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The progress of metastatic colorectal cancer (mCRC) depends essentially on two signaling pathways: the first mediated by vascular endothelial growth factor (VEGF) and the second by epidermal growth factor receptor (EGFR). In colorectal cancer (CRC), the balance between pro-angiogenic and anti-angiogenic factors is disturbed in favor of a proangiogenic outcome (angiogenic switch) early in the neoplastic progression of adenomas, thus, resulting in neovascularization and eventually in malignant tumor progression. Furthermore, angiogenesis plays an important role in tumor growth and the formation of metastases. Several angiogenic growth factors have been identified to be highly expressed during the progression and metastatic spread of CRC, but VEGFA is the predominant angiogenic cytokine and the most consistently expressed factor during the metastatic process. Agents targeting VEGF/VEGFR signaling have shown efficacy in the treatment of mCRC and are currently approved in this setting. In this review, we summarize the role of antiangiogenic tyrosine kinase inhibitors (TKIs) in the treatment of mCRC, focusing on regorafenib. © 2021 International Institute of Anticancer Research. All rights reserved.

Multiple myeloma (MM) is the second most common hematological malignancy, arising from terminally differentiated B cells, namely plasma cells. miRNAs are small non-coding RNAs that participate in the post-transcriptional regulation of gene expression. In this study, we investigated the role of nine miRNAs in MM. CD138+ plasma cells were selected from bone marrow aspi-rates from MM and smoldering MM (sMM) patients. Total RNA was extracted and in vitro polyad-enylated. Next, first-strand cDNA synthesis was performed using an oligo-dT–adapter primer. For the relative quantification of the investigated miRNAs, an in-house real-time quantitative PCR (qPCR) assay was developed. A functional in silico analysis of the miRNAs was also performed. miR-16-5p and miR-155-5p expression was significantly lower in the CD138+ plasma cells of MM patients than in those of sMM patients. Furthermore, lower levels of miR-15a-5p, miR-16-5p, and miR-222-3p were observed in the CD138+ plasma cells of MM patients with osteolytic bone lesions, compared to those without. miR-125b-5p was also overexpressed in the CD138+ plasma cells of MM patients with bone disease that presented with skeletal-related events (SREs). Furthermore, lower levels of miR-223-3p were associated with significantly worse overall survival in MM patients. In conclusion, we propose a miRNA signature with putative clinical utility in MM. © 2021 by the authors. Licensee MDPI, Basel, Switzerland.

Triple-negative breast cancer (TNBC) accounts for approximately 15–20% of all breast cancers and is characterized by a lack of immunohistochemical expression of estrogen receptors (ER), progesterone receptors (PR) and HER2. TNBC is associated with poor long-term outcomes compared with other breast cancer subtypes. Many of these tumors are also basal-like cancers which are characterized by an aggressive biological behavior with a distant recurrence peak observed early at 3 years following diagnosis. Furthermore, metastatic TNBC bears a dismal prognosis with an average survival of 12 months. Although the prevalence of genetic alterations among women with TNBC differs significantly by ethnicity, race and age, BRCA mutations (including both germline mutations and somatic genetic aberrations) are found in up to 20–25% of unselected patients and especially in those of the basal-like immunophenotype. Therefore, defects in the DNA repair pathway could represent a promising therapeutic target for this subgroup of TNBC patients. Poly(ADP-ribose) polymerase (PARP) inhibitors exploit this deficiency through synthetic lethality and have emerged as promising anticancer therapies, especially in BRCA1 or BRCA2 mutation carriers. Several PARP inhibitors are currently being evaluated in the adjuvant, neo-adjuvant, and metastatic setting for the treatment of breast cancer patients with a deficient homologous recombination pathway. In this article, we review the major molecular characteristics of TNBC, the mechanisms of homologous recombination, and the role of PARP inhibition as an emerging therapeutic strategy. © 2018 Elsevier Ltd

Background: Recognizing resistance or susceptibility to the current standard cisplatin and paclitaxel treatment could improve therapeutic outcomes of metastatic or recurrent cervical cancer. Methods: Forty-five tissue samples from patients participating in a phase II trial of cisplatin and ifosfamide, with or without paclitaxel were collected for retrograde analysis. Immunohistochemistry and genotyping was performed to test ERCC1, III Β-tubulin, COX-2, CD4, CD8 and ERCC1 (C8092A and N118 N) and MDR1 (C3435T and G2677 T) gene polymorphisms, as possible predictive and prognostic markers. Results were statistically analyzed and correlated with patient characteristics and outcomes. Results: Patients with higher levels of ERCC1 expression had shorter PFS and OS than patients with low ERCC1 expression (mPFS:5.1 vs 10.2 months, p = 0.027; mOS:10.5 vs. 21.4 months, p = 0.006). Patients with TT in the site of ERCC1 N118 N and GT in the site of MDR1 G2677 T polymorphisms had significantly longer PFS (p = 0.006 and p = 0.027 respectively). ERCC1 expression and the ERCC1 N118 N polymorphism remained independent predictors of PFS. Interestingly, high III beta tubulin expression was associated with chemotherapy resistance and fewer responses [5/20 (25%)] compared to lower III Β-tubulin expression [15/23 (65.2%)] (p = 0.008). Finally, III Β-tubulin levels and chemotherapy regimen were independent predictors of response to treatment. Conclusions: ERCC1 expression proved to be a significant prognostic factor for survival in our metastatic or recurrent cervical cancer population treated with cisplatin based chemotherapy. ERCC1 N118 N and MDR1 G2677 T polymorphism also proved of prognostic significance for disease progression, while overexpression of III Β-tubulin was positively correlated with chemotherapy resistance. © 2017 The Author(s).

