Overcoming Microbiome-Acquired Gemcitabine Resistance in Pancreatic Ductal Adenocarcinoma.

Gastrointestinal cancers (GICs) are one of the most recurrent diseases in the world. Among all GICs, pancreatic cancer (PC) is one of the deadliest and continues to disrupt people's lives worldwide. The most frequent pancreatic cancer type is pancreatic ductal adenocarcinoma (PDAC), representing 90 to 95% of all pancreatic malignancies. PC is one of the cancers with the worst prognoses due to its non-specific symptoms that lead to a late diagnosis, but also due to the high resistance it develops to anticancer drugs. Gemcitabine is a standard treatment option for PDAC, however, resistance to this anticancer drug develops very fast. The microbiome was recently classified as a cancer hallmark and has emerged in several studies detailing how it promotes drug resistance. However, this area of study still has seen very little development, and more answers will help in developing personalized medicine. PC is one of the cancers with the highest mortality rates; therefore, it is crucial to explore how the microbiome may mold the response to reference drugs used in PDAC, such as gemcitabine. In this article, we provide a review of what has already been investigated regarding the impact that the microbiome has on the development of PDAC in terms of its effect on the gemcitabine pathway, which may influence the response to gemcitabine. Therapeutic advances in this type of GIC could bring innovative solutions and more effective therapeutic strategies for other types of GIC, such as colorectal cancer (CRC), due to its close relation with the microbiome.

Associations between Aging and Vitamin D Status with Whole-Body Nitric Oxide Production and Markers of Endothelial Function.

BACKGROUND: Aging and vitamin D deficiency have been associated with reduced nitric oxide (NO) synthesis and impaired endothelial function (EF) but the evidence in humans remains weak. OBJECTIVES: Two independent cross-sectional studies were designed to evaluate the association between age, sex, and plasma vitamin D concentrations with physiological and biochemical biomarkers of NO synthesis and EF in young and older healthy participants (Study 1) and in overweight and obese postmenopausal females (Study 2). METHODS: In Study 1, 40 young (20-49 y) and older (50-75 y) males and females (10 participants per age and sex group) were included. Resting blood pressure and ear-to-finger peripheral pulse wave velocity (PWV) were measured. A stable-isotopic method was used to determine whole-body NO production. Plasma 25-hydroxyvitamin D (25(OH)D), nitrate, nitrite, and asymmetric dimethylarginine (ADMA) concentrations were determined. In Study 2, 80 older overweight and obese females (age 61.2 ± 6.2 y, body mass index 29.5 ± 4.4 kg/m2) were recruited. Postocclusion reactive hyperemia (PORH) and peripheral PWV were measured. Plasma concentrations of 25(OH)D, nitrate, cyclic guanosine monophosphate, 3-nitrotyrosine (3-NT), endothelin-1, vascular endothelial growth factor, and ADMA were determined. RESULTS: In Study 1, whole-body NO production was significantly greater in young compared with older participants (0.61 ± 0.30 µmol·h-1·kg-1 compared with 0.39 ± 0.10 µmol·h-1·kg-1, P = 0.01) but there was no evidence of a sex difference (P = 0.81). Plasma 25(OH)D concentration was not associated with PWV (r = 0.18, P = 0.28) or whole-body NO production (r = -0.20, P = 0.22). Plasma ADMA concentration was associated positively with age (r = 0.35, P = 0.03) and negatively with whole-body NO production (r = -0.33, P = 0.04). In Study 2, age was associated with lower PORH (r = -0.28, P = 0.02) and greater ADMA concentrations (r = 0.22, P = 0.04). Plasma 25(OH)D concentration was inversely associated with 3-NT concentrations (r = -0.31, P = 0.004). CONCLUSIONS: Older age was associated with lower whole-body NO production. Plasma vitamin D concentrations were not associated with NO production or markers of EF but showed a weak, significant correlation with oxidative stress in postmenopausal overweight females.

How Can the Microbiome Induce Carcinogenesis and Modulate Drug Resistance in Cancer Therapy?

