The effect of glucagon-like peptide-2 on arterial blood flow and cardiac parameters

BackgroundGlucagon-like peptide-2 (GLP-2) is known to increase mesenteric blood flow. The aim of the study was to evaluate the effect of GLP-2 on blood flow in different vascular sites, and dynamic changes in cardiac parameters.Methods10 healthy volunteers were given 450 nmol subcutaneous (SC) GLP-2 or isotonic saline (5 subjects) in a single blinded manner. During the following 90 min, blood flow in the superior mesenteric artery (SMA), celiac artery (CA), renal artery (RA), common carotid artery (CCA) was measured using Doppler ultrasound (US), and cardiovascular variables were measured by impedance cardiography and finger plethysmography. Plasma GLP-2 was measured at times 0, 30 and 60 min.ResultsCompared to the placebo group, GLP-2 elicited a 27% decrease in the resistance index (RI) and a 269.4% increase in Time Averaged Maximal Velocity (TAMV) in the SMA (P < 0.01). CA, RA and CCA: There were no significant changes in RI or TAMV in the GLP-2 or placebo group, and no change in CA diameter.Cardiac parameters: GLP-2 increased cardiac output (CO), stroke volume (SV) and heart rate (HR) compared to baseline (respectively: 15.3, 4.81 and 8.2% (P < 0.001, P < 0.01 and P < 0.01)). The CO, SV and HR changes were not significantly different from the placebo group.Mean plasma GLP-2 serum levels in the placebo group at times 0, 30 and 60 min were 22.8, 23.4 and 23.2 pmol/l. In the GLP-2 group 20.3, 1273 and 1725 pmol/l.ConclusionSC GLP-2 increased SMA blood flow, as previously shown, but elicited no changes in other vascular sites. CO and HR increased significantly, presumably due to the increased mesenteric blood flow.     

Prognostic implications of ENE and LODDS in relation to lymph node-positive colorectal cancer location

BackgroundExtranodal extension (ENE) and log odds of positive lymph nodes (LODDS) are associated with the aggressiveness of both colon and rectal cancers. The current study evaluated the clinicopathological significance and the prognostic impact of ENE and LODDS in the colon and rectal patients independently.MethodsThe clinical and histological records of 389 colorectal cancer (CRC) patients who underwent curative surgery were reviewed.ResultsFor the ENE system, 244 patients were in the ENE1 group and 145 in the ENE2 system. Compared with the ENE1 system, the patients included in the ENE2 system were prone to nerve invasion (P < 0.001) and vessel invasion (P < 0.001) with higher TNM (P = 0.009), higher T category (P = 0.003), higher N category (P < 0.001), advanced differentiation (P = 0.013), more number of positive lymph nodes (NPLN) (P < 0.001), more lymph node ratio (LNR) (P < 0.001), and a higher value of LODDS (P < 0.001). ENE was more frequent in patients with left and rectal than right cancer. For the LODDS system, 280 patients were in the LODDS1 group, and 109 in the LODDS2 group. Compared to the LODDS1 group, the patients included in the LODDS2 group were more prone to nerve invasion (P = 0.0351) and vessel invasion (P < 0.001) with a higher rate of N2 stage, less NDLN (P < 0.001), more NPLN (P < 0.001), more LNR (P < 0.001), and a higher value of ENE (P < 0.001). Based on the results in the univariable analysis, the N, NPLN, LNR, LODDS, and ENE were separately incorporated into five different Cox regression models combined with the same confounders. The multivariable Cox regression analysis demonstrated that all the five staging systems were independent prognostic factors for overall survival.ConclusionThe current study confirmed that the LODDS stage is an independent influence on the prognosis of both CRC and CC patients. ENE is an independent influencing factor on the prognosis of both CRC and CC patients, and the prognostic impact of extracapsular lymph node was observed in both CRC and CC. The frequency of ENE increases from the proximal (right) to the distal (left) colon as well as the rectum. Therefore, combining ENE and LODDS into the current TNM system to compensate for the inadequacy of pN staging needs further investigation.     

Long-term outcomes of induction chemotherapy followed by intensity-modulated radiotherapy and adjuvant chemotherapy in nasopharyngeal carcinoma patients with N3 disease

ObjectivesTo evaluate long-term outcomes of induction chemotherapy (IC) followed by intensity-modulated radiotherapy (IMRT) and adjuvant chemotherapy (AC) in nasopharyngeal carcinoma (NPC) patients with N3 disease.Materials and methodsFrom September 2005 to August 2016, 143 patients confirmed NPC with the 8th AJCC/UICC staging criteria N3 were reviewed. All patients received IC followed by IMRT and AC.ResultsAfter a median follow-up of 67 months, the 5-year and 10-year overall survival (OS), progression-free survival (PFS), distant metastasis free survival (DMFS), local progression-free survival (LPFS) and regional progression-free survival (RPFS) were 75.7% and 61.6%, 61.2% and 53.4%, 73.1% and 72.1%, 92.4% and 87%, 88.9% and 81.8%, respectively. Multivariate analyses indicated that T stage (P = 0.001) appeared to be prognostic factors for OS. T stage (P = 0.001 and P = 0.002) and neck lymph node necrosis (P = 0.015 and P = 0.045) were independent predictors of PFS and DMFS. The acute toxicities were mainly grade 1/2 hematologic toxicities in patients treated with IC+IMRT+AC, and severe toxicities were uncommon.ConclusionsIC followed by IMRT and AC achieved satisfactory long-term survival outcomes in NPC patients with N3 disease. Neck lymph node necrosis and late T stage served as predictors of poor prognosis for patients.     

