Sporadic deficient mismatch repair in colorectal cancer increases the risk for non-colorectal malignancy: A European multicenter cohort study.

BACKGROUND AND OBJECTIVES: Disparities between tumors arising via different sporadic carcinogenetic pathways have not been studied systematically. This retrospective multicenter cohort study evaluated the differences in the risk for non-colorectal malignancy between sporadic colorectal cancer (CRC) patients from different DNA mismatch repair status. METHODS: A retrospective European multicenter cohort study including in total of 1706 CRC patients treated between 1996 and 2019 in three different countries. The proficiency (pMMR) or deficiency (dMMR) of mismatch repair was determined by immunohistochemistry. Cases were analyzed for tumor BRAFV600E mutation, and BRAF mutated tumors were further analyzed for hypermethylation status in the promoter region of MLH1 to distinguish between sporadic and hereditary cases. Swedish and Finish patients were matched with their respective National Cancer Registries. For the Czech cohort, thorough scrutiny of medical files was performed to identify any non-colorectal malignancy within 20 years before or after the diagnosis of CRC. Poisson regression analysis was performed to identify the incidence rates of non-colorectal malignancies. For validation purposes, standardized incidence ratios were calculated for the Swedish cases adjusted for age, year, and sex. RESULTS: Of the 1706 CRC patients included in the analysis, 819 were female [48%], median age at surgery was 67 years [interquartile range: 60-75], and sporadic dMMR was found in 188 patients (11%). Patients with sporadic dMMR CRC had a higher incidence rate ratio (IRR) for non-colorectal malignancy before and after diagnosis compared to patients with a pMMR tumor, in both uni- (IRR = 2.49, 95% confidence interval [CI] = 1.89-3.31, p = 0.003) and multivariable analysis (IRR = 2.24, 95% CI = 1.67-3.01, p = 0.004). This association applied whether or not the non-colorectal tumor developed before or after the diagnosis of CRC in both uni- (IRR = 1.91, 95% CI = 1.28-2.98, p = 0.004), (IRR = 2.45, 95% CI = 1.72-3.49, p = 0.004) and multivariable analysis (IRR = 1.67,95% CI = 1.05-2.65, p = 0.029), (IRR = 2.35, 95% CI = 1.63-3.42, p = 0.005), respectively. CONCLUSION: In this retrospective European multicenter cohort study, patients with sporadic dMMR CRC had a higher risk for non-colorectal malignancy than those with pMMR CRC. These findings indicate the need for further studies to establish the need for and design of surveillance strategies for patients with dMMR CRC.

Ischemic Postconditioning and Nitric Oxide Administration Failed to Confer Protective Effects in a Porcine Model of Extracorporeal Cardiopulmonary Resuscitation.

The protective effects of ischemic postconditioning (IPC) and nitric oxide (NO) administration have been demonstrated in several ischemic scenarios. However, current evidence regarding the effect of IPC and NO in extracorporeal cardiopulmonary resuscitation remains lacking. Fifteen female swine (body weight 45 kg) underwent veno-arterial extracorporeal membrane oxygenation (ECMO) implantation; cardiac arrest-ventricular fibrillation was induced by rapid ventricular pacing. After 20 min of cardiac arrest, blood flow was restored by increasing the ECMO flow rate to 4.5 L/min. The animals (five per group) were then randomly assigned to receive IPC (three cycles of 3 min ischemia and reperfusion), NO (80 ppm via oxygenator), or mild hypothermia (HT; 33.0°C). Cerebral oximetry and aortic blood pressure were monitored continuously. After 90 min of reperfusion, blood samples were drawn for the measurement of troponin I, myoglobin, creatine-phosphokinase, alanine aminotransferase, neuron-specific enolase, cystatin C, and reactive oxygen metabolite (ROM) levels. Significantly higher blood pressure and cerebral oxygen saturation values were observed in the HT group compared with the IPC and NO groups (P < 0.05). The levels of troponin I, myoglobin, creatine phosphokinase, and alanine aminotransferase were significantly lower in the HT group (P < 0.05); levels of neuron-specific enolase, cystatin C, and ROM were not significantly different. IPC and NO were comparable in all monitored parameters. The results of the present study indicate that IPC and NO administration are not superior interventions to HT for the maintenance of blood pressure, cerebral oxygenation, organ protection, and suppression of oxidative stress following extracorporeal cardiopulmonary resuscitation.

