Feasibility of reducing the irradiation dose in regions of active neurogenesis for prophylactic cranial irradiation in patients with small-cell lung cancer.

Prophylactic cranial irradiation (PCI) is performed on patients with limited or extensive small-cell lung cancer to reduce incidence of brain metastases and prolong survival. PCI may induce neurocognitive impairment. Decreasing irradiation of neural stem cells (NSC) might reduce PCI-induced toxicity. We tested the feasibility of reducing irradiation doses to neural stem cell (NSC) regions while maintaining prescribed doses to the planned target volume (PTV). Irradiation plans utilizing intensity-modulated radiotherapy (IMRT), helical TomoTherapy, and RapidArc for 10 consecutive lung cancer patients were evaluated. The dose distribution, dose-volume histograms, and dose homogeneity indexes were analyzed. Planned and actual dose distributions were compared by dosimetric analysis. Both helical tomotherapy and LINAC-based IMRT reduced the radiation dose to the NSC regions by approximately 45% while maintaining the full dose to the rest of brain. Measured dose distributions matched the planned dose distributions.Protecting the regions of active neurogenesis is technically feasible. Whether reducing the dose by 35% to 45% is sufficient to reduce treatment toxicity, however, can only be addressed in a randomized study. Further reducing the dose within the NSC region might also significantly decrease the dosage to the PTV.

Optimizing of MALDI-ToF-based low-molecular-weight serum proteome pattern analysis in detection of breast cancer patients; the effect of albumin removal on classification performance.

Mass spectrometry-based analysis of the serum proteome allows identifying multi-peptide patterns/signatures specific for blood of cancer patients, thus having high potential value for cancer diagnostics. However, because of problems with optimization and standardization of experimental and computational design, none of identified proteome patterns/signatures was approved for diagnostics in clinical practice as yet. Here we compared two methods of serum sample preparation for mass spectrometry-based proteome pattern analysis aimed to identify biomarkers that could be used in early detection of breast cancer patients. Blood samples were collected in a group of 92 patients diagnosed at early (I and II) stages of the disease before the start of therapy, and in a group of age-matched healthy controls (104 women). Serum specimens were purified and analyzed using MALDI-ToF spectrometry, either directly or after membrane filtration (50 kDa cut-off) to remove albumin and other large serum proteins. Mass spectra of the low-molecular-weight fraction (2-10 kDa) of the serum proteome were resolved using the Gaussian mixture decomposition, and identified spectral components were used to build classifiers that differentiated samples from breast cancer patients and healthy persons. Mass spectra of complete serum and membrane-filtered albumin-depleted samples have apparently different structure and peaks specific for both types of samples could be identified. The optimal classifier built for the complete serum specimens consisted of 8 spectral components, and had 81% specificity and 72% sensitivity, while that built for the membrane-filtered samples consisted of 4 components, and had 80% specificity and 81% sensitivity. We concluded that pre-processing of samples to remove albumin might be recommended before MALDI-ToF mass spectrometric analysis of the low-molecular-weight components of human serum Keywords: albumin removal; breast cancer; clinical proteomics; mass spectrometry; pattern analysis; serum proteome.

Late dissemination via cerebrospinal fluid of papillary tumor of the pineal region: a case report and literature review.

Papillary tumor of the pineal region (PTPR) represents a recently described entity and was included in the 2007 World Health Organization (WHO) classification of central nervous system tumors. The biological and clinical behavior of PTPR is variable and may correspond to WHO grades II or III. Papillary tumor of the pineal region can show aggressive biological behavior with local relapses and dissemination via the cerebrospinal fluid. Several cases of PTPR with leptomeningeal seeding and multiple lesions or spinal metastasis have been reported. We present an unusual clinical history of papillary tumor of the pineal region with ventricular and spinal dissemination five years after primary surgical treatment.

Split-course accelerated hyperfractionation (CHA-CHA) for advanced head and neck cancers -- preliminary results.

