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.

Hyperfractionated or accelerated radiotherapy in lung cancer: an individual patient data meta-analysis.

PURPOSE: In lung cancer, randomized trials assessing hyperfractionated or accelerated radiotherapy seem to yield conflicting results regarding the effects on overall (OS) or progression-free survival (PFS). The Meta-Analysis of Radiotherapy in Lung Cancer Collaborative Group decided to address the role of modified radiotherapy fractionation. MATERIAL AND METHODS: We performed an individual patient data meta-analysis in patients with nonmetastatic lung cancer, which included trials comparing modified radiotherapy with conventional radiotherapy. RESULTS: In non-small-cell lung cancer (NSCLC; 10 trials, 2,000 patients), modified fractionation improved OS as compared with conventional schedules (hazard ratio [HR] = 0.88, 95% CI, 0.80 to 0.97; P = .009), resulting in an absolute benefit of 2.5% (8.3% to 10.8%) at 5 years. No evidence of heterogeneity between trials was found. There was no evidence of a benefit on PFS (HR = 0.94; 95% CI, 0.86 to 1.03; P = .19). Modified radiotherapy reduced deaths resulting from lung cancer (HR = 0.89; 95% CI, 0.81 to 0.98; P = .02), and there was a nonsignificant reduction of non-lung cancer deaths (HR = 0.87; 95% CI, 0.66 to 1.15; P = .33). In small-cell lung cancer (SCLC; two trials, 685 patients), similar results were found: OS, HR = 0.87, 95% CI, 0.74 to 1.02, P = .08; PFS, HR = 0.88, 95% CI, 0.75 to 1.03, P = .11. In both NSCLC and SCLC, the use of modified radiotherapy increased the risk of acute esophageal toxicity (odds ratio [OR] = 2.44 in NSCLC and OR = 2.41 in SCLC; P < .001) but did not have an impact on the risk of other acute toxicities. CONCLUSION: Patients with nonmetastatic NSCLC derived a significant OS benefit from accelerated or hyperfractionated radiotherapy; a similar but nonsignificant trend was observed for SCLC. As expected, there was increased acute esophageal toxicity.

Antivascular effects of neoadjuvant androgen deprivation for prostate cancer: an in vivo human study using susceptibility and relaxivity dynamic MRI.

PURPOSE: The antivascular effects of androgen deprivation have been investigated in animal models; however, there has been minimal investigation in human prostate cancer. This study tested the hypothesis that androgen deprivation causes significant reductions in human prostate tumor blood flow and the induction of hypoxia at a magnitude and in a time scale relevant to the neoadjuvant setting before radiotherapy. METHODS AND MATERIALS: Twenty patients were examined, each with five multi-parameter magnetic resonance imaging scans: two scans before the commencement of androgen suppression, one scan after 1 month of hormone treatment, and two further scans after 3 months of therapy. Quantitative parametric maps of the prostate informing on relative blood flow (rBF), relative blood volume (rBV), vascular permeability (transfer constant [K(trans)]), leakage space (v(e)) and blood oxygenation (intrinsic relaxivity [R(2)∗]) were calculated. RESULTS: Tumor blood volume and blood flow decreased by 83% and 79%, respectively, in the first month (p < 0.0001), with 74% of patients showing significant changes. The proportion of individual patients who achieved significant changes in T1 kinetic parameter values after 3 months of androgen deprivation for tumor measurements was 68% for K(trans) and 53% for v(e) By 3 months, significant increases in R(2)∗ had occurred in prostate tumor, with a rise of 41.1% (p < 0.0001). CONCLUSIONS: Androgen deprivation induces profound vascular collapse within 1 month of starting treatment. Increased R(2)∗ in regions of prostate cancer and a decrease in blood volume suggest a reduction in tumor oxygenation.

Radiotherapy with concurrent carbogen and nicotinamide in bladder carcinoma.