[Diffuse tenosynovial giant cell tumor of the cervical spine destroying vertebra C6 - a case report]. / Difúzní obrovskobunecný tumor slachových pochev krcní pátere s destrukcí obratle C6 - kazuistika.

Presented is a case of 59-year-old woman with longstanding neck pain who has been promptly operated for spinal cord compression. Imaging studies disclosed ill-defined cervical paravertebral soft tissue mass at the level of vertebra C5/6 abutting left-sided intervertebral joint and destroying neighboring both vertebral arch and processus spinosus. Submitted specimen was interpreted as a possible metastatic skeletal process by clinicians and referring pathologist favored diagnosis of giant cell tumor/osteoclastoma of the bone. Microscopic features were consistent with giant cell lesion where uniform mononuclear mosaic stromal component dominated the unevenly distributed loose clusters of osteoclast-like giant cells frequently imparting appearance of peculiar pseudoalveolar spaces. Additionally, alternating geographic xanthomatous and densely hyalinized/ osteoid-like zones with speckled, coarsely granular haemosiderin pigment completed the variegated structural composition. The tumor infiltrated adjacent striated muscles; either original bone structures and/or extracellular matrix deposits were not identified. Immunohistochemical stains with p63, SATB2, desmin, EMA, clusterin and S100protein turned out to be completely negative. FISH analysis revealed no rearrangement of CSF1 gene. The diagnosis of the diffuse tenosynovial giant cell tumor was rendered.

Increasing venoarterial extracorporeal membrane oxygenation flow negatively affects left ventricular performance in a porcine model of cardiogenic shock.

BACKGROUND: The aim of this study was to assess the relationship between extracorporeal blood flow (EBF) and left ventricular (LV) performance during venoarterial extracorporeal membrane oxygenation (VA ECMO) therapy. METHODS: Five swine (body weight 45 kg) underwent VA ECMO implantation under general anesthesia and artificial ventilation. Subsequently, acute cardiogenic shock with signs of tissue hypoxia was induced. Hemodynamic and cardiac performance parameters were then measured at different levels of EBF (ranging from 1 to 5 L/min) using arterial and venous catheters, a pulmonary artery catheter and a pressure-volume loop catheter introduced into the left ventricle. RESULTS: Myocardial hypoxia resulted in a decline in mean (±SEM) cardiac output to 2.8 ± 0.3 L/min and systolic blood pressure (SBP) to 60 ± 7 mmHg. With an increase in EBF from 1 to 5 L/min, SBP increased to 97 ± 8 mmHg (P < 0.001); however, increasing EBF from 1 to 5 L/min significantly negatively influences several cardiac performance parameters: cardiac output decreased form 2.8 ± 0.3 L/min to 1.86 ± 0.53 L/min (P < 0.001), LV end-systolic volume increased from 64 ± 11 mL to 83 ± 14 mL (P < 0.001), LV stroke volume decreased from 48 ± 9 mL to 40 ± 8 mL (P = 0.045), LV ejection fraction decreased from 43 ± 3 % to 32 ± 3 % (P < 0.001) and stroke work increased from 2096 ± 342 mmHg mL to 3031 ± 404 mmHg mL (P < 0.001). LV end-diastolic pressure and volume were not significantly affected. CONCLUSIONS: The results of the present study indicate that higher levels of VA ECMO blood flow in cardiogenic shock may negatively affect LV function. Therefore, it appears that to mitigate negative effects on LV function, optimal VA ECMO blood flow should be set as low as possible to allow adequate tissue perfusion.

The Cortisol to Cortisone Ratio during Cardiac Catheterisation in Sows.

