Pseudohypoxia in paraganglioma and pheochromocytoma is associated with an immunosuppressive phenotype.

Metastatic pheochromocytoma and paraganglioma (PPGL) have poor prognosis and limited therapeutic options. The recent advent of immunotherapies showing remarkable clinical efficacies against various cancer types offers the possibility of novel opportunities also for metastatic PPGL. Most PPGLs are pathogenically linked to inactivating mutations in genes encoding different succinate dehydrogenase (SDH) subunits. This causes activation of the hypoxia-inducible factor 2 (HIF2)-mediated transcriptional program in the absence of decreased intratumoral oxygen levels, a phenomenon known as pseudohypoxia. Genuine hypoxia in a tumor creates an immunosuppressive tumor microenvironment. However, the impact of pseudohypoxia in the immune landscape of tumors remains largely unexplored. In this study, tumoral expression of programmed death-ligand 1 (PD-L1) and HIF2α and tumor infiltration of CD8 T lymphocytes (CTLs) were examined in PPGL specimens from 102 patients. We assessed associations between PD-L1, CTL infiltration, HIF2α expression, and the mutational status of SDH genes. Our results show that high PD-L1 expression levels in tumor cells and CTL tumor infiltration were more frequent in metastatic than nonmetastatic PPGL. However, this phenotype was negatively associated with SDH mutations and high HIF2α protein expression. These data were validated by analysis of mRNA levels of genes expressing PD-L1, CD8, and HIF2α in PPGL included in The Cancer Genome Atlas database. Further, PD-L1 and CD8 expression was lower in norepinephrine than epinephrine-secreting PPGL. This in silico analysis also revealed the low PD-L1 or CD8 expression levels in tumors with inactivating mutations in VHL or activating mutations in the HIF2α-coding gene, EPAS1, which, together with SDH-mutated tumors, comprise the pseudohypoxic molecular subtype of PPGL. These findings suggest that pseudohypoxic tumor cells induce extrinsic signaling toward the immune cells promoting the development of an immunosuppressive environment. It also provides compelling support to explore the differential response of metastatic PPGL to immune checkpoint inhibitors. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Effectiveness of Pharmacokinetic/Pharmacodynamic-Guided Meropenem Treatment in Critically Ill Patients: A Comparative Cohort Study.

BACKGROUND: The proper dosage of antibiotics is a key element in the effective treatment of infection, especially in critically ill patients. This study aimed to evaluate the efficacy of optimized meropenem regimens based on pharmacokinetic/pharmacodynamic criteria in patients admitted to the intensive care unit. METHODS: This observational, naturalistic, retrospective, unicentric cohort study was performed between May 2011 and December 2017. The clinical and bacteriologic responses of 77 control intensive care unit patients receiving meropenem were compared with those of 77 propensity score-balanced patients who received meropenem dose adjusted by therapeutic drug monitoring. The primary end point of clinical response was a reduction at the end of treatment of at least 80% of the maximum procalcitonin (PCT) value recorded during the meropenem treatment. RESULTS: The primary end point was met by 55 patients (71.4%) in the adjusted group compared with 41 (53.3%) patients in the control group (mean difference 18.1%, P = 0.02). Fifty-one patients (66.2%) in the adjusted group required a meropenem dose adjustment, being necessary in 46 of them (90.2%) to decrease the dose. The reduction of PCT was the greatest in the adjusted group compared with the unadjusted group (93% versus 85%, P = 0.004); a greater percentage of patients reached a PCT level < 0.5 ng/mL (63.6% versus 41.6%, P = 0.006), and there was a trend toward an improved bacteriologic response (relative risk = 1.27; 95% confidence interval: 0.92-1.56). There were no differences in early mortality or safety between groups. CONCLUSIONS: Adjustment of meropenem therapy by monitoring is a useful strategy for improving meropenem effectiveness in the treatment of infection in critically ill patients, with no impact on safety.

Evaluation of a non-parametric modelling for meropenem in critically ill patients using Monte Carlo simulation.