Long-term outcomes of induction chemotherapy followed by intensity-modulated radiotherapy and adjuvant chemotherapy in nasopharyngeal carcinoma patients with N3 disease

ObjectivesTo evaluate long-term outcomes of induction chemotherapy (IC) followed by intensity-modulated radiotherapy (IMRT) and adjuvant chemotherapy (AC) in nasopharyngeal carcinoma (NPC) patients with N3 disease.Materials and methodsFrom September 2005 to August 2016, 143 patients confirmed NPC with the 8th AJCC/UICC staging criteria N3 were reviewed. All patients received IC followed by IMRT and AC.ResultsAfter a median follow-up of 67 months, the 5-year and 10-year overall survival (OS), progression-free survival (PFS), distant metastasis free survival (DMFS), local progression-free survival (LPFS) and regional progression-free survival (RPFS) were 75.7% and 61.6%, 61.2% and 53.4%, 73.1% and 72.1%, 92.4% and 87%, 88.9% and 81.8%, respectively. Multivariate analyses indicated that T stage (P = 0.001) appeared to be prognostic factors for OS. T stage (P = 0.001 and P = 0.002) and neck lymph node necrosis (P = 0.015 and P = 0.045) were independent predictors of PFS and DMFS. The acute toxicities were mainly grade 1/2 hematologic toxicities in patients treated with IC+IMRT+AC, and severe toxicities were uncommon.ConclusionsIC followed by IMRT and AC achieved satisfactory long-term survival outcomes in NPC patients with N3 disease. Neck lymph node necrosis and late T stage served as predictors of poor prognosis for patients.     

Adding Rapid-Acting Insulin or Glp-1 Receptor Agonist to Basal Insulin: Outcomes in A Community Setting

ObjectiveTo evaluate real-world outcomes in patients with type 2 diabetes mellitus (T2DM) receiving basal insulin who initiate add-on therapy with a rapid-acting insulin (RAI) or a glucagon-like peptide 1 (GLP-1) receptor agonist.MethodsData were extracted retrospectively from a U.S. health claims database. Adults with T2DM on basal insulin who added an RAI (basal + RAI) or GLP-1 receptor agonist (basal + GLP-1) were included. Propensity score matching (with a 1 up to 3 ratio) was used to control for differences in baseline demographics, clinical characteristics, and health resource utilization. Endpoints included prevalence of hypoglycemia, pancreatic events, all-cause and diabetes-related resource utilization, and costs at 1-year follow-up.ResultsOverall, 6,718 matched patients were included: 5,013 basal + RAI and 1,705 basal + GLP1. Patients in both groups experienced a similar proportion of any hypoglycemic event (P = .4079). Hypoglycemic events leading to hospitalization were higher in the basal + RAI cohort (2.7% vs. 1.8%; P = .0444). The basal + GLP-1 cohort experienced fewer all-cause (13.55% vs. 18.61%; P < .0001) and diabetes-related hospitalizations (11.79% vs. 15.68%; P < .0001). The basal + GLP-1 cohort had lower total all-cause health care costs ($18,413 vs. $20,821; P = .0002) but similar diabetes-related costs ($9,134 vs. $8,985; P < .0001) compared with the basal + RAI cohort.ConclusionsAdd-on therapy with a GLP-1 receptor agonist in T2DM patients receiving basal insulin was associated with fewer hospitalizations and lower total all-cause costs compared with add-on therapy using an RAI and could be considered as an alternative to an RAI in certain patients with T2DM who do not achieve effective glycemic control with basal insulin. (Endocr Pract. 2015; 21:68-76)     

Patterns of treatment failure for PD-(L)1 refractory extensive-stage small cell lung cancer in continued PD-(L)1 treatment

