MRI in radiotherapy - Is it time to rethink the current radiotherapy fixation solutions?

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Cell kinetic changes in human squamous cell carcinomas during radiotherapy studied using the in vivo administration of two halogenated pyrimidines.

The aim of this study was to investigate cell cycle changes during radiation treatment and establish whether treatment intervention could be considered if these changes helped to predict outcome. 33 patients with head and neck cancer were administered iododeoxyuridine (IdUrd) prior to treatment and a second administration of bromodeoxyuridine (BrdUrd) prior to the fifth fraction of 2 Gy. Biopsies were taken several hours after each injection and flow cytometry was used to calculate changes in the cellular kinetics and cell cycle delay in vivo. The kinetic response of the tumour cells was variable; some showed an increase in proliferation during the first week of treatment, whilst the majority showed an inhibition of proliferation. Reduction in the labelling index (LI) and the pretreatment DNA ploidy status and not delays in G2 were the only parameters to correlate with clinical outcome. A lack of reduction in the LI after 1 week of radiotherapy and DNA aneuploidy predicted a group of patients where radiotherapy failed. This information could be helpful in planning future treatment interventions.

ImmunoCyt a useful method in the follow-up protocol for patients with urinary bladder carcinoma.

OBJECTIVE: To evaluate the ImmunoCyt test--a urine-bound test for the detection of malignant transitional cells. PATIENTS AND METHODS: ImmunoCyt was compared with the standard investigation at our hospital for bladder cancer--cystoscopy, cytological examination of bladder wash material and, if necessary, a histological examination. A voided urine sample was collected before cystoscopy. We investigated 121 patients; seven specimens could not be evaluated. RESULTS: Thirty-one of the 114 patients had a histologically proven urinary bladder carcinoma. All 31 cases were positive in the ImmunoCyt test. Twenty-six of the 83 negative cases were ImmunoCyt positive. The sensitivity was 100% and the specificity was 68.7%. CONCLUSION: ImmunoCyt is easily applicable in a small laboratory and has high sensitivity and acceptable specificity.

Selective urological evaluation in men with febrile urinary tract infection.

OBJECTIVE: To investigate the prevalence and clinical importance of urological abnormalities in men with community-acquired febrile urinary tract infection (UTI). PATIENTS AND METHODS: In this prospective study, 85 men (median age 63 years, range 18--86) were followed for 1 year after an episode of febrile UTI. They were investigated by excretory urography, cysto-urethroscopy, uroflowmetry, digital rectal examination and measurement of postvoid residual urine volume by abdominal ultrasonography. RESULTS: The radiological examination of the upper urinary tract in 83 patients revealed 22 abnormal findings in 19 men. Relevant clinical abnormalities leading to surgical intervention were found in only one patient who had renal calyceal stones. The lower urinary tract investigation disclosed 46 findings in 35 men. In all, surgically correctable disorders were found in 20 patients, of whom 15 had previously unrecognized abnormalities. All patients who required surgery were identified either by a history of voiding difficulties, acute urinary retention at the time of infection, the presence of microscopic haematuria at follow-up after one month, or early recurrent symptomatic UTI. CONCLUSION: Routine imaging studies of the upper urinary tract seem dispensable in men with febrile UTI. To reveal abnormalities of clinical importance, any urological evaluation should primarily be focused on the lower urinary tract.

Transrectal ultrasound anatomy of the prostate and seminal vesicles in healthy men.

OBJECTIVE: This study involved transrectal ultrasound (TRUS) examination of the prostate and seminal vesicles in healthy males, for use as a reference. MATERIAL AND METHODS: A total of 125 men (aged 20-69 years) with no history or symptoms of urogenital disease underwent TRUS. Prostate size (both total and central gland), focal lesions such as calcifications, hyper- and hypoechoic areas, cysts, and size and lobulation of the seminal vesicles were noted and related to age. RESULTS: The prostate measured 19.2 +/- 4 cm3 and calcifications were found in 23.1% of men aged 20-29 years compared with 35.5 +/- 12.5 cm3 and 83% for men aged 60-69 years. Overall, hyperechoic areas were found in 59.2% of those examined, cysts in 16.8% and hypoechoic areas in about 11%, predominantly in the peripheral zone. Totally normal sonograms were seen in 29% of the men under the age of 40 and in 5% of the men aged 40 or older. CONCLUSIONS: TRUS examinations of healthy males are seldom without sonographic changes. This study provides the frequencies with which these changes occur in healthy males of various ages, all without urogenital symptoms, and may be used for future comparisons with different pathological conditions.

