Markers Of Treatment Response Research Articles

A CSF marker of nusinersen treatment response.

A CSF marker of nusinersen treatment response.

Imaging of Cancer Immunotherapy: Response Assessment Methods, Atypical Response Patterns, and Immune-Related Adverse Events, From the AJR Special Series on Imaging of Inflammation.

The introduction of immunotherapy with immune-checkpoint inhibitors (ICIs) has revolutionized cancer treatment paradigms. Since FDA approval of the first ICI in 2011, multiple additional ICIs have been approved and granted marketing authorization, and many promising agents are in early clinical adoption. Due to the distinctive biologic mechanisms of ICIs, the patterns of tumor response and progression seen with immunotherapy differ from those observed with cytotoxic chemothera-pies. With increasing clinical adoption of immunotherapy, it is critical for radiologists to recognize different response patterns and common pitfalls to avoid misinterpretation of imaging studies or prompt premature cessation of potentially effective treatment. This review provides an overview of ICIs and their mechanisms of action and discusses anatomic and metabolic immune-related response assessment methods, typical and atypical patterns of immunotherapy response (including pseudoprogression, hyperprogression, dissociated response, and durable response), and common imaging features of immune-related adverse events. Future multicenter trials are needed to validate the proposed immune-related response criteria and identify the functional imaging markers of early treatment response and survival.

Poliosis Is Associated with Response to Checkpoint-Inhibitor Therapy: A Case Report of Two Patients with Multifocal Metastatic Melanoma

The advent of immune-checkpoint inhibitors (ICIs) led to significant improvements in the treatment of patients with advanced melanoma and resulted in durable tumor responses in a considerable number of advanced melanoma patients. Next to the immune-mediated anti-neoplastic effects, ICIs may cause various immune-related adverse events (irAEs), often requiring early discontinuation of therapy. By contrast, cutaneous irAE rarely enforce treatment discontinuation but may represent simple and robust predictive markers for treatment response. The relevance of irAEs as clinical markers for an improved response to immunotherapy is still debated. We report here on two patients with multifocal metastatic melanoma who developed the rare event of generalized poliosis during combined immunotherapy with ipilimumab plus nivolumab, followed by a near-complete and durable response. Our observations suggest that poliosis may be a useful and simple clinical indicator of anti-tumor immunity, clinical response and favorable survival outcome in advanced melanoma patients treated with ICI.

Plasma RANKL level is not a reliable marker to monitor the bone destruction in mice model of osteomyelitis.

Objectives In this experimental study, we aimed to investigate the specific value of receptor activator of nuclear factor kappa-Β ligand (RANKL) plasma level in osteomyelitis to show the bone destruction and to determine its correlation with classical markers of infection in mice model of osteomyelitis.Materials and methods Sixty Balb/c female mice (30 to 40 g weight, 3.5 to 4 month-old) were divided into two groups: Controls (n=15) and study group (n=45). All mice underwent tibial decortication and received an injection of sclerosing agent into the intramedullary cavity. The next process was proceeded in two steps to observe the detectability of osteomyelitis-induced bone destruction (step 1) and treatment response (step 2) using the variables examined in our study. In step 1, the study group received 1 mL solution containing Staphylococcus aureus (S. aureus) bacteria (2X108 per mL) into the intramedullary cavity. Five mice from each group were sacrificed every seven days for three weeks and tibia and blood samples were obtained. In step 2, the remaining 30 infected mice were further divided into two groups to investigate the possible value of RANKL plasma level as a marker of treatment response. Fifteen of these mice received teicoplanin 20 mg/kg for four weeks, while the rest did not receive antibiotics. Eight mice from each group were sacrificed at the end of the second week and the remaining 14 mice were sacrificed at the end of four weeks. Complete blood count, procalcitonin level, C-reactive protein (CRP), and RANKL concentrations were measured from blood samples of each sacrificed mouse.Results Median RANKL concentration of the control subjects was significantly higher than recipients of intervention at the first and third weeks in step 1 where bone destruction of osteomyelitis was examined. No significant changes occurred in groups receiving and not receiving antimicrobial treatment in terms of RANKL, CRP, and procalcitonin levels throughout four weeks in step 2. The RANKL concentration was significantly correlated with colony growth in subjects allocated to the S. aureus inoculation group (r=-0.547, p=0.035).Conclusion The RANKL levels in mice with S. aureus osteomyelitis are not correlated with colony growth or other markers of inflammation and not useful for monitoring the response to antimicrobial treatment during osteomyelitis.

