Mismatch repair status predicts survival after adjuvant treatment in stage II colon cancer patients.

BACKGROUND AND OBJECTIVES: Stage II colon cancer is primarily a surgical disease. Only a still not well-defined subset of patients may benefit from postoperative adjuvant chemotherapy. The relationship between adjuvant chemotherapy and survival after relapse is furthermore still not definitely explored in this group of patients. A number of reports suggest some association between defective mismatch repair (dMMR) and colorectal cancer stage II prognosis, but due to contradictory results from existing studies, the exact predictive role is still not fully understood. METHODS: Retrospective multicenter study including 451 stage II colon cancer patients. The proficiency or deficiency of mismatch repair was tested using immunohistochemistry and analyzed in relationship to two survival outcomes: overall survival (OS) and postrelapse survival. RESULTS: Patients with dMMR (20.4%) derived no OS benefit from adjuvant chemotherapy (hazard ratio [HR], 1.05; 95% confidence interval [CI], 0.47-2.38; P = .897). Patients with proficient mismatch repair (pMMR) tumors receiving adjuvant chemotherapy had the significantly better OS in comparison to those not receiving chemotherapy (HR, 0.54; 95% CI, 0.35-0.82; P = .004). This relationship remained significant in multivariable analysis (HR, 0.42; 95% CI, 0.22-0.78; P = .007). Patients with pMMR relapsing after adjuvant treatment lived significantly longer than those relapsing without previous adjuvant treatment (HR, 0.55; 95% CI, 0.32-0.96; P = .033) and this result remained significant in the multivariable model (HR, 0.49; 95% CI, 0.26-0.93; P = .030). CONCLUSION: In stage II CC patients, adjuvant chemotherapy improves therapeutic outcomes only in patients with pMMR tumors. Survival after relapse in patients having received adjuvant chemotherapy is significantly longer for patients with pMMR. No survival benefit from adjuvant chemotherapy was seen among patients with dMMR tumors.

Determination of small field synthetic single-crystal diamond detector correction factors for CyberKnife, Leksell Gamma Knife Perfexion and linear accelerator.

PURPOSE: The aim of this study was to determine small field correction factors for a synthetic single-crystal diamond detector (PTW microDiamond) for routine use in clinical dosimetric measurements. MATERIALS AND METHODS: Correction factors following small field Alfonso formalism were calculated by comparison of PTW microDiamond measured ratio MQclinfclin/MQmsrfmsr with Monte Carlo (MC) based field output factors ΩQclin,Qmsrfclin,fmsr determined using Dosimetry Diode E or with MC simulation itself. Diode measurements were used for the CyberKnife and Varian Clinac 2100C/D linear accelerator. PTW microDiamond correction factors for Leksell Gamma Knife (LGK) were derived using MC simulated reference values from the manufacturer. RESULTS: PTW microDiamond correction factors for CyberKnife field sizes 25-5 mm were mostly smaller than 1% (except for 2.9% for 5 mm Iris field and 1.4% for 7.5 mm fixed cone field). The correction of 0.1% and 2.0% for 8 mm and 4 mm collimators, respectively, needed to be applied to PTW microDiamond measurements for LGK Perfexion. Finally, PTW microDiamond MQclinfclin/MQmsrfmsr for the linear accelerator varied from MC corrected Dosimetry Diode data by less than 0.5% (except for 1 × 1 cm2 field size with 1.3% deviation). CONCLUSIONS: Regarding low resulting correction factor values, the PTW microDiamond detector may be considered an almost ideal tool for relative small field dosimetry in a large variety of stereotactic and radiosurgery treatment devices.

The effects of 100% wild blueberry (Vaccinium angustifolium) juice consumption on cardiometablic biomarkers: a randomized, placebo-controlled, crossover trial in adults with increased risk for type 2 diabetes.