The purpose of the study was to evaluate toxicity and effectiveness of the split course, accelerated hyperfractionation with a planned gap (CHA-CHA) on a base of the pilot group treatment results. The material consisted of 27 patients with advanced (T2N2c-3, T3-4N2), oral cavity, oro- hypopharynx and larynx cancers, irradiated with a df 1.6 Gy twice a day, with 6-hour gap, up to TD 64 Gy in 28 days, with 8-day gap in a middle. Mean tumor dimensions were 4.2 and 3.9 cm in X and Y axes, respectively and mean nodes dimensions 3.9 cm in both axes. The course and intensity of the mucositis were evaluated in the Dische scale together with the degree of a tumor and nodes regression. Survival analysis and dependencies evaluation between physical/biological factors and treatment results were performed. The mucositis intensity was high from 2nd to 5th week (the highest mean - 15 Dische points in 4th week), but on acceptable level. 54.5% of CR of the tumor and 57.1% of nodes were noted. Survival analysis showed 44% of a 2-year and 35% of a 4-year OS and 44% of a 2-year and 38% of a 4-year survival excluding deaths from distant metastases. Correlation between the hemoglobin level and the nodal regression two months after the radiotherapy (p=0.01), showed the tumor diameter and TCP (p=0.047), the OS and the nodes diameter (p=0.004), the PS (p=0.02) and the hemoglobin level (p=0.04). CHA-CHA could be a valid method in advanced head and neck cancer treatment but its efficacy should be confirmed in randomized phase of trial.

Selective augmentation of radiation effects by 5-fluorocytosine on murine B16(F10) melanoma cells transfected with cytosine deaminase gene.

We report that in vitro 5-fluorocytosine sensitizes B16(F10) melanoma cells to radiation damage when they are transfected with cytosine deaminase gene (CD). The greatest enhancement of radiation cytotoxicity was observed when B16(F10)/CD cells were incubated in medium with 500 microM 5-fluorocytosine for 3 hours, with incubation starting 1 hour after irradiation. 5-Fluorocytosine did not change radiosensitivity of parental, nontransfected cells. The isoeffective dose for CD-transfected cells treated with 5-fluorocytosine was reduced by 20% at a 2-Gy level of effect for nontransfected cells. We believe that the observed outcome is related to 5-fluorouracil generated by CD and subsequent 5-fluorouracil anabolites. Our results support the development of in vivo models for tumor radiosensitization using the CD gene/5-fluorocytosine system.

Changes in elastin in human atherosclerotic aorta: carbon-13 magic angle sample-spinning NMR studies.

The dipolar-decoupled, natural abundance Fourier transform and cross polarization [13C] NMR spectra of human elastin isolated from atherosclerotic aorta and aortas free of atherosclerotic lesions, bovine insoluble elastin and bovine kappa-elastin were obtained at 75 MHz, with 5-7 kHz magic angle sample spinning. Spin-lattice rotating frame relaxation parameters were measured for protons (T1pH) and for carbons (T1pC) at room temperature. Proton relaxation times were shorter for bovine kappa-elastin (T1pH = 1.7 ms) than for bovine elastin (T1pH) = 3.5 ms). Calculation of T1pH showed no differences between human normal and atherosclerotic elastins. T1pC were shorter for bovine kappa-elastin than for bovine elastin. While alpha-carbons of human atherosclerotic elastin had shorter T1pC than normal elastin alpha carbons, carbons from hydrophobic amino acid side chains had longer T1pC for atherosclerotic then for normal elastin. Biochemical studies of aortic wall and purified elastin showed significantly increased content of lipids (atherosclerotic 67.7 mmol/g elastin, control 54.7 mmol/g elastin) and calcium (atherosclerotic 38.3 mmol/g elastin, control 19.6 mmol/g elastin). Changes in relaxation parameter values may be caused by the structural and biochemical changes in human elastin. Increased mobility of polypeptide chains as based on the model kappa-elastin studies is caused by the action of elastase. Restriction of mobility is expected to be caused by the accumulation of lipids and calcium.

