To summarize the four recent sodium-glucose cotransporter 2 inhibitor (SGLT2i) trials: Dapagliflozin Effect on CardiovascuLAR Events (DECLARE-TIMI 58), CANagliflozin CardioVascular Assessment Study ...(CANVAS) Program, Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients-Removing Excess Glucose (EMPA-REG OUTCOME), Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE), and explore the potential determinants for their cardiovascular, renal, and safety outcomes.
The composite renal outcome event rates per 1000 patient-years for drug and placebo, as well as the corresponding relative risk reductions, were 3.7, 7.0, 47%; 5.5, 9.0, 40%; 6.3, 11.5, 46%; 43.2, 61.2, 30% for DECLARE-TIMI 58, CANVAS, EMPA-REG OUTCOME, and CREDENCE, respectively (event definitions varied across trials). The major adverse cardiovascular (CV) event rates per 1000 patient-years for drug and placebo, as well as the corresponding relative risk reductions, were 22.6, 24.2, 7%; 26.9, 31.5, 14%; 37.4, 43.9, 14%; 38.7, 48.7, 20% for DECLARE-TIMI 58, CANVAS, EMPA-REG OUTCOME, and CREDENCE, respectively. DECLARE-TIMI 58 had the fewest cardiorenal events and CREDENCE the most. These differences were presumably due to varying inclusion criteria resulting in DECLARE-TIMI 58 having the best baseline renal filtration function and CREDENCE the worst (mean estimated glomerular filtration rate 85.2, 76.5, 74, 56.2 mL/min/1.73 m
for DECLARE-TIMI 58, CANVAS, EMPA-REG OUTCOME, and CREDENCE, respectively). Additionally, CREDENCE had considerably higher rates of albuminuria (median urinary albumin-creatinine ratios (UACR) were 927, 12.3, and 13.1 mg/g for CREDENCE, CANVAS, and DECLARE-TIMI 58, respectively; EMPA-REG OUTCOME had 59.4% UACR < 30, 28.6% UACR > 30-300, 11.0% UACR > 300 mg/g).
Dapagliflozin, empagliflozin, and canagliflozin have internally and externally consistent and biologically plausible class effects on cardiorenal outcomes. Baseline renal filtration function and degree of albuminuria are the most significant indicators of risk for both CV and renal events. Thus, these two factors also anticipate the greatest clinical benefit for SGLT2i.
Adaptive immunity provides life-long protection by generating central and effector memory T cells and the most recently described tissue resident memory T (TRM) cells. However, the cellular origin of ...CD4 TRM cells and their contribution to host defense remain elusive. Using IL-17A tracking-fate mouse models, we found that a significant fraction of lung CD4 TRM cells derive from IL-17A-producing effector (TH17) cells following immunization with heat-killed Klebsiella pneumonia (Kp). These exTH17 TRM cells are maintained in the lung by IL-7, produced by lymphatic endothelial cells. During a memory response, neither antibodies, γδ T cells, nor circulatory T cells are sufficient for the rapid host defense required to eliminate Kp. Conversely, using parabiosis and depletion studies, we demonstrated that exTH17 TRM cells play an important role in bacterial clearance. Thus, we delineate the origin and function of airway CD4 TRM cells during bacterial infection, offering novel strategies for targeted vaccine design.
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•A significant fraction of CD4 TRM cells derive from effector TH17 cells•Maintenance of resting ex TH17 TRM cells is mediated by IL-7•Ex TH17 TRM cells play an important role in bacterial clearance
Fate-mapping studies reveal that CD4+ tissue resident-memory cells are derived from effector TH17 cells and play essential roles in response to bacterial infections.
