Stroke associated with sarcoidosis: A systematic review of reported cases.

BACKGROUND: Sarcoidosis can be associated with stroke. Whether granulomatous vasculitis directly causes stroke in patients with sarcoidosis remains unclear. This systematic review aims to consolidate reports of concurrent sarcoidosis and stroke. METHODS: Medline and Embase were searched for terms encompassing sarcoidosis and stroke with a censoring date of March 25, 2023. Cases were reviewed by two authors, with the inclusion criteria: biopsy-confirmed systemic sarcoidosis, stroke confirmed by imaging or pathology, clinical description of individual patient history, and English language publications. RESULTS: Of 1628 articles screened, 51 patients from 49 articles were included (65% male, mean age 41 years). Seventy-one percent of strokes were ischemic and 29% were hemorrhagic. Lesions were supratentorial in 78% of cases, infratentorial in 34%, and multifocal in 45%. Presenting symptoms were variable, with the most common being headache (38%) followed by weakness (35%). 10 patients had recurrent strokes. Stroke was the presenting symptom of sarcoidosis in 65%. 21 patients had brain biopsies. The most common neuropathologic findings were perivascular (33%) or intramural (33%) non-caseating granulomas. On imaging, 32 patients had findings suggestive of neurosarcoidosis, including 35% with evidence of meningeal enhancement. 63% of patients were treated with corticosteroids and/or other immunomodulatory therapy, with varying clinical improvement. CONCLUSIONS: Stroke associated with sarcoidosis generally follows trends in stroke incidence, with infarction being more common than hemorrhage and male sex carrying a higher risk. Most patients were diagnosed with sarcoidosis during or following their stroke episode. Brain biopsy infrequently shows clear granulomatous vasculitis.

Neurologic disease activity in people with multiple sclerosis treated with immune checkpoint inhibitors.

BACKGROUND: There is concern that immune checkpoint inhibitors (ICPIs) can provoke relapses in people with multiple sclerosis (pwMS). OBJECTIVE: Analyze outcomes of pwMS who received ICPI treatment for malignancy. METHODS: We electronically identified pwMS who received ICPI treatment at Mass General Brigham hospital system. We retrospectively obtained information about patients' MS, cancer, treatment, and outcomes. RESULTS: Sixteen patients were identified with an average (standard deviation (SD)) age of 67.4 (11.9) years. Eleven (68.8%) had no relapses since MS diagnosis. None had MS relapses after ICPI treatment or new MS lesions. CONCLUSION: ICPI use was not associated with increased clinical disease activity in this cohort of older patients with inactive MS.

Driving Impairment Cases Involving Flualprazolam.

Flualprazolam is a novel psychoactive substance in the benzodiazepine class that is increasing in prevalence in the USA. This study describes 19 cases of drivers stopped for impaired driving where flualprazolam was detected. This represents ∼9% of the total cases submitted to the Sedgwick County Regional Forensic Science Center toxicology laboratory between July 2019 and May 2020. Blood concentrations of flualprazolam ranged from 4 to 69 ng/mL, with mean and median concentrations of 20.9 ng/mL and 15 ng/mL, respectively. The increased prevalence in which laboratories are detecting flualprazolam along with the low concentrations necessary for pharmacological effects illustrates the importance of laboratories to remain vigilant in testing for novel psychoactive substances.

Driving Impairment Cases Involving Etizolam and Flubromazolam.

This study describes 12 cases of drivers stopped for impaired driving, where a designer benzodiazepine was detected, specifically etizolam or flubromazolam. Etizolam was detected in three cases, with blood concentrations ranging from 40 to 330 ng/mL. Two of these cases had low concentrations of methamphetamine and/or amphetamine, and in the third case tetrahydrocannabinol (THC) was detected. Flubromazolam was detected in nine cases; in all cases, at least one other drug was detected, with THC being the most prevalent. The mean blood concentration of flubromazolam was 16.3 ng/mL and had a median concentration of 17.0 ng/mL, ranging from 7.0 to 31 ng/mL. The low concentrations of designer benzodiazepines that produce pharmacological effects may allow many of these drugs to go undetected using routine testing in laboratories; therefore, it is necessary to include these novel compounds within validated analytical methods to reduce the chance of reporting false negative results. The prevalence in which laboratories are detecting the presence of novel benzodiazepines in impaired drivers illustrates the increased threat to public safety. These case studies demonstrate the importance of investigating agencies and forensic laboratories to be vigilant in monitoring the emerging novel psychoactive substances in their region.

Fentanyl and Driving Impairment.