BackgroundAlthough immunotherapy greatly extends overall survival (OS) of patients with extensive-stage small cell lung cancer (ES-SCLC), a number of patients develop immunotherapy resistance (IR). Patterns of failure in ES-SCLC are not clarified. Our study aims to explore the clinical pattern of IR and prognostic factors for these patients.MethodsThe study was conducted from 117 ES-SCLC patients with immunotherapy between 2018 and 2022. Chi-square tests and Fishers' exact tests was used to explore failure patterns in different populations. Survival analyses of different progression patterns and subsequent treatment regimens were conducted by Kaplan–Meier curves and log-rank test.Results86 (73.5%) patients experienced IR. The patients with smoking (never smoker vs. current or ex-smoker, 59.5 % vs. 81.3%, P = 0.010), liver metastasis (extrahepatic metastasis vs. intrahepatic metastasis, 73.6 % vs. 90.9%, P = 0.050), and distant metastasis status (no distant metastasis vs. distant metastasis, 39.1 % vs. 81.9%, P<0.001) were associated with IR rates. Liver progression had a lower incidence in 1st line immunotherapy (1st line vs. ≥2nd lines, 14.0 % vs. 41.7%, P = 0.004) and a higher incidence in multiple progression (multiple progression vs. Oligo-progression, 39.4 % vs. 17.0%, P = 0.021). Cranial (41.7 % vs. 16.1%, P = 0.012) and distant lymph node (16.7 % vs. 3.2%, P = 0.049) progression were the main failure model for acquired IR in comparison to primary IR. Patients with new lesion progression only (17.73 vs. 9.17 months, P = 0.013) and non-hepatic progression (14.23 vs. 11.67 months, P = 0.042) had a longer OS. Patients in cross-line immunotherapy after IR had a favourable prognosis (17.07 vs. 11.93 months, P = 0.007).ConclusionThe most common failure pattern of immunotherapy for ES-SCLC was lung and regional lymph node progression. Brain and liver progression were the most common extra thoracic failure sites for 1st line and 2nd and more lines immunotherapy, respectively. There was a higher probability of primary IR in 2 lines and above immunotherapy. Patients with new only progression site and cross-line rechallenge immunotherapy had a better prognosis.     

Upregulation of NKG2D ligands in acute lymphoblastic leukemia and non-Hodgkin lymphoma cells by romidepsin and enhanced in vitro and in vivo natural killer cell cytotoxicity

Background aimsThere is a critical need to prevent and/or treat hematological relapse after allogeneic hematopoietic stem cell transplantation. The activating NKG2D receptor expressed on natural killer (NK) cells, when engaged by its corresponding ligands (MIC A/B), activates NK cells to become cytotoxic against malignant cells.MethodsWe incubated acute lymphoblastic leukemia and non-Hodgkin lymphoma cells for 24 h with 10 ng/mL of romidepsin. Flow cytometry was performed to demonstrate changes in surface expression of NKG2D ligands MIC A/B. In vitro and in vivo cytotoxicity was measured by means of modified Europium assay, and non-obese diabetic/severe combined immunodeficiency mice were xenografted with RS 4:11 cells.ResultsWe demonstrated an approximately 50, 200, 1300 and 180-fold increase in the number of cells positive for the surface expression of MIC A/B in RS 4:11 (P < 0.001), REH (P < 0.001), Ramos (P < 0.001) and Jurkat cells (P < 0.001), respectively. We further demonstrated a significant increase in NK cell–mediated in vitro cytotoxicity against RS 4:11 (P < 0.004), Ramos (P < 0.05), Jurkat (P < 0.001) and REH cells (P < 0.01), respectively. Romidepsin-mediated NK cytotoxicity was blocked by pre-incubating NK cells with anti-NKG2D-Fc in RS 4:11 (P < 0.03) and Ramos cells (P < 0.01), respectively. Finally, non-obese diabetic/severe combined immunodeficiency mice xenografted with RS 4:11 cells had a significant increase in survival (P < 0.02) in mice treated with romidepsin and interleukin-2–activated NK cells compared with each of these other treatment groups.ConclusionsRomidepsin significantly enhanced in vitro and in vivo NK cell cytotoxicity mediated in part by increased MIC A/B expression on malignant cells. This translational approach of the use of romidepsin and interleukin-2–activated NK cells should be considered in patients with relapsed/refractory leukemia or lymphoma.     

Systematic review and meta-analysis of the association between bridging therapy and outcomes of chimeric antigen receptor T cell therapy in patients with large B cell lymphoma

BackgroundThe existing evidence about the impact of bridging therapy (BT) on chimeric antigen receptor (CAR)-T cell therapy in patients with large B cell lymphoma (LBCL) is conflicting. Therefore, we reviewed all available evidence to examine the association between BT and CAR-T therapy outcomes by systematic review and meta-analysis approach.MethodsTwo reviewers independently searched Embase, PubMed, Web of Science, and Cochrane library to identify all records that described BT for LBCL treated with CAR-T. We then applied a fixed- or random-effects meta-analysis to estimate the pooled hazard ratios (HRs) and rate ratio (RRs) for efficacy and safety endpoints and assessed differences across various BT modalities. The Newcastle-Ottawa Scale was used to evaluate study quality.ResultsTwenty-six reports from 24 studies involving 2014 patients were included in the analysis. Pooled results showed that patients requiring BT had significantly worse 1-year overall survival rate (RR = 0.76, 95% confidence interval [CI] 0.68–0.85, P < 0.001), 1-year progression-free survival rate (RR = 0.71, 95% CI 0.60–0.85, P < 0.001), progression-free survival (HR = 1.35, 95% CI 1.07–1.69, P = 0.01), overall response rate (RR = 0.88, 95% CI 0.81–0.95, P = 0.001), complete response rate (RR = 0.78, 95% CI 0.65–0.93, P = 0.005), and grade ≥3 immune effector cell-associated neurotoxicity syndrome (RR = 1.43, 95% CI 1.10–1.87, P = 0.007), and tended to have poorer overall survival (HR = 1.42, 95% CI 0.99–2.02, P = 0.056) and grade ≥3 cytokine release syndrome (RR = 1.59, 95% CI 0.92–2.75, P = 0.096). Prolonged cytopenias were the common toxicity event associated with BT. Radiotherapy may serve as a promising BT option that can provide safe and effective disease control for patients with LBCL before CAR-T infusion. The inconsistency of patient baselines in the current study hindered further comparisons between different BT modalities. Most of the available evidence was rated as low quality because of concerns over low comparability.ConclusionBT appears to be associated with comparatively poor efficacy and safety outcomes after CAR-T infusion. However, due to the considerable heterogeneity between the BT and non-BT cohorts at disease baseline, no definitive conclusions can be made for the true impact of BT on CAR-T until further randomized studies are conducted.     