The effect of high-flux hemodialysis membranes on patient survival has not been unequivocally determined. In this prospective, randomized clinical trial, we enrolled 738 incident hemodialysis patients, stratified them by serum albumin < or = 4 and >4 g/dl, and assigned them to either low-flux or high-flux membranes. We followed patients for 3 to 7.5 yr. Kaplan-Meier survival analysis showed no significant difference between high-flux and low-flux membranes, and a Cox proportional hazards model concurred. Patients with serum albumin < or = 4 g/dl had significantly higher survival rates in the high-flux group compared with the low-flux group (P = 0.032). In addition, a secondary analysis revealed that high-flux membranes may significantly improve survival of patients with diabetes. Among those with serum albumin < or = 4 g/dl, slightly different effects among patients with and without diabetes suggested a potential interaction between diabetes status and low serum albumin in the reduction of risk conferred by high-flux membranes. In summary, we did not detect a significant survival benefit with either high-flux or low-flux membranes in the population overall, but the use of high-flux membranes conferred a significant survival benefit among patients with serum albumin < or = 4 g/dl. The apparent survival benefit among patients who have diabetes and are treated with high-flux membranes requires confirmation given the post hoc nature of our analysis.

Background: Geographical differences in disease prevalence and mortality have been described in the general population and in chronic kidney disease patients in Europe. In this secondary analysis of the Membrane Permeability Outcome (MPO) study, we addressed differences in patient and treatment patterns, and whether these affect patient outcomes. Methods: Participating countries were grouped according to geographical location; thus study centers in France, Greece, Italy, Portugal and Spain were allocated to southern Europe (n=499), and those in all other countries (Belgium, Germany, Poland and Sweden) to northern Europe (n=148). Descriptive analysis of patient and treatment patterns at study start, as well as survival analysis, was performed. Results: In patients from the northern European countries, a higher prevalence of diabetes mellitus and of cardiovascular disease was observed than in those from southern Europe (diabetes 35.1% vs. 21.0%, p=0.0007; cardiovascular disease 40.5% vs. 22.8%, p

Data regarding the use of fluoroquinolones in critically ill children are scarce. We present our experience regarding the use of ciprofloxacin in this specific patient population. We prospectively identified all paediatric patients who received ciprofloxacin treatment in the intensive care unit of the tertiary care P. & A. Kyriakou Children's Hospital during a three year period (2005 to 2008). Eighteen paediatric patients (mean age 23 months, 12 females) who received intravenous ciprofloxacin were identified. Various underlying diseases, including malignancy and immunodeficiency, were observed. None of the evaluated patients had cystic fibrosis. Fourteen patients had bacteraemia (mainly caused from Gram-negative pathogens), one had Stenotrophomonas maltophilia pneumonia, while no pathogen was identified in three patients. The latter patients received ciprofloxacin due to the severity of their clinical manifestations. All patients with microbiologically documented infections recovered. Three deaths attributed to the underlying diseases were noted. Within a 10-day follow-up, two cases of diarrhoea, one case of vomiting and one case of reversible supraventricular tachycardia were noted. No case of QT prolongation was noted. The short-term follow-up hampered any assessment of joint and cartilage toxicity, potentially associated with ciprofloxacin treatment. Our study suggests that ciprofloxacin may be a useful option for critically ill children without cystic fibrosis. Even though firm conclusions regarding the safety profile of ciprofloxacin in critically ill children could not be drawn, our study provides useful information regarding short-term adverse events associated with ciprofloxacin.

A carbapenem-resistant Escherichia coli isolate was recovered from rectal swab of a 12-day-old female neonate, which was admitted to a Greek neonatal intensive care unit (NICU). Phenotypic testing, polymerase chain reaction assays with sequencing, and plasmid analysis revealed that the isolate harbored a plasmid-mediated blaVIM-1 metallo-β-lactamase gene. The appearance of a metallo-β-lactamase-producing E. coli in NICU is worrisome. Further surveys are needed to determine whether such Enterobacteriaceae may also be spreading in other NICUs. Copyright © 2011, Mary Ann Liebert, Inc.

Optimization of methods for ruling out Bacillus anthracis leads to increased yields, faster turnaround times, and a lighter workload. We used 72 environmental non-B. anthracis bacilli to validate methods for ruling out B. anthracis. Most effective were the use of horse blood agar, motility testing after isolates had a 2-h incubation in trypticase soy broth, and screening isolates with a B. anthracis-selective agar.