Optimized MLC-beam arrangements for tangential breast irradiation.

BACKGROUND AND PURPOSE: Very large numbers of women are treated with tangential breast irradiation after breast-conserving surgery due to mammary carcinoma. The aim of this study was to improve a conventional treatment plan by modifying the dose intensity in the beams to reduce the absorbed dose outside the planning target volume (PTV) and to reduce the absorbed dose variation inside the PTV diotherapy of mammary carcinoma. MATERIALS AND METHODS: Treatment planning was performed both with conventional technique and with a simple intensity modulation technique for 12 consecutive patients. RESULTS: In all cases a higher degree of dose conformity was obtained with the dose intensity modulation technique. The relative gain was found to be similar for all patients irrespective of the size of the target volume or the irradiated lung volume. CONCLUSION: Simple manual intensity modulation can be used to improve the dose distribution in tangential breast irradiation. With modern accelerators the increased time for this technique is less than 2 min per fraction.

Prostatic involvement in men with febrile urinary tract infection as measured by serum prostate-specific antigen and transrectal ultrasonography.

OBJECTIVE: To determine the frequency of prostatic involvement in men with community-acquired febrile urinary tract infection. PATIENTS AND METHODS: This prospective study included 70 men (18-85 years old) who had a fever of >/=38.0 degrees C, symptoms or signs of urinary tract infection and a positive urine culture. Serum prostate-specific antigen (PSA) was measured and transrectal ultrasonography of the prostate and seminal vesicles performed during the acute phase of the disease and during a 1-year follow-up. RESULTS: Although only six patients had a tender prostate on digital rectal examination, the initial serum PSA level was elevated in 58 (83%) patients (median 14 ng/mL, range 0.54-140). There was no correlation between PSA levels, patient age, inflammatory response to infection or presence of positive blood cultures. Despite a rapid decline in PSA level after one month, there was a protracted decrease in some patients. After 3 months the median prostate volume was reduced by 31% (range 11-54; P<0.001) in 46 of 55 patients examined, and the width of the right and left seminal vesicle was reduced by 14% and 22%, respectively. The reductions in PSA and prostate volume were significantly correlated (r=0.36, 95% confidence interval 0.09-0.58; P=0.01). CONCLUSION: These results show that the prostate and seminal vesicles are frequently involved in men with febrile urinary tract infection and that PSA may be a useful marker of prostatic infection. The slow decline of PSA levels in some patients after appropriate antibiotic treatment indicates a protracted healing process and should be considered when PSA is used to detect prostate cancer.

The value of pretreatment cell kinetic parameters as predictors for radiotherapy outcome in head and neck cancer: a multicenter analysis.

PURPOSE: The aim of this study was to assess the potential of pre-treatment cell kinetic parameters to predict outcome in head and neck cancer patients treated by conventional radiotherapy. MATERIALS AND METHODS: Data from 11 different centers were pooled. Inclusion criteria were such that the patients received radiotherapy alone, and that the radiotherapy was given in an overall time of at least 6 weeks with a dose of at least 60 Gy. All patients received a tracer dose of either iododeoxyuridine (IdUrd) or bromodeoxyuridine (BrdUrd) intravenously prior to treatment and a tumor biopsy was taken several hours later. The cell kinetic parameters labeling index (LI), DNA synthesis time (Ts) and potential doubling time (Tpot) were subsequently calculated from flow cytometry data, obtained on the biopsies using antibodies against I/BrdUrd incorporated into DNA. Each center carried out their own flow cytometry analysis. RESULTS: From the 11 centers, a total of 476 patients conforming to the inclusion criteria were analyzed. Median values for overall time and total dose were 49 days and 69 Gy, respectively. Fifty one percent of patients had local recurrences and 53% patients had died, the majority from their disease. Median follow-up was 20 months; being 30 months for surviving patients. Multivariate analysis revealed that T-stage, maximum tumor diameter, differentiation grade, N-stage, tumor localization and overall time correlated with locoregional control, in decreasing order of significance. For the cell kinetic parameters, univariate analysis showed that only LI was significantly associated with local control (P=0.02), with higher values correlating with a worse outcome. Ts showed some evidence that patients with longer values did worse, but this was not significant (P=0.06). Tpot showed no trend (P=0.8). When assessing survival in a univariate analysis, neither LI nor Tpot associated with outcome (P=0.4, 0.4, respectively). Surprisingly, Ts did correlate with survival, with longer values being worse (P=0.02). In the multivariate analysis of local control, LI lost its significance (P=0.16). CONCLUSIONS: The only pretreatment kinetic parameter for which some evidence was found for an association with local control (the best end-point for testing the present hypothesis) was LI, not Tpot, and this evidence disappeared in a multivariate analysis. It therefore appears that pretreatment cell kinetic measurements carried out using flow cytometry, only provide a relatively weak predictor of outcome after radiotherapy in head and neck cancer.