Correlations of selenium and selenoprotein P with asymmetric dimethylarginine and lipid profile in patients with polycystic ovary syndrome

BackgroundPolycystic ovary syndrome (PCOS) is associated with an increased risk of cardiovascular diseases (CVD). Accumulating evidence has suggested that selenium (Se) is of importance for optimal function of the cardiovascular system. This study aimed to investigate the associations of selenium and selenoprotein P (SePP) with asymmetric dimethylarginine (ADMA) and lipid profile in women with PCOS.MethodsIn this cross-sectional study, 125 females aged 18–45 years diagnosed with PCOS were recruited. An interviewer-administered questionnaire was applied to gather the relevant demographic characteristics, detailed clinical information, and lifestyle habits of participants. Fasting blood samples were obtained to measure biochemical parameters. Serum concentrations of total testosterone, sex hormone-binding globulin (SHBG), ADMA, and lipid profiles as well as anthropometric measurements were assessed across tertiles of serum Se and SePP concentrations.ResultsThere was a positive correlation between serum Se and SePP concentrations (r = 0.434, p < 0.001). Serum Se level was inversely correlated with ADMA (r = −0.21, p = 0.025) and TG (r = −0.17, p = 0.041) concentrations. There were also inverse correlations between SePP and ADMA (r = −0.34, p < 0.001), TG (r = −0.21, p = 0.019), and oxidized low density lipoprotein (ox-LDL) (r = −0.25, p = 0.007) levels. No significant relationship was found between serum Se and SePP concentrations with total cholesterol, low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C), apolipoprotein-A1 (Apo-A1), apolipoprotein-B (Apo-B100), total testosterone, SHBG, and free androgen index as well as anthropometric parameters (All p > 0.05).ConclusionThe present study found that Se and SePP levels were inversely correlated with ADMA and TG concentrations as well as ox-LDL levels.     

The Effectiveness of Thyroid Hormone Replacement Therapy on Heart Failure and Low-Triiodothyronine Syndrome: An Updated Systematic Review and Meta-analysis of Randomized Controlled Trials

ObjectiveThe purpose of this study was to conduct a systematic review and meta-analysis evaluating the role of thyroid hormone therapy in patients with heart failure and low-triiodothyronine syndrome.MethodsThe electronic databases PubMed, Embase, Cochrane Library, China National Knowledge Infrastructure, China Science and Technology Journal Database, Wanfang Database, and China Biology Medicine disc were systematically searched to identify eligible studies published before November 27, 2021. The mean difference was pooled for randomized controlled trials using a random-effects model.ResultsThe meta-analysis showed that thyroid hormone treatment improved the left ventricular ejection fraction (weighted mean difference [WMD] 5.61, 95% confidence interval [CI]: 4.38 to 6.85, I² = 63.12%, P < 0.01). The cardiac output improved with thyroid hormone therapy (WMD 0.65, 95% CI: 0.42 to 0.89, I² = 84.28%, P < 0.01). The early-to-late diastolic transmitral flow velocity in the thyroid hormone group was also improved compared to the control group (WMD 0.29, 95% CI: 0.15 to 0.42, I² = 95.08%, P < 0.01). The left ventricular diastolic dysfunction was decreased with thyroid hormone treatment (WMD ?5.17, 95% CI: ?7.47 to ?2.88, I² = 90.18%, P < 0.01). The brain natriuretic peptide decreased with thyroid hormone treatment (standardized mean difference ?1.49, 95% CI: ?2.15 to ?0.84, I² = 90.18%, P < 0.01). Noradrenaline decreased with thyroid hormone therapy (WMD ?349.86, 95% CI: ?401.05 to ?298.67, I² = 0%, P < 0.01). Free triiodothyronine increased with thyroid hormone treatment (standardized mean difference 2.18, 95% CI: 0.75 to 2.60, I² = 98.20%, P < 0.01).ConclusionThis meta-analysis showed that thyroid hormone replacement therapy was effective in patients with heart failure and low-triiodothyronine syndrome.     