PURPOSE: Phase II clinical studies suggest that hypoxic modification with carbogen and nicotinamide (CON) may increase the efficacy of radiotherapy (RT). PATIENTS AND METHODS: Three hundred thirty-three patients with locally advanced bladder carcinoma were randomly assigned to RT alone versus RT with CON. A schedule of either 55 Gy in 20 fractions in 4 weeks or 64 Gy in 32 fractions in 6.5 weeks was used. The primary end point was cystoscopic control at 6 months (CC(6m)) and secondary end points were overall survival (OS), local relapse-free survival (RFS), urinary and rectal morbidity. RESULTS: CC(6m) was 81% for RT + CON and 76% for RT alone (P = .3); however, just more than half of patients underwent cystoscopy at that time. Three-year estimates of OS were 59% and 46% (P = .04) and 3-year estimates of RFS were 54% and 43% (P = .06) for RT + CON versus RT alone. Risk of death was 14% lower with RT + CON (P = .04). In multivariate comparison, RT + CON significantly reduced the risk of relapse (P = .05) and death (P = .03). There was no evidence that differences in late urinary or GI morbidity between treatment groups or between fractionation schedules were significant. CONCLUSION: RT + CON produced a small nonsignificant improvement in CC(6m). Differences in OS, risk of death, and local relapse were significantly in favor of RT + CON. Late morbidity was similar in both trial arms. Results indicate a benefit of adding CON to radical RT.

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.

The potential advantages of (18)FDG PET/CT-based target volume delineation in radiotherapy planning of head and neck cancer.

PURPOSE: This study investigated two fixed threshold methods to delineate the target volume using (18)FDG PET/CT before and during a course of radical radiotherapy in locally advanced squamous cell carcinoma of the head and neck. MATERIALS AND METHODS: Patients were enrolled into the study between March 2006 and May 2008. (18)FDG PET/CT scans were carried out 72h prior to the start of radiotherapy and then at 10, 44 and 66Gy. Functional volumes were delineated according to the SUV Cut Off (SUVCO) (2.5, 3.0, 3.5, and 4.0bwg/ml) and percentage of the SUVmax (30%, 35%, 40%, 45%, and 50%) thresholds. The background (18)FDG uptake and the SUVmax within the volumes were also assessed. RESULTS: Primary and lymph node volumes for the eight patients significantly reduced with each increase in the delineation threshold (for example 2.5-3.0bwg/ml SUVCO) compared to the baseline threshold at each imaging point. There was a significant reduction in the volume (p⩽0.0001-0.01) after 36Gy compared to the 0Gy by the SUVCO method. There was a negative correlation between the SUVmax within the primary and lymph node volumes and delivered radiation dose (p⩽0.0001-0.011) but no difference in the SUV within the background reference region. The volumes delineated by the PTSUVmax method increased with the increase in the delivered radiation dose after 36Gy because the SUVmax within the region of interest used to define the edge of the volume was equal or less than the background (18)FDG uptake and the software was unable to effectively differentiate between tumour and background uptake. CONCLUSIONS: The changes in the target volumes delineated by the SUVCO method were less susceptible to background (18)FDG uptake compared to those delineated by the PTSUVmax and may be more helpful in radiotherapy planning. The best method and threshold have still to be determined within institutions, both nationally and internationally.

Mature results of a randomized trial of accelerated hyperfractionated versus conventional radiotherapy in head-and-neck cancer.

PURPOSE: To evaluate long-term late adverse events and treatment outcome of a randomized, multicenter Phase III trial of continuous, hyperfractionated, accelerated radiotherapy (CHART) compared with conventional radiotherapy (CRT) in 918 patients with advanced squamous cell carcinomas of the head and neck. METHODS AND MATERIALS: Survival estimates were obtained for locoregional relapse-free survival, local relapse-free survival, overall survival, disease-specific survival, disease-free survival and for late adverse events. RESULTS: The 10-year estimates (+/-1 standard error) for locoregional relapse-free survival, overall survival, disease-free survival, and disease-specific survival were 43% +/- 2% for CHART and 50% +/- 3% with CRT (log-rank p = 0.2); 26% +/- 2% and 29% +/- 3% (p = 0.4), respectively; 41% +/- 2% and 46% +/- 3% (p = 0.3), respectively; and 56% +/- 3% and 58% +/- 3% (p = 0.5), respectively. There was a small but significant reduction in the incidence of slight or worse and moderate or worse epidermal adverse events with CHART (p = 0.002 to 0.05). Severe xerostomia, laryngeal edema, and mucosal necrosis were also significantly lower with CHART (p = 0.02 to 0.05). CONCLUSIONS: Despite the reduction in total dose from 66 Gy to 54 Gy, control of locoregional disease and survival with CHART were similar to those with CRT. These findings, together with the low incidence of long-term severe adverse events, suggest that CHART is a treatment option for patients with low-risk disease and for those unable to withstand the toxicity of concurrent chemoradiotherapy.

