Reproducibility and correlation between quantitative and semiquantitative dynamic and intrinsic susceptibility-weighted MRI parameters in the benign and malignant human prostate.

PURPOSE: To assess the reproducibility of relaxivity- and susceptibility-based dynamic contrast-enhanced magnetic resonance imaging (MRI) in the benign and malignant prostate gland and to correlate the kinetic parameters obtained. MATERIALS AND METHODS: Twenty patients with prostate cancer underwent paired scans before and after androgen deprivation therapy. Quantitative parametric maps for T(1)- and T(2)*-weighted parameters were calculated (K(trans), k(ep),v(e), IAUC(60), rBV, rBF, and R(2)*). The reproducibility of and correlation between each parameter were determined using standard methods at both timepoints. RESULTS: T(1)-derived parameters are more reproducible than T(2)*-weighted measures, both becoming more variable following androgen deprivation (variance coefficients for prostate K(trans) and rBF increased from 13.9%-15.8% and 42.5%-90.8%, respectively). Tumor R(2)* reproducibility improved after androgen ablation (23.3%-11.8%). IAUC(60) correlated strongly with K(trans), v(e), and k(ep) (all P < 0.001). R(2)* did not correlate with other parameters. CONCLUSION: This study is the first to document the variability and repeatability of T(1)- and T(2)*-weighted dynamic MRI and intrinsic susceptibility-weighted MRI for the various regions of the human prostate gland before and after androgen deprivation. These data provide a valuable source of reference for groups that plan to use dynamic contrast-enhanced MRI or intrinsic susceptibility-weighted MRI for the assessment of treatment response in the benign or malignant prostate.

Carbogen and nicotinamide in locally advanced bladder cancer: early results of a phase-III randomized trial.

PURPOSE: Phase II studies in laryngeal and bladder carcinoma of accelerated radiotherapy with carbogen and nicotinamide (RT+CON) suggested a therapeutic advantage. Therefore, a randomized phase-III trial of RT+CON in locally advanced bladder carcinoma compared to radiotherapy (RT) alone was undertaken. METHODS: One hundred and sixty-five patients with muscle-invasive transitional cell bladder carcinoma were randomized to RT alone and 168 to RT+CON. This paper reports on compliance and toxicity to nicotinamide (NAM) and carbogen and on early radiation-induced adverse bowel and urinary events. RESULTS: Of those receiving RT+CON, 65-69% accepted all doses of NAM. Sixty-four percent of patients presented Grade 1 NAM toxicity (nausea or vomiting), which was severe in 13%. Compliance to carbogen was 85% and none (32 fractions) and 2% (20 fractions) of patients presented severe toxicity. The highest prevalence of severe radiation acute morbidity was seen for urinary frequency (RT: 18% and RT+CON: 15%) and for diarrhea (RT: 3% and RT+CON: 5%). CONCLUSIONS: There is no indication of an increase in radiation-induced morbidity by combining the tumour radiosensitizers carbogen and nicotinamide with radiotherapy. Late morbidity and treatment outcome will ultimately determine if there is a therapeutic benefit.

[(64)Cu]diacetyl-bis(N(4)-methyl-thiosemicarbazone) - a radiotracer for tumor hypoxia.

Positron emission tomography scanning using the radiotracer-labeled copper (II)-diacetyl-bis(N(4)-methylthiosemicarbazone) has been proposed as a noninvasive method for evaluating tumor hypoxia. Tumor hypoxia results in a more aggressive tumor phenotype together with resistance to both radiotherapy and chemotherapy. A noninvasive technique for evaluation of tumor hypoxia is not currently available. Validation of this technique would provide clinicians with a tool for determining the most appropriate cancer therapy, prognostic information, and subvolume delineation for the radiotherapy dose escalation to the radioresistant hypoxic regions within a tumor. This review article describes the background to the development of this tracer, its proposed retention mechanism, biodistribution dosimetry and the preclinical and clinical studies to date. It outlines the potential use of this radiotracer for imaging in the field of oncology.