Associations between insulin-like growth factor binding protein-2 and lipoprotein kinetics in men

Low circulating concentrations of insulin-like growth factor binding protein-2 (IGFBP-2) have been associated with dyslipidemia, notably with high triglyceride (TG) levels. However, the determinants by which IGFBP-2 influences lipoprotein metabolism, especially that of TG-rich lipoproteins (TRLs), are poorly understood. Here, we aimed to assess the relationships between IGFBP-2 levels and lipoprotein production and catabolism in human subjects. Fasting IGFBP-2 concentrations were measured in the plasma of 219 men pooled from previous lipoprotein kinetics studies. We analyzed production rate and fractional catabolic rates of TRLapoB-48, and LDL-, IDL-, and VLDLapoB-100 by multicompartmental modeling of l-[5,5,5-D3] leucine enrichment data after a 12 h primed constant infusion in individuals kept in a constant nutritional steady state. Subjects had an average BMI of 30 kg/m², plasma IGFBP-2 levels of 157 ng/ml, and TG of 2.2 mmol/l. After adjustments for age and BMI, IGFBP-2 levels were negatively associated with plasma TG (r = ?0.29; P < 0.0001) and positively associated with HDL-cholesterol (r = 0.26; P < 0.0001). In addition, IGFBP-2 levels were positively associated with the fractional catabolic rate of VLDLapoB-100 (r = 0.20; P < 0.01) and IDLapoB-100 (r = 0.19; P < 0.05) and inversely with the production rate of TRLapoB-48 (r = ?0.28; P < 0.001). These correlations remained statistically significant after adjustments for age, BMI, and the amount of fat given during the tracer infusion. These findings show that the association between low plasma IGFBP-2 and high TG concentrations could be due to both an impaired clearance of apoB-100-containing VLDL and IDL particles and an increased production of apoB-48-containing chylomicrons. Additional studies are necessary to investigate whether and how IGFBP-2 directly impacts the kinetics of TRL.     

Current evidence on mesenchymal stem cell therapy for traumatic spinal cord injury: systematic review and meta-analysis

Background aimsThe authors aim to analyze the evidence in the literature regarding the efficacy and safety of mesenchymal stem cell (MSC) therapy in human subjects with traumatic spinal cord injury (SCI) and identify its potential role in the management of SCI.MethodsThe authors conducted independent and duplicate searches of electronic databases, including PubMed, Embase and the Cochrane Library, until May 2020 for studies analyzing the efficacy and safety of stem cell therapy for SCI. American Spine Injury Association (ASIA) impairment scale (AIS) grade improvement, ASIA sensorimotor score, activities of daily living score, residual urine volume, bladder function improvement, somatosensory evoked potential (SSEP) improvement and adverse reactions were the outcomes analyzed. Analysis was performed in R platform using OpenMeta[Analyst] software.ResultsNineteen studies involving 670 patients were included for analysis. On analysis, the intervention group showed statistically significant improvement in AIS grade (P < 0.001), ASIA sensory score (P < 0.017), light touch (P < 0.001), pinprick (P = 0.046), bladder function (P = 0.012), residual urine volume (P = 0.023) and SSEP (P = 0.002). However, no significant difference was noted in motor score (P = 0.193) or activities of daily living score (P = 0.161). Although the intervention group had a significant increase in complications (P < 0.001), no serious or permanent adverse events were reported. On subgroup analysis, low concentration of MSCs (<5 × 10⁷ cells) and initial AIS grade A presentation showed significantly better outcomes than their counterparts.ConclusionsThe authors’ analysis establishes the efficacy and safety of MSC transplantation in terms of improvement in AIS grade, ASIA sensory score, bladder function and electrophysiological parameters like SSEP compared with controls, without major adverse events. However, further research is needed to standardize dose, timing, route and source of MSCs used for transplantation.     

A multi-institutional observational study evaluating the incidence and the clinicopathological characteristics of NeoRAS wild-type metastatic colorectal cancer