BACKGROUND: Wild blueberries have a high content of polyphenols, but there is limited data evaluating their health benefits in adults at risk for type 2 diabetes. The objective of the study was to investigate whether consumption of 100% wild blueberry juice improves cardiometabolic biomarkers associated with type 2 diabetes risk. METHODS: A single-blind, randomized, placebo-controlled, crossover design trial was conducted in which adults (women, n = 19, ages 39-64 y) at risk for type 2 diabetes consumed 240 mL of wild blueberry juice or a placebo beverage as part of their free-living diet for 7 days. Blood was collected to determine various biomarkers such as fasting plasma glucose, fasting serum insulin, surrogate markers of insulin sensitivity, triglycerides, inflammation (interleukin-6, interleukin-10, high-sensitivity C-reactive protein, tumor necrosis factor-alpha, serum amyloid A), adhesion molecules (soluble intercellular adhesion molecule-1, soluble vascular adhesion molecule-1), oxidative stress (LDL-oxidation, total 8-isoprostanes), and nitric oxide. Endothelial function and blood pressure were also assessed. RESULTS: Wild blueberry juice consumption for 7 days produced no significant changes in glucose, insulin, insulin sensitivity, triglycerides, inflammatory markers, adhesion molecules, oxidative stress, endothelial function or blood pressure. However, wild blueberry juice consumption showed a trend for lowering systolic blood pressure: 120.8 ± 2.2 mmHg in the placebo group vs 116.0 ± 2.2 mmHg in the blueberry juice group (P = 0.088). Serum concentrations of nitrates and nitrites, an index of nitric oxide production, increased from 2.9 ± 0.4 µM after placebo drink to 4.1 ± 0.4 µM after drinking wild blueberry juice (P = 0.039). CONCLUSIONS: Short-term consumption of wild blueberry juice may promote cardioprotective effects, by improving systolic blood pressure, possibly through nitric oxide production, in adults at risk for type 2 diabetes. This outcome warrants longer-term human studies of blueberries, including defined amounts of either the whole fruit or juice, to clarify whether polyphenol-rich foods can be efficacious for improving cardiometabolic biomarkers in adults at risk for type 2 diabetes. TRIAL REGISTRATION: NCT02139878, clinicaltrials.gov; date of registration: May 4, 2014.

Long-term outcome of patients with newly diagnosed chronic myeloid leukemia: a randomized comparison of stem cell transplantation with drug treatment.

Tyrosine kinase inhibitors represent today's treatment of choice in chronic myeloid leukemia (CML). Allogeneic hematopoietic stem cell transplantation (HSCT) is regarded as salvage therapy. This prospective randomized CML-study IIIA recruited 669 patients with newly diagnosed CML between July 1997 and January 2004 from 143 centers. Of these, 427 patients were considered eligible for HSCT and were randomized by availability of a matched family donor between primary HSCT (group A; N=166 patients) and best available drug treatment (group B; N=261). Primary end point was long-term survival. Survival probabilities were not different between groups A and B (10-year survival: 0.76 (95% confidence interval (CI): 0.69-0.82) vs 0.69 (95% CI: 0.61-0.76)), but influenced by disease and transplant risk. Patients with a low transplant risk showed superior survival compared with patients with high- (P<0.001) and non-high-risk disease (P=0.047) in group B; after entering blast crisis, survival was not different with or without HSCT. Significantly more patients in group A were in molecular remission (56% vs 39%; P=0.005) and free of drug treatment (56% vs 6%; P<0.001). Differences in symptoms and Karnofsky score were not significant. In the era of tyrosine kinase inhibitors, HSCT remains a valid option when both disease and transplant risk are considered.

A round-robin gamma stereotactic radiosurgery dosimetry interinstitution comparison of calibration protocols.

PURPOSE: Absorbed dose calibration for gamma stereotactic radiosurgery is challenging due to the unique geometric conditions, dosimetry characteristics, and nonstandard field size of these devices. Members of the American Association of Physicists in Medicine (AAPM) Task Group 178 on Gamma Stereotactic Radiosurgery Dosimetry and Quality Assurance have participated in a round-robin exchange of calibrated measurement instrumentation and phantoms exploring two approved and two proposed calibration protocols or formalisms on ten gamma radiosurgery units. The objectives of this study were to benchmark and compare new formalisms to existing calibration methods, while maintaining traceability to U.S. primary dosimetry calibration laboratory standards. METHODS: Nine institutions made measurements using ten gamma stereotactic radiosurgery units in three different 160 mm diameter spherical phantoms [acrylonitrile butadiene styrene (ABS) plastic, Solid Water, and liquid water] and in air using a positioning jig. Two calibrated miniature ionization chambers and one calibrated electrometer were circulated for all measurements. Reference dose-rates at the phantom center were determined using the well-established AAPM TG-21 or TG-51 dose calibration protocols and using two proposed dose calibration protocols/formalisms: an in-air protocol and a formalism proposed by the International Atomic Energy Agency (IAEA) working group for small and nonstandard radiation fields. Each institution's results were normalized to the dose-rate determined at that institution using the TG-21 protocol in the ABS phantom. RESULTS: Percentages of dose-rates within 1.5% of the reference dose-rate (TG-21+ABS phantom) for the eight chamber-protocol-phantom combinations were the following: 88% for TG-21, 70% for TG-51, 93% for the new IAEA nonstandard-field formalism, and 65% for the new in-air protocol. Averages and standard deviations for dose-rates over all measurements relative to the TG-21+ABS dose-rate were 0.999±0.009 (TG-21), 0.991±0.013 (TG-51), 1.000±0.009 (IAEA), and 1.009±0.012 (in-air). There were no statistically significant differences (i.e., p>0.05) between the two ionization chambers for the TG-21 protocol applied to all dosimetry phantoms. The mean results using the TG-51 protocol were notably lower than those for the other dosimetry protocols, with a standard deviation 2-3 times larger. The in-air protocol was not statistically different from TG-21 for the A16 chamber in the liquid water or ABS phantoms (p=0.300 and p=0.135) but was statistically different from TG-21 for the PTW chamber in all phantoms (p=0.006 for Solid Water, 0.014 for liquid water, and 0.020 for ABS). Results of IAEA formalism were statistically different from TG-21 results only for the combination of the A16 chamber with the liquid water phantom (p=0.017). In the latter case, dose-rates measured with the two protocols differed by only 0.4%. For other phantom-ionization-chamber combinations, the new IAEA formalism was not statistically different from TG-21. CONCLUSIONS: Although further investigation is needed to validate the new protocols for other ionization chambers, these results can serve as a reference to quantitatively compare different calibration protocols and ionization chambers if a particular method is chosen by a professional society to serve as a standardized calibration protocol.

