International Society of Urological Pathology (ISUP)-Grade Grouping in Prostatic Adenocarcinoma and its Prognostic Implications.

In this study, we evaluated the association of ISUP/WHO-grade groups with various pathological prognostic parameters and cancer-specific survival in patients with prostatic adenocarcinoma. We found 27 (15.7%) cases of grade group 1, 22 (12.8%) grade group 2, 30 (17.4%) grade group 3, 40 (23.3%) grade group 4 and 53 (30.8%) grade group 5 prostatic adenocarcinoma. We found that high-grade tumors (grade 3-5) had a higher frequency of perineural invasion and higher tumor volumes (>50%). Moreover, a significant association of tumor grade was noted with cancer-specific survival of patients, signifying prognostic significance of grade grouping in prostatic adenocarcinoma.

CD30-Positive Anaplastic Variant of Diffuse Large B-cell Lymphoma: Frequency and Association With Clinicopathological Parameters.

Introduction Diffuse large B-cell lymphoma (DLBCL) is an aggressive B-cell lymphoma and is the most common type of non-Hodgkin's lymphoma (NHL) worldwide. The World Health Organization (WHO) classification of hematopoietic tumors has recognized three morphological variants of DLBCL: centroblastic, immunoblastic, and anaplastic. Some studies have shown that the anaplastic variant of DLBCL is associated with aggressive clinicopathological features. Anaplastic DLBCL is rare, and the clinicopathological characteristics of this subtype of DLBCL are not widely studied in our population. Therefore, in this study, we evaluated the frequency of the anaplastic variant of DLBCL and its association with other clinicopathological parameters. Methods A retrospective study was conducted in the Department of Histopathology at the Liaquat National Hospital and Medical College over a period of six years, from January 2015 to December 2020. All cases diagnosed as DLBCL based on morphology and immunohistochemical (IHC) profile were included in the study. The diagnosis of anaplastic DLBCL was rendered based on morphology (large bizarre pleomorphic cells in a cohesive or sheet-like growth pattern), combined with CD30 IHC expression. Results The mean age of the patients was 52.90 ±16.42 years, and the mean Ki67 index was 73.18 ±16.52%. Of the 220 cases of DLBCL, 47.3% cases were germinal center B-cell (GCB) subtype, and 59.1% cases were nodal. BCL-2, BCL-6, MUM1, c-MYC, and CD10 positivity were noted in 60%, 45.5%, 40.9%, 44.1, and 38.6% cases, respectively. Only 14 cases (6.4%) were recognized as anaplastic variants of DLBCL according to the previously defined criterion. The only significant association of anaplastic-variant DLBCL was noted with a lack of BCL-2 expression. No significant association of anaplastic-variant DLBCL was noted with age, gender, Ki67 index, DLBCL subtype, or any other IHC marker expression. Conclusion We found a low frequency of the anaplastic variant of DLBCL in our study. No significant association of this DLBCL variant was noted with any of the clinicopathological parameters, except for the lack of BCL-2 expression. Alternatively, from a pathological perspective, it is important to recognize this variant of DLBCL as it often mimics other CD30-positive lymphoma and undifferentiated carcinoma.

Clinicopathological Features of Primary Neuroendocrine Tumors of Gastrointestinal/Pancreatobiliary Tract With Emphasis on High-Grade (Grade 3) Well-Differentiated Neuroendocrine Tumors.