PURPOSE: In critically ill patients treated with meropenem, the proposed pharmacokinetics/pharmacodynamics (PK/PD) efficacy index is to keep the free drug concentration 4-5 times above the minimum inhibitory concentration (MIC) of the germ isolated, for 100% of the interval regimen. The objectives were to design a population pharmacokinetics model for meropenem in critically ill patients and to evaluate different dosage schemes that achieve the optimal PK/PD objectives. METHODS: This retrospective, observational, single-centre study included 80 critically ill patients (154 samples) treated with meropenem between May 2011 and December 2017. Patient data, concentrations, treatment and bacteriological variables were collected from electronic medical records. Total and free concentrations of meropenem were modelled in Pmetrics. Monte Carlo simulations were performed to assess the probability of achieving the PK/PD target for different dosage regimens. For patients with available data, the number of patients with a free concentration 4 times higher or lower than the observed MIC for the P. aeruginosa and E. coli was investigated. RESULTS: A one-compartment model with first-order elimination adequately described serum total and free meropenem concentrations. The only variable that significantly influenced the elimination constant of meropenem was the creatinine clearance (CLcr) calculated using the CKD-EPI formula. The highest probability of achieving the pharmacodynamic objective was with 3-h infusion dosage regimens. Sixty percent and 89% of patients attained a free drug concentration 4 times above the MIC for P. aeruginosa and E. coli respectively. CONCLUSIONS: This study proposed different dosing regimens depending on renal clearance strata and the MIC of the germ targeted.

Weight-loss diet alone or combined with progressive resistance training induces changes in association between the cardiometabolic risk profile and abdominal fat depots.

BACKGROUND/AIMS: A weight-loss diet alone or combined with a progressive resistance training program induced different adaptations on cardiometabolic risk, i.e. regional changes in visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) volume distribution patterns. We hypothesized that a heterogeneous adipose tissue metabolism may exist between visceral fat at different discal levels. METHODS: Thirty-four obese women, aged 40-60 years, were randomized to three groups: a control group (n = 9), a diet group (WL; n = 12) with a caloric restriction of 500 kcal/day during 16 weeks, or a diet-plus-resistance-training group (WL+RT; n = 13) with the same caloric restriction and a 16-week resistance training of 2 sessions per week. RESULTS: The association pattern between abdominal fat depots and glucose metabolism variables showed a change from the L4-L5 region (preintervention) to VAT L2-L3 and SAT L2-L3 in the WL and WL+RT groups, respectively. It is noteworthy that accumulation of fat in the midthigh was not characterized by a more favorable lipid profile or glucose metabolism. CONCLUSION: Our results reinforce the importance of considering L2-L3 images to predict insulin resistance after a weight-loss diet, alone or combined with resistance training.

Resistance training improves cardiovascular risk factors in obese women despite a significative decrease in serum adiponectin levels.

Increased circulating adiponectin and insulin sensitivity are usually observed after body fat loss induced by a weight-loss diet. Progressive resistance training (PRT) without a concomitant weight-loss diet significantly decreases visceral fat, thus improving insulin sensitivity. Therefore, the purpose of this study was to ascertain the effects of combined 16-week PRT and weight-loss diet on circulating adiponectin and insulin sensitivity index. Thirty-four obese (BMI: 30-40 kg/m(2)) women, aged 40-60 year, were randomized to three groups: a control group (C; n = 9); a diet group (WL; n = 12) with a caloric restriction of 500 kcal/d; and a diet plus resistance training group (WL+RT; n = 13) with the same caloric restriction as group WL and a 16-week supervised whole body PRT of two sessions/week. Both WL and WL+RT groups showed similar decreases in body mass (-6.3% and -7.7%) and visceral fat (-19.9% and -20.5%). WL resulted in an expected increase in circulating levels of adiponectin (P = 0.07) and insulin sensitivity. However, circulating total adiponectin decreased (P < 0.05) in WL+RT group, whereas an improvement in different cardiovascular risk factors (insulin sensitivity, low-density lipoprotein cholesterol (LDL-C), etc.) was observed. In conclusion, in obese women a 16-week combined PRT and weight-loss diet is accompanied by significant improvements in different cardiovascular risk factors in spite of a significant decrease of circulating adiponectin.