[Adenosine and its role in physiology]. / Adenosin a jeho role ve fyziologii.

Adenosine is not just a major component of adenine nucleotides and ribonucleic acids, but also has its own signaling functions. ExtraceIlular level of adenosine in an organism is strictly maintained through the balance between its formation, degradation and transport. Adenosine is formed by enzymatic degradation of adenosine triphosphate and eliminated by phosphorylation to adenosine monophosphate or by deamination to inosine. Transport of adenosine across the cell membrane is ensured by equilibrative and concentrative nucleoside transporters. All these processes participate in maintenance of adenosine level under normal conditions, but a balanced equilibrium can be disrupted in some pathophysiological situations. Extracellular adenosine as a signaling molecule binds to adenosine receptors, which may trigger via their cognate trimeric G proteins different signaling pathways. In this way, adenosine regulates energy homeostasis and affects the function of various organs. Targeted pharmacological manipulations of specific adenosine receptor subtypes or enzymes involved in its metabolism can potentially be used for therapeutic purposes.

A modular Geant4 model of Leksell Gamma Knife Perfexion™.

This work presents a Monte Carlo model of Leksell Gamma Knife Perfexion as well as the main parameters of the dose distribution in the standard phantom obtained using this model. The model is developed in the Geant4 simulation toolkit in a modular way which enables its reuse in other Perfexion studies. Large phase space files were created, containing particles that are entering the inner machine cavity after being transported through the collimation system. All 14 output factors of the machine and effective output factors for both the 4 mm (0.830 ± 0.009) and 8 mm (0.921 ± 0.004) collimators were calculated. Dose profiles along the main axes are also included for each collimator size. All results are compared to the values obtained from the treatment planning system, from experiments, and from other Monte Carlo models.

Long-term stability of the Leksell Gamma Knife® Perfexion™ patient positioning system (PPS).

PURPOSE: To assess the long-term mechanical stability and accuracy of the patient positioning system (PPS) of the Leksell Gamma Knife(®) Perfexion™ (LGK PFX). METHODS: The mechanical stability of the PPS of the LGK PFX was evaluated using measurements obtained between September 2007 and June 2011. Three methods were employed to measure the deviation of the coincidence of the radiological focus point (RFP) and the PPS calibration center point (CCP). In the first method, the onsite diode test tool with single diode detector was used together with the 4 mm collimator on a daily basis. In the second method, a service diode test tool with three diode detectors was used biannually at the time of the routine preventive maintenance. The test performed with the service diode test tool measured the deviations for all three collimators 4, 8, and 16 mm and also for three different positions of the PPS. The third method employed the conventional film pin-prick method. This test was performed annually for the 4 mm collimator at the time of the routine annual QA. To estimate the effect of the patient weight on the performance of the PPS, the focus precision tests were also conducted with varying weights on the PPS using a set of lead bricks. RESULTS: The average deviations measured from the 641 daily focus precision tests were 0.1 ± 0.1, 0.0 ± 0.0, and 0.0 ± 0.0 mm, respectively, for the 4 mm collimator in the X (left/right of the patient), Y (anterior/posterior of the patient), and Z (superior/inferior of the patient) directions. The average of the total radial deviations as measured during ten semiannual measurements with the service diode test tool were 0.070 ± 0.029, 0.060 ± 0.022, and 0.103 ± 0.028 mm, respectively for the central, long, and short diodes for the 4 mm collimator. Similarly, the average total radial deviations measured during the semiannual measurements for the 4, 8, and 16 mm collimators and using the central diode were 0.070 ± 0.029, 0.097 ± 0.025, 0.159 ± 0.028 mm, respectively. The average values of the deviations as obtained from the five annual film pin-prick tests for the 4 mm collimator were 0.10 ± 0.06, 0.06 ± 0.09, and 0.03 ± 0.03 mm for the X, Y, Z stereotactic directions, respectively. Only a minor change was observed in the total radial deviations of the PPS as a function of the simulated patient weight up to 202 kg on the PPS. CONCLUSIONS: Excellent long-term mechanical stability and high accuracy was observed for the PPS of the LGK PFX. No PPS recalibration or any adjustment in the PPS was needed during the monitored period of time. Similarly, the weight on the PPS did not cause any significant disturbance in the performance of the PPS for up to 202 kg simulated patient weight.

