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Long-Term Outcomes of Radical Radiation Therapy with Hypoxia Modification with Biomarker Discovery for Stratification: 10-Year Update of the BCON (Bladder Carbogen Nicotinamide) Phase 3 Randomized Trial (ISRCTN45938399).
Song, YP, Mistry, H, Irlam, J, Valentine, H, Yang, L, Lane, B, West, C, Choudhury, A, Hoskin, PJ
International journal of radiation oncology, biology, physics. 2021;(5):1407-1415
Abstract
PURPOSE Many muscle-invasive bladder cancers are hypoxic, which limits the efficacy of radiation therapy. Hypoxia modification using carbogen and nicotinamide has been tested in a phase 3 trial, Bladder Carbogen Nicotinamide. We present mature follow-up data with biomarker predictions of outcomes. METHODS AND MATERIALS Bladder Carbogen Nicotinamide is a prospective, phase 3, multicenter, randomized, 2-arm, nonblinded clinical trial. Participants were randomized to receive radical radiation therapy (RT; control arm) alone or with the addition of carbogen (98% O2; 2% CO2) and nicotinamide (CON). Patients with muscle-invasive or high-grade non-muscle invasive bladder cancer were included. Tumor tissue was collected at entry and was analyzed for tumor necrosis, hypoxia (24-gene signature), and basal and luminal tumor molecular subtypes. Overall survival (OS) and disease-free survival and relationships with biomarker status outcomes are analyzed using multivariable Cox regression and log-rank analysis. RESULTS We analyzed 333 patients with a median follow-up of 10.3 years. The 10-year OS rates were 30% (95% confidence interval [CI], 0.23-0.39) in RT + CON patients and 24% (95% CI, 0.18-0.33) in the RT-alone patients (hazard ratio [HR], 0.80; 95% CI, 0.61-1.04; P = .08). The greatest benefit from CON was seen in patients with tumor necrosis (n = 79; 5-year OS, 53% vs. 33% in patients without tumor necrosis; HR, 0.59; 95% CI, 0.36-0.99; P = .04). Cases with a high hypoxia gene score (n = 75) had a 5-year OS rate of 51%, compared to 34% for a low score (HR, 0.64; 95% CI, 0.38-1.08; P = .09); those with the basal molecular subtype (n = 70) had a 5-year OS rate of 58%, compared to 38% for those with the luminal subtype (HR, 0.58; 95% CI, 0.32-1.06; P = .08). CONCLUSIONS Although the improvement in long-term OS in the whole population is not statistically significant, patients selected by necrosis and high hypoxia gene score benefitted from hypoxia modification.
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Effect of sodium-chloride ion difference on pH regulation.
Nozawa, H, Tsuboi, N, Nariai, R, Nishimura, N, Nakagawa, S
Clinical biochemistry. 2021;:75-77
Abstract
BACKGROUND In the Stewart approach, the difference between the cation and anion concentrations, especially between sodium, accounting for the majority of cations, and chloride, comprising the majority of anions, is an important factor in pH regulation. This study investigated the effect of sodium-chloride ion difference (SCD) on pH regulation comparing with those of PaCO2 and lactate. METHODS Arterial blood gas samples measured at our pediatric intensive care unit of a tertiary children's hospital between January and June 2020 were included. Samples that met the following criteria were excluded: samples collected from patients taking potassium bromide and samples with lactate concentration of >25 mmol/L. From the eligible data, pH was chosen as the dependent variable and SCD, lactate, and PaCO2 as independent variables, and then, a multiple regression analysis was performed. RESULTS In total, 5360 samples were included. Of these, five samples were excluded according to the exclusion criteria. Finally, 5355 samples were analyzed. As the variance inflation factors were <2.0 for all three variables, there was no multicollinearity. The following model was derived: pH = 7.384 + [0.97 × SCD (mEq/L) - 0.66 × PaCO2 (mmHg) - 1.33 × Lac (mmol/L)] × 10-2 (adjusted R-squared = 0.73; P value < 0.001). Based on the standardized partial regression coefficients (β), pH was affected in the order of PaCO2 (βPaCO2 = -0.95), SCD (βSCD = 0.72), and lactate (βlactate = -0.33). CONCLUSIONS The prevention of SCD reduction, together with respiratory and metabolic management, is important for pH regulation.