Hyperfractionated or accelerated radiotherapy in head and neck cancer: a meta-analysis.

BACKGROUND: Several trials have studied the role of unconventional fractionated radiotherapy in head and neck squamous cell carcinoma, but the effect of such treatment on survival is not clear. The aim of this meta-analysis was to assess whether this type of radiotherapy could improve survival. METHODS: Randomised trials comparing conventional radiotherapy with hyperfractionated or accelerated radiotherapy, or both, in patients with non-metastatic HNSCC were identified and updated individual patient data were obtained. Overall survival was the main endpoint. Trials were grouped in three pre-specified categories: hyperfractionated, accelerated, and accelerated with total dose reduction. FINDINGS: 15 trials with 6515 patients were included. The median follow-up was 6 years. Tumours sites were mostly oropharynx and larynx; 5221 (74%) patients had stage III-IV disease (International Union Against Cancer, 1987). There was a significant survival benefit with altered fractionated radiotherapy, corresponding to an absolute benefit of 3.4% at 5 years (hazard ratio 0.92, 95% CI 0.86-0.97; p=0.003). The benefit was significantly higher with hyperfractionated radiotherapy (8% at 5 years) than with accelerated radiotherapy (2% with accelerated fractionation without total dose reduction and 1.7% with total dose reduction at 5 years, p=0.02). There was a benefit on locoregional control in favour of altered fractionation versus conventional radiotherapy (6.4% at 5 years; p<0.0001), which was particularly efficient in reducing local failure, whereas the benefit on nodal control was less pronounced. The benefit was significantly higher in the youngest patients (hazard ratio 0.78 [0.65-0.94] for under 50 year olds, 0.95 [0.83-1.09] for 51-60 year olds, 0.92 [0.81-1.06] for 61-70 year olds, and 1.08 [0.89-1.30] for over 70 year olds; test for trends p=0.007). INTERPRETATION: Altered fractionated radiotherapy improves survival in patients with head and neck squamous cell carcinoma. Comparison of the different types of altered radiotherapy suggests that hyperfractionation has the greatest benefit.

Acute tumor vascular effects following fractionated radiotherapy in human lung cancer: In vivo whole tumor assessment using volumetric perfusion computed tomography.

PURPOSE: To quantitatively assess the in vivo acute vascular effects of fractionated radiotherapy for human non-small-cell lung cancer using volumetric perfusion computed tomography (CT). METHODS AND MATERIALS: Sixteen patients with advanced non-small-cell lung cancer, undergoing palliative radiotherapy delivering 27 Gy in 6 fractions over 3 weeks, were scanned before treatment, and after the second (9 Gy), fourth (18 Gy), and sixth (27 Gy) radiation fraction. Using 16-detector CT, multiple sequential volumetric acquisitions were acquired after intravenous contrast agent injection. Measurements of vascular blood volume and permeability for the whole tumor volume were obtained. Vascular changes at the tumor periphery and center were also measured. RESULTS: At baseline, lung tumor vascularity was spatially heterogeneous with the tumor rim showing a higher vascular blood volume and permeability than the center. After the second, fourth, and sixth fractions of radiotherapy, vascular blood volume increased by 31.6% (paired t test, p = 0.10), 49.3% (p = 0.034), and 44.6% (p = 0.0012) respectively at the tumor rim, and 16.4% (p = 0.29), 19.9% (p = 0.029), and 4.0% (p = 0.0050) respectively at the center of the tumor. After the second, fourth, and sixth fractions of radiotherapy, vessel permeability increased by 18.4% (p = 0.022), 44.8% (p = 0.0048), and 20.5% (p = 0.25) at the tumor rim. The increase in permeability at the tumor center was not significant after radiotherapy. CONCLUSION: Fractionated radiotherapy increases tumor vascular blood volume and permeability in human non-small-cell lung cancer. We have established the spatial distribution of vascular changes after radiotherapy; greater vascular changes were demonstrated at the tumor rim compared with the center.