Intensity modulation with electrons: calculations, measurements and clinical applications.

Intensity modulation of electron beams is one step towards truly conformal therapy. This can be realized with the MM50 racetrack microtron that utilizes a scanning beam technique. By adjusting the scan pattern it is possible to obtain arbitrary fluence distributions. Since the monitor chambers in the treatment head are segmented in both x- and y-directions it is possible to verify the fluence distribution to the patient at any time during the treatment. Intensity modulated electron beams have been measured with film and a plane parallel chamber and compared with calculations. The calculations were based on a pencil beam method. An intensity distribution at the multileaf collimator (MLC) level was calculated by superposition of measured pencil beams over scan patterns. By convolving this distribution with a Gaussian pencil beam, which has propagated from the MLC to the isocentre, a fluence distribution at isocentre level was obtained. The agreement between calculations and measurements was within 2% in dose or 1 mm in distance in the penumbra zones. A standard set of intensity modulated electron beams has been developed. These beams have been implemented in a treatment planning system and are used for manual optimization. A clinical example (prostate) of such an application is presented and compared with a standard irradiation technique.

Scanned intensity modulations for 50 MV photons.

Optimization of the dose distributions by individual beam compensation is a useful tool in conformal radiation therapy. Intensity modulation by electromagnetic scanning of a narrow elementary beam allows fast dose delivery and causes little change in beam quality compared with other methods, especially for high energies such as 50 MV. Intensity modulated beams from the MM50 accelerator were measured and compared with calculations based on Monte Carlo simulations. Good agreement between measurements and calculations were found, typically within 1% for central dose profiles. The steepest wedge angle that was produced with the scanning beam technique was of 45 degrees or 3.5% cm(-1) for a 20 cm x 20 cm field, slightly varying with depth. The elementary 50 MV photon 'pencil beam' for a full range, high-z bremsstrahlung target, is a wide dose distribution at 10 cm depth in water which limits the modulation gradient and hence the complexity of the modulation by the scanning of a photon pencil beam only. Scanned wedge beam distributions were modelled in the treatment planning system and a pelvic treatment with three fields was used to illustrate a clinical application. The resulting dose volume data were compared for different radiation qualities but with similar beam portals. 'Energy modulation' by field matching with lower photon energies was performed to sharpen the penumbra towards organs at risk.

Systematic heterogeneity and prognostic significance of cell proliferation in colorectal cancer.

The prognosis of colorectal cancer has not significantly changed during the last 30 years. While evaluation of tumour cell proliferation may provide prognostic information, results obtained so far have been contradictory Heterogeneity in tumour cell proliferation may explain these contradictions. With in vivo injection of iododeoxyuridine (IdUrd), estimation of labelling index (LI), S-phase transit time (Ts) and potential doubling time (Tpot) may be performed from a single sample. A total of 109 colorectal cancers were studied after in vivo injection of IdUrd before surgical removal. From each cancer, four to eight samples were processed for both flow cytometrical (FCM) and immunohistochemical (IHC) visualization of IdUrd incorporation. LI/IHC was morphometrically quantified at both the luminal border and the invasive margin of these tumours. LI was significantly higher at the luminal border compared with the invasive margin, although they were correlated with each other. Using combined IHC and FCM methods, rapidly growing colorectal cancers (high LI and/or low Tpot) showed an increased survival (significant for LI at the invasive margin and for Tpot at both the invasive margin and the luminal border) in the entire unselected material and for radically removed Dukes' B tumours. FCM data alone did not discriminate for survival, with the exception of Ts in diploid and radically removed Dukes' B tumours.

Predictive value of potential doubling time in head and neck cancer patients treated by conventional radiotherapy.