Prognostic value of hemoglobin concentration in radiotherapy for cancer of supraglottic larynx.

PURPOSE: The aim of this work is the estimation of correlations between hemoglobin concentration either before or after radiotherapy and local tumor control probability for laryngeal cancer. METHODS AND MATERIALS: Retrospective analysis of 847 cases of laryngeal supraglottic squamous cell carcinoma treated with radiation alone was performed using maximum likelihood estimations, and step-wise logistic regression. All patients were in good initial performance status (Karnofsky index >70). The minimum follow-up time was 3 years. RESULTS: Logistic regression showed that the hemoglobin concentration after radiotherapy is an important prognostic factor. There was a very strong correlation between hemoglobin concentration and tumor local control probability. Hemoglobin concentration at the beginning of radiotherapy does not correlate with treatment outcome, but any decrease of hemoglobin during therapy is a strong prognostic factor for treatment failure. CONCLUSIONS: Although regression models with many variables may be instable, the present results suggest that hemoglobin concentration after treatment is at least as important as overall treatment time. It was not possible to find out whether the low concentration of hemoglobin is an independent cause of low TCP or whether it reflects other mechanisms that may influence both hemoglobin level and the TCP.

Clinical radiobiology of glottic T1 squamous cell carcinoma.

PURPOSE: Radiation therapy is the treatment of choice for early glottic squamous cell cancer in many institutions over the world. Despite a relatively homogenous clinical model of T1 glottic tumors for the fractionation studies, the relationships between dose-time parameters remain unclear. To analyze the influence of fractionation parameters and hemoglobin level on tumor cure, this study has been performed. MATERIALS AND METHODS: This is a retrospective review of 235 patients with T1N0M0 glottic cancer treated by radiation therapy alone given in a conventional schedule with 5 fractions each week. The individual total dose, dose per fraction, and overall treatment time (OTT) ranged from 51-70 Gy, 1.5-3.0 Gy, and 24-79 days, respectively. The median follow-up was 48 months. Patient data--total dose, dose per fraction, OTT, and hemoglobin level (Hb) measured before the radiation treatment--were fitted by the mixed LQ/log-logistic model. RESULTS: The 5-year local relapse-free survival rate was 84%. All parameters included in the mixed LQ/log-logistic model improved the fit significantly. The dose-response curve for 235 patients with T1 glottic cancer was well defined and steep, and showed significant decrease in tumor control probability (TCP) when total doses were below 61 Gy. The 10-day prolongation of OTT, from 45 to 55 days, decreased the TCP by 13%. The dose of 0.35 Gy/day, compensated repopulation during the 1 day of prolongation, which indicates a potential doubling time (Tpot) for glottic T1 tumor clonogens of 5.5 days. The drop of Hb level of 1 g/dl (from 13.8 g/dl to 12.8 g/dl) gave a 6% decrease of TCP, provided that OTT was 45 days. CONCLUSION: The significant correlation between the total dose, overall treatment time, hemoglobin concentration, and tumor control probability has been found for T1 glottic cancer.

The radiosensitivity of recurrent clones of an irradiated murine squamous cell carcinoma in the in vitro megacolony system.

PURPOSE: To measure changes in spontaneous growth rate and radiation response in the progeny of irradiated squamous cell carcinoma cells. MATERIALS AND METHODS: Murine SCC cells of the line AT478 were grown as epithelial megacolonies in vitro, using both the original line and two subsequent passages derived from a clone that had recurred after a high radiation dose. Radiosensitivity was evaluated in terms of local control following single dose irradiation of standard size megacolonies (0.8 cm2). In addition, original megacolonies were given a priming dose of 20 Gy and the recurrent clones arising in situ were retreated at three dose levels for analysis of curability. RESULTS: A marked increase in radiosensitivity was observed in the megacolonies grown from irradiated progeny as compared to original megacolonies, reflected in a shift of the TCD50 from 24.5 to 16.5 Gy. Direct parameter estimation from the cure data suggested that the underlying change was a lowered number of clonogenic 'stem' cells rather than increased cellular sensitivity. A similar decrease in clonogen density was also apparent for the recurrent clones in situ. The change in megacolony curability was paralleled by a substantial growth retardation. CONCLUSION: The data demonstrate persistent changes in the progeny of irradiated SCC tumour cells that affect both growth and radiosensitivity and are compatible with the expression of delayed reproductive death.