PurposeAs circulating tumor DNA (ctDNA) measurement becomes more widespread, the “NeoRAS” phenomenon, where tissue rat sarcoma viral oncogene homolog (RAS) status converts from mutant (MT) to wild-type (WT) after treatment in metastatic colorectal cancer (mCRC), is gaining attention because ineffective epidermal growth factor receptor (EGFR) inhibitors may made effective. This study investigated its incidence and clinicopathological characteristics.Patients and MethodsIn total, 107 mCRC patients (refractory or intolerant to previous chemotherapies) with tissue RAS MT were enrolled in four institutions from June 2021 to August 2022. The RAS status in ctDNA was assessed using OncoBEAM™ RAS CRC assay. Clinicopathologic features were compared between patients according to their RAS status in ctDNA, whether WT conversion was noted or not.ResultsThe incidence rate of NeoRAS WT mCRC was 21.5% (23/107). According to tissue RAS mutation sites, NeoRAS WT frequency in patients with KRAS mutation in exon 2 was significantly lower than those in exon 3 and 4 or NRAS (18.2% [18/99] vs 62.5% [5/8], P = 0.011). Regarding clinical background, there were significant differences in NeoRAS WT frequency between male vs female patients (30.6% [19/62] vs 8.9% [4/45], P = 0.008), and absence vs presence of liver metastasis (38.6% [17/44] vs 9.5% [6/63], P < 0.001). Comparing the two groups divided by the median value, NeoRAS WT was associated with smaller tumor diameter (>60.9 mm vs ≤, 3.8% [2/53] vs 38.9% [21/54], P < 0.001), lower carcinoembryonic antigen level (>38.2 ng/ml vs ≤, 11.3% [6/53] vs 31.5% [17/54], P = 0.018), and lower carbohydrate antigen 19–9 level (>158.0 U/ml vs ≤, 9.4% [5/53] vs 33.3% [18/54], P = 0.004). In the logistic regression multivariate analysis, liver metastasis absence (Odds ratio [OR], 4.62; P = 0.019), smaller tumor diameter (OR, 7.92; P = 0.012), and tissue RAS MT in other than KRAS exon 2 (OR, 9.04; P = 0.026) were significantly related to the conversion to NeoRAS WT in ctDNA.ConclusionsOriginal RAS variants in tissue, tumor diameter, and liver metastasis are related to conversion to NeoRAS WT mCRC in ctDNA.     

Positive Thyroid Peroxidase Antibody and Thyroglobulin Antibody are Associated With Better Clinicopathologic Features of Papillary Thyroid Cancer

ObjectiveTo compare the thyroid autoantibody status of patients with papillary thyroid cancer (PTC) and benign nodular goiter as well as possible associations between thyroid autoantibodies and clinicopathologic features of PTC.MethodsA total of 3934 participants who underwent thyroidectomy were enrolled in this retrospective study. Patients were divided into PTC and benign nodule groups according to pathological diagnosis. Based on the preoperative serum antibody results, PTC patients were divided into thyroid peroxidase antibody (TPOAb)-positive, thyroglobulin antibody (TgAb)-positive, dual TPOAb- and TgAb-positive, or antibody-negative groups.ResultsOf the 3934 enrolled patients, 2926 (74.4%) were diagnosed with PTC. Multivariate regression analyses suggested that high thyroid-stimulating hormone levels (adjusted odds ratio [OR] = 1.732, 95% CI [1.485-2.021], P < .001), positive TgAb (adjusted OR = 1.768, 95% CI [1.436-2.178], P < .001), and positive TPOAb (adjusted OR = 1.452, 95% CI [1.148-1.836], P = .002) were independent risk factors for predicting malignancy of thyroid nodules. Multinomial multiple logistic regression analyses indicated that positive TPOAb alone was an independent predictor of less central lymph node metastasis in PTC patients (adjusted OR = 0.643, 95% CI [0.448-0.923], P = .017), whereas positive TgAb alone was significantly associated with less extrathyroidal extension (adjusted OR = 0.778, 95% CI [0.622-0.974], P = .028). PTC patients with dual-positive TPOAb and TgAb displayed a decreased incidence of extrathyroidal extension (adjusted OR = 0.767, 95% CI [0.623-0.944], P = .012) and central lymph node metastasis (adjusted OR = 0.784, 95% CI [0.624-0.986], P = .037).ConclusionAlthough preoperative positive TPOAb and TgAb are independent predictive markers for PTC, they are also associated with better clinicopathologic features of PTC.     

Luminal (Her2 negative) prognostic index and survival of breast cancer patients

PurposeThe group of luminal (Her2 negative) is distinguished from other subtypes of breast cancer. We aimed to produce a prognostic index specific for luminal (Her2 negative) subtype breast cancer that could assist clinical treatment.MethodsThe test set comprised 406 consecutive luminal (Her2 negative) breast cancer patients. The relationship of 11 clinicopathologic factors including survivin with the 5-year disease-free survival was analyzed.ResultsIn univariate analysis, TNM stage, surgery, tumor size, lymph node involvement, and survivin expression were prognostic factors. In multivariate analysis, tumor size [HR (95% CI): 1.98 (1.12–3.49), p = 0.019], the number of lymph node metastasis [HR (95% CI): 1.75 (1.33–2.29), p < 0.0001] and the expression of progesterone receptor [HR (95% CI): 0.58 (0.36–0.95), p = 0.029] can independently predict prognosis. Prognostic index (PI) was calculated as 0.68 × tumor size + 0.56 × the number of lymph node metastasis − 0.54 × PR. According to the PI, patients were categorized into three groups: low, middle, and high risk group with the 5-year disease-free survival rates of 91.91%, 84.97% and 70.47%, respectively (P < 0.001). In the validation set, the luminal prognostic index (LPI) remained significant.ConclusionThe LPI may be a useful tool for evaluating the outcome of patients with luminal (Her-2 negative) breast cancer.     