Introduction The two broad subcategories of neuroendocrine neoplasms (NENs) are well-differentiated neuroendocrine tumors (WDNETs) and poorly differentiated neuroendocrine carcinomas (PDNECs), based on tumor architecture and cytology. Grade 3 WDNETs are a subset of WDNETs that not only are high grade by mitotic activity or proliferative index but exhibit a well-differentiated histology. In this study, we evaluated the clinicopathological features of primary neuroendocrine tumors of the gastrointestinal (GI)/pancreatobiliary tract with emphasis on high-grade WDNETs, as it is a newly defined entity. Methods We conducted a retrospective observational study, including a total number of 122 cases of primary GI and pancreatobiliary tract NENs. Slides and blocks of all cases were retrieved from the departmental archives. Immunohistochemical stains including Ki67 were applied to selected tissue blocks of all cases. Tumors were then evaluated for their histological differentiation and tumor grade. Results Our results showed that the mean age of patients was 46.8 ± 17.1 years. Majority of the NENs were GI tract origin (86.9%). The most common site of tumor in gastroenteropancreatic tract was the small bowel (31.1%), followed by the stomach (26.2%). Ninety five percent of the tumors were WDNETs, of which the most common grade was G2. The mean Ki67 index was 15.8 ± 23.8. Grade 3 WDNETs were noted to have an older mean age than grades 1 and 2 WDNETs. Ten out of 102 (9.8%) WDNETs of GI tract were grade 3, compared with four out of 14 (28.6%) of pancreatobiliary tract.  Conclusion In this study, we found that high-grade (grade 3) WDNETs were more frequent in pancreatobiliary tract than GI tract. Moreover, high-grade WDNETs were associated with a higher mean age than low-grade (grade 1-2) WDNETs. It is extremely important to recognize this subset (high grade) of WDNETs and to distinguish it from PDNECs, as the latter are known to be associated with a worse overall survival. Despite high mitotic rate/proliferative index, high-grade WDNETs are characterized by organoid architecture and monomorphic cell population.

Time-dynamic pulse modulation of spinal cord stimulation reduces mechanical hypersensitivity and spontaneous pain in rats.

Enhancing the efficacy of spinal cord stimulation (SCS) is needed to alleviate the burden of chronic pain and dependence on opioids. Present SCS therapies are characterized by the delivery of constant stimulation in the form of trains of tonic pulses (TPs). We tested the hypothesis that modulated SCS using novel time-dynamic pulses (TDPs) leads to improved analgesia and compared the effects of SCS using conventional TPs and a collection of TDPs in a rat model of neuropathic pain according to a longitudinal, double-blind, and crossover design. We tested the effects of the following SCS patterns on paw withdrawal threshold and resting state EEG theta power as a biomarker of spontaneous pain: Tonic (conventional), amplitude modulation, pulse width modulation, sinusoidal rate modulation, and stochastic rate modulation. Results demonstrated that under the parameter settings tested in this study, all tested patterns except pulse width modulation, significantly reversed mechanical hypersensitivity, with stochastic rate modulation achieving the highest efficacy, followed by the sinusoidal rate modulation. The anti-nociceptive effects of sinusoidal rate modulation on EEG outlasted SCS duration on the behavioral and EEG levels. These results suggest that TDP modulation may improve clinical outcomes by reducing pain intensity and possibly improving the sensory experience.

The frequency of radial artery occlusion following cardiac catheterization with the use of transradial pneumatic compression band.

OBJECTIVES: Radial artery occlusion is a silent complication of a transradial approach to cardiac catheterization that may complicate subsequent transradial procedures in patients undergoing cardiac catheterization. A transradial band reduces vascular complications and provides brisk, powerful and effective haemostasis. The purpose of this study was to assess the frequency of radial artery occlusion in 180 patients undergoing transradial coronary catheterization. RESULTS: The median age of the study cohort was 58 years. Radial artery occlusion was found in 14 (7.8%) patients. When stratifying by age group and sex, there was no significant difference in radial artery occlusion between age groups and sex. It was likewise found that comorbidities such as diabetes mellitus, hypertension and smoking, increased the risk of radial artery occlusion however this was observed to be significant only for diabetes mellitus. We therefore conclude that a transradial pneumatic pressure band is an extremely helpful and safe strategy to prevent radial artery occlusion.

Pain phenotypes classified by machine learning using electroencephalography features.

Pain is a multidimensional experience mediated by distributed neural networks in the brain. To study this phenomenon, EEGs were collected from 20 subjects with chronic lumbar radiculopathy, 20 age and gender matched healthy subjects, and 17 subjects with chronic lumbar pain scheduled to receive an implanted spinal cord stimulator. Analysis of power spectral density, coherence, and phase-amplitude coupling using conventional statistics showed that there were no significant differences between the radiculopathy and control groups after correcting for multiple comparisons. However, analysis of transient spectral events showed that there were differences between these two groups in terms of the number, power, and frequency-span of events in a low gamma band. Finally, we trained a binary support vector machine to classify radiculopathy versus healthy subjects, as well as a 3-way classifier for subjects in the 3 groups. Both classifiers performed significantly better than chance, indicating that EEG features contain relevant information pertaining to sensory states, and may be used to help distinguish between pain states when other clinical signs are inconclusive.

