Myeloid-derived suppressor cells and regulatory T cells share common immunoregulatory pathways-related microRNAs that are dysregulated by acute lymphoblastic leukemia and chemotherapy

BackgroundRelapse remains a critical challenge in children with acute lymphoblastic leukemia (ALL). The emergence of immunoregulatory cells, including myeloid-derived suppressor cells (MDSCs), and T regulatory (T_reg) cells, has been considered one potential mechanism of relapse in children with ALL.AimThis study aimed to address the microRNAs (miRNAs) related to MDSCs and T_reg cells and to explore their targeted immunoregulatory pathways.MethodsAffymetrix microarray was used for global miRNA profiling in B-ALL pediatric patients before, during, and after induction of chemotherapy. Bioinformatics analysis was performed on MDSCs and T_reg cells-related dysregulated miRNAs, and miR-Pathway analysis was performed to explore their targeted immunoregulatory pathways.Results516 miRNAs were dysregulated in ALL patients as compared to the healthy donor. Among them, 13 miRNAs and 8 miRNAs related to MDSCs and T_reg cells, respectively, were common in all patients. Besides, 12 miRNAs were shared between MDSCs and T_reg cells; 4 of them were common in all patients. Four immune-related pathways; TNF, TGF-β, FoxO, and Hippo were found implicated.ConclusionOur pilot study concluded certain miRNAs related to MDSCs and T_reg cells, these miRNAs were linked to immunoregulatory pathways. Our results open avenues for testing those miRNA as molecular biomarkers for the immunosuppressive tumor microenvironment.     

Diagnostic Performance of 68Ga-DOTATATE PET/CT, 18F-FDG PET/CT and 131I-MIBG Scintigraphy in Mapping Metastatic Pheochromocytoma and Paraganglioma

Purpose

To evaluate the diagnostic performance of ⁶⁸Ga-DOTATATE ¹⁸F-fluorodeoxyglucose (¹⁸F-FDG) positron emission tomography (PET)/computed tomography (CT), ¹⁸F-FDG PET/CT and ¹³¹I-MIBG scintigraphy in the mapping of metastatic pheochromocytoma and paraganglioma.

Materials and Methods

Seventeen patients (male = 8, female = 9; age range, 13–68 years) with clinically proven or suspicious metastatic pheochromocytoma or paraganglioma were included in this prospective study. Twelve patients underwent all three modalities, whereas five patients underwent ⁶⁸Ga-DOTATATE and ¹³¹I-MIBG without ¹⁸F-FDG. A composite reference standard derived from anatomical and functional imaging findings, along with histopathological information, was used to validate the findings. Results were analysed on a per-patient and on per-lesion basis. Sensitivity and accuracy were assessed using McNemar’s test.

Results

On a per-patient basis, 14/17 patients were detected in ⁶⁸Ga-DOTATATE, 7/17 patients in ¹³¹I-MIBG, and 10/12 patients in ¹⁸F-FDG. The sensitivity and accuracy of ⁶⁸Ga-DOTATATE, ¹³¹I-MIBG and ¹⁸F-FDG were (93.3 %, 94.1 %), (46.7 %, 52.9 %) and (90.9 %, 91.7 %) respectively. On a per-lesion basis, an overall of 472 positive lesions were detected; of which 432/472 were identified by ⁶⁸Ga-DOTATATE, 74/472 by ¹³¹I-MIBG, and 154/300 (patient, n = 12) by ¹⁸F-FDG. The sensitivity and accuracy of ⁶⁸Ga-DOTATATE, ¹³¹I-MIBG and ¹⁸F-FDG were (91.5 %, 92.6 % p < 0.0001), (15.7 %, 26.0 % p < 0.0001) and (51.3 %, 57.8 % p < 0.0001) respectively. Discordant lesions were demonstrated on ⁶⁸Ga-DOTATATE, ¹³¹I-MIBG and ¹⁸F-FDG.

Conclusions

Ga-DOTATATE PET/CT shows high diagnostic accuracy than ¹³¹I-MIBG scintigraphy and ¹⁸F-FDG PET/ CT in mapping metastatic pheochromocytoma and paraganglioma.     