A possible effect of mini-invasive heart intervention on a response of hypothalamo-pituitary-adrenal stress axis and conversion of cortisone to cortisol were studied. We have analysed two stress markers levels (cortisol, cortisone) and cortisol/cortisone ratio in 25 sows using minimally invasive heart catheterisation as the stress factor. The values of studied parameters were assessed in four periods of the experiment: (1) the baseline level on the day before intervention, (2) after the introduction of anaesthesia, (3) after conducting tissue stimulation or ablation, and (4) after the end of the catheterisation. For statistical analyses we used the non-parametric Friedman test for four dependent samples (including all four stages of the operation) or three dependent samples (influence of operation only, baseline level was excluded). Statistically significant differences in both Friedman tests were found for cortisol and for cortisone. We have found the highest level of cortisol/cortisone ratio in unstressed conditions, then it decreased to the minimal level at the end of the intervention. We have concluded that cortisol levels are blunted by the influence of anaesthesia after its administration, and therefore decrease back to the baseline at the end of the operation.

The availability of HEPA-filtered rooms and the incidence of pneumonia in patients after haematopoietic stem cell transplantation (HSCT): results from a prospective, multicentre, eastern European study.

AIMS AND OBJECTIVES: To establish the availability of High Efficiency Particulate Air (HEPA)- and nonHEPA-filtered rooms in eastern European transplant centres and to investigate the impact on incidence of pneumonia and mortality after haematopoietic stem cell transplantation (HSCT). BACKGROUND: Barrier nursing in HEPA-filtered rooms is generally recommended for patients undergoing HSCT. There are only limited data on the availability of HEPA-filtered rooms and the impact on incidence of pneumonia and mortality. DESIGN: A prospective, observational, international study. METHODS: Monitoring cards were distributed within the East Forum EBMT-Nurses Group cooperating centres, and 689 consecutive patients were registered in 1/2010-6/2012. Patients were monitored for 100 days post-transplant. RESULTS: In patients undergoing autologous HSCT, pneumonia developed in 14/400 (3·5%) and was the cause of death in 2/14 (14%) of patients. There was no significant difference in mortality between HEPA-filtered and nonHEPA-filtered groups (4·5% vs. 4·9%, respectively). 239/400 (59%) transplantations were performed in single-bed rooms [190/239 (79%) HEPA-filtered] and 161 (41%) in two-bed rooms [28/161 (17%) HEPA-filtered]. In allogeneic transplantation, pneumonia developed in 24/289 (8·3%) and was the cause of death in 11/24 (45%) of patients. There was no significant difference in mortality between HEPA-filtered and non-HEPA-filtered groups (14% vs. 17%, respectively). 281/289 (97%) of allogeneic transplantations were performed in single-bed rooms [254/281 (90%) HEPA-filtered], and pneumonia was more frequent in patients on corticosteroids and in rooms without HEPA. CONCLUSION: The incidence of pneumonia in the autologous transplantation setting is low. More pneumonia was observed in the allogeneic HSCT group, especially in patients on corticosteroids. There was a trend towards a lower incidence of pneumonia in allogeneic HSCT patients treated in HEPA-filtered rooms. RELEVANCE TO CLINICAL PRACTICE: Autologous HSCT transplantation may safely be performed without HEPA filtration. HEPA filtration might be preferable in patients undergoing allogeneic transplantation.

Mild therapeutic hypothermia is superior to controlled normothermia for the maintenance of blood pressure and cerebral oxygenation, prevention of organ damage and suppression of oxidative stress after cardiac arrest in a porcine model.