Randomized clinical trial on 7-day-continuous accelerated irradiation (CAIR) of head and neck cancer - report on 3-year tumour control and normal tissue toxicity.

PURPOSE: To evaluate tumour and normal tissues 3-year response to 7-day-a-week continuous accelerated irradiation (CAIR) compared to a conventional treatment (5 days per week) in a randomized trial. MATERIALS AND METHODS: One hundred patients with squamous cell carcinoma of the head and neck in stage T(2-4)N(0-1)M(0) were entered into the trial between December 1, 1993 and June 30, 1996. Dose per fraction of 2.0 Gy (to the end of 1994), and 1.8 Gy (since January 1, 1995) was the same in both arms and delivered once a day at regular 24-h intervals to total dose in the range of 66-72 Gy (depending on tumour stage). The only difference was overall treatment time being 5 weeks in the CAIR and 7 weeks in control arm. RESULTS: Actuarial 3-year local tumour control was 82% in the CAIR and 37% in the control group (P<0.0001) with reduction in local recurrence rate of 83%. Actuarial 3-year overall survival was 78 and 32% (P<0.0001), respectively. Confluent mucositis was significantly more severe and lasted longer in the CAIR than in control arm. After 2.0 Gy fractions five of 23 patients (22%) in the CAIR developed early necroses over a period of 2-4 months of follow-up which can be considered as a consequential to severe protracted acute mucosal reactions (CLE). For this reason dose per fraction was lowered to 1. 8 Gy and the CLE was not observed again until now. Thus the overall rate of CLE decreased to 10%. CONCLUSIONS: The gain in tumour control is likely the effect of shortening of overall treatment time by 14 days and regular continuous dose delivery during the whole course of radiation therapy including weekends. A 7-day schedule produces more severe acute mucosal reactions lasting longer than in conventional fractionation, however tolerable by patients. Relatively high rate (22%) of CLE in the 7-day arm observed during the first year of the study was eliminated by decreasing dose per fraction from 2.0 Gy to 1.8 Gy.

Changes of certain pharmacological and biochemical indices in acute methylglyoxal poisoning.

Methylglyoxal in doses over 25 mg/kg injected intravenously in cats and rabbits produces distinct changes in the cardiovascular and respiratory systems, but has no effect on respiration or circulation when injected intraperitoneally even in doses up to 1 g/kg. The effect of MG on blood pressure depends on the species of the animal. The effects of MG are dose-related and dependent on the route of its administration. Biochemical studies showed a significant rise in serum activities of creatine kinase (EC 2-7-3-2), lactate dehydrogenase (EC 1-1-1-27) and aspartate aminotransferase (EC 2-6-1-1-) after intraperitoneal injection of MG in the dose of 200 mg/kg in rabbits and 500 mg/kg in rats. The observed changes probably indicate damage of muscle tissue by MG, presumably as a result of low content of one of the glyoxalases in the muscles of the experimental animals. Elevation of glucose levels by MG was probably an adrenergic effect. These biochemical changes can serve to evaluate toxicity of MG preparations, which exhibit variations probably owing to varying degree of polymerization.

Role of short TE 1H-MR spectroscopy in monitoring of post-operation irradiated patients.