Colorectal liver metastases: disappearing lesions in the era of Eovist hepatobiliary magnetic resonance imaging

Background

Hepatobiliary contrast enhanced MRI is known to be the most sensitive imaging modality for detection of colorectal hepatic metastasis. To date no study has investigated the rate of disappearing lesions with gadoxetic acid MR (Eovist/Primovist), or characterized the pathologic response of lesions which disappear on gadoxetic acid MR.

Methods

Retrospective review of hepatic resections for colorectal metastases between 01/2008 and 01/2014 was performed to evaluated the rate of disappearance of lesions on gadoxetic acid MR and the rate of complete pathologic response in the lesions that disappear. “Disappearing lesions” were lesions on baseline imaging that were not identifiable on pre-operative Eovist MRI. Complete pathologic response was defined as no viable tumor on pathology or by lack of recurrence within 1 year.

Results

In 23 patients, 200 colorectal metastases were identified on baseline imaging. On pre-operative Eovist MR 77 of the 200 lesions (38.5%) were “disappearing” lesions. At surgical pathology or 1 year follow-up imaging, 42 of 77 lesions (55%) demonstrated viable tumor (21) or recurrence (21). Thirty of 77 lesions (39%) were nonviable at pathology (10) or without evidence of recurrence at 1 year (20). 5 lesions were indeterminate.

Discussion

Despite disappearance on Eovist MR imaging (the most sensitive available imaging modality), 38.5% of all colorectal metastases disappeared and of those, 55% were viable.     

Prevalence and outcome of severe chronic obstructive pulmonary disease exacerbations caused by multidrug-resistant bacteria

PURPOSE OF REVIEW: A bacterial cause is found in about half of all severe chronic obstructive pulmonary disease exacerbations. The aim of this review is to discuss recent findings regarding prevalence, risk factors and outcome of severe chronic obstructive pulmonary disease exacerbations caused by multidrug-resistant bacteria. RECENT FINDINGS: According to the results of recent studies, multidrug-resistant bacteria represented a large proportion of bacteria isolated in chronic obstructive pulmonary disease exacerbations. Prior antibiotic treatment, prior endotracheal intubation, long-term inhaled or systemic corticosteroid use and severe impairment of lung function were identified as risk factors for severe chronic obstructive pulmonary disease exacerbations related to multidrug-resistant bacteria. Although the mortality rate was higher in patients with multidrug-resistant bacteria as compared with patients with other bacteria, multidrug resistance was not independently associated with mortality in these patients. Multidrug-resistant bacteria were, however, significantly associated with inappropriate initial antibiotic treatment. Higher rates of subsequent ventilator-associated pneumonia and mortality were found in patients with severe chronic obstructive pulmonary disease exacerbation who received inappropriate initial antibiotic treatment when compared with those who received appropriate treatment. SUMMARY: Further studies should determine whether administration of broad-spectrum antibiotic treatment could improve the outcome of patients with severe chronic obstructive pulmonary disease exacerbation caused by multidrug-resistant bacteria.     

Adaptation to hypotension may involve the cerebral hemispheres

Arterial vasodilatation was obtained by a slow injection of nicardipine (0.1 microgram/20 min) to normotensive Long Evans rats. Reflex tachycardia was a consequence of a sympathetic activation as labetalol injected prior to nicardipine prevented the calcium antagonist-induced heart rate changes. The slope of the mean blood pressure (mmHg) - heart period (msec) curve was reproducible after a 75 min interval. This index of baroreflex sensitivity was calculated before and after a transient cerebral ischemia. Hemispheric ischemia was induced by electrocauterization of the vertebral arteries and a transient occlusion of the common carotid arteries for 10 min. Brainstem perfusion was maintained with this protocol. The second dose of nicardipine was injected 15 min after recirculation. The tachycardic response to the vasodilatation was markedly reduced after ischemia (1st slope: 0.48 +/- 0.05 msec/mmHg, 2nd slope: 0.12 +/- 0.05 msec/mmHg, n = 12, p less than 0.001, paired t test). We conclude that nicardipine injection is applicable to the study of baroreflex sensitivity in rats. The impairment of baroreflex sensitivity after a transient hemispheric ischemia could reflect a hemispheric interference with brainstem cardiovascular centres involved in the baroreceptor-heart rate reflex.     