BACKGROUND: Mild therapeutic hypothermia (HT) has been implemented in the management of post cardiac arrest (CA) syndrome after the publication of clinical trials comparing HT with common practice (ie, usually hyperthermia). Current evidence on the comparison between therapeutic HT and controlled normothermia (NT) in CA survivors, however, remains insufficient. METHODS: Eight female swine (sus scrofa domestica; body weight 45 kg) were randomly assigned to receive either mild therapeutic HT or controlled NT, with four animals per group. Veno-arterial extracorporeal membrane oxygenation (ECMO) was established and at minimal ECMO flow (0.5 L/min) ventricular fibrillation was induced by rapid ventricular pacing. After 20 min of CA, circulation was restored by increasing the ECMO flow to 4.5 L/min; 90 min of reperfusion followed. Target core temperatures (HT: 33°C; NT: 36.8°C) were maintained using the heat exchanger on the oxygenator. Invasive blood pressure was measured in the aortic arch, and cerebral oxygenation was assessed using near-infrared spectroscopy. After 60 min of reperfusion, up to three defibrillation attempts were performed. After 90 min of reperfusion, blood samples were drawn for the measurement of troponin I (TnI), myoglobin (MGB), creatine-phosphokinase (CPK), alanin-aminotransferase (ALT), neuron-specific enolase (NSE) and cystatin C (CysC) levels. Reactive oxygen metabolite (ROM) levels and biological antioxidant potential (BAP) were also measured. RESULTS: Significantly higher blood pressure and cerebral oxygenation values were observed in the HT group (P<0.05). Sinus rhythm was restored in all of the HT animals and in one from the NT group. The levels of TnI, MGB, CPK, ALT, and ROM were significantly lower in the HT group (P<0.05); levels of NSE, CysC, and BAP were comparable in both groups. CONCLUSIONS: Our results from animal model of cardiac arrest indicate that HT may be superior to NT for the maintenance of blood pressure, cerebral oxygenation, organ protection and oxidative stress suppression following CA.

Synthesis and structural characterization of heteroboroxines with MB2O3 core (M = Sb, Bi, Sn).

Reaction of organoantimony and organobismuth oxides (LSbO)(2) and (LBiO)(2) (where L is [2,6-bis(dimethylamino)methyl]phenyl) with four equivalents of the organoboronic acids gave new heteroboroxines LM[(OBR)(2)O] 1a-2c (for M = Sb: R = Ph (1a), 4-CF(3)C(6)H(4) (1b), ferrocenyl (1c); for M = Bi: R = Ph (2a), 4-CF(3)C(6)H(4) (2b), and ferrocenyl (2c)). Analogously, reaction between organotin carbonate L(Ph)Sn(CO(3)) and two equivalents of organoboronic acids yielded compounds L(Ph)Sn[(OBR)(2)O] (where R = Ph (3a), 4-CF(3)C(6)H(4) (3b), and ferrocenyl (3c)). All compounds were characterized by elemental analysis and NMR spectroscopy. Their structure was described both in solution (NMR studies) and in the solid state (X-ray diffraction analyses 1a, 1c, 2b, 3b, and 3c). All compounds contain a central MB(2)O(3) core (M = Sb, Bi, Sn), and the bonding situation within these rings and their potential aromaticity was investigated by the help of computational methods.

P27 as a prognostic factor of early cervical carcinoma.

OBJECTIVE: The aim of this study was to clarify whether the evaluation of cell-cycle regulatory protein p27 can serve as a prognostic factor in patients with International Federation of Gynecology and Obstetrics (FIGO) stage IB cervical carcinoma. PATIENTS AND METHODS: A retrospective study was performed on 130 surgically treated patients with FIGO stage IB cervical carcinoma with at least a 5-year follow-up. The expression of p27 was investigated independently by 2 experienced pathologists using immunohistochemistry. The prognostic significance of established prognostic factors and p27 expression were analyzed using univariate and multivariate analyses. RESULTS: In a univariate analysis, lymph node status, tumor diameter, Gynecologic Oncology Group (GOG) score, lymph vascular space invasion, and p27 expression were significant prognostic factors for overall survival (OS). We found a correlation between p27 expression and lymph node status, tumor diameter, invasion, and GOG score. The p27 expression was a statistically significant prognostic factor for OS in a univariate analysis (log-rank test, P = 0.03). In a multivariate analysis, only lymph node status and tumor diameter were statistically significant prognostic factors for OS. CONCLUSIONS: This study demonstrated that a low p27 expression is associated with lymph node metastasis, deep stromal invasion, tumor diameter more than 20 mm, and high GOG score and had a prognostic influence on OS in a univariate analysis in a series of 130 women with FIGO stage IB cervical carcinoma. Lymph node status and the diameter of the tumor were the only statistically significant prognostic factors in multivariate analysis.

Serum citrulline levels as a marker of enterocyte function in patients after allogeneic hematopoietic stem cells transplantation - a pilot study.