Bad and Bid - potential background players in preneoplastic to neoplastic shift in human endometrium.

The most common malignancies of the female genital tract are endometrial carcinomas, whose are generally proceeded by hyperplasia. The maintenance of tissue homeostasis is to great extent governed by apoptosis, whose defects can lead to the preneoplastic and/or cancerous changes. Endometrial apoptosis involves among others three groups of proteins of the Bcl-2 family. First group contains anti-apoptotic proteins (e. g. Bcl-2, Bcl-xL). The other two groups belong to the pro-apoptotic proteins with three (e. g. Bax, Bak) or one (e. g. Bad, Bid) so-called BH domains. Bad and Bid trigger the oligomerization of Bak and Bax protein, which permeabilize the outer mitochondrial wall. Unlike Bid, Bad cannot directly trigger apoptosis. Instead, Bad lowers the threshold at which apoptosis is induced, by binding anti-apoptotic Bcl-2 proteins. However, their mutual counterbalance or synergism in the human endometrium has not been reported yet.In this study, the levels of Bid and Bad were measured using SDS-PAGE and Western blotting with specific antibodies, with the aim to analyse expression of Bid and Bad proteins in normal (NE), hyperplastic (HE) and cancerous (CE) endometrium. We demonstrated that Bid expression in CE reached only 47% and 50% of this observed in NE and HE. Conversely, Bad expression in HE reached only 40% and 36% of this observed in NE and CE, respectively. We detected no significant changes of Bid expression between HE and NE, and levels of Bad protein were not different between CE and NE.Trend of Bid and Bad protein expression is clearly opposite in HE and CE. We hypothesise that disrupted apoptotic program in CE seems to be reduced further by lowering levels of direct apoptotic trigger protein Bid. We suggest that the adenocarcinoma tissue of human endometrium thus tries to strengthen its apoptotic effort by lowering the apoptotic threshold via higher Bad levels.

[Results of gamma-knife radiosurgery treatment for intracranial metastases of renal-cell cancer and prognostic factors influencing on the survival (joint study of three Eastern European Centers)].

Gamma-Knife radiosurgery treatment for intracranial metastases of renal-cell cancer results are presented. Treatments were made in 3 Eastern European Centers: in Prague, Moscow and St. Petersburg from 2000 to 2011. 312 patients were treated. Median survival was 8 months (1-91 months). Follow up data were collected for 210 patients. Neurologic state worsening had place at 12% patients, but only 4% of deterioration cases are connected to GKRS. Causes of the rest cases are related to new metastases. Neurologic improvement was found at 29% of patients. Post-RS MRI data were available for 188 patients. Volume enlargement was observed at 10% of cases, but only 5% caused by continued growth. New metastases appeared at 53% of patients. Actuarial analysis didn't detect statistically significant differences in survival for such parameters as patient age, volume and number of metastases. Favorable prognostic factors (p < 0.05) were found to be Karnofsky state equal or more than 70, controlled primary tumor and absence of extracranial metastases, as well as marginal dose for largest metastasis more than 20 Gy. Now RS is one of the basic method of the discussed pathology treatment, that demonstrates high efficacy in relation to the tumor growth and the patient Quality of Life. It is noteworthy that the length of survival is determined by the depth of the complex treatment of primary disease and success of such treatment.

Oolong tea does not improve glucose metabolism in non-diabetic adults.