Quantitative helical dynamic contrast enhanced computed tomography assessment of the spatial variation in whole tumour blood volume with radiotherapy in lung cancer.

We aim to assess the spatial distribution of blood volume (BV) in whole lung tumours in patients undergoing radiotherapy using helical dynamic contrast enhanced computed tomography (DCE-CT), and to determine whether conventional single level, or whole tumour measurements is more representative of the vascular effects of radiotherapy. Following ethical approval and informed consent, 15 patients with histologically proven non-small cell lung cancer underwent paired helical DCE-CT studies at baseline to assess repeatability, and after two fractions of radiotherapy (9 Gy total dose). Tumour BV was calculated for individual contiguous 10mm axial slices, and for the entire tumour volume on a pixel-per-pixel basis. Baseline tumour BV was heterogeneous varying by 15.33%+/-17.11 between adjacent 10mm axial slices. Within subject coefficient of variation was 36.72% with conventional single tumour level evaluation, and 13.62% with whole tumour measurements. Following radiotherapy, one patient had an increase in BV greater than baseline variation (derived from the 95% limits of change) using single level evaluation; in contrast, seven patients had an increase in BV when the whole tumour was assessed. As a group, following radiotherapy, mean BV increased by 17.27% (paired t-test, p=0.20) with single level evaluation and 19.26% (p=0.049) with whole tumour assessment. Tumour BV measured using DCE-CT is spatially heterogeneous. Given the slice-by-slice variation in blood volume, our results demonstrate that whole tumour DCE-CT measurements are more repeatable, and may be a better predictor of vascular changes following therapy, compared to conventional single tumour level evaluations.

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.

Accelerated radiotherapy, carbogen, and nicotinamide (ARCON) in the treatment of advanced bladder cancer: mature results of a Phase II nonrandomized study.

PURPOSE: We previously showed that accelerated radiotherapy combined with carbogen and nicotinamide (ARCON) was an effective approach to use in the radical treatment of patients with advanced bladder carcinoma. Interim analysis from this Phase II study showed that it achieved a high level of locoregional control and overall survival (OS) and an acceptable level of adverse events. METHODS AND MATERIALS: From 1994 to 2000, a total of 105 consecutive patients with high-grade superficial or muscle-invasive bladder carcinoma were given accelerated radiotherapy (50-55 Gy in 4 weeks) with carbogen alone or ARCON. End points of the study were OS, disease-specific, and local regional relapse-free survival, and for late adverse events, urinary (altered urination frequency, incontinence, hematuria, and urgency) and bowel dysfunction (stool frequency and blood loss). RESULTS: At 5 and 10 years, local regional relapse-free survival rates were 44% after ARCON excluding the effect of salvage treatment and 62% after ARCON including the effect of salvage treatment (p = 0.04). Five- and 10-year rates were 35% and 27% for OS and 47% and 46% for disease-specific survival. The highest actuarial rate for Grade 3 or worse late urinary or bowel dysfunction was observed for altered urinary frequency (44% of patients had urinary events every 1 hour or less) and stool frequency of four or more events (26% at 5 years). CONCLUSIONS: Historic comparisons with other studies indicate no evidence of an increase in severe or worse adverse events and good permanent control of bladder disease after ARCON radiotherapy.

[(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.

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.

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.

Intra-oral tactile sensation and aging in a community-based population.