PURPOSE: The goal of this study was to investigate the clinical utility of pretreatment measurements of tumor cell kinetics to predict the outcome of patients with squamous cell carcinoma of the head and neck receiving conventional radiotherapy. METHODS AND MATERIALS: All patients received between 64 and 70 Gy as 2 Gy fractions, five fractions per week. Cell kinetics were assayed rapidly and quantitatively using flow cytometric evaluation of iododeoxyuridine (IdUrd) incorporation, in vivo, from a biopsy removed several hours after the administration of the DNA precursor to the patient prior to the start of treatment. RESULTS: The measured proliferation parameters were not related to the clinicopathological features of the tumors, emphasizing the independent nature of these parameters. In univariate analysis, nodal involvement was the most important clinical feature of the tumors related to local control followed by Tpot, DNA aneuploidy, and attainment of complete regression at 6 weeks. Of these only Tpot and nodal status maintained significance in multivariate analysis, with respect to loco-regional control. In subgroup analysis, Tpot was able to stratify patients into high or low rate of loco-regional control in node negative patients, in aneuploid tumors and in patients who did achieve complete regression at 6 weeks. For cause specific survival, N-stage was the only parameter that significantly discriminated the prognosis in these patients. CONCLUSIONS: The conclusion of this study is that Tpot provides clinically important information that can predict patients with a low probability of achieving long-term local control with conventional fractionation. Further improvements to the methodology to address the shortcomings of analyzing diploid tumors may increase the predictive power of the measurement.

Exploration of new treatment modalities offered by high energy (up to 50 MeV) electrons and photons.

BACKGROUND AND PURPOSE: A number of deep seated tumours are difficult to treat conformally with photon beams mainly due to the almost exponential dose decrease with depth. MATERIALS AND METHODS: In order to improve the conformity of these treatments a number of useful characteristics of high energy (above 20 MeV) electron beams of the MM50 Racetrack Microtron have been systematically investigated and clinically applied. RESULTS: A typical characteristic of electron beams with energies up to 20 MeV is the sharp dose fall-off with depth. At higher energies this effect is less pronounced but may be improved by adding a small fraction of photons with a matching dose gradient (wedge). With this technique, high energy electrons can be used close to sensitive organs down to 17 cm depth. Another physical characteristic of high energy electrons is the sharp penumbra at depths down to 4-5 cm and the possibility to use opposed electron beams in order to enhance the dose centrally or near the centre of a body. Skin sparing by delivering a part of the absorbed dose with photons through the same beam portal as the electrons has also been systematically studied. These characteristics of the high-energy electron beams have been utilised in the optimisation of some clinical treatments. CONCLUSIONS: Electron beams in this high energy region give increased possibilities to achieve dose conformity. Enhanced conformity can be obtained especially if electrons and photons are combined to augment some specific characteristics of the electron beams.

Matching of electron beams for conformal therapy of target volumes at moderate depths.

The basic requirements for conformal electron therapy are an accelerator with a wide range of energies and field shapes. The beams should be well characterised in a full 3-D dose planning system which has been verified for the geometries of the current application. Differences in the basic design of treatment units have been shown to have a large influence on beam quality and dosimetry. Modern equipment can deliver electron beams of good quality with a high degree of accuracy. A race-track microtron with minimised electron scattering and a multi-leaf collimator (MLC) for electron collimating will facilitate the isocentric technique as a general treatment technique for electrons. This will improve the possibility of performing combined electron field techniques in order to conform the dose distribution with no or minimal use of a bolus. Furthermore, the isocentric technique will facilitate multiple field arrangements that decrease the problems with distortion of the dose distribution due to inhomogeneities, etc. These situations are demonstrated by clinical examples where isocentric, matched electron fields for treatment of the nose, thyroid and thoracic wall have been used.

Cell kinetic analysis of non-Hodgkin's lymphomas using in vivo iododeoxyuridine incorporation and flow cytometry.

The aim of this study was to analyse dynamic cell proliferation parameters in non-Hodgkin's lymphomas. Sixty-one patients with newly diagnosed or with recurrent disease were given iododeoxyuridine (IdUrd) intravenously near 4 h prior to tumour biopsy. After staining with an IdUrd reactive antibody and propidium iodide, S-phase fraction (SPF), labelling index (LI), S-phase duration time (Ts) and potential tumour doubling time (Tpot) were determined by flow cytometry. Thirty-eight samples, 15 low grade (LGM) and 23 high grade (HGM) malignant lymphomas, were possible to evaluate. Twenty-three cases were excluded due to aneuploidy, insufficient amount of material or technical problems. Tpot values varied between 0.8-32.9 days (mean 7.0 days). HGM lymphomas had shorter mean Tpot times than LGM lymphomas (4.8 versus 10.4 days, p = 0.05). For Ts the range was 4.2-20.1 h (mean 9.1 h), and a difference between the two histological groups was demonstrated with a longer mean Ts for HGM compared with LGM cases (10.0 versus 7.8 h, p = 0.04). Tpot showed a negative correlation with SPF (P = 0.003), and Ts demonstrated a positive correlation to SPF (p = 0.02). The clinical significance of the dynamic cell proliferation parameters studied remains to be clarified, but the interrelationships between Ts/SPF and Ts/morphologic subtype might be factors of interest for future prognostic studies in malignant lymphomas.