Post-surgical radiation therapy is a routine procedure in the treatment of primary malignant brain tumors. Along with modest therapeutic effects conventional fractionated radiotherapy, in spite of any modifications, produces damage to non-malignant brain tissues lying within the treatment volume, the extent of which depends on radiation dose. Serial 1H-MRS allows non-invasive investigation of tissue metabolic profiles. In the present study the ratios of resonance signals assigned to the major 1H-MRS-visible metabolites (N-acetylaspartate, choline, creatine, inositol, lactate and lipid methylene group) were evaluated before, during and after post-surgical fractionated radiotherapy in brain regions close to and more distant from the tumor bed, receiving different radiation exposures (60 and < 40 Gy, respectively). The study group consisted of ten patients (aged 28-51). A MRI/MRS system (Elscint 2T Prestige) operating at the field strength of 2 T and the proton resonance frequency of 81.3 MHz has been used and the 1H-MR spectra were acquired using single voxel double-spin-echo PRESS sequence with a short TE. The spectra were post-processed with automatic fitting in the frequency domain. It was found that although the metabolite profiles depend on the dose obtained, but other stress factors (like surgery) seem to contribute to the overall picture of the metabolic status of the brain as well. In studies of early irradiation injuries, an increase of choline related ratios may serve rather as cell proliferation indictors than as cell injury ones, whereas the mI/Cr ratio appears as one of the first indicators of local irradiation injury. In order to establish the prognostic marker for early radiation damage, however, it seems necessary to analyze all visible metabolites as well. None of the metabolites separately may serve as such an indicator due to the complexity of tissue metabolism. Interestingly, MRI reveals no changes during the therapy process, whereas the metabolite ratios are being affected in the course of time, thus supporting the presumption that the 1H-MRS is a valuable method of radiation therapy monitoring.

The impact of delivered dose errors on local control of irradiated advanced laryngeal cancer.

On the basis of 1,015 entrance and 863 exit dose in vivo measurements, 863 calculations of midline dose were done, and the average deviation and ranges of its value were estimated. Data of 710 advanced larynx cancers were reviewed in order to achieve dose-response relationship. Patients data were fitted directly to L-Q model using maximum likelihood estimation. In 16.5% of measurements the deviation of midline dose was larger than -5.2%. A steep dose response relationship for TCP was found. Considering -5.2% deviation of 2 Gy fraction and 72 Gy of total dose, the 17% (from 48 to 31%) decrease of TCP was found. It shows that deviations of delivered dose influence the tumor control probability and that after systematic error finding during fractionated radiotherapy the value of remaining fraction size and total dose should be modified to compensate the change of TCP.

Sequential combination of radio-chemotherapy (5-fluorouracil, cis-platinum and irradiation) in the management of locally advanced head and neck cancers.

Thirty-seven previously untreated patients with advanced, inoperable head and neck were treated with a sequential courses combining hypofractionated irradiation with chemotherapy (5-fluorouracil and cis-platinum). Each course was repeated every 4 weeks. Tumor response was evaluated and for 15 patients (41%) with a partial or complete regression after 3 radio-chemotherapy courses conventional radiotherapy was added. Eleven percent of all patients were in complete remission at the end of a treatment. This tumor response rate and the 50% rate of pain subside after first course for symptomatic patients contributed for a good palliative effect in the present study. However, the median survival of 7.2 months was considered unsatisfactory.

Carbon-13 NMR studies of alpha-elastin.

NMR investigations of model protein of elastic fibre is presented. Detailed conformation of alpha-elastin polypeptide chain is discussed by comparison with the conformation of synthetic repeat peptides of elastin. Amino acid composition of alpha-elastin obtained from C-13 NMR spectra correlates with the results of sequencing of tropoelastin.

[Measurements of amylase isoenzymes in sera and saliva of patients after radiotherapy because of larynx carcinoma]. / Aktywnosc izoenzymów amylazy sliny i osocza krwi pacjentów poddanych radioterapii z powodu nowotworów krtani.

Serum and salivary alpha-amylase were measured for controls and patients with laryngeal carcinoma before, and after localised irradiation including salivary glands. Additionally amylase isoenzymes in sera were measured using mini-column method. A significant increase in amylasemia was observed after irradiation. Alpha-amylase activity in saliva was decreased after irradiation but differences were not statistically significant due to the significant decrease of protein in saliva of irradiated group. An increase of salivary isoenzyme S activity was observed while pancreatic isoenzyme activity was not altered. This method allows easy differentiation of hyperamylasemia due to irradiation of parotid gland and disorders of the pancreas. Alpha-amylase activity measurements may detect metabolic changes in salivary glands after irradiation.