Tumor antivascular effects of radiotherapy combined with combretastatin a4 phosphate in human non-small-cell lung cancer.

PURPOSE: The tumor vascular effects of radiotherapy and subsequent administration of the vascular disrupting agent combretastatin A4 phosphate (CA4P) were studied in patients with advanced non-small-cell lung cancer using volumetric dynamic contrast-enhanced computed tomography (CT). PATIENTS AND METHODS: Following ethical committee approval and informed consent, 8 patients receiving palliative radiotherapy (27 Gy in six fractions, twice weekly) also received CA4P (50 mg/m(2)) after the second fraction of radiotherapy. Changes in dynamic CT parameters of tumor blood volume (BV) and permeability surface area product (PS) were measured for the whole tumor volume, tumor rim, and center after radiotherapy alone and after radiotherapy in combination with CA4P. RESULTS: After the second fraction of radiotherapy, 6 of the 8 patients showed increases in tumor PS (23.6%, p = 0.011). Four hours after CA4P, a reduction in tumor BV (22.9%, p < 0.001) was demonstrated in the same 6 patients. Increase in PS after radiotherapy correlated with reduction in BV after CA4P (r = 0.77, p = 0.026). At 72 h after CA4P, there was a sustained reduction in tumor BV of 29.4% (p < 0.001). Both increase in PS after radiotherapy and reduction in BV after CA4P were greater at the rim of the tumor. The BV reduction at the rim was sustained to 72 h (51.4%, p = 0.014). CONCLUSION: Radiotherapy enhances the tumor antivascular activity of CA4P in human non-small-cell lung cancer, resulting in sustained tumor vascular shutdown.

Hypoxia in prostate cancer: correlation of BOLD-MRI with pimonidazole immunohistochemistry-initial observations.

PURPOSE: To investigate the ability of blood oxygen level-dependent (BOLD) MRI to depict clinically significant prostate tumor hypoxia. METHODS AND MATERIALS: Thirty-three patients with prostate carcinoma undergoing radical prostatectomy were studied preoperatively, using gradient echo sequences without and with contrast medium enhancement, to map relative tissue oxygenation according to relaxivity rates and relative blood volume (rBV). Pimonidazole was administered preoperatively, and whole-mount sections of selected tumor-bearing slices were stained for pimonidazole fixation and tumor and nontumor localization. Histologic and imaging parameters were independently mapped onto patient prostate outlines. Using 5-mm grids, 861 nontumor grid locations were compared with 237 tumor grids (with >50% tumor per location) using contingency table analysis with respect to the ability of imaging to predict pimonidazole staining. RESULTS: Twenty patients completed the imaging and histologic protocols. Pimonidazole staining was found in 33% of nontumor and in 70% of tumor grids. The sensitivity of the MR relaxivity parameter R(2)* in depicting tumor hypoxia was high (88%), improving with the addition of low rBV information (95%) without changing specificity (36% and 29%, respectively). High R(2)* increased the positive predictive value for hypoxia by 6% (70% to 76%); conversely, low R(2)* decreased the likelihood of hypoxia being present by 26% (70% to 44%) and by 41% (71% to 30%) when combined with rBV information. CONCLUSION: R(2)* maps from BOLD-MRI have high sensitivity but low specificity for defining intraprostatic tumor hypoxia. This together with the negative predictive value of 70% when combined with blood volume information makes BOLD-MRI a potential noninvasive technique for mapping prostatic tumor hypoxia.

Evaluation of normal FDG uptake in palatine tonsil and its potential value for detecting occult head and neck cancers: a PET CT study.