Post-Processing Bias Field Inhomogeneity Correction for Assessing Background Parenchymal Enhancement on Breast MRI as a Quantitative Marker of Treatment Response.

Background parenchymal enhancement (BPE) of breast fibroglandular tissue (FGT) in dynamic contrast-enhanced breast magnetic resonance imaging (MRI) has shown an association with response to neoadjuvant chemotherapy (NAC) in patients with breast cancer. Fully automated segmentation of FGT for BPE calculation is a challenge when image artifacts are present. Low spatial frequency intensity nonuniformity due to coil sensitivity variations is known as bias or inhomogeneity and can affect FGT segmentation and subsequent BPE measurement. In this study, we utilized the N4ITK algorithm for bias correction over a restricted bilateral breast volume and compared the contralateral FGT segmentations based on uncorrected and bias-corrected images in three MRI examinations at pre-treatment, early treatment and inter-regimen timepoints during NAC. A retrospective analysis of 2 cohorts was performed: one with 735 patients enrolled in the multi-center I-SPY 2 TRIAL and the sub-cohort of 340 patients meeting a high-quality benchmark for segmentation. Bias correction substantially increased the FGT segmentation quality for 6.3–8.0% of examinations, while it substantially decreased the quality for no examination. Our results showed improvement in segmentation quality and a small but statistically significant increase in the resulting BPE measurement after bias correction at all timepoints in both cohorts. Continuing studies are examining the effects on pCR prediction.

Clinical Variables Associated with Survival and Treatment Response in Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma

<h3>Purpose/Objective(s)</h3> Despite recent changes in treatment for unresectable recurrent or metastatic head and neck squamous cell carcinoma (R/M HNC) survival remains poor. Clinical trials fail to capture the diversity of patients and spectrum of disease presentation. This study examines clinically pertinent prognostic variables, efficacy of treatment regimens, and factors associated with response to first line treatment at a high-volume NCI cancer center. <h3>Materials/Methods</h3> A retrospective analysis of patients diagnosed with R/M HNC between 1998- 2018 was performed (n=477). Bivariate and multivariate Cox regression analysis identified independent predictors of survival. Covariates included HPV status, primary site, smoking, ECOG performance status, Charleson comorbidity index, organ dysfunction, BMI, neutrophil/lymphocyte ratio (NLR), tumor volume, platinum sensitivity, location of metastases, and disease-free interval (DFI, time from definitive therapy to R/M diagnosis). Variables with significant bivariate comparisons and no collinearity were included in multivariate analysis. Given retrospective nature of the database, time on treatment was used as a surrogate marker of treatment response. We examined clinical variables associated with time on treatment and patterns of metastasis using T tests and Chi square analyses. <h3>Results</h3> Median overall survival (OS) improved from 6.7 mo (95% CI 4.6-8.7) in 1998- 2007 to 11.8 mo (95% CI 10.0-13.6) in 2008- 2018 (p<0.01). Mean DFl was 11.7 mo (SD 22.2 mo). Patients who recurred within 6 mo of receiving platinum chemotherapy had worse OS compared to those sensitive to platinum agents (6.9 vs 11.1 mo, p<0.05). Predictors of worse OS included HPV negativity (HR 1.5, 95% CI 1.1-2.2), high NLR (HR 1.0, 95% CI 1.0-1.1), DFI ≤6 mo (HR 1.4, 95% CI 1.0-1.9), and poor performance status (ECOG ≥2, HR 1.8, 95% CI 1.0-3.0). Patients with oligometastatic disease amenable to local treatment had improved OS over those receiving systemic therapy (26.1 vs 12.1 mo, p<0.01). Immune checkpoint inhibitor (ICI) in combination with EGFR inhibition was associated with the longest time on treatment compared to other systemic therapies (265 vs 120 d, p<0.001). HPV+ patients were more likely to respond to ICI compared to HPV- (243 vs 119 d, p<0.05). Patients with locoregional recurrence and/or bone metastases were more likely to respond to ICIs compared to other systemic therapies (p=0.01). Platinum sensitive patients were more likely to respond to VEGF inhibition compared to platinum refractory (196 vs 76 d, p<0.05). <h3>Conclusion</h3> These data support the promising activity of novel agents in R/M HNC while highlighting the efficacy of ICIs and improved survival of patients over time. The patterns of distant metastasis and treatment failures in R/M HNC can help guide development of surveillance guidelines especially with the advent of non-invasive biomarkers.

