gene expression of three proteins that are important regulators of angiogenesis: vascular endothelial growth factor (VEGF), heparin affin regulatory peptide (HARP) and inducible nitric oxide synthase (iNOS). MATERIALS AND METHODS: An area of 1 cm2 of the CAM, restricted by a plastic ring was irradiated at room temperature. The expression of the genes was studied using RT-PCR and the amounts of the mRNAs were quantified using image analysis of the corresponding agarose gels of the RT-PCR products. RESULTS: VEGF mRNA was decreased 6 h after irradiation. However, at later time points, VEGF expression was significantly increased compared with the nonirradiated tissue. Similarly, X-rays down-regulated both HARP and iNOS expression 6 h after irradiation and the effect was reversed at later time points, similarly to the effect of X-rays on VEGF. CONCLUSION: These data support the notion that X-rays increase the expression of genes that favor angiogenesis.

X-rays modulate extracellular matrix in vivo.

X-rays have an antiangiogenic effect in the chicken embryo chorioallantoic membrane (CAM) model of in vivo angiogenesis. Our study demonstrates that X-rays induce an early apoptosis of CAM cells, modulate the synthesis and deposition of extracellular matrix (ECM) proteins involved in regulating angiogenesis and affect angiogenesis induced by tumour cells implanted onto the CAM. Apoptosis was evident within 1-2 hr, but not later than 6 hr after irradiation. Fibronectin, laminin, collagen type I, integrin alpha(v)beta3 and MMP-2 protein amounts were all decreased 6 hr after irradiation. In contrast, collagen type IV, which is restricted to basement membrane, was not affected by irradiation of the CAM. There was a similar decrease of gene expression for fibronectin, laminin, collagen type I and MMP-2, 6 hr after irradiation. The levels of mRNA for integrin alpha(v)beta3 and collagen type IV were unaffected up to 24 hr after irradiation. The decrease in both protein and mRNA levels was reversed at later time points and 48 hr after irradiation, there was a significant increase in the expression of all the genes studied. When C6 glioma tumour cells were implanted on irradiated CAMs, there was a significant increase in the angiogenesis induced by tumour cells, compared to that in non-irradiated CAMs. Therefore, although X-rays have an initial inhibitory effect on angiogenesis, their action on the ECM enhances new vessel formation induced by glioma cells implanted on the tissue.

Randomized comparison of early versus late hyperfractionated thoracic irradiation concurrently with chemotherapy in limited disease small-cell lung cancer: a randomized phase II study of the Hellenic Cooperative Oncology Group (HeCOG).

BACKGROUND: Concurrent platinum etoposide chemotherapy given in combination with hyperfractionated thoracic radiation therapy (HTRT) in limited disease (LD) small cell lung cancer (SCLC) is associated with a high response rate and significant prolongation of survival. Given these results, the Hellenic Cooperative Oncology Group (HeCOG) performed a multicenter randomized phase II study in patients with LD SCLC to evaluate the timing of HTRT (early vs. late) when given concurrently with chemotherapy. PATIENTS AND METHODS: To be eligible for the study, patients were required to have histologically or cytologically proven LD SCLC, confined to one hemithorax and/or ipsilateral mediastinal or supraclavicular lymphnodes and absence of pleural effusion or controlateral supraclavicular lymphnode involvement. Moreover, patients had to have a good performance status and adequate haematological, liver and renal function. Patients with LD SCLC were randomized to receive HTRT either concurrently with the first (Group A) or with the fourth (Group B) cycle of chemotherapy. Chemotherapy consisted of carboplatin administered at an AUC of six given as an i.v. 1-hour-infusion immediately followed by etoposide at a dose of 100 mg/m2 i.v. as a two-hour infusion for three consecutive days every three weeks up to a total of six cycles. Prophylactic cranial irradiation was also given to patients achieving a complete response. RESULTS: 42 and 39 patients, were eligible for efficacy evaluation in group A and B respectively. The overall response rate was 76% in group A and 92.5% in group B (P = 0.07) with a complete response rate of 40.5% and 56.5%, respectively. After a median follow-up of 35 months, time to progression was 9.5 months in group A and 10.5 in group B (NS) while overall median survival was 17.5 and 17 months respectively (NS). The 2-year survival was 36% in group A and 29% in group B (NS) and the 3-year survival 22% and 13%, respectively (NS). The distant relapse rate was 38% in group A and 61% in group B (P = 0.046). Severe grade 3 4 anemia was recorded in 19% of group A and 12.5% of group B (NS), while severe leucopenia was recorded in 35.5% and 20.5% (P = 0.09) and neutropenic fever in 5% and 2.5% (NS), respectively. Severe thrombocytopenia did not differ significantly between the two treatment groups being 21.5% and 23%, respectively. Severe grade 2-3 esophageal toxicity was 19% in group A and 23% in group B (NS), while grade 3 lung toxicity was 5% and 7.5% (NS), respectively. No toxicity-related deaths were recorded. CONCLUSION: Concurrent administration of HTRT with carboplatin etoposide is associated with a high response and survival rate. Although a trend for higher response rate was recorded in the group of patients who received late HTRT, the overall median, 2-year and 3-year survival rates did not differ significantly between the two treatment groups. The toxicity of this promising therapeutic approach was acceptable. Comparative phase III studies with an adequate number of patients are recommended in order to answer this question.

bcl-2/bax ratio as a predictive marker for therapeutic response to radiotherapy in patients with rectal cancer.