OBJECTIVE: The aims of the study were to (1) evaluate the range of physiological FDG uptake in normal pharyngeal palatine tonsil, and (2) investigate the possibility of establishing a cut-off threshold to distinguish between normal pharyngeal palatine tonsil FDG uptake from occult pharyngeal palatine tonsil primary cancer. METHODS: FDG PET CT of 43 consecutive patients with a low risk of head and neck cancer were reviewed by two observers. Axial PET CT was used to identify foci of FDG uptake related to the pharyngeal palatine tonsil. The highest standardized uptake value, SUVmax, of the left and right pharyngeal palatine tonsil was calculated. Similar analysis was performed on 10 consecutive patents with histologically proven occult pharyngeal palatine tonsil primary cancer. RESULTS: The mean SUVmax of the 43 right pharyngeal palatine tonsils was 4.82 (range, 1.16-12.74) and 4.68 (range, 0.88-13.65) for the 43 left pharyngeal palatine tonsils with no statistical difference observed (P=0.4). Normal pharyngeal palatine tonsil uptake was generally symmetrical and there was a positive correlation between SUVmax from the left and right sides which was statistically significant (r=0.9, P<0.0001). In the same patient the difference in SUVmax between left and right pharyngeal palatine tonsil ranged from 0.01 to 2.66 and patients with occult pharyngeal palatine tonsil primary cancer it ranged from 0.85 to 11.08. ROC analysis showed that an 'SUVmax difference' cut-off of 0.83 would achieve a sensitivity of 100% and specificity of 81% for detecting occult pharyngeal palatine tonsil primary cancers. CONCLUSIONS: There is considerable variation of pharyngeal palatine tonsil FDG uptake in patients with no pharyngeal palatine tonsil primary cancer. However, in the same patient there is generally only a small difference in uptake between left and right sides. The absolute difference in SUVmax between left and right pharyngeal palatine tonsil is a potentially useful parameter for distinguishing between normal FDG uptake in pharyngeal palatine tonsil from occult pharyngeal palatine tonsil primary cancer.

Epidermal growth factor receptor expression in pretreatment biopsies from head and neck squamous cell carcinoma as a predictive factor for a benefit from accelerated radiation therapy in a randomized controlled trial.

PURPOSE: Accelerated repopulation is a main reason for locoregional failure after fractionated radiotherapy for head and neck squamous cell carcinoma (HNSCC). Epidermal growth factor receptor (EGFR) is a key controller of cellular proliferation in HNSCC, which stimulated the current study to look for a direct link between EGFR status and a possible clinical advantage of accelerated radiotherapy. PATIENTS AND METHODS: Immunohistochemical staining for EGFR was performed in 304 patients with available pretreatment tumor biopsy material among 918 patients randomized to receive continuous hyperfractionated accelerated radiotherapy versus conventionally fractionated radiotherapy. The EGFR index was estimated as the proportion of tumor cells with EGFR membrane staining. RESULTS: Significant benefit in locoregional tumor control from continuous hyperfractionated accelerated radiotherapy was seen in patients with HNSCC with high EGFR expression (2P = .010) but not in those with low EGFR expression (2P = .85). EGFR status had no significant effect on survival or rate of distant metastases. The EGFR index was significantly associated with histologic grade and microvessel density. There was moderate support for an association between EGFR status and subsite within the head and neck region but no significant association with Ki-67 index, Ki-67 pattern, p53 index, p53 intensity, bcl-2 expression, or cyclin D1 index. CONCLUSION: This study indicates a key role for the EGFR receptor in determining the proliferative cellular response to fractionated radiotherapy in HNSCC. It also shows that we can select the dose-fractionation regime that has the greatest chance of benefiting the patient. These results also encourage further development of EGFR targeting combined with fractionated radiotherapy in HNSCC.

Pre-treatment proliferation and the outcome of conventional and accelerated radiotherapy.