BACKGROUND AND AIMS: Intra-oral sensory function plays an important role in swallowing and food intake, yet the impact of aging on oral tactile perception is uncertain. This study examined the effects of age, ethnicity, and gender on tactile perception at specific intra-oral sites in a community-based sample of 372 Mexican-Americans (MAs) and European-Americans (EAs). METHODS: Four levels of air-pressure were delivered to sites on the anterior and posterior thirds of the tongue and on the velum. Intensity judgments for suprathreshold air puffs were obtained with a direct scaling procedure. Data were analyzed by mixed model multivariate repeated measures ANOVA. RESULTS: Mean judgments of intensity, slopes of intensity functions and intraclass correlation coefficients (ICCs) for intensity judgments, indicated that stimuli delivered to the anterior tongue elicited significantly larger and more consistent responding than at the other sites. MAs produced lower mean stimulus intensity judgments for all sites compared to EAs. No significant age-, gender- or ethnic group-related differences were found at any of the sites for the slopes of the intensity functions or for ICCs. CONCLUSIONS: Stimuli are judged more intense at the anterior tongue compared to the posterior tongue or velum and EAs gave higher estimates of intensity than did MAs. However, there are no age-, gender-, or ethnic group-related differences for the repeatability of intensity judgments or the slopes of intensity functions. Intra-oral tactile perception seems to be preserved during aging.

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.

Effect of nitric-oxide synthesis on tumour blood volume and vascular activity: a phase I study.

BACKGROUND: Nitric oxide has been implicated in tumour angiogenesis and in the maintaining of vasodilator tone of tumour blood vessels. The tumour vascular effects of inhibition of nitric-oxide synthesis have not been investigated in patients with cancer. METHODS: Seven women and 11 men (12 with non-small-cell lung cancer, five prostate cancer, and one cervical cancer) were recruited onto a phase I dose-escalation study and received a single dose of the nitric oxide synthase inhibitor, N-nitro-L-arginine (L-NNA). Dose escalation was done by a modified Fibonacci scale with three patients at each dose level, starting with 0.1 mg/kg. Changes in dynamic contrast-enhanced CT measures of tumour relative blood volume and transfer constant (K) were measured at 1 h and 24 h after L-NNA administration. FINDINGS: In the 18 patients, toxic effects were self-limiting cardiovascular changes: three patients had Common Toxicity Criteria version 2.0 grade 1 hypertension; two had grade 1 sinus bradycardia; and one had grade 1 palpitation. L-NNA area under the curve (AUC) increased linearly with dose from 163 micromol min(-1) L(-1) at 0.1 mg/kg L-NNA to 2150 micromol min(-1) L(-1) at 0.9 mg/kg L-NNA. In eight patients that underwent dynamic CT scanning, tumour blood volume decreased 1 h after L-NNA treatment (mean 42.9% [range 12.0-62.1]; paired t test p=0.0070), which was sustained for up to 24 h (mean 33.9% [range 6.5-64.9]; p=0.035). This decrease in blood volume was associated with an increase in the number of non-perfused pixels from 7.3% (SD 5.5) at baseline to 25.1% (15.3; p=0.0089) at 1 h, and 18.2% (12.9; p=0.050) at 24 h. There was a significant correlation between L-NNA plasma AUC and the reduction in tumour blood volume at 24 h after L-NNA (r=0.83; p=0.010). INTERPRETATION: We have shown in vivo in patients with cancer that nitric oxide has a role in maintaining tumour blood supply, and we provide early clinical evidence that inhibition of nitric-oxide synthesis has tumour antivascular activity.

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.

Oral health issues in the nutrition of institutionalized elders.

Oral health is critical to systemic health and quality of life for the elderly, especially the institutionalized elderly, who are at high risk for oral and nutritional problems. Oral health is an integral component of overall nutritional health, just as nutrition plays a vital role in overall oral health. This article reviews the critical factors in the relationship among oral, nutritional, and systemic health and urges ongoing collaboration of providers of health care to reduce the rate of morbidity and mortality in institutionalized elders.

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.

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.