BACKGROUND: Studies of the influence of tea on glucose metabolism have produced inconsistent results, possibly because of the lack of dietary control and/or unclear characterization of tea products. METHODS: Therefore, a double-blind crossover study was conducted in which healthy males (n = 19) consumed each of three oolong tea products or a control beverage as part of a controlled diet. Treatment beverages (1.4 l/day) were consumed for 5 days, followed by assessment of fasting plasma glucose, fasting serum insulin and an oral glucose tolerance test. Tea products included oolong tea, oolong tea with added catechins and oolong tea with added oolong tea polyphenols, and control beverages included caffeinated water and unsupplemented water. On the fifth day of each treatment period, treatment beverages were consumed with a standardized meal, and glucose and insulin responses were assessed for 240 min. RESULTS: No significant differences were detected for fasting plasma glucose, fasting serum insulin, incremental plasma glucose area under the concentration time curve (AUC), total plasma glucose AUC or total serum insulin AUC. CONCLUSIONS: Neither oolong tea nor oolong tea supplemented with catechins or other polyphenols produced improved glucose metabolism in healthy adult volunteers on the basis of this highly controlled dietary intervention trial.

Population-based study of BRCA1/2 mutations: family history based criteria identify minority of mutation carriers.

The two major susceptibility genes, BRCA1 and BRCA2, are involved in hereditary breast and ovarian cancer syndrome. Early detection of mutation carriers has crucial clinical importance, as it allows identification of women who may benefit from intensive clinical follow-up or prophylactic surgery. Generally accepted inclusion criteria for BRCA1/2 mutation testing are based either upon family history of breast or ovarian cancer or young age at cancer diagnosis. In order to analyze the impact of BRCA1/2 mutations on breast cancer development in the Czech population and to confront the clinical and histopathological data of mutation carriers with current criteria for mutation testing we examined the frequency of mutations in unselected breast cancer cases. Mutational analysis of BRCA1/2 genes performed in 679 unselected female breast cancer patients included all recurrent deleterious alterations previously identified in the Prague area and truncating mutations in the whole exon 11 of BRCA1. Within analyzed gene sequences more than 80% of mutations were identified previously in high-risk patients. A total of 16 breast cancer patients (2.4%) carried a mutation. BRCA1 mutations were identified in 14 (2.1%) whereas BRCA2 in 2 (0.3%) women. Family history of ovarian cancer was a strong predictor of a BRCA1/2 mutation (OR = 8.3; p = 0.01), however, family history of breast cancer was not indicative of carrier status. A significant association between medullary breast cancer and mutation status was observed. Current criteria for BRCA1/2 mutation testing would distinguish only 6 out of 16 (37.5%) carriers identified in our study. Ten breast cancer patients with confirmed BRCA1/2 germ-line mutation exhibited no clinical characteristics that would predict their carrier status. Therefore, we believe that the testing for BRCA1/2 mutations in the Czech Republic may not be restricted only to high-risk patients. Our results indicate that analysis of locally prevalent BRCA1/2 mutations in all breast cancer patients might extend substantially the percentage of identified mutation carriers.

CYP1B1 gene polymorphism modifies pancreatic cancer risk but not survival.

UNLABELLED: Pancreatic cancer represents one of the biggest problems of current oncology. The risk factors of pancreatic cancer development, as well as factors affecting survival are poorly understood. Since biotransformation enzymes modify detoxification of carcinogens, we supposed, that arelationship between their polymorphism and the risk of pancreatic cancer development and eventually its clinical outcome may exist.
Associations of so far not studied cytochrome P450 1B1 (CYP1B1) polymorphisms with pancreatic cancer risk were investigated by case-control study. Atotal of 754 participants were recruited during study period. All patients were followed to determine their treatment and overall survival.
Carriers of rare genotype Val/Val in codon 432 of CYP1B1 (rs1056836) were under significantly lower risk of pancreatic cancer than wild type carriers (p=0.035). Carriers of heterozygous genotype (p=0.033) and rare allele Val (p=0.015) were also under lower risk than wild type carriers. When histology-verified patients were analyzed separately, even more significant associations were found (p=0.016, p=0.009, p=0.003, respectively). On the contrary, CYP1B1 polymorphism in codon 453 (rs1800440) did not significantly associate with pancreatic cancer risk. Median survival of patients with rare homozygous genotype Val/Val in CYP1B1-codon 432 was longer but not significantly different from those with wild-type homozygotes. The same was true for CYP1B1-codon 453 wild-type homozygotes in comparison with Ser/Ser rare homozygotes.
CYP1B1 polymorphism in codon 432 seems to modify the risk of pancreatic cancer development and should be further studied. KEYWORDS: Pancreatic cancer, CYP1B1, polymorphism, risk, survival.