This study investigated the influence of pre-treatment proliferation characteristics, assessed by Ki-67 staining, in patients treated in the CHART trial of accelerated radiotherapy in head and neck cancer. Histological material from 402 patients was collected and stained for the presence and pattern of Ki-67 staining. Locoregional control and overall survival were the main clinical endpoints. Increasing Ki-67 positivity was associated with decreasing differentiation (P < 0.001) and increasing N-stage (P < 0.004). Increasing N-stage was also associated with the progression of proliferation pattern from marginal to random (P < 0.001). Using a multivariate model, a trend was seen towards a greater benefit from CHART in the lower Ki-67 tumours (P = 0.08); this became significant by pooling the low and intermediate Ki-67 groups in comparison with the high Ki-67 group (P = 0.032). Tumours with marginal proliferation pattern showed a lower hazard ratio with CHART versus conventional for locoregional control (P = 0.005). The data presented in this study do not support that a high pre-treatment Ki-67 is associated with a therapeutic benefit from accelerated radiotherapy.

An immunohistochemical assessment of hypoxia in prostate carcinoma using pimonidazole: implications for radioresistance.

PURPOSE: To investigate the presence of hypoxia in human prostate carcinoma by using pimonidazole immunohistochemical labeling in radical prostatectomy specimens. METHODS AND MATERIALS: Forty-three patients (median age, 69 years; range, 49-83 years) with localized prostate adenocarcinoma received 0.5 gm/m2 i.v. pimonidazole 16-24 h before radical prostatectomy. Hypoxia was detected with a monoclonal antibody directed against pimonidazole and scored in formalin-fixed, paraffin-embedded sections. Median and maximal vessel counts were measured with CD34. RESULTS: Thirty-seven patients completed the study. Pimonidazole binding was present in prostate carcinomas in 34 of 37 patients (92%) and in benign prostatic hyperplasia in 35 of 37 patients (95%). A positive correlation of 3+ pimonidazole binding with Gleason score was demonstrated (Spearman's rank, p = 0.044). Vascularity scores did not correlate with hypoxic status or clinical prognostic parameters. CONCLUSION: Prostate carcinoma and benign prostatic hyperplasia have significant areas of hypoxia; greater hypoxia scores are seen with more aggressive prostate cancer. It is postulated that a hypoxic microenvironment within the prostate might be responsible for the promotion of secondary genetic alterations and angiogenic stimulation, leading to malignant progression, a more aggressive cell phenotype, and greater radioresistance. Modification of radiation regimens to specifically target hypoxia might improve local tumor control.

Quantitative assessment of lung cancer perfusion using MDCT: does measurement reproducibility improve with greater tumor volume coverage?

OBJECTIVE: To date, quantitative assessment of tumor vascularity using perfusion CT has been limited to a single tumor level, with the potential for measurement error in heterogeneous tumors. We aimed to determine if greater z-axis tumor coverage improves the reproducibility of perfusion CT measurements in lung cancer. SUBJECTS AND METHODS: Paired perfusion studies were performed on 10 patients who had histologically confirmed advanced non-small cell lung cancer. Using 16-MDCT, multiple sequential volumetric acquisitions encompassing the entire tumor were acquired after infusion of i.v. contrast material. Using Patlak analysis, median values of tumor permeability (mL/100 mL/min) and blood volume (mL/100 mL) were measured for 10-mm z-axis coverage, and for 40-mm z-axis coverage in each of the paired perfusion studies. Measurement reproducibility was evaluated using Bland-Altman statistics. RESULTS: Mean difference (95% limits of agreement) for tumor permeability was 1.4 (-4.0 to 6.8) for 10-mm coverage and 0.8 (-3.6 to 5.2) for 40-mm coverage. Mean difference (95% limits of agreement) for blood volume was 1.9 (-5.1 to 8.9) for 10-mm coverage and 1.4 (-3.7 to 6.6) for 40-mm coverage. The coefficient of variation for permeability was 18.7% for 10-mm coverage, improving to 11.9% for 40-mm coverage. The coefficient of variation for blood volume was 41.7% for 10-mm coverage, improving to 32.6% for 40-mm coverage. CONCLUSION: Our results show that an improvement in tumor perfusion measurement reproducibility may be achieved with greater z-axis coverage.