We provide an innovative, bioengineering, mechanobiology-based approach to rapidly (2-h) establish the
in vivo
metastatic likelihood of patient tumor-samples, where results are in direct agreement ...with clinical histopathology and patient outcomes. Cancer-related mortality is mostly due to local recurrence or to metastatic disease, thus early prediction of tumor-cell-fate may critically affect treatment protocols and survival rates. Metastasis and recurrence risks are currently predicted by lymph-node status, tumor size, histopathology and genetic testing, however, these are not infallible and results may require days/weeks. We have previously observed that subpopulations of invasive cancer-cells will rapidly (1–2 h) push into the surface of physiological-stiffness, synthetic polyacrylamide gels, reaching to cell-scale depths, while normal or noninvasive cells do not considerably indent gels. Here, we evaluate the mechanical invasiveness of established breast and pancreatic cell lines and of tumor-cells from fresh, suspected pancreatic cancer tumors. The mechanical invasiveness matches the
in vitro
metastatic potential in cell lines as determined with Boyden chamber assays. Moreover, the mechanical invasiveness directly agrees with the clinical histopathology in primary-site, pancreatic-tumors. Thus, the rapid, patient-specific, early prediction of metastatic likelihood, on the time-scale of initial resection/biopsy, can directly affect disease management and treatment protocols.
Clinical guidelines recommend statins for patients with atherosclerotic cardiovascular disease (ASCVD), but many remain untreated. The goal of this study was to assess the impact of statin use on ...recurrent major adverse cardiovascular events (MACE). This study used medical records and insurance claims from 4 health care systems in the United States. Eligible adults who survived an ASCVD hospitalization from September 2013 to September 2014 were followed for 1 year. A multivariable extended Cox model examined the outcome of time-to-first MACE, then a multivariable joint marginal model investigated the association between post-index statin use and nonfatal and fatal MACE. There were 8,168 subjects in this study; 3,866 filled a statin prescription ≤90 days before the index ASCVD event (47.33%) and 4,152 filled a statin prescription after the index ASCVD event (50.83%). These post-index statin users were younger, with more co-morbidities. There were 763 events (315/763, 41.3% terminal) experienced by 686 (8.4%) patients. The adjusted overall MACE risk reduction was 18% (HR 0.82, 95% CI 0.70 to 0.95, p = 0.007) and was more substantial in the first 180 days (HR 0.72, 95% CI 0.60 to 0.86, p <0.001). There was a nonsignificant 19% reduction in the number of nonfatal MACE (rate ratio 0.81, 95% CI 0.49 to 1.32, p = 0.394) and a 65% reduction in the risk of all-cause death (HR 0.35, 95% CI 0.22 to 0.56, p <0.001). In conclusion, we found a modest increase in statin use after an ASCVD event, with nearly half of the patients untreated. The primary benefit of statin use was protection against early death. Statin use had the greatest impact in the first 6 months after an ASCVD event; therefore, it is crucial for patients to quickly adhere to this therapy.
Expression of programmed death ligand (PD-L1/B7-H1/CD274) represents a mechanism of immune escape for renal cell carcinoma (RCC) cells. Drugs blocking PD-L1 or its receptor are in clinical ...development and early data suggests that tumor PD-L1 expression may predict response.
A tissue microarray (TMA) consisting of four biopsy cores from 34 matched pairs of nephrectomy and metastatic sites of clear cell RCC was used to assess PD-L1 expression by quantitative immunofluorescence. Assessment of intra- and inter-tumor heterogeneity and primary and metastatic tumor expression was performed using a method of Automated Quantitative Analysis (AQUA).
The median AQUA scores were higher in metastatic than primary specimens (P < 0.0001). The correlation between PD-L1 expression in matched primary and metastatic specimens was weak (R= 0.24). Within a given tumor, variable PD-L1 staining heterogeneity was seen, however the degree of heterogeneity was similar in primary and metastatic sites (P = 0.482).
The weak correlation between PD-L1 expression in primary and metastatic sites for a given patient suggests that expression in nephrectomy specimens cannot be used to select metastatic RCC patients for PD-L1 and PD-1 inhibitors. The intra-tumor heterogeneity seen in both primary and metastatic specimens indicates that a single core biopsy might not be sufficient to determine PD-L1 expression.