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MECCIAS trial: Metabolic consequences of continuous veno-venous hemofiltration on indirect calorimetry.
Jonckheer, J, Demol, J, Lanckmans, K, Malbrain, MLNG, Spapen, H, De Waele, E
Clinical nutrition (Edinburgh, Scotland). 2020;(12):3797-3803
Abstract
BACKGROUND and aims: Caloric prescription based on resting energy expenditure (REE) measured with indirect calorimetry (IC) improves outcome and is the gold standard in nutritional therapy of critically ill patients. Until now continuous renal replacement therapy (CRRT) precluded the use of IC due to several mechanisms. We investigated the impact of CRRT on V̇CO2, V̇O2 and REE to facilitate indirect calorimetry during CRRT. METHODS In 10 critically ill ventilated patient in need of continuous veno-venous hemofiltration (CVVH) using citrate predilution we performed IC in 4 different states: baseline, high dose, baseline with NaCl predilution and without CVVH. CO2 content of effluent fluid was measured by a point of care blood gas analyzer. Carbon dioxide production (V̇CO2) measured with IC was adapted by adding the CO2 flow of effluent and deducing CO2 flow in postdilution fluid to calculate a true V̇CO2. True REE was calculated with the Weir equation using the true V̇CO2. RESULTS CO2 removal in effluent during baseline, high dose and NaCl predilution was respectively 24 mL/min, 38 mL/min and 23 mL/min. Together with the CO2 delivery by the postdilution fluid this led to an adaptation of REE respectively by 34 kcal/d or 2% (p = 0,002), 44 kcal/d or 3% (p = 0,002) and 33 kcal/d or 2% (p = 0,002). Compared to the true REE during baseline of 1935 ± 921 kcal/d, true REE during high dose was 1723 ± 752 kcal/d (p = 0.65), during NaCl predilution it was 1604 ± 633 kcal/d (p = 0.014) and without CRRT it was 1713 ± 704 kcal/d (p = 0.193). CONCLUSIONS CO2 alterations due to CVVH are clinically of no importance so no correction factor of REE is needed with or without CVVH. IC must be performed during CVVH as CVVH seems to alter metabolism. These changes may be mainly explained by the use of citrate predilution.
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CO2 and O2 removal during continuous veno-venous hemofiltration: a pilot study.
Jonckheer, J, Spapen, H, Debain, A, Demol, J, Diltoer, M, Costa, O, Lanckmans, K, Oshima, T, Honoré, PM, Malbrain, M, et al
BMC nephrology. 2019;(1):222
Abstract
BACKGROUND Carbon dioxide (CO2) accumulation is a challenging issue in critically ill patients. CO2 can be eliminated by renal replacement therapy but studies are scarce and clinical relevance is unknown. We prospectively studied CO2 and O2 behavior at different sample points of continuous veno-venous hemofiltration (CVVH) and build a model to calculate CO2 removal bedside. METHODS In 10 patients receiving standard CVVH under citrate anticoagulation, blood gas analysis was performed at different sample points within the CVVH circuit. Citrate was then replaced by NaCl 0.9% and sampling was repeated. Total CO2 (tCO2), CO2 flow (V̇CO2) and O2 flow (V̇O2) were compared between different sample points. The effect of citrate on transmembrane tCO2 was evaluated. Wilcoxon matched-pairs signed rank test was performed to evaluate significance of difference between 2 data sets. Friedman test was used when more data sets were compared. RESULTS V̇CO2 in the effluent (26.0 ml/min) correlated significantly with transmembrane V̇CO2 (24.2 ml/min). This represents 14% of the average expired V̇CO2 in ventilated patients. Only 1.3 ml/min CO2 was removed in the de-aeration chamber, suggesting that CO2 was almost entirely cleared across the membrane filter. tCO2 values in effluent, before, and after the filter were not statistically different. Transmembrane tCO2 under citrate or NaCl 0.9% predilution also did not differ significantly. No changes in V̇O2 were observed throughout the CVVH circuit. Based on recorded data, formulas were constructed that allow bedside evaluation of CVVH-attributable CO2 removal. CONCLUSION A relevant amount of CO2 is removed by CVVH and can be quantified by one simple blood gas analysis within the circuit. Future studies should assess the clinical impact of this observation. TRIAL REGISTRATION The trial was registered at https://clinicaltrials.gov with trial registration number NCT03314363 on October 192,017.