Molecular marker profiles predict locoregional control of head and neck squamous cell carcinoma in a randomized trial of continuous hyperfractionated accelerated radiotherapy.

PURPOSE: Identification of factors that assist prediction of tumor response to radiotherapy may aid in refining treatment strategies and improving outcome. Possible association of molecular marker expression profiles with locoregional control of head and neck squamous cell carcinoma was investigated in a randomized trial of conventional versus continuous hyperfractionated accelerated radiotherapy (CHART). EXPERIMENTAL DESIGN: Tumor material was obtained from 402 patients. Immunohistochemistry was used to assess Ki-67, CD31, p53, Bcl-2, and cyclin D1 expression. A hierarchical clustering algorithm with a Bayesian information criterion was used to group tumors with similar marker expression; resulting expression profiles were then compared in terms of their difference in outcome after CHART and conventionally fractionated radiotherapy. RESULTS: Molecular marker profile was an independent prognostic factor for locoregional control. This was confirmed in multivariate analysis, including clinical variables such as tumor and nodal status, primary site, histological grade, age, and gender (P < 0.001 and P = 0.006 for local and nodal relapse, respectively). In particular, Bcl-2-positive tumors responded significantly better than average in both arms of the trial. Tumors negative for p53- and Bcl-2, with high and randomly patterned Ki-67 expression, responded worse than average with no benefit from CHART. Tumors with similarly negative p53 and Bcl-2, but low Ki-67 staining, with an organized pattern, benefit significantly from CHART schedule. CONCLUSIONS: This study demonstrates the potential of molecular profiles to predict radiotherapy response of head and neck squamous cell carcinoma and for treatment stratification. Distinct expression profiles correlate with three distinct clinical phenotypes, including good locoregional control, poor locoregional control, and an outcome strongly dependent upon fractionation schedule.

Potential novel application of dual time point SUV measurements as a predictor of survival in head and neck cancer.

OBJECTIVES: To examine the potential of pre-treatment dual time point [18F]fluoro-2-deoxy-D-glucose positron emission tomography (FDG PET) as a tool for improving the assessment of head and neck cancer. Two main areas were investigated: (a) optimum time to start FDG scanning post-injection and (b) potential of SUV obtained from dual time point scanning as a prognostic indicator of survival. METHODS: Twelve patients with advanced head and neck cancer were prospectively studied. Each patient was scanned using a Siemen's Ecat Exact-47 PET scanner at 1 h and 2 h post-injection. Maximum tumour uptake (SUVt) and ratio of maximum tumour/normal tissue uptake (SUVt/n) were recorded. The optimal time to initiate scanning was investigated by comparing SUVt and SUVt/n with the decision made by two experienced observers as to which scan they preferred to report from, given the choice of the 1 h and 2 h scan in each patient. RESULTS: A significant difference between 1 h and 2 h SUVt (P<0.004, paired t-test) and between 1 h and 2 h SUVt/n (P<0.0003, paired t-test) was observed. All 2 h SUVt and SUVt/n were greater in magnitude than their respective 1 h SUVt and SUVt/n counterparts. The two observers reported an identical number of lesions from the 1 h and 2 h scans but preferred the 2 h data. CONCLUSIONS: Tumour stage and the percentage difference in 1 h and 2 h SUVt showed potential as prognostic indicators of long-term survival.

Geriatric medical education and training in the United States.