Cancer cells acquire several traits that allow for their survival and progression, including the ability to evade the host immune response. However, the mechanisms by which cancer cells evade host ...immune responses remain largely elusive. Here we study the phenomena of immune evasion in malignant melanoma cells. We find that the tumor suppressor phosphatase and tensin homolog (PTEN) is an important regulator of the host immune response against melanoma cells. Mechanistically, PTEN represses the expression of immunosuppressive cytokines by blocking the phosphatidylinositide 3-kinase (PI3K) pathway. In melanoma cells lacking PTEN, signal transducer and activator of transcription 3 activates the transcription of immunosuppressive cytokines in a PI3K-dependent manner. Furthermore, conditioned media from PTEN-deficient, patient-derived short-term melanoma cultures and established melanoma cell lines blocked the production of the interleukin-12 (IL-12) in human monocyte-derived dendritic cells. Inhibition of IL-12 production was rescued by restoring PTEN or using neutralizing antibodies against the immunosuppressive cytokines. Furthermore, we report that PTEN, as an alternative mechanism to promote the host immune response against cancer cells, represses the expression of programmed cell death 1 ligand, a known repressor of the host immune response. Finally, to establish the clinical significance of our results, we analyzed malignant melanoma patient samples with or without brisk host responses. These analyses confirmed that PTEN loss is associated with a higher percentage of malignant melanoma samples with non-brisk host responses compared with samples with brisk host responses. Collectively, these results establish that PTEN functions as a melanoma tumor suppressor in part by regulating the host immune response against melanoma cells and highlight the importance of assessing PTEN status before recruiting melanoma patients for immunotherapies.
HSP90 chaperones molecules critical for cell survival and malignant progression, including mutated B-raf. HSP90-targeting agents are in clinical trials. No large studies have been conducted on ...expression of HSP90 in melanomas.
Tissue microarrays containing 414 nevi, 198 primary and 270 metastatic melanomas were assessed using our automated quantitative analysis (AQUA) method of in situ protein measurement; we use S-100 to define pixels as melanocytes (tumor mask) within the array spot, and measure HSP90 expression within the mask using Cy5-conjugated antibodies.
HSP90 expression was higher in melanomas than nevi (P<0.0001) and higher in metastatic than primary specimens (P<0.0001). No association was seen between high HSP90 expression and survival in the primary or metastatic patient subsets. In primary melanomas, high HSP90 expression was associated with higher Clark level (P=0.0167) and increased Breslow depth (P<0.0001).
HSP90 expression was significantly higher in tumors than nevi and was associated with disease progression, indicating that it might be a valuable drug target in melanoma, as well as a useful diagnostic marker. Prospective studies are needed to confirm the diagnostic role of HSP90, as well as the predictive role of HSP90 expression in patients treated with HSP90 inhibitors.
Background
Neck ultrasound (US) and Technetium-99 m Sestamibi (MIBI) scan are the most commonly used imaging studies for preoperative localization of parathyroid adenomas. The aim of this study was ...to determine the added value of MIBI scan and its effect on the operative plan via a hypothetical model where a stepwise approach is conducted and MIBI is considered only after the ultrasound is evaluated.
Methods
Patients who underwent parathyroidectomy for primary hyperparathyroidism (PHPT) between 2012 and 2019 at two tertiary centers were included. Data collected included demographic data, preoperative workup, operative findings and follow-up. The added value of MIBI scans was determined for patients with positive ultrasound.
Results
A total of 513 patients with positive US result and a MIBI scan were included. If a stepwise approach was conducted then MIBI scan would not change the operative plan in 492 (95.9%). Among the remaining 21 patients, MIBI scan would correctly change the ultrasound-based operative plan in only 12 (2.3%) patients, while incorrectly change the plan in 9 (1.8%), resulting in unnecessary exploration of the contralateral side. In patients with sonographic appearance of a parathyroid gland larger than 1.2 cm, MIBI scan would correctly change the operative plan in only 1 of the 287 (0.35%) patients.
Conclusions
Our study suggests that the routine use of MIBI scans may have limited added value in patients with PHPT and a positive neck ultrasound, especially in those with adenoma size larger than 1.2 cm. Positive ultrasound alone may be sufficient for the preoperative localization of parathyroid disease.
Acute calculus cholecystitis is a very common disease with several area of uncertainty. The World Society of Emergency Surgery developed extensive guidelines in order to cover grey areas. The ...diagnostic criteria, the antimicrobial therapy, the evaluation of associated common bile duct stones, the identification of "high risk" patients, the surgical timing, the type of surgery, and the alternatives to surgery are discussed. Moreover the algorithm is proposed: as soon as diagnosis is made and after the evaluation of choledocholitiasis risk, laparoscopic cholecystectomy should be offered to all patients exception of those with high risk of morbidity or mortality. These Guidelines must be considered as an adjunctive tool for decision but they are not substitute of the clinical judgement for the individual patient.
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