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Shear-mediated dilation of the internal carotid artery occurs independent of hypercapnia.
Hoiland, RL, Smith, KJ, Carter, HH, Lewis, NCS, Tymko, MM, Wildfong, KW, Bain, AR, Green, DJ, Ainslie, PN
American journal of physiology. Heart and circulatory physiology. 2017;(1):H24-H31
Abstract
Evidence for shear stress as a regulator of carotid artery dilation in response to increased arterial CO2 was recently demonstrated in humans during sustained elevations in CO2 (hypercapnia); however, the relative contributions of CO2 and shear stress to this response remains unclear. We examined the hypothesis that, after a 30-s transient increase in arterial CO2 tension and consequent increase in internal carotid artery shear stress, internal carotid artery diameter would increase, indicating shear-mediated dilation, in the absence of concurrent hypercapnia. In 27 healthy participants, partial pressures of end-tidal O2 and CO2, ventilation (pneumotachography), blood pressure (finger photoplethysmography), heart rate (electrocardiogram), internal carotid artery flow, diameter, and shear stress (high-resolution duplex ultrasound), and middle cerebral artery blood velocity (transcranial Doppler) were measured during 4-min steady-state and transient 30-s hypercapnic tests (both +9 mmHg CO2). Internal carotid artery dilation was lower in the transient compared with steady-state hypercapnia (3.3 ± 1.9 vs. 5.3 ± 2.9%, respectively, P < 0.03). Increases in internal carotid artery shear stress preceded increases in diameter in both transient (time: 16.8 ± 13.2 vs. 59.4 ± 60.3 s, P < 0.01) and steady-state (time: 18.2 ± 14.2 vs. 110.3 ± 79.6 s, P < 0.01) tests. Internal carotid artery dilation was positively correlated with shear rate area under the curve in the transient (r2 = 0.44, P < 0.01) but not steady-state (r2 = 0.02, P = 0.53) trial. Collectively, these results suggest that hypercapnia induces shear-mediated dilation of the internal carotid artery in humans. This study further promotes the application and development of hypercapnia as a clinical strategy for the assessment of cerebrovascular vasodilatory function and health in humans.NEW & NOTEWORTHY Shear stress dilates the internal carotid artery in humans. This vasodilatory response occurs independent of other physiological factors, as demonstrated by our transient CO2 test, and is strongly correlated to shear area under the curve. Assessing carotid shear-mediated dilation may provide a future avenue for assessing cerebrovascular health and the risk of cerebrovascular events.
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A Simple Diagnostic Test to Confirm Correct Placement of Dysfunctional Central Venous Catheters Before Chemotherapy in Children.
Keidan, I, Ben-Menachem, E, Berkenstadt, H, Toren, A
Journal of pediatric hematology/oncology. 2016;(1):78-80
Abstract
BACKGROUND In children undergoing intravenous chemotherapy, partial dysfunction of the central venous catheter (CVC) is common. Fluids can be infused into the catheter; however, blood cannot be aspirated. In those situations, chemotherapy is withheld and a catheter investigation is performed. Usually, a radiographic study with contrast media or therapy with thrombolytic drugs followed by rechecking for blood return is undertaken. AIM: To evaluate if a previously described method using dilute sodium bicarbonate injection and the resultant rise in measured end-tidal carbon dioxide tracing can confirm correct intravascular placement of a dysfunctional CVC in children at the bedside. PATIENTS Cohort group of 22 children scheduled for chemotherapy with partial dysfunction of a CVC in a tertiary hematology-oncology care facility. RESULTS All children with a partial dysfunctional CVC that was proven to be intravascular after venogram or thrombolytic therapy had a distinct and predictable increase in end-tidal carbon dioxide response to injected bicarbonate. CONCLUSION Injection of 1 mL/kg (maximum 20 mL) of 4.2% dilute sodium bicarbonate is a quick, simple, bedside test allowing confirmation of intravascular location of dysfunctional CVC.