BACKGROUND: Citrulline is an amino acid produced by enterocytes. Serum citrulline concentration has been proposed as a marker of enterocyte mass and function. Our study focused on evaluation of citrulline levels in patients with diarrhea related to toxic intestinal damage (mucositis), intestinal graft versus host disease (GVHD), and other etiology of diarrhea (e.g., dysmicrobia) after allogeneic stem cells transplantation (SCT). MATERIAL AND METHODS: This was a prospective study in 11 adults (18 blood samples) with diarrhea developed after allogeneic SCT in 4/2011-1/2012 compared to twenty healthy control samples. RESULTS: The median (interquartile range) of citrulline levels was significantly lower in the transplanted patients group compared to healthy controls: 9.3 (3.62-15.38) vs. 33.3 (26.82-36.23) µmol/L, p<0.0001. The median values of citrulline in patients with post-transplant toxic intestinal mucositis (n=8, days 1-22 post-transplant) vs. intestinal GVHD (n=7, day 43-142) vs. other etiology of diarrhea (e.g., dysmicrobia) (n=3, day 120-127) were: 9.55 (2.95-12.03) vs. 5 (3.85-9.05) vs. 15.6 (15.45-18.3) mol/L resp. Serum citrulline levels were significantly higher in other (eg, dysmicrobic) etiology of diarrhea in comparison with mucositis (p=0.0336) and GVHD (p=0.0152). CONCLUSIONS: Citrulline levels are very low shortly after the myeloablative FLU/MEL or BuCY2 conditioning allogeneic SCT due to the toxic intestinal damage. Significantly low levels of citrulline were also in patients with intestinal GVHD later on. Other observations in larger groups of patients are necessary before any specific recommendation for citrulline levels monitoring in intestinal GVHD can be made.

PreCNet: Next-Frame Video Prediction Based on Predictive Coding.

Predictive coding, currently a highly influential theory in neuroscience, has not been widely adopted in machine learning yet. In this work, we transform the seminal model of Rao and Ballard (1999) into a modern deep learning framework while remaining maximally faithful to the original schema. The resulting network we propose (PreCNet) is tested on a widely used next-frame video prediction benchmark, which consists of images from an urban environment recorded from a car-mounted camera, and achieves state-of-the-art performance. Performance on all measures (MSE, PSNR, and SSIM) was further improved when a larger training set (2M images from BDD100k) pointed to the limitations of the KITTI training set. This work demonstrates that an architecture carefully based on a neuroscience model, without being explicitly tailored to the task at hand, can exhibit exceptional performance.

Coronary versus carotid blood flow and coronary perfusion pressure in a pig model of prolonged cardiac arrest treated by different modes of venoarterial ECMO and intraaortic balloon counterpulsation.

INTRODUCTION: Extracorporeal membrane oxygenation (ECMO) is increasingly used in cardiac arrest (CA). Adequacy of carotid and coronary blood flows (CaBF, CoBF) and coronary perfusion pressure (CoPP) in ECMO treated CA is not well established. This study compares femoro-femoral (FF) to femoro-subclavian (FS) ECMO and intraaortic balloon counterpulsation (IABP) contribution based on CaBF, CoBF, CoPP, myocardial and brain oxygenation in experimental CA managed by ECMO. METHODS: In 11 female pigs (50.3 ± 3.4 kg), CA was randomly treated by FF versus FS ECMO ± IABP. Animals under general anesthesia had undergone 15 minutes of ventricular fibrillation (VF) with ECMO flow of 5 to 10 mL/kg/min simulating low-flow CA followed by continued VF with ECMO flow of 100 mL/kg/min. CaBF and CoBF were measured by a Doppler flow wire, cerebral and peripheral oxygenation by near infrared spectroscopy. CoPP, myocardial oxygen metabolism and resuscitability were determined. RESULTS: CaBF reached values > 80% of baseline in all regimens. CoBF > 80% was reached only by the FF ECMO, 90.0% (66.1, 98.6). Addition of IABP to FF ECMO decreased CoBF to 60.7% (55.1, 86.2) of baseline, P = 0.004. FS ECMO produced 70.0% (49.1, 113.2) of baseline CoBF, significantly lower than FF, P = 0.039. Addition of IABP to FS did not change the CoBF; however, it provided significantly higher flow, 76.7% (71.9, 111.2) of baseline, compared to FF + IABP, P = 0.026. Both brain and peripheral regional oxygen saturations decreased after induction of CA to 23% (15.0, 32.3) and 34% (23.5, 34.0), respectively, and normalized after ECMO institution. For brain saturations, all regimens reached values exceeding 80% of baseline, none of the comparisons between respective treatment approaches differed significantly. After a decline to 15 mmHg (9.5, 20.8) during CA, CoPP gradually rose with time to 68 mmHg (43.3, 84.0), P = 0 .003, with best recovery on FF ECMO. Resuscitability of the animals was high, both 5 and 60 minutes return of spontaneous circulation occured in eight animals (73%). CONCLUSIONS: In a pig model of CA, both FF and FS ECMO assure adequate brain perfusion and oxygenation. FF ECMO offers better CoBF than FS ECMO. Addition of IABP to FF ECMO worsens CoBF. FF ECMO, more than FS ECMO, increases CoPP over time.