The incidence of fentanyl in forensic toxicology analyses in the USA has dramatically increased over the past several years. The increase in death cases has been well studied; however, little has been reported on the impact to drug impaired driving. Fentanyl driving while under the influence of drugs (DUID) case data from 2014 to 2019 is presented. The data were obtained from three toxicology laboratories in the Northeast, Southeast, and Midwest regions of the USA. Fentanyl whole blood concentrations ranged from 0.1 to 157 ng/mL in living drivers with a 466% to 524% increase in fentanyl-positive DUID cases from 2014 to 2019, depending on the US region. The vast majority of fentanyl cases involved poly-drug use. Twenty case histories are presented where fentanyl was the only drug identified. The mean (standard deviation) fentanyl concentration for these cases was 5.2 ± 3.8 ng/mL with a median of 3.7 ng/mL, and the concentrations ranged from 2.0 to 16 ng/mL. Naloxone administration was documented in exactly half of these cases similar to another study involving carfentanil-impaired driving. The case histories also demonstrate that some recreational opioid users may display limited signs of impairment either due to tolerance or naloxone administration. The top three observations in common among the cases were the driver was found unresponsive behind the wheel, the vehicle left the travel lane or roadway, and the driver was involved in a crash. The increase in fentanyl use not only poses a risk for overdose and death, but is also a significant concern for traffic safety. This study supports the movement of fentanyl from a Tier II drug to Tier I due to its significant potential for impairment and increase in prevalence in impaired driving cases.

A Pipeline for ctDNA Detection Following Primary Tumor Profiling Using a Cancer-Related Gene Sequencing Panel.

Circulating tumor DNA (ctDNA) is emerging as a promising biomarker for cancer diagnosis. However, the system to detect gene mutations with very low frequencies from plasma remains to be established in terms of technical aspects of sequencing technologies and cost for universal use. One strategy is to employ a cancer sequencing panel to detect mutations in a primary tumor in a time- and cost-effective manner, and subsequently assess these mutations with a digital PCR technology from plasma ctDNA. This strategy enables the accurate detection of low frequency mutations (i.e., less than 1% allele frequency) from ctDNA, since both comprehensive coverage of genes and quantitative mutation detection with very low frequencies are required for cancer diagnosis from plasma samples. Here, we present a pipeline can be used to detect mutations from plasma ctDNA with very low allele frequencies using a next-generation sequencing technology for comprehensive coverage of primary tumors and droplet digital PCR for sensitive detection from plasma ctDNA.

Inhibition of PI3K suppresses propagation of drug-tolerant cancer cell subpopulations enriched by 5-fluorouracil.

Drug-tolerant cancer cell subpopulations are responsible for relapse after chemotherapy. By continuously exposing the gastric cancer cell line MKN45 to 5-FU for >100 passages, we established a 5-fluorouracil (5-FU)-tolerant line, MKN45/5FU. Orthotopic xenografts of MKN45/5FU cells in the stomach of nude mice revealed that these cells had a high potential to metastasize to sites such as the liver. Levels of phosphorylated phosphatidylinositide 3-kinase (PI3K) increased both in 5-FU-tolerant subpopulations according to the 5-FU dose, and in gastric submucosal orthotopic xenografts of MKN45/5FU cells. Sequential administration of 5-FU and a PI3K inhibitor, GDC-0941, targeted the downstream ribosomal S6 kinase phosphorylation to significantly suppress 5-FU-tolerant subpopulations and tumor propagation of orthotopic MKN45/5FU xenografts. These results suggest that administration of 5-FU followed by GDC-0941 may suppress disease relapse after 5-FU-based gastric cancer chemotherapy.

α-Amanitin Restrains Cancer Relapse from Drug-Tolerant Cell Subpopulations via TAF15.

Cancer relapse occurs with substantial frequency even after treatment with curative intent. Here we studied drug-tolerant colonies (DTCs), which are subpopulations of cancer cells that survive in the presence of drugs. Proteomic characterization of DTCs identified stemness- and epithelial-dominant subpopulations, but functional screening suggested that DTC formation was regulated at the transcriptional level independent from protein expression patterns. We consistently found that α-amanitin, an RNA polymerase II (RNAPII) inhibitor, effectively inhibited DTCs by suppressing TAF15 expression, which binds to RNA to modulate transcription and RNA processing. Sequential administration of α-amanitin and cisplatin extended overall survival in a cancer-relapse mouse model, namely peritonitis carcinomatosa. Therefore, post-treatment cancer relapse may occur through non-distinct subpopulations and may be effectively prevented by α-amanitin to disrupt transcriptional machinery, including TAF15.

Individualized Mutation Detection in Circulating Tumor DNA for Monitoring Colorectal Tumor Burden Using a Cancer-Associated Gene Sequencing Panel.

