Many patients with metastatic spinal cord compression (MSCC) live long enough to develop a recurrence in the irradiated spinal area. This is the first prospective study that has compared local ...control of different radiotherapy schedules for MSCC.
A total of 265 patients treated with radiotherapy alone were included in this prospective nonrandomized study. The primary goal was to compare local control from short-course (1 × 8 Gy/5 × 4 Gy, n = 131) and long-course radiotherapy (10 × 3 Gy/15 × 2.5 Gy/20 × 2 Gy, n = 134). Secondary end points were motor function and survival. The analysis of local control (no MSCC recurrence in the irradiated spinal area) included the 224 patients with improvement or no change of motor deficits during radiotherapy. Eleven additional factors were evaluated for outcomes.
One-year local control was 61% after short-course and 81% after long-course radiotherapy (p = 0.005). On multivariate analysis (MVA), improved local control was associated with long-course radiotherapy (p = 0.018). Motor function improved in 37% after short-course and 39% after long-course radiotherapy (p = 0.95). Improved motor function was associated with better performance status (p = 0.015), favorable tumor type (p = 0.034), and slower development of motor deficits (p < 0.001). One-year survival rates were 23% after short-course and 30% after long-course radiotherapy (p = 0.28). On MVA, improved survival was associated with better performance status (p < 0.001), no visceral metastases (p < 0.001), involvement of only one to three vertebrae (p = 0.040), ambulatory status (p = 0.038), and bisphosphonate administration after radiotherapy (p < 0.001).
Long-course radiotherapy was associated with better local control, similar functional outcome, and similar survival compared to short-course radiotherapy. Patients with a relatively favorable expected survival should receive long-course radiotherapy.
The relevance of angiogenesis inhibition in the treatment of glioblastoma multiforme (GBM) should be considered in the unique context of malignant brain tumours. Although patients benefit greatly ...from reduced cerebral oedema and intracranial pressure, this important clinical improvement on its own may not be considered as an anti-tumour effect.
GBM can be roughly separated into an angiogenic component, and an invasive or migratory component. Although this latter component seems inert to anti-angiogenic therapy, it is of major importance for disease progression and survival. We reviewed all relevant literature. Published data support that clinical symptoms are tempered by anti-angiogenic treatment, but that tumour invasion continues. Unfortunately, current imaging modalities are affected by anti-angiogenic treatment too, making it even harder to define tumour margins. To illustrate this we present MRI, biopsy and autopsy specimens from bevacizumab-treated patients.Moreover, while treatment of other tumour types may be improved by combining chemotherapy with anti-angiogenic drugs, inhibiting angiogenesis in GBM may antagonise the efficacy of chemotherapeutic drugs by normalising the blood-brain barrier function.
Although angiogenesis inhibition is of considerable value for symptom reduction in GBM patients, lack of proof of a true anti-tumour effect raises concerns about the place of this type of therapy in the treatment of GBM.
To assess long-term functional outcome and survival among patients with meningioma World Health Organization (WHO) grade I.
Retrospective analysis of 205 patients after resection of WHO grade I ...intracranial meningioma from 1985 through 2003. Expected age- and sex-specific survival was calculated by applying Dutch life-table statistics to each patient for the individual duration of follow-up. Long-term functional outcome was assessed using a mailed questionnaire to the general practitioner.
The mean duration of follow-up was 11.5 years. Survival at 5, 10, 15, and 20 years was 92%, 81%, 63%, and 53%, respectively, which is significantly lower than the expected survival (94%, 86%, 78%, and 66%, respectively). Survival was worse with higher age (P < .001). Survival among patients younger than 45 years and older than 65 years was comparable to the expected survival but significantly worse among patients aged 45-65 years. Analysis of the cause of death suggests an excess mortality associated with both brain tumor death and stroke (P = .07). Recurrence rates at 5, 10, and 15 years were 18%, 26%, and 32%, respectively. Higher Simpson grade (P < .001) and lower age (P = .02) were associated with a higher recurrence rate. In 29 patients (14%) receiving radiotherapy, the 5-year recurrence rate was 18% and the 5-year survival was only 58%. Long-term functioning (≥ 5 years after last treatment) could be assessed in 89 long-term survivors: 29 patients (33%) showed no deficits, and 60 (67%) showed at least 1 neurological symptom, of whom 24 (27%) were unable to perform normal daily activities.