Human factors application for healthcare teams in low- and medium-income countries (LMIC) to help improve patient safety and performance.

Mistakes will always happen whether at work or in our personal lives. We can never completely eliminate error, but learning and disseminating lessons from these mistakes to others is essential. Human factors application for colleagues in healthcare, particularly in low- and medium-income countries (LMIC) can greatly improve patient safety and aid better team working and staff morale. Factors such as hunger, dehydration anger, and tiredness, all reduce personal performance and can raise the risk of personal error. It is vital that we understand and optimize interaction within the healthcare team members. As part of this, ineffective communication, steep hierarchy and loss of situational awareness can lead to compromised patient safety and potentially serious error. In this paper, we provide a brief overview of human factors for healthcare colleagues in LMIC. We highlight ways to reduce the chances of error and improve patient safety by recognizing and applying various human factors to our day to day practices.

Changes of cytokine levels during granulocyte-colony-stimulating factor stem cell mobilization in healthy donors: association with mobilization efficiency and potential predictive significance.

BACKGROUND: Peripheral blood stem cells are an important source of hematopoietic stem cells (HSCs) for allogeneic transplantations. Some allogeneic donors mobilize HSCs poorly in response to the granulocyte--colony-stimulating factor (G-CSF). The estimation of the mobilization result in an individual donor is difficult due to the absence of suitable predictive factors. STUDY DESIGN AND METHODS: We analyzed the concentrations and kinetics of certain cytokines induced by G-CSF in 76 healthy donors and compared them with the mobilization efficiency. RESULTS: The levels of the most cytokines increased after the G-CSF application: sICAM, sVCAM, MMP-9, interleukin (IL)-6, TNF-α, sE-selectin, and fibronectin. The concentrations of SDF-1α and IL-8 decreased and VEGF and fractalkine remained unchanged. The premobilization concentrations of IL-6 (p = 0.0093) and TNF-a (p = 0.0006) correlated with preapheresis CD34+ cell count. The comparison of premobilization cytokine levels between better and worse mobilizers showed a difference for TNF-α (p = 0.0006) and IL-6 (p = 0.0682). The TNF-α level below cutoff of 3.6 pg/mL implied approximately 20 times higher risk of poor mobilization (odds ratio, 19.9; p = 0.0002). The immunophenotyping of CD34+ cells suggested a negative correlation between Day +5 CD34+ count and expression of CD11a (p = 0.0319) and a positive correlation with CD44 antigen expression (p = 0.0096). CONCLUSION: The concentrations of certain cytokines corresponded to the quality of HSC mobilization in healthy donors. Their levels measured before mobilization could probably serve as predictive factors for mobilization efficacy and prospectively detect donors who might profit from new mobilization molecules.

NCN-chelated organoantimony(III) and organobismuth(III) phosphates: synthesis and solid-state and solution structures.

