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CD147 also known as EMMPRIN, basigin, and HAb18G, is a single-chain type I transmembrane protein shown to be overexpressed in aggressive human cancers of CNS, head and neck, breasts, lungs, gastrointestinal, genitourinary, skin, hematological, and musculoskeletal. In these malignancies, the molecule is integral to the diverse but complimentary hallmarks of cancer: it is pivotal in cancerous proliferative signaling, growth propagation, cellular survival, replicative immortality, angiogenesis, metabolic reprogramming, immune evasion, invasion, and metastasis. CD147 also has regulatory functions in cancer-enabling characteristics such as DNA damage response (DDR) and immune evasion. These neoplastic functions of CD147 are executed through numerous and sometimes overlapping molecular pathways: it transduces signals from upstream molecules or ligands such as cyclophilin A (CyPA), CD98, and S100A9; activates a repertoire of downstream molecules and pathways including matrix metalloproteinases (MMPs)-2,3,9, hypoxia-inducible factors (HIF)-1/2α, PI3K/Akt/mTOR/HIF-1α, and ATM/ATR/p53; and also functions as an indispensable chaperone or regulator to monocarboxylate, fatty acid, and amino acid transporters. Interestingly, induced loss of functions to CD147 prevents and reverses the acquired hallmarks of cancer in neoplastic diseases. Silencing of Cd147 also alleviates known resistance to chemoradiotherapy exhibited by malignant tumors like carcinomas of the breast, lung, pancreas, liver, gastric, colon, ovary, cervix, prostate, urinary bladder, glioblastoma, and melanoma. Targeting CD147 antigen in chimeric and induced-chimeric antigen T cell or antibody therapies is also shown to be safer and more effective. Moreover, incorporating anti-CD147 monoclonal antibodies in chemoradiotherapy, oncolytic viral therapy, and oncolytic virus-based-gene therapies increases effectiveness and reduces on and off-target toxicity. This study advocates the expedition and expansion by further exploiting the evidence acquired from the experimental studies that modulate CD147 functions in hallmarks of cancer and cancer-enabling features and strive to translate them into clinical practice to alleviate the emergency and propagation of cancer, as well as the associated clinical and social consequences.
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Background: The role of platelet-lymphocyte ratio (PLR) and neutrophil-lymphocyte ratio (NLR) as independent prognostic markers in different tumors is well established. However, there is a limited review of the potential of NLR and PLR as predictors of treatment outcomes from immune checkpoint inhibitors (ICIs). Objective: To establish a correlation between NLR and PLR and the potential of clinical benefit from ICIs. Methods: The literature search was performed for studies that reported the association between NLR, PLR, and treatment outcomes among cancer patients treated with ICIs. The outcomes of interest were objective response rate (ORR), disease control rate (DCR), and progressive disease (PD). ORR was the summation of patients who achieved complete response and partial response. DCR included patients who achieved stable disease. PD was the proportion of patients who progressed, relapsed, or discontinued the treatment. Statistical analysis was performed using the STATA 12.0 package. Heterogeneity was determined by the I2 value. Quality assessment was performed using the Newcastle-Ottawa Scale. Egger's test was used to establish publication bias and sensitivity analysis. Results: A total of 40 papers that met the inclusion criteria were included in the systematic review. However, only 17 studies were used in the meta-analysis to determine the correlation between NLR, PLR, and treatment response. We found that treatment with ICIs and monitoring of outcomes and adverse events using PLR and NLR parameters have been studied in different tumors. Our analysis showed that low NLR correlated with higher ORR (OR = 0.62 (95% CI 0.47-0.81, p = 0.001) and higher DCR (OR = 0.23, 95% CI 0.14-0.36, p < 0.001). Higher NLR predicted a higher probability of PD (OR = 3.12, 95% CI 1.44, 6.77, p = 0.004). Similarly, low PLR correlated with higher ORR (OR = 0.69, 95% CI 0.5, 0.95, p = 0.025). Generally, patients with low NLR and PLR were more likely to achieve clinical benefit and better response (p-value < 0.001). Meanwhile, patients with high ratios were more likely to progress (p-value < 0.005), although there was significant heterogeneity among studies. There was no significant publication bias observed. Conclusion: The study showed that high NLR and PLR either at baseline or during treatment is associated with poorer treatment outcome. Therefore, these ratios can be utilized in clinical practice with other markers to determine treatment efficacy from immunotherapy.