Over the years, cancer has been affecting the lives of many people globally and it has become one of the most studied diseases. Despite the efforts to understand the cell mechanisms behind this complex disease, not every patient seems to respond to targeted therapies or immunotherapies. Drug resistance in cancer is one of the limiting factors contributing to unsuccessful therapies; therefore, understanding how cancer cells acquire this resistance is essential to help cure individuals affected by cancer. Recently, the altered microbiome was observed to be an important hallmark of cancer and therefore it represents a promising topic of cancer research. Our review aims to provide a global perspective of some cancer hallmarks, for instance how genetic and epigenetic modifications may be caused by an altered human microbiome. We also provide information on how an altered human microbiome can lead to cancer development as well as how the microbiome can influence drug resistance and ultimately targeted therapies. This may be useful to develop alternatives for cancer treatment, i.e., future personalized medicine that can help in cases where traditional cancer treatment is unsuccessful.

A sudden turner of events.

The authors report the case of an 18-year-old woman with Turner Syndrome and aortic coarctation, who developed aortic dissection after percutaneous stenting. Surgical treatment was necessary as the lesion progressed. This case highlights both the importance of awareness as well as multidisciplinary management of this potential complication.

Echocardiographic Versus Angiographic Assessment of Patent Arterial Duct in Percutaneous Closure: Towards X-ray Free Duct Occlusion?

Device selection and procedural guidance for percutaneous ductal closure strongly rely upon angiographic and echocardiographic imaging. Current literature recognises 2D echocardiography as an essential tool for diagnosis and assessment but does not define a consistent methodology to optimise ductal measurement. There is little research comparing echocardiography with gold standard angiography for ductal measurement. Proving 2D echocardiographic ductal measurement to be equivalent to angiography could pave the way for its use as the primary modality in image guidance for percutaneous closure of the ductus. This was a retrospective study of 100 consecutive paediatric patients who underwent percutaneous ductal closure. Echocardiographic images were studied to determine ductal (a) morphology (b) dimensions (length, aortic ampulla, pulmonary end, minimum diameter) (c) size of device that would be appropriate for closure. These data were compared to corresponding measurements generated by angiographic images. Inter and intra-observer ratings were calculated to assess levels of agreement. There were significant differences between the imaging methods in classifying the morphological sub-type and ductal measurements (p < 0.005), except for length which was not found to be significantly different between modalities. Prediction of device selection from angiographic images showed excellent agreement (weighted k = 0.81). Predictions based on echocardiographic images showed a poor level of agreement (weighted k = 0.14). We found poor correlation between echocardiography and angiography for measurement, morphological assessment and device selection. Based on our findings, percutaneous arterial duct occlusion without angiographic guidance in this age group cannot be advocated.

Percutaneous valve implantation in "tricuspid" position after a Fontan-Björk operation.

BACKGROUND: A 30-year-old female with tricuspid valve atresia, ventricular septal defect, and atrial septal defect had a neonatal modified Blalock Taussig shunt and a Fontan-Björk operation performed at five years of age. She did well initially but progressively developed signs of systemic congestion due to severe homograft stenosis and underwent successful percutaneous implantation of a Melody® pulmonary valve (Medtronic, Minneapolis, MN, USA) in the "tricuspid" position.

Acute kidney injury, long-term renal function and mortality in patients undergoing major abdominal surgery: a cohort analysis.

BACKGROUND: Acute kidney injury (AKI) is frequent during hospitalization and may contribute to adverse consequences. We aimed to evaluate long-term adverse renal function and mortality after postoperative AKI in a cohort of patients undergoing major abdominal surgery. METHODS: We performed a retrospective analysis of adult patients who underwent major non-vascular abdominal surgery between January 2010 and February 2011 at the Department of Surgery II of Hospital de Santa Maria-Centro Hospitalar Lisboa Norte, Portugal. Exclusion criteria were as follows: chronic kidney disease on renal replacement therapy, undergoing renal replacement therapy the week before surgery, death before discharge and loss to follow-up through January 2014. Patients were categorized according to the development of postoperative AKI in the first 48 h after surgery using the Kidney Disease: Improving Global Outcomes classification. AKI was defined by an increase in absolute serum creatinine (SCr) ≥0.3 mg/dL or by a percentage increase in SCr ≥50% and/or by a decrease in urine output to <0.5 mL/kg/h for >6 h. Adverse renal outcomes (need for long-term dialysis and/or a 25% decrease in estimated glomerular filtration rate after hospital discharge) and mortality after discharge were evaluated. Cumulative mortality was analysed with the Kaplan-Meier method and log-rank test and outcome predictive factors with the Cox regression. Significance was set at P < 0.05. RESULTS: Of 390 selected patients, 72 (18.5%) developed postoperative AKI. The median follow-up was 38 months. Adverse renal outcomes and death after hospital discharge were more frequent among AKI patients (47.2 versus 22.0%, P < 0.0001; and 47.2 versus 20.5%, P < 0.0001, respectively). The 4 year cumulative probability of death was 44.4% for AKI patients, while it was 19.8% for patients with no AKI (log-rank test, P < 0.0001). In multivariate analysis, AKI was a risk factor for adverse renal outcomes (adjusted hazard ratio 1.6, P = 0.046) and mortality (adjusted hazard ratio 1.4, P = 0.043). CONCLUSIONS: AKI after major abdominal surgery was independently associated with the risk of long-term need for dialysis and/or renal function decline and with the risk of death after hospital discharge.