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Improved recurrence-free survival with ARCON for anemic patients with laryngeal cancer.
Janssens, GO, Rademakers, SE, Terhaard, CH, Doornaert, PA, Bijl, HP, van den Ende, P, Chin, A, Takes, RP, de Bree, R, Hoogsteen, IJ, et al
Clinical cancer research : an official journal of the American Association for Cancer Research. 2014;(5):1345-54
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Abstract
PURPOSE Anemia is associated with poor tumor control. It was previously observed that accelerated radiotherapy combined with carbogen breathing and nicotinamide (ARCON) can correct this adverse outcome in patients with head and neck cancer. The purpose of this study was to validate this observation based on data from a randomized trial. EXPERIMENTAL DESIGN Of 345 patients with cT2-4 laryngeal cancer, 174 were randomly assigned to accelerated radiotherapy and 171 to ARCON. Hemoglobin levels, measured before treatment, were defined as low when <7.5 mmol/L for women and <8.5 mmol/L for men. The hypoxia marker pimonidazole was used to assess the oxygenation status in tumor biopsies. Data were analyzed 2 years after inclusion of the last patient. RESULTS Pretreatment hemoglobin levels were available and below normal in 27 of 173 (16%) accelerated radiotherapy and 27 of 167 (16%) ARCON patients. In patients with normal pretreatment, hemoglobin levels treatment with ARCON had no significant effect on 5-year loco-regional control (LRC, 79% versus 75%; P = 0.44) and disease-free survival (DFS, 75% vs. 70%; P = 0.46) compared with accelerated radiotherapy. However, in patients with low pretreatment, hemoglobin levels ARCON significantly improved 5-year LRC (79% vs. 53%; P = 0.03) and DFS (68% vs. 45%; P = 0.04). In multivariate analysis including other prognostic factors, pretreatment hemoglobin remained prognostic for LRC and DFS in the accelerated radiotherapy treatment arm. No correlation between pretreatment hemoglobin levels and pimonidazole uptake was observed. CONCLUSION Results from the randomized phase III trial support previous observations that ARCON has the potential to correct the poor outcome of cancer patients with anemia (ClinicalTrials.gov number, NCT00147732).
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Pattern of CAIX expression is prognostic for outcome and predicts response to ARCON in patients with laryngeal cancer treated in a phase III randomized trial.
Rademakers, SE, Hoogsteen, IJ, Rijken, PF, Oosterwijk, E, Terhaard, CH, Doornaert, PA, Langendijk, JA, van den Ende, P, Takes, R, De Bree, R, et al
Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology. 2013;(3):517-22
Abstract
BACKGROUND AND PURPOSE In a phase III trial in patients with advanced stage laryngeal carcinoma comparing ARCON (accelerated radiotherapy with carbogen breathing and nicotinamide) to accelerated radiotherapy alone (AR) the prognostic and predictive value of CAIX, a hypoxia-associated protein, was investigated. MATERIAL AND METHODS 261 Paraffin embedded tumor biopsies and 79 fresh frozen biopsies from patients entered in the trial were immunohistochemically stained for CAIX. CAIX-fraction and CAIX expression pattern were related to tumor control and patient survival. RESULTS Low CAIX-fraction was prognostic for worse regional control and overall survival in patients treated with AR. Patients with a low CAIX-fraction treated with ARCON had better regional control and metastasis-free survival compared to AR (RC 97% vs 71%, p < 0.01 and MFS 92% vs 69%, p = 0.06). Patients with a perinecrotic CAIX staining pattern had a significantly worse local control, metastasis-free and overall survival compared to patients with a diffuse pattern (65% vs 84%, p = 0.01, 70% vs 96%, p < 0.01 and 42% vs 71%, p < 0.01 respectively), and this could not be improved with ARCON. After multivariate analysis CAIX pattern and N-stage emerged as significant predictors for metastasis-free survival and overall survival. CONCLUSIONS ARCON improves regional control and metastasis-free survival only in patients with low CAIX expression. The different patterns of CAIX expression suggest different mechanisms of upregulation and have important prognostic value.