Medical education in geriatrics is an important requirement to ready the profession to provide comprehensive health care to the world's and also Taiwan's aging population. The predoctoral curricula and postdoctoral training programs in the United States were developed and supported by government agencies and professional education societies. Geriatric medical education in American medical schools has improved in the past 20 years, yet is still facing many challenges. The purposes of this paper are to review the current progress of, and propose some main principles and policies for the development of geriatric medical education and current progress in the United States. Geriatric medical education should be mandatory to adequately prepare medical students, residents, fellows, and practicing physicians to treat the elderly. The current progress and practice of geriatric medical education at the University of Texas Health Science Center at San Antonio are presented as an example.

Secretion of salivary statherin is compromised in uncontrolled diabetic patients.

BACKGROUND: Statherin is an important salivary protein for maintaining oral health. The purpose of the current study was to determine if differences in statherin levels exist between diabetic and healthy subjects. METHODS: A total of 48 diabetic and healthy controls were randomly selected from a community-based database. Diabetic subjects (n=24) had fasting glucose levels >180 mg/dL, while controls (n=24) had levels <110 mg/dL. Parotid saliva (PS) and sublingual/submandibular saliva (SS) were collected and salivary flow rates determined. Salivary statherin levels were determined by densitometry of Western blots. Blood hemoglobin A1c (HbA1c) and total protein in saliva were also obtained. RESULTS: SS, but not PS, salivary flow rate and total protein in diabetics were significantly less than in healthy controls (p=0.021 & p<0.001 respectively). Correlation analysis revealed the existence of a negative correlation between PS statherin levels and HbA1c (p=0.012) and fasting glucose (p=0.021) levels, while no such correlation was found for SS statherin levels. When statherin levels were normalized to total salivary protein, the proportion of PS statherin, but not SS statherin, in diabetics was significantly less than controls (p=0.032). In contrast, the amount of statherin secretion in SS, but not PS, was significantly decreased in diabetics compared to controls (p=0.016). CONCLUSIONS AND GENERAL SIGNIFICANCE: The results show that synthesis and secretion of statherin is reduced in diabetics and this reduction is salivary gland specific. As compromised salivary statherin secretion leads to increased oral health risk, this study indicates that routine oral health assessment of these patients is warranted.

Molecular biomarkers and site of first recurrence after radiotherapy for head and neck cancer.

The prognostic significance of a panel of molecular biomarkers in head and neck squamous cell carcinoma (HNSCC) for first failure site (primary (T), nodal (N) or distant (M)) was analysed in 309 patients randomised to continuous hyperfractionated accelerated radiotherapy (CHART) vs. conventionally fractionated radiotherapy. Multivariate competing risks analysis was performed using an accelerated failure-time model. First-order interactions between each marker and trial arm were also tested. Bcl2-positivity increased the time to T- and N-failures, increasing cyclin D1 score decreased the time to N-failures. A random proliferative pattern and low Ki-67 decreased the time to M-failures. A high CD31 score was associated with a significantly longer time to T-failure after CHART, but not after conventional fractionation. Risks of T-, N- and M-failures could be estimated for individual patients. Competing risks analysis of failure sites allows the rational selection of patients for more aggressive loco-regional or systemic therapy.

Low dose hyper-radiosensitivity in metastatic tumors.

INTRODUCTION: The laboratory phenomenon of low dose hyper-radiosensitivity (LDHRS) describes excess cell kill at doses below 1 Gy relative to that predicted by the linear quadratic model. These data have stimulated the investigation of whether LDHRS can be exploited clinically. METHODS: Patients with metastatic tumor nodules to skin were recruited. The nodules were measured in three dimensions, consecutively numbered according to volume, and randomized, in matched pairs, to receive either conventionally fractionated radiotherapy (1.5 Gy/day) or ultrafractionated radiotherapy (0.5 Gy TDS: 4-h gap). Both groups were treated for 12 days. Measurements were taken Days 0, 5, 8, 12, and 26 and monthly until regrowth occurred. Tumor volumes were normalized to those on Day 0 and plotted against time from the start of treatment. Time to regrowth to original volume was calculated and compared between groups using the Wilcoxon signed rank test. RESULTS: Eight patients with a total of 40 paired nodules were analyzed; 36 nodules have regrown and are therefore evaluable. Analysis of the whole data set demonstrates a two-tailed p-value of 0.14 in favor of the "ultrafractionated" treatment. Analysis of the tumors generally accepted as being radioresistant and known to show LDHRS in vitro demonstrates a two-tailed p value of 0.009. CONCLUSIONS: LDHRS can be demonstrated in tumors clinically. An "ultrafractionated" radiotherapy regime produces significantly increased growth delay in radioresistant malignant tumors.