.Organoantimony(III) and organobismuth(III) phosphates (LM)(3)(PO(4))(2) [M = Sb (3) and Bi (4)], containing the NCN-chelating ligand L [L = 2,6-(CH(2)NMe(2))(2)C(6)H(3)], were prepared by the simple treatment of parent oxides 1 and 2 with H(3)PO(4). Both compounds were characterized by elemental analysis, electrospray ionization mass spectrometry, and IR and NMR spectroscopy and in the case of 3 by X-ray diffraction techniques. Compound 3 has an interesting behavior in solution, i.e., the formation of two possible conformational isomers, which was studied by (1)H, (13)C, and (31)P NMR spectroscopy.

Significant oral graft-versus-host disease after allogeneic stem cell transplantation with the FLU/MEL conditioning regimen.

BACKGROUND: Oral graft-versus-host disease (GVHD) is a significant complication after allogeneic stem cell transplantation (SCT) and there is no consistent information about its characteristics in patients after reduced-intensity conditioning regimen FLU/MEL (fludarabine 120 mg/m² and melphalan 140 mg/m²). MATERIAL/METHODS: This was a single-centre prospective observational study of patients after allogeneic SCT with FLU/MEL conditioning performed during the period 1/2005-12/2007. Characteristics of oral GVHD were observed in 71 patients. The observation was discontinued due to death, donor lymphocyte infusion (DLI) or new chemotherapy administration. RESULTS: In 10/2010, the median duration of the observation of the cohort of the patients was 13 (0.2-69) months, and 42 (35-69) months in the still-ongoing 20/71 (28%) patients. Oral acute GVHD had sporadic 7% incidence, whereas oral chronic GVHD was observed in 33% of patients and persisted with median duration of 188 (11-665) days. Clinical and histopathological features were similar in both acute and chronic oral GVHD and included mucosal lichenoid changes, erythema, ulcerations and pseudomembranes, satellite necrosis, apoptotic bodies and lichenoid interface inflammation. CONCLUSIONS: It is necessary to consider complex clinical symptomatology and pathological correlations when classifying the oral GVHD, because local oral symptoms and histopathological features in both acute and chronic oral GVHD forms can be similar. Even though the oral chronic GVHD was mild in the majority of patients, it can be considered as clinically significant due to its incidence, duration and symptomatology. The FLU/MEL conditioning regimen should not be considered as low-risk protocol in this context.

The effect of polyvinylpyrrolidone-sodium hyaluronate gel (Gelclair) on oral microbial colonization and pain control compared with other rinsing solutions in patients with oral mucositis after allogeneic stem cells transplantation.

BACKGROUND: Gelclair is an oral lubricating gel used in the management of oral mucositis (OM). We evaluated its efficacy, tolerance and impact on oral cavity microbial colonization in patients with OM after allogeneic hematopoietic stem cells transplantation. MATERIAL/METHOD: Gelclair was administered in a group of 22 patients with active OM. A control group of 15 patients used other rinsing solutions (chlorhexidine, benzydamine, salvia). Tests with oral cavity swabs for microbiology analysis were performed once a week. RESULTS: The characteristics of OM in both groups were comparable, and rinsing solutions had satisfactory tolerability. There was no difference in the median improvement of oral intake and OM-related pain relief, which was assessed mostly as "slight effect". In the Gelclair group, the effect duration was longer (median 3 [0-5] vs. 1 [0-3] hours, p = 0.001). There was significant increase of Enterococcus faecalis and Candida sp. colonization of the oral cavity over the course of the hospitalization and significantly reduced incidence of such colonization in patients with OM in the Gelclair group: 1/22 (5%) vs. 6/15 (40%), p = 0.01. In vitro tests showed inhibited growth of Enterococcus faecalis and Candida sp. colonies within the area of the Gelclair application. CONCLUSIONS: Gelclair may be individually helpful in the management of OM and pain in patients after allogeneic stem cells transplantation. Its use did not lead to worsened oral bacterial and yeast colonization and probably even helped to protect mucosa from Enterococcus and Candida sp. Further studies based on larger cohorts are needed.

Expression of immune-modulatory molecules HLA-G and HLA-E by tumor cells in glioblastomas: an unexpected prognostic significance?