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Background and Purpose: To date, there is no specific treatment guideline for the benign childhood epilepsy with centrotemporal spikes (BECTS). Several countries recommend levetiracetam, carbamazepine, sodium valproate, oxcarbazepine, and lamotrigine as first-line drugs. Nevertheless, some of these drugs are associated with cognitive decline. Available studies that investigated the efficacy of levetiracetam and sodium valproate on BECTS involved small sample sizes. This study aimed to evaluate the efficacy of levetiracetam and sodium valproate on cognition, and to investigate the prognostic factors for BECTS as whole. Methods: Clinical data and treatment status of all patients with BECTS at Xiangya Hospital, Central South University followed from 2008 to 2013 were analyzed retrospectively. Since electrical status epilepticus in sleep (ESES) has been confirmed to play a role in cognitive deterioration, in order to evaluate the response to drugs and their cognitive effects, we created two groups of patients according to the levels of spike wave index (SWI): group 1; 0-50% SWI and group 2; >50% SWI at the last follow up. Results: A total of 195 cases were enrolled: 49.7% received monotherapies, 24.1% duotherapies and 27.2% polytherapies. Medications included; levetiracetam plus other drug (s) (75.9%), levetiracetam alone (32.8%), sodium valproate plus other drug (s) (31.3%), and sodium valproate alone (5.1%). After 2 years of treatment and follow up, 71% of the cases had a good seizure outcome, 15.9% had an improvement of SWI, and 91.7% had a normal DQ/IQ. Sodium valproate combined with levetiracetam, and sodium valproate alone correlated with good improvement of SWI, whereas, focal spikes were linked with poor improvement. For both groups (group 1 and group 2): monotherapy, levetiracetam alone, and a normal DQ/IQ at seizure onset correlated with good cognitive outcomes, in contrast, polytherapy, sodium valproate plus other drug (s), levetiracetam plus sodium valproate, an initial SWI of ≥85%, and multifocal spikes were linked to cognitive deterioration. Conclusions: Monotherapy, particularly levetiracetam seems to be a good first-line therapy which can help in normalizing the electroencephalograph and preventing cognitive decline. Polytherapy, mostly the administration of sodium valproate seems to relate with poor cognition, therefore, it is recommended to avoid it.
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Immune checkpoint inhibitors (ICIs) have increased modern anticancer armamentarium portfolios, with 15%-60% of cancer patients deriving clinical benefit while others progress, including some occurrences of accelerated progressions. ICIs have also introduced a new pattern of immune-related adverse events (irAEs). Recently, a mechanistic link was proposed in which patients who develop ICIs-related irAEs derive a survival benefit compared to those who do not, suggesting an overlap between toxicities and the treatment efficacy. Identifying predictive biomarkers to optimally identify patients who will benefit from ICIs is a contemporary research area in Oncology. However, the data remains sparse, with only several smaller studies showing a plausible direct proportionality of a therapeutic effect across tumours. In contrast, the overall survival and progression-free survival rate depend on the tumour type, degree of toxicities, duration of exposure, affected system/organs and inherent patient characteristics. Furthermore, the occurrence of irAEs appears to be more associated with a clinical benefit from programmed death 1 and programmed death-ligand 1 inhibitors than anti-cytotoxic T-lymphocyte-associated antigen 4. Several questions remain unanswered, including the association between survival benefit and specific type of organ system toxicities, toxicity grade, if the benefit is entirely due to immortal-time biases (ITBs), presence of patients confounding comorbidities like autoimmune diseases, and finally, immune heterogeneities. Considering ITB represents a key element in interpreting these studies since patients with precipitated death or with an earlier disease progresses rarely develop irAEs; in fact, such patients have not stayed in the study long enough to experience such irAEs. Conversely, patients that stayed in the study for a longer period have a higher risk of developing irAEs. Landmark analysis is key in these studies if a real association is to be found. Overall response and disease control rates are mainly higher in those who develop irAEs due to immune activation. So, this review aims to summarise the evidence from key studies that addressed this important clinical question.
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BACKGROUND: A number of published literature has reported that, physiologically, heart rate variability (HRV) in patients with postural orthostatic tachycardia syndrome (POTS) to be greatly confounded by age, sex, race, physical fitness, and circadian rhythm. The purpose of this study was to compare between POTS patients versus healthy participants, in terms of heart rate (HR) and HRV after Head-Up tilt test (HUTT), by systematic review and meta-analysis of available published literature. METHODS: MEDLINE (using PubMed interphase), EMBASE and SCOPUS were systematically searched for observational studies comparing POTS patients versus healthy patients, in terms of HR and HRV. HRV was grouped into Time and frequency domain outcome measurements. The time domain was measured as mean RR- interval and mean the square root of the mean of squares of successive R-R waves (rMSSD) in milliseconds. The frequency domain was measured as mean values of Low frequency power (LF), High frequency power (HF), LF/HF-ratio, LF-normalized units (LF(n.u)) and HF-normalized units (HF(n.u)). Demographic data, comorbidities, and mean values of HR, RR- interval, rMSSD, LF, HF, LF/HF-ratio, LF-(n.u) and H.F-n.u were extracted from each group and compared, by their mean differences as an overall outcome measure. Computer software, RevMan 5.3 was utilized, at a 95% significance level. RESULTS: Twenty (20) eligible studies were found to report 717 POTS and 641 healthy participants. POTS group had a higher mean HR (p < 0.05), lower mean RR-Interval (p < 0.05), lower rMSSD (p < 0.05) than healthy participants. Furthermore, POTS group had lower mean HF(p > 0.05), lower mean LF(p > 0.05), and lower mean HF(n.u) (p > 0.05), higher LF/HF-Ratio (p > 0.05) and higher LF(n.u) (p > 0.05) as compared to healthy participants. CONCLUSION: POTS patients have a higher HR than healthy patients after HUTT and lower HRV in terms of time domain measure but not in terms of frequency domain measure. HR and time domain analyses of HRV are more reliable than frequency domain analysis in differentiating POTS patients from the healthy participants. We call upon sensitivity and specificity studies.