In this prospective study, the 24-hour gastric aspirate volume was carefully recorded before, 24 and 48 h after administering 1.7 mg/kg/8-hourly of oral erythromycin to 16 ventilated neonates less than 32 weeks of gestation. Their median gestational age was 28.5 weeks (range 2331 weeks), their median birthweight was 1,045 g (range 690-1,560 g) and the median day of life at which erythromycin was commenced was 9.5 days (range 4-16 days). Prior to administering erythromycin median 24-hour gastric aspirate volume, expressed as a percentage of the milk volume given over the same period, was 38.5% (range 20.0-100%). It was significantly lower 24 h (median 12%, range 0-41%, p = 0.0004) and 48 h (median 5%, range 0-21%, p = 0.0004) after commencing erythromycin. There was also significant reduction of gastric aspirate volume between 24 and 48 h after commencing erythromycin (p = 0.0024). Milk volume increment over the same period was not significant (p = 0.1022). These preliminary results warrant further evaluation through a randomised controlled trial.

The purpose of this study was to assess the incidence and evolution of mild dilatation confined to the renal pelvis in term neonates with urinary tract infection developing within 2 weeks from birth, Twenty-two neonates with mild dilatation of the renal pelvis out of 180 neonates with urinary tract infection were identified giving an incidence of 12.2% for this finding. Male to female ratio was 6.3:1. The left kidney was twice as frequently involved (68 vs. 32 %). At follow-up, the dilatation had disappeared in 20 neonates (90.9%) by a mean age of 2.7 years with only one neonate developing two further episodes of urinary tract infection in the infantile period. No other morbidity was noted. Copyright (C) 2001 S. Karger AG, Basel.

The aim of this retrospective study was to evaluate the clinical efficacy in terms of mortality and long-term morbidity of third generation cephalosporins and amikacin in combination for the treatment of gram-negative bacterial meningitis in a homogeneous group of neonates, A 15-year experience (1983-1997) with 72 term neonates without central nervous system anomalies and with gramnegative organisms grown in their cerebrospinal fluid treated with the above combination of antibiotics is presented. All isolated organisms were sensitive to cefotaxime or ceftazidime and to amikacin but 80% were resistant to ampicillin, The predominant infecting organism was Escherichia coli (68.0%) which was sensitive to both cefotaxime and amikacin in all cases but resistant to ampicillin in 48% of cases. Survival at discharge was 97.2% but ultimate survival was reduced to 94.4%, as 2 patients died a few months following discharge of conditions unrelated to meningitis. Ventriculitis was diagnosed in 10 neonates (13.8%). Among survivors, 1 neonate (1.3%) developed hydrocephalus needing shunting and 1 neonate (1.3%) with Proteus mirabilis developed a brain abscess with relapse of meningitis which was successfully treated with a 6-week course of chloramphenicol. At follow-up at an age greater than 6 months, 91.1% of the surviving infants were normal, while 92.3% of survivors at an age greater than 6 years were normal and attended normal school. These results, despite any reservations due to the nature of the study (retrospective, uncontrolled study), strongly support the use of third generation cephalosporins and amikacin in combination for the treatment of neonatal gram-negative bacterial meningitis, Copright (C) 2000 S.Karser AG, Basel.

In babies of very low birth weight (< 1500 g) we studied the effect of head up tilting on oxygenation, respiratory rate, heart rate and blood pressure (n = 23), on gastric emptying (n = 10), and on weight gain (n = 6). Head up tilting to 45-degrees achieved the best oxygenation at the angles studied, and decreased the respiratory and heart rates; there was no significant change in blood pressure. Residue in the stomach was also significantly less at 45-degrees, and the neonates’ weight gain was higher. We conclude that nursing stable very low birthweight infants with a higher head up tilt than is conventional may have some advantages.

In 15 healthy mongrel dogs the kidneys were exposed bilaterally, the renal pedicle was clamped on one side (control kidneys) and verapamil, 0.5 mg/kg body weight, was given intravenously. Ten minutes later the renal pedicle on the other side was clamped (verapamil group). At the end of a 60-minute ischaemic period, blood flow was re-established. The mean time to initiation of diuresis was shorter in the verapamil group and creatinine clearance was significantly higher. At the end of the two-hour experiment the mean fractional excretion of sodium and the mean urinary excretion of LDH were higher in the control group. CNa, CK, Cosm and Curea were significantly higher in the verapamil group during the two-hour period of study after revascularisation. On a statistical basis 60 minute acute ischaemic renal failure is significantly modified by the administration of verapamil.

The changes in left ventricular anatomy in 30 patients with end-stage renal disease and stable cardiac function, undergoing regular haemodialysis (10 patients), continuous ambulatory peritoneal dialysis (10 patients) and after successful renal transplantation (10 patients) were evaluated by M-mode echocardiography. Initially all had evidence of left ventricular hypertrophy and dilatation. Reevaluation after a mean follow-up of 22 months on each mode of treatment showed that in the haemodialysis group the left ventricular mass and volume were increased, while in continuous ambulatory peritoneal dialysis (CAPD) and, especially renal transplantation, the hypertrophy and dilatation were reversed. This improvement was probably due to a reduction of cardiac workload.