The role of nonclassical human leukocyte antigens G and E (HLA-G and HLA-E) was originally thought to be restricted to the protection of the fetus from a maternal allorecognition. Now it is known that HLA-G and HLA-E exert multiple immunoregulatory functions. A prognostic significance of the expression of HLA-G and HLA-E by neoplastic cells in glioblastoma is not well characterized. In this study, we evaluated the expression of HLA-G and HLA-E by neoplastic cells in 39 cases of glioblastoma. We found the production of HLA-G and HLA in a majority of cases. There was an unexpected positive correlation between the expression of HLA-E and length of survival. We speculate that the expression of this molecule by neoplastic cells may represent a coincidental selective pro-host advantage related to better response to subsequent therapeutic modalities. Mechanisms of glioblastoma cell pathophysiology and mechanisms of responses to therapeutic interventions in respect to the expression of these molecules deserves further study.

Colon cancer patients with mismatch repair deficiency are more likely to present as acute surgical cases.

BACKGROUND: The effect of the genetic imprint on the emergency presentation of colon cancer remains unclear. The disparity between tumours evolving along different carcinogenetic pathways has not been studied systematically. This retrospective multicenter cohort study evaluates the association between mismatch repair status and the risk for acute surgery of colon cancer. PATIENTS AND METHODS: A retrospective multicenter cohort study including in total 870 patients from three different countries. Scandinavian cohort (Finland and Sweden), including a total of 412 patients operated between January 1, 1995 and December 31, 2010, was validated against a cohort from the Czech Republic, including a total of 458 patients, operated between January 1, 2018 and December 31, 2019. The proficiency or deficiency of mismatch repair was determined by immunohistochemistry. Primary outcome was the risk for acute colon cancer surgery given as the Odds Ratio (OR) in the univariable and multivariable analyses. Acute colon cancer surgery was defined as surgery performed during the same hospital admission as when the diagnosis of colon cancer was made. RESULTS: Of the 870 patients (399 females [46%]) included in the analyses, median age at surgery was 69 [interquartile range, 61-76] years, deficient Mismatch Repair (dMMR) status was found in 190 patients (22%), and 179 patients (21%) underwent acute surgery during the same hospital admission as when the diagnosis of colon cancer was made. In the Scandinavian cohort, a significant association between dMMR status and acute surgery was seen in both the univariable (OR 1.82, 95% CI 1.11-3.02, P = 0.017) and the multivariable (OR = 2.21, 95% CI 1.28-3.95, P = 0.005) analyses. This was confirmed in the Czech validation cohort in both the univariable (OR = 1.94, 95% CI 1.09-3.26, P = 0.022) and the multivariable (OR = 1.77, 95% CI 1.15-3.18, P = 0.021) analyses. CONCLUSION: This multicenter study reveals a strong association between acute colon cancer surgery and dMMR tumour status.

A phase II trial of oral vinorelbine and capecitabine in anthracycline pretreated patients with metastatic breast cancer.

BACKGROUND: Optimal chemotherapy (CT) for advanced breast treatment should be effective, well tolerated and convenient. In this study the efficacy and safety of the fully oral combination of oral vinorelbine (Navelbine Oral) plus capecitabine (Xeloda) in metastatic breast cancer (MBC) patients pretreated with anthracycline, was evaluated. PATIENTS AND METHODS: In this phase II multicenter study, this combination CT was given as a first- or second-line therapy for MBC. The treatment schedule was: oral vinorelbine 60 mg/m2 day 1 and day 8 plus capecitabine 1,000 mg/m2 twice daily from day 1 to day 14, every 21 days. RESULTS: One hundred and fifteen patients were included in this trial. The median age was 58 years (range: 40-75). All the patients had received prior anthracycline-based chemotherapy. The combination was well tolerated, with, in particular, only 0.8% of patients presenting with febrile neutropenia. In the intention-to-treat (ITT) population, an objective response was achieved in 65 patients (56.5%). A complete response was achieved in 22 patients (19.1%); partial response in 43 patients (37.4%); stable disease in 36 patients (31.3%), and progressive disease was observed in 14 patients (12.2%). After a median follow-up of 10.0 months, the median progression-free survival (PFS) was 10.5 months and the median survival was 17.5 months. CONCLUSION: Oral vinorelbine-capecitabine shows very promising activity and low toxicity in MBC treatment, with high compliance of the patients.