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An exploratory study of respiratory quotient calibration and association with postmenopausal breast cancer.
Prentice, RL, Neuhouser, ML, Tinker, LF, Pettinger, M, Thomson, CA, Mossavar-Rahmani, Y, Thomas, F, Qi, L, Huang, Y
Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. 2013;(12):2374-83
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BACKGROUND The respiratory quotient (RQ), defined as the ratio of carbon dioxide exhaled to oxygen uptake, reflects substrate utilization when energy is expended. Fat and alcohol have RQ values of approximately 0.7, compared with 1.0 for carbohydrate, and approximately 0.8 for protein. Here, the association between RQ and postmenopausal breast cancer risk is studied. METHODS Paired RQ measurements were obtained, separated by approximately 6 months, for women in the reliability subset of a Women's Health Initiative (WHI) Nutrition and Physical Activity Assessment Study. Linear regression of the average of the paired log RQ assessments on a corresponding log food quotient (FQ) average and other study subject characteristics, including age, body mass index, race, and education, yielded calibration equations for predicting RQ. RESULTS Calibration equations, using any of food frequency, food record, or dietary recall data, explained an appreciable fraction of measured log RQ variation, and these were used to compute calibrated RQ estimates throughout WHI cohorts. Calibrated RQ estimates using 4-day food record (4DFR) data related inversely (P = 0.004) to (invasive) breast cancer risk in the WHI Dietary Modification trial comparison group, and corresponding RQ estimates using food-frequency data related inversely (P = 0.002) to breast cancer incidence in this cohort combined with the larger WHI observational study. CONCLUSION Although preliminary, these analyses suggest a substantially higher postmenopausal breast cancer risk among women having relatively low RQ. IMPACT RQ elevation could provide a novel target for breast cancer risk reduction.
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Necrosis predicts benefit from hypoxia-modifying therapy in patients with high risk bladder cancer enrolled in a phase III randomised trial.
Eustace, A, Irlam, JJ, Taylor, J, Denley, H, Agrawal, S, Choudhury, A, Ryder, D, Ord, JJ, Harris, AL, Rojas, AM, et al
Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology. 2013;(1):40-7
Abstract
BACKGROUND AND PURPOSE Addition of carbogen and nicotinamide (hypoxia-modifying agents) to radiotherapy improves the survival of patients with high risk bladder cancer. The study investigated whether histopathological tumour features and putative hypoxia markers predicted benefit from hypoxia modification. MATERIALS AND METHODS Samples were available from 231 patients with high grade and invasive bladder carcinoma from the BCON phase III trial of radiotherapy (RT) alone or with carbogen and nicotinamide (RT+CON). Histopathological tumour features examined were: necrosis, growth pattern, growing margin, and tumour/stroma ratio. Hypoxia markers carbonic anhydrase-IX and glucose transporter-1 were examined using tissue microarrays. RESULTS Necrosis was the only independent prognostic indicator (P=0.04). Necrosis also predicted benefit from hypoxia modification. Five-year overall survival was 48% (RT) versus 39% (RT+CON) (P=0.32) in patients without necrosis and 34% (RT) versus 56% (RT+CON) (P=0.004) in patients with necrosis. There was a significant treatment by necrosis strata interaction (P=0.001 adjusted). Necrosis was an independent predictor of benefit from RT+CON versus RT (hazard ratio [HR]: 0.43, 95% CI 0.25-0.73, P=0.002). This trend was not observed when there was no necrosis (HR: 1.64, 95% CI 0.95-2.85, P=0.08). CONCLUSIONS Necrosis predicts benefit from hypoxia modification in patients with high risk bladder cancer and should be used to select patients; it is simple to identify and easy to incorporate into routine histopathological examination.