Evaluation of the prognostic value of lymphadenectomy for low-grade serous ovarian cancer: A case-control multicenter retrospective study

BackgroundThe prognostic value of lymphadenectomy in low-grade serous ovarian cancer (LGSOC) remains uncertain.Materials and methodsA retrospective analysis of 155 patients with LGSOC who underwent surgery over a ten-year period (2011–2020) was performed. The propensity score matching (PSM) algorithm was performed between the lymphadenectomy and no lymphadenectomy groups, and Kaplan-Meier analyses were conducted to evaluate clinical prognosis. Finally, univariate and multivariate Cox proportional hazards regression analyses were performed to analyze high-risk factors associated with clinical prognosis.ResultsIn the pre-PSM cohort, 110 (71.0%) patients underwent lymphadenectomy. Of these, 54 (34.8%) experienced recurrence, and 27 (17.4%) died. There were statistical differences in disease-free survival (DFS) (P = 0.018) and overall survival (OS) (P = 0.016) in the post-PSM cohort. In the subgroup analysis, there were no statistically significant differences in DFS (P = 0.449) or OS (P = 0.167) in the FIGO I/II cohort. However, in the FIGO III/IV cohort, DFS (P = 0.011) and OS (P = 0.046) were statistically different between the two groups. Age > 50 years, FIGO stage III/IV, and suboptimal cytoreductive surgery were risk factors associated with prognosis. In the lymphadenectomy group, the histological status of pelvic lymph nodes had no significant effect on DFS (P = 0.205) or OS (P = 0.114).ConclusionLymphadenectomy was associated with DFS and OS, particularly in patients with advanced LGSOC patients. Age > 50 years, advanced FIGO stage III/IV, and suboptimal cytoreductive surgery were high-risk factors associated with clinical prognosis in patients with LGSOC.     

Incomplete chimerism following myeloablative and anti-thymocyte globulin-conditioned hematopoietic cell transplantation is a risk factor for relapse and chronic graft-versus-host disease

Background aimsThe value of routine chimerism determination after myeloablative hematopoietic cell transplantation (HCT) is unclear, particularly in the setting of anti-thymocyte globulin (ATG)-based graft-versus-host disease (GVHD) prophylaxis.MethodsBlood samples were collected at 3 months post-HCT from 558 patients who received myeloablative conditioning and ATG-based GVHD prophylaxis. Chimerism was assessed using multiplex polymerase chain reaction of short tandem repeats in sorted T cells (CD3+) and leukemia lineage cells (CD13+CD33+ for myeloid malignancies and CD19+ for B-lymphoid malignancies). ATG exposure was determined using a flow cytometry-based assay. The primary outcomes of interest were relapse and chronic GVHD (cGVHD).ResultsIncomplete (<95%) T-cell chimerism and leukemia lineage chimerism were present in 17% and 4% of patients, respectively. Patients with incomplete T-cell chimerism had a significantly greater incidence of relapse (36% versus 22%, subhazard ratio [SHR] = 2.03, P = 0.001) and lower incidence of cGVHD (8% versus 25%, SHR = 0.29, P < 0.001) compared with patients with complete chimerism. In multivariate modeling, patients with high post-transplant ATG area under the curve and any cytomegalovirus (CMV) serostatus other than donor/recipient seropositivity (non-D+R+) had an increased likelihood of incomplete T-cell chimerism. Patients with incomplete leukemia lineage chimerism had a significantly greater incidence of relapse (50% versus 23%, SHR = 2.70, P = 0.011) and, surprisingly, a greater incidence of cGVHD (45% versus 20%, SHR = 2.64, P = 0.003).ConclusionsHigh post-transplant ATG exposure and non-D+R+ CMV serostatus predispose patients to incomplete T-cell chimerism, which is associated with an increased risk of relapse. The increased risk of cGVHD with incomplete B-cell/myeloid chimerism is a novel finding that suggests an important role for recipient antigen-presenting cells in cGVHD pathogenesis.     

Bone marrow toxicity and immune reconstitution in melanoma and non-melanoma solid cancer patients after non-myeloablative conditioning with chemotherapy and checkpoint inhibition