Automated and rapid self-report of nociception in transgenic mice.

There are currently no rapid, operant pain behaviors in rodents that use a self-report to directly engage higher-order brain circuitry. We have developed a pain detection assay consisting of a lick behavior in response to optogenetic activation of predominantly nociceptive peripheral afferent nerve fibers in head-restrained transgenic mice expressing ChR2 in TRPV1 containing neurons. TRPV1-ChR2-EYFP mice (n = 5) were trained to provide lick reports to the detection of light-evoked nociceptive stimulation to the hind paw. Using simultaneous video recording, we demonstrate that the learned lick behavior may prove more pertinent in investigating brain driven pain processes than the reflex behavior. Within sessions, the response bias of transgenic mice changed with respect to lick behavior but not reflex behavior. Furthermore, response similarity between the lick and reflex behaviors diverged near perceptual threshold. Our nociceptive lick-report detection assay will enable a host of investigations into the millisecond, single cell, neural dynamics underlying pain processing in the central nervous system of awake behaving animals.

Burst Suppression: Causes and Effects on Mortality in Critical Illness.

BACKGROUND: Burst suppression in mechanically ventilated intensive care unit (ICU) patients is associated with increased mortality. However, the relative contributions of propofol use and critical illness itself to burst suppression; of burst suppression, propofol, and critical illness to mortality; and whether preventing burst suppression might reduce mortality, have not been quantified. METHODS: The dataset contains 471 adults from seven ICUs, after excluding anoxic encephalopathy due to cardiac arrest or intentional burst suppression for therapeutic reasons. We used multiple prediction and causal inference methods to estimate the effects connecting burst suppression, propofol, critical illness, and in-hospital mortality in an observational retrospective study. We also estimated the effects mediated by burst suppression. Sensitivity analysis was used to assess for unmeasured confounding. RESULTS: The expected outcomes in a "counterfactual" randomized controlled trial (cRCT) that assigned patients to mild versus severe illness are expected to show a difference in burst suppression burden of 39%, 95% CI [8-66]%, and in mortality of 35% [29-41]%. Assigning patients to maximal (100%) burst suppression burden is expected to increase mortality by 12% [7-17]% compared to 0% burden. Burst suppression mediates 10% [2-21]% of the effect of critical illness on mortality. A high cumulative propofol dose (1316 mg/kg) is expected to increase burst suppression burden by 6% [0.8-12]% compared to a low dose (284 mg/kg). Propofol exposure has no significant direct effect on mortality; its effect is entirely mediated through burst suppression. CONCLUSIONS: Our analysis clarifies how important factors contribute to mortality in ICU patients. Burst suppression appears to contribute to mortality but is primarily an effect of critical illness rather than iatrogenic use of propofol.

Risk Assessment of Patients After ST-Segment Elevation Myocardial Infarction by Killip Classification: An Institutional Experience.

Introduction The Killip classification system was introduced for clinical assessment of patients with acute myocardial infarction (MI). It stratifies individuals according to the severity of their post-MI heart failure. This system provides effective stratification of long-term and short-term outcomes in patients with acute MI and influences the treatment strategies. Revalidation of Killip class in our local population is mandatory. We planned this study to increase cardiologist's readiness to tackle the risks associated with increased mortality in each class post ST-segment elevation MI (STEMI). Objectives were to determine the frequency of Killip classes I, II, III, and IV and in-hospital mortality in each Killip class in patients with left ventricular failure secondary to STEMI. Methods A retrospective cross-sectional study was conducted in the Department of Cardiology, Jinnah Hospital, Lahore, over a period of three years. Patients with STEMI were stratified using Killip classification, and validation was performed by determining the within 15 days in-hospital mortality in each Killip class. Results The frequency (percentage) of patients with STEMI in each Killip class from I to IV was 395 (81.4%), 46 (9.5%), 27 (5.6%), and 17 (3.5%), respectively, while the in-hospital mortality in each Killip class came out to be 39 (9.9%), 4 (8.7%), 25 (92.6%) and 17 (100%), respectively. The presence of diabetes, history of smoking, and body mass index (BMI) of more than 30 kg/m2 were significant contributors to mortality, along with higher Killip class and age of presentation. Conclusions It is concluded that the Killip classification system is a valid tool for risk stratification for patients after STEMI, especially in resource-limited countries.