Prevalence and causes of blindness and diabetic retinopathy in Southern Saudi Arabia

Objectives:

To determine the prevalence and causes of blindness and diabetic retinopathy (DR) in Jazan district, Southern Saudi Arabia.

Methods:

Using the standardized Rapid Assessment for Avoidable Blindness (RAAB) and DR cross-sectional methodology, 3800 subjects were randomly selected from the population of ≥50 years of age in Jazan, Saudi Arabia between November 2011 and January 2012. Participants underwent screening comprised of interview, random blood glucose test, and ophthalmic assessment including visual acuity (VA) and fundus examination. Among participants with VA <6/18 in either eye, the cause(s) of visual impairment was determined. Participants were classified as diabetic if they had previous diagnoses of diabetes, or random blood glucose >200 mg/dl. Diabetic participants were assessed for DR using dilated fundus examination. All data were recorded using the RAAB + DR standardized forms.

Results:

The prevalence of bilateral blindness <3/60 was 3.3% (95% confidence interval [CI]: 2.74 - 3.90). Cataract was the leading cause of blindness (58.6%); followed by posterior segment diseases (20%), which included DR (7; 3.3%). The prevalence of diabetes mellitus (DM) was 22.4%, (95% CI: 21.09 - 23.79), among them; 27.8% had DR. The prevalence of sight-threatening DR was 5.7%.

Conclusion:

The prevalence of DM and the corresponding proportion of DR in this region is lower than that reported in other regions of Saudi Arabia. However, the prevalence of blindness not related to DR is relatively higher than the other studies.The Kingdom of Saudi (KSA) ranks seventh in the global burden of diabetes mellitus (DM), with an estimated prevalence of 23.5% for age groups 20-79 years.1 Ocular complications are quite common among diabetic patients. It is well established that within 15 years of diabetes approximately 2% of diabetics may turn legally blind, and approximately 10% may develop severe visual impairment. Diabetic retinopathy (DR) is one of the serious potential complications. It occurs in approximately 77% of the type 2 diabetics within 10 years of the diabetes onset, and almost in all type 1 diabetics.2 A global review of diabetic retinopathy reported that on average, 34.6% of all diabetic patients have some forms of DR.3 Recent studies in KSA have reported a high prevalence of DR among diabetics in different regions of the country. A recent population based study in Taif,4 in the Western region of KSA reported that 33% of all diabetics have some form of DR; while another hospital based study in the Madinah region reported the same estimate at 36%.5 With this high burden of the disease, the Saudi Ministry of Health (MoH) in collaboration with the Saudi National Prevention of Blindness Committee (NPBC) commissioned more studies to determine the magnitude of the problem in other regions of the vast country. Thus, a population-based survey was conducted to estimate both prevalence and pattern of DR, in addition to the magnitude and causes of blindness and visual impairment in the Jazan district, in the Southwestern region of KSA. Jazan covers an area of 11,670 Km², and has a population of 1,533,496 inhabitants. It lies to the Southwest coast of the Red Sea and is bordered by Yemen to the south. The study adopted the Rapid Assessment for Avoidable Blindness and Diabetic Retinopathy (RAAB+DR) technique, which is a survey methodology developed by the International Centre for Eye Health, London School of Hygiene and Tropical Medicine (ICEH-LSHTM), London, United Kingdom.6 The RAAB+DR is a simple and cost effective cross-sectional community-based survey of persons 50 years and older, that focuses primarily on the prevalence of avoidable blindness. It estimates the prevalence of blindness and visual impairment, their causes, and magnitude of DR in a specific geographical area, usually at the district, or province level. The RAAB+DR methodology has concrete proven reliability and validity.4,7