Precision Medicine in Inflammatory Bowel Diseases: Challenges and Considerations for the Path Forward

Precision Medicine in Inflammatory Bowel Diseases: Challenges and Considerations for the Path Forward

Impact of Alternate b-Value Combinations and Metrics on the Predictive Performance and Repeatability of Diffusion-Weighted MRI in Breast Cancer Treatment: Results from the ECOG-ACRIN A6698 Trial.

In diffusion-weighted MRI (DW-MRI), choice of b-value influences apparent diffusion coefficient (ADC) values by probing different aspects of the tissue microenvironment. As a secondary analysis of the multicenter ECOG-ACRIN A6698 trial, the purpose of this study was to investigate the impact of alternate b-value combinations on the performance and repeatability of tumor ADC as a predictive marker of breast cancer treatment response. The final analysis included 210 women who underwent standardized 4-b-value DW-MRI (b = 0/100/600/800 s/mm2) at multiple timepoints during neoadjuvant chemotherapy treatment and a subset (n = 71) who underwent test–retest scans. Centralized tumor ADC and perfusion fraction (fp) measures were performed using variable b-value combinations. Prediction of pathologic complete response (pCR) based on the mid-treatment/12-week percent change in each metric was estimated by area under the receiver operating characteristic curve (AUC). Repeatability was estimated by within-subject coefficient of variation (wCV). Results show that two-b-value ADC calculations provided non-inferior predictive value to four-b-value ADC calculations overall (AUCs = 0.60–0.61 versus AUC = 0.60) and for HR+/HER2− cancers where ADC was most predictive (AUCs = 0.75–0.78 versus AUC = 0.76), p < 0.05. Using two b-values (0/600 or 0/800 s/mm2) did not reduce ADC repeatability over the four-b-value calculation (wCVs = 4.9–5.2% versus 5.4%). The alternate metrics ADCfast (b ≤ 100 s/mm2), ADCslow (b ≥ 100 s/mm2), and fp did not improve predictive performance (AUCs = 0.54–0.60, p = 0.08–0.81), and ADCfast and fp demonstrated the lowest repeatability (wCVs = 6.71% and 12.4%, respectively). In conclusion, breast tumor ADC calculated using a simple two-b-value approach can provide comparable predictive value and repeatability to full four-b-value measurements as a marker of treatment response.

Intra-topic latency as an automated behavioral marker of treatment response in autism spectrum disorder

Data science advances in behavioral signal processing and machine learning hold the promise to automatically quantify clinically meaningful behaviors that can be applied to a large amount of data. The objective of this study was to identify an automated behavioral marker of treatment response in social communication in children with autism spectrum disorder (ASD). First, using an automated computational method, we successfully derived the amount of time it took for a child with ASD and an adult social partner (N pairs = 210) to respond to each other while they were engaged in conversation bits (“latency”) using recordings of brief, natural social interactions. Then, we measured changes in latency at pre- and post-interventions. Children with ASD who were receiving interventions showed significantly larger reduction in latency compared to those who were not receiving interventions. There was also a significant group difference in the changes in latency for adult social partners. Results suggest that the automated measure of latency derived from natural social interactions is a scalable and objective method to quantify treatment response in children with ASD.

Oncologic Outcome and Immune Responses of Radiotherapy with Anti-PD-1 Treatment for Brain Metastases Regarding Timing and Benefiting Subgroups.