DNA damage in human endothelial cells after irradiation in anoxia.

Endothelial cells and fibroblasts have been reported to respond differently to oxidative stress. Both the effects of high oxygen tension and radiation involve the action of free radicals. DNA damage (single strand breaks, SSB, and double strand breaks, DSB) was assayed in human umbilical cord vein (HUV) cells and in Chinese hamster fibroblasts (V79) after irradiation under oxic or anoxic conditions. The cells were exposed to single doses in the range of 2-18 Gy of gamma-radiation from 60Co. Significantly more DNA damage was induced in the V79 cells than in the HUV cells. As a consequence, a higher oxygen enhancement ratio was obtained for the HUV cells (6.3) as compared to the V79 cells (2.8). The repair of SSB was slower in the HUV cells than in the V79 cells, irrespective of oxic state. For the higher doses, the damage remaining at 60 min after anoxic irradiation, i.e. DSB, was only detected in the V79 cells.

p53 expression and cell proliferation in squamous cell carcinomas of the head and neck.

BACKGROUND: In squamous cell carcinoma of the head and neck (SCCHN), overexpression of the p53 protein has been found in 34-80% of the tumors studied. No data are available regarding p53 expression versus tumor cell proliferation and prognosis for this tumor type. METHODS: p53 protein levels were studied by immunohistochemical staining of 33 primary SCCHN using 3 antibodies (DO7, PAb 1801, and CM1) that react with different epitopes of the p53 protein. The cellular expression of p53 was compared with in vivo incorporation of the thymidine analog iododeoxyuridine (IdUrd) and expression of proliferating cell nuclear antigen (PCNA). RESULTS: Twenty-one tumors (64%) had a positive nuclear staining for p53 with the monoclonal antibody DO7, which reacts with a denaturation-resistant epitope in wild-type and mutant p53. PAb 1801 and CM1 reacted with 19 and 20 tumors, respectively, all of which were DO7-positive. No correlation was found between incorporation of IdUrd and p53 expression or between PCNA and p53 expression. The data indicate that intracellular accumulation of the p53 protein was related to tumor stage and localization of the tumor. No indication of a clinical or prognostic significance of p53 expression in SCCHN was found. CONCLUSIONS: No association between p53 deregulation and tumor cell proliferation was found.

Radiosensitizing effect of estramustine in malignant glioma in vitro and in vivo.

Estramustine-phosphate (EMP), a combination of nornitrogen mustard and 17 beta-estradiol, has been demonstrated to exert specific antiproliferative effects on human glioma cells in vitro. The cytotoxic effect is, at least partially, mediated by inhibiting microtubule function. In this study the combined effect of EMP and radiation was evaluated in the human glioma cell-lines, 251-MG and 105-MG, in vitro, and in the rat glioma BT4C in vitro and in vivo. In all cell-lines an additive effect of EMP and radiation was obtained in vitro. Assuming equal effect of EMP is obtained in subsequent radiation fractions, the cell kill will be increased from 2-3 to 5-10 logs if delivering 30 fractions of 2 Gy combined with EMP. In the BT4C rat model the combined effect was found to be synergistic. Flow cytometry demonstrated an arrest in G2/M phase in all cell-lines after EMP treatment. This block in G2/M phase in addition to the previously demonstrated induction of free oxygen radicals, and the increase of blood flow with an assumed subsequent increase of oxygenation, might provide an explanation for the observed radiosensitizing effect of estramustine.

Effects of sucralfate on mucositis during and following radiotherapy of malignancies in the head and neck region. A double-blind placebo-controlled study.

Radiotherapy of head and neck malignancies is accompanied by oral discomforts, such as epithelitis, pain and functional impairment. This can lead to chronic sequalae with subjective distress such as loss of taste and xerostomia and pronounced decrease in quality of life. Thus, the need to reduce the mucosal damage following radiotherapy is obvious. Therefore, we investigated the possible ability of sucralfate, an aluminium hydroxide complex of sulphated sucrose used in the treatment of gastric ulcer, in preventing oral discomfort in patients treated with curative intent for malignancies in the head and neck region. The study was double-blind, placebo-controlled and randomized and included 50 consecutive patients. The study demonstrated that the proportion of patients with severe mucosal reactions was significantly lower in the sucralfate group than in the placebo group.