BACKGROUND: Circulating tumor DNA (ctDNA) carries information on tumor burden. However, the mutation spectrum is different among tumors. This study was designed to examine the utility of ctDNA for monitoring tumor burden based on an individual mutation profile. METHODOLOGY: DNA was extracted from a total of 176 samples, including pre- and post-operational plasma, primary tumors, and peripheral blood mononuclear cells (PBMC), from 44 individuals with colorectal tumor who underwent curative resection of colorectal tumors, as well as nine healthy individuals. Using a panel of 50 cancer-associated genes, tumor-unique mutations were identified by comparing the single nucleotide variants (SNVs) from tumors and PBMCs with an Ion PGM sequencer. A group of the tumor-unique mutations from individual tumors were designated as individual marker mutations (MMs) to trace tumor burden by ctDNA using droplet digital PCR (ddPCR). From these experiments, three major objectives were assessed: (a) Tumor-unique mutations; (b) mutation spectrum of a tumor; and (c) changes in allele frequency of the MMs in ctDNA after curative resection of the tumor. RESULTS: A total of 128 gene point mutations were identified in 27 colorectal tumors. Twenty-six genes were mutated in at least 1 sample, while 14 genes were found to be mutated in only 1 sample, respectively. An average of 2.7 genes were mutated per tumor. Subsequently, 24 MMs were selected from SNVs for tumor burden monitoring. Among the MMs found by ddPCR with > 0.1% variant allele frequency in plasma DNA, 100% (8 out of 8) exhibited a decrease in post-operation ctDNA, whereas none of the 16 MMs found by ddPCR with < 0.1% variant allele frequency in plasma DNA showed a decrease. CONCLUSIONS: This panel of 50 cancer-associated genes appeared to be sufficient to identify individual, tumor-unique, mutated ctDNA markers in cancer patients. The MMs showed the clinical utility in monitoring curatively-treated colorectal tumor burden if the allele frequency of MMs in plasma DNA is above 0.1%.

No effect of switching to high-dose rosuvastatin, add-on nicotinic acid, or add-on fenofibrate on serum vitamin D levels in patients with mixed dyslipidemia.

BACKGROUND: Low 25-hydroxy-vitamin D [25(OH)VitD] levels may represent a novel cardiovascular disease risk factor. Several statins may increase 25(OH)VitD concentration. The effect of other lipid-lowering drugs is unknown. AIM: To investigate whether switching to high-dose rosuvastatin, add-on-statin nicotinic acid or add-on-statin fenofibrate would alter 25(OH)VitD levels in patients with mixed dyslipidemia who are already on a conventional statin dose. METHODS: This is a prespecified analysis of a previously published study. Forty-four patients with mixed dyslipidemia not at treatment goal despite treatment with simvastatin 10-40 mg or atorvastatin 10-20 mg or rosuvastatin 5-10 mg were randomly allocated to switch to rosuvastatin 40 mg (n=17), add-on-statin extended release nicotinic acid (ER-NA)/laropiprant (LRPT) (1000/20 mg first four weeks and 2000/40 mg thereafter) (n=14), or add-on-statin micronized fenofibrate (200 mg) for three months. The endpoint for this analysis was between-group difference in changes in 25(OH)VitD levels. RESULTS: Serum 25(OH)VitD levels did not significantly change in any group. In the switch to the highest dose of rosuvastatin group and the add-on-statin ER-NA/LRPT group there was an insignificant decrease in 25(OH)VitD levels {-4.7% [from 16.8 (3.2-37) to 16.0 (7.9-51.6)] and -14.8% [from 12.8 (2.0-54.8) to 10.9 (2.4-34)], respectively]}, while in the add-on-statin fenofibrate group there was an insignificant increase [+13% (from 14.5 (1.0-42) to 16.4 (4.4-30.4) ng/mL)]. No significant difference between groups was found. CONCLUSION: In patients already on a conventional statin dose, neither switching to high-dose rosuvastatin (40 mg) nor add-on-statin ER-NA/LRPT or fenofibrate were associated with significant changes in 25(OH)VitD serum levels. Hippokratia 2015; 19 (2):136-140.

Comparison of switch to the highest dose of rosuvastatin vs. add-on nicotinic acid vs. add-on fenofibrate for mixed dyslipidaemia.