Long-term survival in WHO grade I meningioma is challenged in patients more than 45 years of age. Excess mortality seems to be associated with both tumor recurrence and stroke. The majority of patients have long-term neurological problems.
Hyperthermia treatment planning (HTP) is valuable to optimize tumor heating during thermal therapy delivery. Yet, clinical hyperthermia treatment plans lack quantitative accuracy due to uncertainties ...in tissue properties and modeling, and report tumor absorbed power and temperature distributions which cannot be linked directly to treatment outcome. Over the last decade, considerable progress has been made to address these inaccuracies and therefore improve the reliability of hyperthermia treatment planning. Patient-specific electrical tissue conductivity derived from MR measurements has been introduced to accurately model the power deposition in the patient. Thermodynamic fluid modeling has been developed to account for the convective heat transport in fluids such as urine in the bladder. Moreover, discrete vasculature trees have been included in thermal models to account for the impact of thermally significant large blood vessels. Computationally efficient optimization strategies based on SAR and temperature distributions have been established to calculate the phase-amplitude settings that provide the best tumor thermal dose while avoiding hot spots in normal tissue. Finally, biological modeling has been developed to quantify the hyperthermic radiosensitization effect in terms of equivalent radiation dose of the combined radiotherapy and hyperthermia treatment. In this paper, we review the present status of these developments and illustrate the most relevant advanced elements within a single treatment planning example of a cervical cancer patient. The resulting advanced HTP workflow paves the way for a clinically feasible and more reliable patient-specific hyperthermia treatment planning.
Human papillomavirus (HPV) is associated with cervical cancer, the third most common cancer in women. The high-risk HPV types 16 and 18 are found in over 70% of cervical cancers and produce the ...oncoprotein, early protein 6 (E6), which binds to p53 and mediates its ubiquitination and degradation. Targeting E6 has been shown to be a promising treatment option to eliminate HPV-positive tumor cells. In addition, combined hyperthermia with radiation is a very effective treatment strategy for cervical cancer. In this study, we examined the effect of hyperthermia on HPV-positive cells using cervical cancer cell lines infected with HPV 16 and 18, in vivo tumor models, and ex vivo-treated patient biopsies. Strikingly, we demonstrate that a clinically relevant hyperthermia temperature of 42 °C for 1 hour resulted in E6 degradation, thereby preventing the formation of the E6-p53 complex and enabling p53-dependent apoptosis and G2-phase arrest. Moreover, hyperthermia combined with p53 depletion restored both the cell-cycle distribution and apoptosis to control levels. Collectively, our findings provide new insights into the treatment of HPV-positive cervical cancer and suggest that hyperthermia therapy could improve patient outcomes.
Radiation is an effective anti-cancer therapy but leads to severe late radiation toxicity in 5%-10% of patients. Assuming that genetic susceptibility impacts this risk, we hypothesized that the ...cellular response of normal tissue to X-rays could discriminate patients with and without late radiation toxicity.
Prostate carcinoma patients without evidence of cancer 2 y after curative radiotherapy were recruited in the study. Blood samples of 21 patients with severe late complications from radiation and 17 patients without symptoms were collected. Stimulated peripheral lymphocytes were mock-irradiated or irradiated with 2-Gy X-rays. The 24-h radiation response was analyzed by gene expression profiling and used for classification. Classification was performed either on the expression of separate genes or, to augment the classification power, on gene sets consisting of genes grouped together based on function or cellular colocalization.X-ray irradiation altered the expression of radio-responsive genes in both groups. This response was variable across individuals, and the expression of the most significant radio-responsive genes was unlinked to radiation toxicity. The classifier based on the radiation response of separate genes correctly classified 63% of the patients. The classifier based on affected gene sets improved correct classification to 86%, although on the individual level only 21/38 (55%) patients were classified with high certainty. The majority of the discriminative genes and gene sets belonged to the ubiquitin, apoptosis, and stress signaling networks. The apoptotic response appeared more pronounced in patients that did not develop toxicity. In an independent set of 12 patients, the toxicity status of eight was predicted correctly by the gene set classifier.
Gene expression profiling succeeded to some extent in discriminating groups of patients with and without severe late radiotherapy toxicity. Moreover, the discriminative power was enhanced by assessment of functionally or structurally related gene sets. While prediction of individual response requires improvement, this study is a step forward in predicting susceptibility to late radiation toxicity.