Compliance to the prescribed dose and overall treatment time in five randomized clinical trials of altered fractionation in radiotherapy for head-and-neck carcinomas.

PURPOSE: To investigate compliance to the prescribed dose-fractionation schedule in five randomized controlled trials of altered fractionation in radiotherapy for head-and-neck carcinoma. METHODS AND MATERIALS: Individual patient data from 2566 patients participating in the European Organization for Research and Treatment of Cancer (EORTC) 22791, EORTC 22811, EORTC 22851, Princess Margaret Hospital (PMH), and continuous hyperfractionated accelerated radiotherapy (CHART) head-and-neck trials were merged in the fractionation IMPACT (Intergroup Merger of Patient data from Altered or Conventional Treatment schedules) study database. The ideal treatment time was defined as the minimum time required to deliver a prescribed schedule. Compliance to the prescribed overall treatment time was quantified as the difference between the actual and the ideal overall time. An overall measure of compliance in an individual patient, the total dose lost (TDL), was calculated as the dose lost due to prolongation of therapy (assuming a D(prolif) of 0.64 Gy/day) plus the difference between the prescribed and the actual dose given. RESULTS: The time in excess of the ideal ranged up to 97 days (average 3.9 days), and 25% of the patients had delays of 6 days or more. World Health Organization (WHO) performance status and nodal stage had a significant effect on TDL. TDL was significantly higher in the conventional than in the altered arm of the EORTC 22851 and CHART trials. In the PMH trial, TDL was significantly higher in the hyperfractionation than in the conventional arm. Centers participating in the three EORTC trials varied significantly in their compliance. There was a significant improvement in compliance in patients treated more recently. CONCLUSIONS: Even in randomized controlled trials, compliance to the prescribed radiation therapy schedule may be relatively poor, especially after conventional fractionation. This affects the interpretation of the outcome of these trials.

The immunohistochemical assessment of hypoxia, vascularity and proliferation in bladder carcinoma.

BACKGROUND AND PURPOSE: Hypoxia and proliferation are important determinants of radiation responsiveness; prospective measures of these before radiotherapy may enable individualisation of treatment schedules. Immunohistochemical techniques offer a potential means of achieving this in routine biopsy material. MATERIAL AND METHODS: Cellular hypoxia as measured by pimonidazole fixation and immunohistochemistry has been evaluated in a series of human bladder cancers with dual staining of sections for pimonidazole and either the vascular markers, CD31/34, or proliferation markers, Ki-67 or cyclin A. Twenty one tumour specimens were examined suitable for the double staining technique. RESULTS: The median hypoxic fraction was 9% (range 0-38). Seven tumours did not stain for pimonidazole and 11 exhibited necrosis. The mean vascular density ranged from 16.7 to 160.6 vessels per mm2. The median hot spot count was 30 (range 16-43). There was a statistically significant increase in vessel density in hypoxic compared to oxic regions measured by both vessel density (P = 0.02) and hot spot count (P = 0.004). Proliferation indices decreased from oxic to hypoxic areas close to blood vessels. CONCLUSIONS: We have demonstrated that bladder cancer exhibits a range of hypoxia, proliferation and vascular density which may be used to form the basis for patient selection for hypoxia modification, accelerated radiotherapy and vascular targeting agents.