Catch-up growth in term and preterm infants after surgical closure of ventricular septal defect in the first year of life.

UNLABELLED: Growth impairment in infants with unrestrictive ventricular septal defects (VSD) is common, and normalisation of growth has been reported after surgical correction. Literature is inconsistent about growth velocity after surgery in term and preterm infants. We aimed to establish the pattern of catch-up growth in term and preterm infants submitted to VSD surgical correction before 1 year of age. Fifty-two infants (41 term, 11 preterm) were studied. Anthropometric data at birth, surgery and 3, 6, 12 and 24 months after surgery were collected retrospectively. Statistic analyses were performed in SPSS® version 21. At the time of surgery, growth was severely impaired in term and preterm infants. Term infants underwent a period of fast growth within the first 6 months after surgery, achieving posteriorly a normal growth pattern, as both weight and height were not significantly different from the reference population at 24 months after surgery. Preterms caught-up later than term infants but with a significant weight gain within 3 months after surgery. CONCLUSION: Early surgical repair of VSD leads to a significant acceleration of growth within 3 to 6 months after surgery, for both groups. WHAT IS KNOWN: • Growth impairment in infants with unrestrictive ventricular septal defects is well documented in literature. • Surgical correction in the first months of life is the current option for most ventricular septal defects, leading to a more favourable growth pattern. • Rapid growth during infancy may be associated with the development of insulin resistance, metabolic syndrome, obesity and cardiovascular disease later in life. What is New: • Literature is inconsistent about catch-up growth velocities after ventricular correction for term infants. • Preterm infants have never been enrolled in previous studies that aimed to establish a pattern of growth after surgery. • This group of children, who underwent a rapid post-surgery catch-up growth that follows a period of failure to thrive, may be at a higher risk of insulin resistance, metabolic syndrome, obesity and cardiovascular disease.

Acute kidney injury after major abdominal surgery: a retrospective cohort analysis.

Background. We analyzed the incidence, risk factors, and prognosis of acute kidney injury (AKI) in a cohort of patients undergoing major abdominal surgery. Methods. A total of 450 patients were retrospectively studied. AKI was defined by an increase in serum creatinine (SCr) ≥ 0.3 mg/dl or by an increase in SCr ≥ 50% and/or by a decrease in urine output to 0.5 ml/kg/hour for 6 hours, in the first 48 hours after surgery. Logistic regression method was used to determine predictors of AKI and in-hospital mortality. A two-tailed P value <0.05 was considered significant. Results. One hundred one patients (22.4%) had postoperative AKI. Age (adjusted odds ratio (OR) 1.02, 95% confidence interval (CI) 1.01-1.05), nonrenal Revised Cardiac Risk Index score (adjusted OR 1.9, 95% CI 1.3-3.1, P = 0.003), intraoperative erythrocytes transfusions (adjusted OR 2.2, 95% CI 1.4-3.5, P <.0001), and nonrenal Simplified Acute Physiology Score II (adjusted OR 1.03, 95% CI 1.01-1.06, P = 0.0191) were associated with postoperative AKI. AKI was associated with increased in-hospital mortality (20.8% versus 2.3%, P <.0001; unadjusted OR 11.2, 95% CI 4.8-26.2, P <.0001; adjusted OR 3.7, 95% CI 1.2-11.7, P = 0.024). Conclusion. AKI was common in patients undergoing major abdominal surgery and was associated with in-hospital mortality.