Glioblastoma multiforme (GBM) is the most common, invasive and deadly primary type of malignant brain tumor. The Phosphatidylinositol-3-Kinase/AKT (PI3K/AKT) pathway is highly active in GBM and has ...been associated with increased survival and resistance to therapy. The aim of this study is to investigate the effects of AKT inhibition in combination with the current standard of care which consists of irradiation and temozolomide (TMZ) on human malignant glioma cells growing adherent and as multicellular spheroids in vitro.
The effects of the allosteric inhibitor MK2206 combined with irradiation and TMZ were assessed on glioma cells growing adherent and as multicellular 3D spheroids. The interaction was studied on proliferation, clonogenic cell survival, cell invasion, -migration and on expression of key proteins in the PI3K-AKT pathway by western blot.
A differential effect was found at low- (1 μM) and high dose (10 μM) MK2206. At 1 μM, the inhibitor reduced phosphorylation of Thr308 and Ser473 residues of AKT in both adherent cells and spheroids. Low dose MK2206 delayed spheroid growth and sensitized spheroids to both irradiation and TMZ in a synergistic way (Combination index <0.35). In contrast, neither low nor high dose MK2206 did enhance therapy sensitivity in adherent growing cells. Effective inhibition of invasion and migration was observed only at higher doses of MK2206 (>5 μM).
The data show that a 3D spheroid model show different sensitivity to irradiation when combined with AKT inhibition. Thereby we show that MK2206 has potential synergistic efficacy to the current standard of care for glioma patients.
Electric properties tomography (EPT) is an imaging modality to reconstruct the electric conductivity and permittivity inside the human body based on B 1 + maps acquired by a magnetic resonance ...imaging (MRI) system. Current implementations of EPT are based on the local Maxwell equations and assume piecewise constant media. The accuracy of the reconstructed maps may therefore be sensitive to noise and reconstruction errors occur near tissue boundaries. In this paper, we introduce a multiplicative regularized CSI-EPT method (contrast source inversion-electric properties tomography) where the electric tissue properties are retrieved in an iterative fashion based on a contrast source inversion approach. The method takes the integral representations for the electromagnetic field as a starting point and the tissue parameters are obtained by iteratively minimizing an objective function which measures the discrepancy between measured and modeled data and the discrepancy in satisfying a consistency equation known as the object equation. Furthermore, the objective function consists of a multiplicative Total Variation factor for noise suppression during the reconstruction process. Finally, the presented implementation is able to simultaneously include more than one B 1 + data set acquired by complementary RF excitation settings. We have performed in vivo simulations using a female pelvis model to compute the B 1 + fields. Three different RF excitation settings were used to acquire complementary B 1 + fields for an improved overall reconstruction. Numerical results illustrate the improved reconstruction near tissue boundaries and the ability of CSI-EPT to reconstruct small tissue structures.
Correct identification of patients with lymph node metastasis from cervical cancer prior to treatment is of great importance, because it allows more tailored therapy. Patients may be spared ...unnecessary surgery or extended field radiotherapy if the nodal status can be predicted correctly. This review captures the existing knowledge on the identification of lymph node metastases in cervical cancer. The risk of nodal metastases increases per 2009 FIGO stage, with incidences in the pelvic region ranging from 2% (stage IA2) to 14–36% (IB), 38–51% (IIA) and 47% (IIB); and in the para-aortic region ranging from 2 to 5% (stage IB), 10–20% (IIA), 9% (IIB), 13–30% (III) and 50% (IV). In addition, age, tumor size, lymph vascular space invasion, parametrial invasion, depth of stromal invasion, histological type, and histological grade are reported to be independent prognostic factors for the risk of nodal metastases. Furthermore, biomarkers can contribute to predict a patient’s nodal status, of which the squamous cell carcinoma antigen (SCC-Ag) is currently the most widely used in squamous cell cervical cancer. Still, pre-treatment lymph node assessment is primarily performed by imaging, of which diffusion-weighted magnetic resonance imaging has the highest sensitivity and 2-deoxy-2-
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Ffluoro-D-glucose positron emission computed tomography the highest specificity. Imaging results can be combined with clinical parameters in nomograms to increase the accuracy of predicting positives nodes. Despite all the progress regarding pre-treatment prediction of lymph node metastases in cervical cancer in recent years, prediction rates are not robust enough to safely abandon surgical staging of the pelvic or para-aortic region yet.
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