An Electroencephalography Bioassay for Preclinical Testing of Analgesic Efficacy.

We present a multimodal method combining quantitative electroencephalography (EEG), behavior and pharmacology for pre-clinical screening of analgesic efficacy in vivo. The method consists of an objective and non-invasive approach for realtime assessment of spontaneous nociceptive states based on EEG recordings of theta power over primary somatosensory cortex in awake rats. Three drugs were chosen: (1) pregabalin, a CNS-acting calcium channel inhibitor; (2) EMA 401, a PNS-acting angiotensin II type 2 receptor inhibitor; and (3) minocycline, a CNS-acting glial inhibitor. Optimal doses were determined based on pharmacokinetic studies and/or published data. The effects of these drugs at single or multiple doses were tested on the attenuation of theta power and paw withdrawal latency (PWL) in a rat model of neuropathic pain. We report mostly parallel trends in the reversal of theta power and PWL in response to administration of pregabalin and EMA 401, but not minocycline. We also note divergent trends at non-optimal doses and following prolonged drug administration, suggesting that EEG theta power can be used to detect false positive and false negative outcomes of the withdrawal reflex behavior, and yielding novel insights into the analgesic effects of these drugs on spontaneous nociceptive states in rats.

Leukadherin-1 ameliorates endothelial barrier damage mediated by neutrophils from critically ill patients.

BACKGROUND: Multi-organ failure occurs during critical illness and is mediated in part by destructive neutrophil-to-endothelial interactions. The ß2 integrin receptor, CR3 (complement receptor 3; Mac-1; CD11b/CD18), which binds endothelial intercellular adhesion molecule-1 (ICAM-1), plays a key role in promoting the adhesion of activated neutrophils to inflamed endothelia which, when prolonged and excessive, can cause vascular damage. Leukadherin-1 (LA-1) is a small molecule allosteric activator of CR3 and has been shown to promote adhesion of blood neutrophils to inflamed endothelium and restrict tissue infiltration. Therefore, LA-1 offers a novel mechanism of anti-inflammatory action by activation, rather than inhibition, of the neutrophil CR3 integrin. However, whether promotion of neutrophil-to-endothelial interaction by this novel therapeutic is of benefit or detriment to endothelial barrier function is not known. METHODS: Critically ill septic and trauma patients were prospectively enrolled from the surgical and the trauma ICU. Blood was collected from these patients and healthy volunteers. Neutrophils were isolated by dextran sedimentation and adhered to TNF-α (tumor necrosis factor-α)-activated human umbilical vein endothelial (HUVEC) monolayers in the presence or absence of fMLP (formylmethionine-leucine-phenylalanine) and/or LA-1. Electric cell-substrate impedance sensing (ECIS) and exposure of underlying collagen were used to quantify endothelial barrier function and permeability. RESULTS: Neutrophils from critically ill trauma and septic patients caused similar degrees of endothelial barrier disruption which exceeded that caused by cells obtained from healthy controls both kinetically and quantitatively. LA-1 protected barrier function in the absence and presence of fMLP which served as a secondary stimulant to cause maximal loss of barrier function. LA-1 protection was also observed by quantifying collagen exposure underlying endothelial cells challenged with fMLP-stimulated neutrophils. LA-1 treatment resulted in decreased migration dynamics of neutrophils crawling on an endothelial monolayer with reduced speed (µm/s = 0.25 ± 0.01 vs. 0.06 ± 0.01, p < 0.05), path length (µm = 199.5 ± 14.3 vs. 42.1 ± 13.0, p < 0.05), and displacement (µm = 65.2 ± 4.7 vs. 10.4 ± 1.3; p < 0.05). CONCLUSION: Neutrophils from patients with trauma or sepsis cause endothelial barrier disruption to a similar extent relative to each other. The CR3 agonist LA-1 protects endothelial barrier function from damage caused by neutrophils obtained from both populations of critically ill patients even when exposed to secondary stimulation.