[The effectiveness of radiotherapy and the prognostic value of Hb level for patients with early glottic cancer (T1N0, T2N0)]. / Ocena skutecznosci radioterapii i wartosci prognostycznej poziomu hemoglobiny u chorych na raka glosni we wczesnym stopniu zaawansowania (T1N0, T2N0).

Effectiveness of radiotherapy as a sole treatment modality was analysed in a group of 225 patients with glottic cancer in stage T1 (153 patients) or T2 (72 patients) without metastases in regional neck lymph nodes. All patients were irradiated with gamma 60Co or 10 MeV photons 5 times per week conventional treatment with the dose of 2.0-2.5 Gy per fraction. The total dose was in the range of 60-70 Gy given in overall treatment time of 30-61 days. 3-year local control rate was 88% for T1 patients and 54% for T2. In group T1 total dose of 65-70 Gy correlated with a high, 94-100%, local rate whereas in group T2 for the same range of total dose, extension of overall treatment time beyond 45 days caused significant decrease in local tumour control of about 3% for each one day of treatment protraction. Moreover, the Hb level was found to be a significant prognostic factor and its value below 12 g/dl correlated with remarkably lower local control of glottic cancer of about 30% comparing with patients with Hb level above 12 g/dl.

[Prognostic factors in radiotherapy for hypopharyngeal cancer]. / Czynniki prognostyczne w radioterapii samodzielnej raka gardla dolnego.

This paper presents influence of selected prognostic factors on results of hypopharyngeal cancer radiotherapy used as only treatment in 97 patients irradiated in Centre of Oncology-Institute in Gliwice between 1980-1987. One-variant analysis showed statistically significant influence of gender, decrease of haemoglobin level during radiotherapy and higher T and N stages. Multivariant analysis demonstrated, that only locoregional status and treatment time has decisive importance on radiotherapy results. Thus, better results of treatment depend on lower T and N stages and correct radiotherapy time.

Linac-based stereotactic radiosurgery for brain arteriovenous malformations.

AIMS: Most papers dealing with radiosurgery for cerebral arteriovenous malformations (AVMs) present the results of gamma-knife treatment, whereas linac radiosurgery is becoming increasingly popular. Moreover, there is still much uncertainty about the rationale of combined endovascular and radiosurgical treatment. The aims of this study were to evaluate obliteration and rebleeding rates, and to determine factors influencing obliteration and adverse effects after linac-based stereotactic radiosurgery for cerebral AVMs. MATERIALS AND METHODS: Records of 62 consecutive patients were analysed. Thirty-one had partial embolisation, five surgery, 29 had no prior treatment. The mean follow-up was 28.4 months. The mean volume treated was 11.7cm(3) and included embolised portions of AVMs. Actuarial obliteration rates and annual bleeding hazard rates after radiosurgery were calculated using Kaplan-Meier survival and life table analyses. RESULTS: Actuarial obliteration rates after 1, 2 and 3 years of follow-up were 17, 36 and 40%, respectively. Prior embolisation did not influence the obliteration rate. In 77.3% of patients, obliteration occurred during the first 2 years of follow-up. Annual bleeding hazard rates after stereotactic radiosurgery were 3.4 and 1.1% during the first and second year of follow-up, respectively. Non-symptomatic imaging abnormalities were detected in 33.9% of patients after a median time of 8.8 months. The Spetzler-Martin grade, AVM score, radiation dose, volume and AVM nidus < 3cm significantly influenced the probability of obliteration. A dose less than 15Gy significantly reduced the probability of obliteration. CONCLUSION: At least a 3 year follow-up is required to accurately assess the outcome. The best effects of the treatment are achieved for small (<3cm), low-grade lesions with a low AVM score. The bleeding risk after stereotactic radiosurgery gradually decreases.