Background aimsLymphodepletion with non-myeloablative (NMA) chemotherapy is currently a prerequisite for adoptive cell therapy (ACT). ACT based on tumor-infiltrating lymphocytes has long been used in malignant melanoma (MM), but with the advance of ACT into new cancer diagnoses, the patient predisposition will change. The authors here evaluate the bone marrow (BM) toxicity of NMA in combination with checkpoint inhibition and a priori risk factors in a wide range of cancer diagnoses.MethodsThirty-one non-MM and MM patients were included from two different clinical trials with ACT. The treatment history was extracted from the medical records, together with the hematology data. Immune monitoring with flow cytometry was performed before and at several time points after therapy.ResultsNMA induced reversible myelosuppression in all patients. No significant differences in BM toxicity between MM and non-MM patients were found. The overall hematology counts were reconstituted within 3–6 months but with great individual heterogeneity, including eight patients who developed a second phase of neutropenia after hospital discharge. A performance status >0 was found, and shorter overall survival and sex were statistically associated with longer duration of anemia. By contrast, high expression of co-stimulatory markers CD28+ and CD27+ on T cells at baseline was significantly correlated with shorter duration of neutropenia (P = 0.010 and P = 0.009, respectively), anemia (P = 0.001 and P = 0.001, respectively) and thrombocytopenia (P = 0.017 and P = 0.030, respectively). In addition, following NMA, the authors saw a significant differentiation of T-cell phenotype associated with old age.ConclusionsACT with NMA and checkpoint inhibition is tolerable in patients with multiple cancer diagnoses and therapy backgrounds but comes with substantial transient BM toxicity that is comparable in both non-MM and MM patients. Baseline T-cell CD28/CD27 expression level is predictive of duration of BM toxicity. Furthermore, NMA conditioning induces changes in the immune system that may affect a patient's immunocompetence for many months following therapy.     

The effect of encapsulated glutamine on gut peptide secretion in human volunteers

ContextWeight loss and improved blood glucose control after bariatric surgery have been attributed in part to increased ileal nutrient delivery with enhanced release of glucagon-like peptide 1 (GLP-1). Non-surgical strategies to manage obesity are required. The aim of the current study was to assess whether encapsulated glutamine, targeted to the ileum, could increase GLP-1 secretion, improve glucose tolerance or reduce meal size.MethodsA single-center, randomised, double blind, placebo-controlled, cross-over study was performed in 24 healthy volunteers and 8 patients with type 2 diabetes. Fasting participants received a single dose of encapsulated ileal-release glutamine (3.6 or 6.0 g) or placebo per visit with blood sampling at baseline and for 4 h thereafter. Glucose tolerance and meal size were studied using a 75 g oral glucose tolerance test and ad libitum meal respectively.ResultsIn healthy volunteers, ingestion of 6.0 g glutamine was associated with increased GLP-1 concentrations after 90 min compared with placebo (mean 10.6 pg/ml vs 6.9 pg/ml, p = 0.004), increased insulin concentrations after 90 min (mean 70.9 vs 48.5, p = 0.048), and increased meal size at 120 min (mean 542 g eaten vs 481 g, p = 0.008). Ingestion of 6.0 g glutamine was not associated with significant differences in GLP-1, glucose or insulin concentrations after a glucose tolerance test in healthy or type 2 diabetic participants.ConclusionsSingle oral dosing of encapsulated glutamine did not provoke consistent increases in GLP-1 and insulin secretion and was not associated with beneficial metabolic effects in healthy volunteers or patients with type 2 diabetes.     

Clinicopathological characteristics of androgen receptor splicing variant 7 (AR-V7) expression in patients with castration resistant prostate cancer: A systematic review and meta‐analysis

Background Studies have shown that AR-V7 may be correlated with the poor prognosis of castration resistant prostate cancer (CRPC), however, clinicopathological characteristics of AR-V7 have not been fully elucidated.ObjectiveThis study aimed at evaluating the clinicopathological features of AR-V7 in CRPC patients.Materials and methodsTo evaluate the clinicopathological features of AR-V7 in CRPC patients. A search of PubMed, Embase, and Web of Science was performed using the keywords prostate cancer, prostate tumor, prostate neoplasm, prostate carcinoma, AR-V7, AR3, androgen receptor splicing variant-7, or androgen receptor-3. Twenty-four trials published by February 2020 were included in this study.ResultsThe proportion of Gleason score ≥ 8 was found to be significantly higher in AR-V7-positive CRPC (69.5%) than negative (54.9%) (OR 1.68, 95% CI 1.25–2.25, p < 0.001), while the rates of T3/T4 stage (OR 1.16, 95% CI 0.60–2.24, p = 0.65) and N1 stage (OR 0.99, 95% CI 0.65–1.51, p = 0.96) were not statistically correlated with AR-V7 status. The AR-V7-positive patients exhibited a significantly higher proportion of any site metastasis (61.3% versus 35.0%; OR 2.19, 95% CI 1.57–3.05, p < 0.001) and bone metastasis (81.7% versus 69.0%; OR 1.97, 95% CI 1.44–2.69, p < 0.001), and a trend close to significance was expected in visceral metastasis (28.8% versus 22.1%; OR 1.29, 95% CI 0.96–1.74, p = 0.09). Incidences of pain in AR-V7-positive CRPC (54.6%) were significantly higher than in negative CRPC (28.1%; OR 4.23, 95% CI 2.52–7.10, p < 0.001), line with worse ECOG performance status (56.7% versus 35.0%, OR 2.18, 95% CI 1.51–3.16, P < 0.001). Limitations of the study include differences in sample sizes and designs, AR-V7 detection assays, as well as disease characteristics of the included studies.ConclusionsAR-V7 positivity is associated with a higher Gleason score, bone or any site metastasis, pain and worse ECOG performance scores in CRPC. However, it is not correlated with tumor stage or lymph node metastasis. More studies are needed to confirm these findings.