Combined radiation therapy and chemotherapy are adjuvant treatments given after surgery to patients with rectal carcinoma. Because apoptosis seems to play a role in tumor response to radiotherapy, the current study investigates whether there is a correlation between the ratio of bcl-2 oncoprotein and bax expression in rectal adenocarcinoma and the clinical response to radiotherapy. Elective colectomy for primary rectal adenocarcinoma followed by adjuvant radiotherapy and chemotherapy was performed on 35 patients. Tumors were staged as B2 (n = 30) and C (n = 5), and were classified as radiation resistant (n = 19, group A) and radiation nonresistant (n = 16, group B). Immunohistochemical study, using the streptavidin-biotin complex technique and monoclonal antibody to bcl-2 and polyclonal antibody to bax protein was used on paraffin sections. Cases were considered positive if at least 5% of tumor cells displayed cytoplasmic staining for bcl-2 or bax. In each tumor, the bcl-2/bax ratio was calculated dividing the percentage of bcl-2-positive cells by the percentage of bax-positive cells. For statistical analysis, the Mann-Whitney rank sum test and Kruskal-Wallis analysis of variance test were used. Rectal tumors of group A displayed significantly greater bcl-2 immunoreactivity (40.2 +/- 4.2) compared with group B (20.2 +/- 3.8). In contrast, expression of bax protein was less in group A (30.3 +/- 3.3) compared with group B (41.3 +/- 2.3). The bcl-2/bax ratio was greater in group A (1.3 +/- 0.1) compared with group B (0.49 +/- 0.1), and was correlated with poor responsiveness to radiotherapy. The current study indicates that in patients with rectal carcinoma an elevated bcl-2/bax ratio in tissue specimens suggests increased tumor resistance to adjuvant radiotherapy. Thus, in such patients, the bcl-2/bax ratio may serve as a potential molecular marker for prediction of tumor prognosis.

Impact of cancer on primary caregivers of patients receiving radiation therapy.

The main objective of this study was to assess the consequences of caregiving on primary caregivers of Greek cancer patients receiving radiotherapy. Sixty-five caregivers participated in the study and data were collected through structured interviews. Our results pointed to a lack of association concerning extent of patients' disease, treatment schedule, performance status or awareness of diagnosis. However, female caregivers with low qualifications, partners, and those living with the patient were more likely to report heightened symptoms of anxiety and depression, severe impact of caregiving on their lives, poor health and low quality of life. In addition, it was shown through multivariate analyses that psychological distress was the sole predictor of overall health and global quality of life. In conclusion, Greek caregivers are to a great extent affected by the disease. Caring for significant others is essential to promoting quality of life for the family and the patient.

An integrated system for the production of field shaping devices in radiotherapy.

A system has been developed in our department that simplifies the production processes of field shaping devices in radiotherapy, integrating an image grabbing and processing facility at a radiotherapy simulator and an automated block cutter. The data acquisition subsystem captures images, processes and corrects them for pincushion distortions, creates a composite radiograph, records user defined contours of blocks and exports data to the block cutter controller. A robotic subsystem drives and controls the polystyrene cutting unit. The system has been experimentally evaluated. Errors in contour definition were found to be less than 1 mm for a broad range of gantry angles and not exceeding 1.5 mm for those gantry orientations that present maximum magnetic field related image intensifier distortion, while the automated block cutter is capable of cutting out contours in polystyrene with an accuracy comparable to that of commercially available systems. The system is expected to contribute to the overall improvement of radiotherapy processes, particularly in low budget radiotherapy departments, introducing improvements in accuracy and efficiency at minimum costs.

Management of non resectable malignant esophageal stricture and fistula.

OBJECTIVE: The palliation of dysphagia caused by esophageal carcinoma and other inoperable tumours obstructing the esophagus presents a challenge for the thoracic surgeon, in particularly when associated with fistula (F). In a prospective study over the last 5 years, we have evaluated the effectiveness of different approaches and types of prostheses to solve the above problem. METHOD: Thirty three patients (mean age: 63.5 years, range 42-76, M/F:24/9) with inoperable tumours obstructing the esophagus underwent intubation and/or palliative surgery according to the following protocol: (1) Preoperative esophagography; (2) endoscopy and biopsy; (3) dilatation and insertion of prosthesis usually under general anaesthesia; and (4) re-evaluation the following day, in 30 days and as required thereafter. Prosthesis used were: Atkinson 3, Wilson-Cook (plain) 12, Wilson-Cook (cuffed) 4, Strecker (metallic self-expandable) 13. The patients were divided in three groups according to the extension of the disease: group A (n = 19) plain malignant strictures, group B (n = 5) strictures with respiratory Fs, group C (n = 9) strictures with mediastinal or pleural Fs. RESULTS: All patients of group A had successful palliation irrespectively of prosthesis used and site of obstruction. One patient required two stents. There was no death and 50% survival at 6 months was 70%. In group B, a cuffed prosthesis successfully closed two bronchoesophageal Fs, while three patients underwent retrosternal bypass surgery. There was one death on the 26th postoperative day. In group C, one Strecker, two plain Wilson-Cook and two cuffed Wilson-Cook stents, although initially succeeded, in due course, failed to block the Fs in five patients who subsequently underwent bypass surgery with one death. With four patients both leak and dysphagia were significantly improved with the use of self-expandable stents therefore, not requiring surgery. Overall, there were two deaths but no failure in palliating dysphagia. Longer survival was 20 months. Patients with fistulae had poorer prognosis as compared to those suffering from plain malignant stricture (P = 0.01). CONCLUSIONS: Plain malignant inoperable oesophageal strictures can be successfully palliated with intubation. Complicated with fistula strictures, however, are difficult to manage and have a poor prognosis. Due to the fact that bypass surgery is associated with an increased mortality, it should be kept for those with late stent failures and fistula recurrences.