BACKGROUND: Use of a statin at a standard dose may be insufficient for the treatment of mixed dyslipidaemia. Whether switch to the highest dose of rosuvastatin (40 mg) or add-on nicotinic acid (NA) or fenofibrate is more efficacious remains unknown. PATIENTS AND METHODS: This was a prospective, randomised, open-label, blinded end-point (PROBE) study. We recruited 100 patients with mixed dyslipidaemia who were treated with a statin at a standard dose but had not achieved lipid targets. Patients were randomised to switch to the highest approved dose of rosuvastatin (40 mg), add-on extended release nicotinic acid (ER-NA)/l-aropiprant (LRPT) or to add-on micronised fenofibrate for 3 months. The primary end-point was the change in non-high-density lipoprotein cholesterol (non-HDL-C) levels. RESULTS: Ninety patients completed the study. Non-HDL-C decreased in all groups (by 23, 24 and 7% in the rosuvastatin, ER-NA/LRPT and fenofibrate group, respectively, p < 0.01 for all compared with baseline and p < 0.01 for all compared with fenofibrate group). Low-density lipoprotein cholesterol (LDL-C) decreased by 23 and 19% in the rosuvastatin and ER-NA/LRPT group, respectively (p < 0.01 compared with baseline), but not in the add-on fenofibrate group. Add-on ER-NA/LRPT was associated with the greatest HDL-C increase, while add-on ER-NA/LRPT and add-on fenofibrate were associated with the greatest triglyceride decrease. Twenty-four per cent of patients initially randomised to add-on ER-NA/LRPT dropped out because of side effects. CONCLUSIONS: In conclusion, switch to the highest dose of rosuvastatin and add-on ER-NA/LRPT may be better options compared with add-on fenofibrate for the management of patients with mixed dyslipidaemia not on treatment goals with a statin at a standard dose.

Lysis syndrome during therapy of visceral leishmaniasis.

INTRODUCTION: Lysis syndrome is a constellation of metabolic disorders usually seen after the initiation of chemotherapy for rapidly proliferating malignancies (tumor lysis syndrome). Reported herein is a tumor lysis-like syndrome after the initiation of anti-infective therapy for visceral leishmaniasis. PATIENTS AND METHODS: Ten consecutive patients with visceral leishmaniasis were administered liposomal amphotericin B. Levels of serum uric acid, phosphate, creatinine, blood urea nitrogen, potassium, calcium, and magnesium were evaluated prior to as well as 4 and 30 days following the initiation of treatment. RESULTS: During the 4th post-treatment day significant increases in the levels of serum uric acid, phosphate, creatinine, and blood urea nitrogen were seen, while the levels of calcium, potassium, and magnesium were not significantly altered. Patients were treated by hydration, urine alkalization, and administration of allopurinol as needed. A recovery of metabolic abnormalities was recorded 1 month later, although some patients had evidence of residual injury. CONCLUSION: A lysis syndrome may complicate the treatment of visceral leishmaniasis. Awareness of this complication can lead to the initiation of prophylactic treatment as well as to early recognition and management of this syndrome in susceptible patients.

Comparison of the effects of simvastatin vs. rosuvastatin vs. simvastatin/ezetimibe on parameters of insulin resistance.

BACKGROUND: Statin treatment may be associated with adverse effects on glucose metabolism. Whether this is a class effect is not known. In contrast, ezetimibe monotherapy may beneficially affect insulin sensitivity. OBJECTIVE: The aim of this study was to compare the effects of three different regimens of equivalent low-density lipoprotein cholesterol (LDL-C) lowering capacity on glucose metabolism. METHODS: A total of 153 patients (56 men), who had not achieved the LDL-C goal recommended by the National Cholesterol Education Program Adult Treatment Panel III (NCEP-ATP III) despite a 3-month dietary and lifestyle intervention, were randomly allocated to receive open-label simvastatin 40 mg or rosuvastatin 10 mg or simvastatin/ezetimibe 10/10 mg for 12 weeks. The primary end point was changes in homeostasis model assessment of insulin resistance (HOMA-IR). Secondary endpoints consisted of changes in fasting insulin levels, fasting plasma glucose (FPG), glycosylated haemoglobin (HbA(1c) ), the HOMA of ß-cell function (HOMA-B) (a marker of basal insulin secretion by pancreatic ß-cells), LDL-C and high sensitivity C reactive protein (hsCRP). RESULTS: At week 12, all three treatment regimens were associated with significant increases in HOMA-IR and fasting insulin levels (p < 0.05 compared with baseline). No significant difference was observed between groups. No change in FPG, HbA(1c) and HOMA-B levels compared with baseline were noted in any of the three treatment groups. Changes in serum lipids and hsCRP were similar across groups. CONCLUSION: To the extent that simvastatin 40 mg, rosuvastatin 10 mg and simvastatin/ezetimibe 10/10 mg are associated with adverse effects on insulin resistance, they appear to be of the same magnitude.

Anticoagulant drugs: what is new?

Heparins and vitamin K antagonists have been the cornerstones of anticoagulation treatment for several decades. Despite their effectiveness, these agents have limitations which can include food and drug interactions and the need for monitoring. It follows that there is a need for new anticoagulants. There are numerous promising agents at various stages of evaluation. Those in the most advanced stages of development are the oral factor Xa and the thrombin inhibitors, which are the focus of this review.