Simple SummaryImmune checkpoint inhibitors (ICIs) and radiotherapy (RT) are widely used for patients with brain metastasis (BM). To evaluate markers for treatment response and find a treatment concept which has the best outcome effects, we analyzed data of 93 patients with BM from different cancer types. Predictive markers for survival were good performance status, melanoma as cancer type, low metastasis volume, normal inflammatory blood parameters, and a stereotactic radiotherapy concept with high doses. We found that the best survival outcome can be achieved with the concurrent use of RT and ICI. Concurrent treatment was particularly beneficial in patients with low inflammatory status and more and larger metastases, and when high doses cannot be administered. In concurrently treated patients, therapeutic response was often delayed compared to sequential treatment. Specific immune responses such as pseudoprogression and abscopal effects were induced by concurrent treatment and associated with prolonged survival.While immune checkpoint inhibitors (ICIs) in combination with radiotherapy (RT) are widely used for patients with brain metastasis (BM), markers that predict treatment response for combined RT and ICI (RT-ICI) and their optimal dosing and sequence for the best immunogenic effects are still under investigation. The aim of this study was to evaluate prognostic factors for therapeutic outcome and to compare effects of concurrent and non-concurrent RT-ICI. We retrospectively analyzed data of 93 patients with 319 BMs of different cancer types who received PD-1 inhibitors and RT at the University Hospital Cologne between September/2014 and November/2020. Primary study endpoints were overall survival (OS), progression-free survival (PFS), and local control (LC). We included 66.7% melanoma, 22.8% lung, and 5.5% other cancer types with a mean follow-up time of 23.8 months. Median OS time was 12.19 months. LC at 6 months was 95.3% (concurrent) vs. 69.2% (non-concurrent; p = 0.008). Univariate Cox regression analysis detected following prognostic factors for OS: neutrophil-to-lymphocyte ratio NLR favoring <3 (low; HR 2.037 (1.184–3.506), p = 0.010), lactate dehydrogenase (LDH) favoring ≤ULN (HR 1.853 (1.059–3.241), p = 0.031), absence of neurological symptoms (HR 2.114 (1.285–3.478), p = 0.003), RT concept favoring SRS (HR 1.985 (1.112–3.543), p = 0.019), RT dose favoring ≥60 Gy (HR 0.519 (0.309–0.871), p = 0.013), and prior anti-CTLA4 treatment (HR 0.498 (0.271–0.914), p = 0.024). Independent prognostic factors for OS were concurrent RT-ICI application (HR 0.539 (0.299–0.971), p = 0.024) with a median OS of 17.61 vs. 6.83 months (non-concurrent), ECOG performance status favoring 0 (HR 7.756 (1.253–6.061), p = 0.012), cancer type favoring melanoma (HR 0.516 (0.288–0.926), p = 0.026), BM volume (PTV) favoring ≤3 cm3 (HR 1.947 (1.007–3.763), p = 0.048). Subgroups with the following factors showed significantly longer OS when being treated concurrently: RT dose <60 Gy (p = 0.014), PTV > 3 cm3 (p = 0.007), other cancer types than melanoma (p = 0.006), anti-CTLA4-naïve patients (p < 0.001), low NLR (p = 0.039), steroid intake ≤4 mg (p = 0.042). Specific immune responses, such as abscopal effects (AbEs), pseudoprogression (PsP), or immune-related adverse events (IrAEs), occurred more frequently with concurrent RT-ICI and resulted in better OS. Other toxicities, including radionecrosis, were not statistically different in both groups. The concurrent application of RT and ICI, the ECOG-PS, cancer type, and PTV had an independently prognostic impact on OS. In concurrently treated patients, treatment response (LC) was delayed and specific immune responses (AbE, PsP, IrAE) occurred more frequently with longer OS rates. Our results suggest that concurrent RT-ICI application is more beneficial than sequential treatment in patients with low pretreatment inflammatory status, more and larger BMs, and with other cancer types than melanoma.

A219 AMINOTRANSFERASE IMPROVEMENTS IN PATIENTS WITH NON-ALCOHOLIC STEATOHEPATITIS ARE ASSOCIATED WITH FIBROSIS REGRESSION IN THE REGENERATE STUDY

Abstract Background The interim analysis of the REGENERATE study showed obeticholic acid (OCA) 25 mg treatment significantly improved liver histology in patients with nonalcoholic steatohepatitis (NASH) and fibrosis. Elevations in aminotransferases are associated with adverse liver-related outcomes in NASH. Aims Here, we evaluate the utility of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) as markers of treatment response to OCA in patients with NASH. Methods Changes in ALT (upper limit of normal [ULN] = 55 U/L) and AST (ULN = 34 U/L) were assessed systematically at 1, 3, 6, 12, and 18 months in 931 NASH patients with stage 2 or 3 fibrosis randomized 1:1:1 to placebo (PBO), OCA 10 mg, or OCA 25 mg in REGENERATE (intent-to-treat population). Least-square mean (LSM) and 95% confidence intervals (CIs) of percentage change from baseline in ALT and AST were analyzed using a mixed-effect repeated-measures model. Results Baseline characteristics were well-balanced across treatment arms: ALT 79±53 U/L; AST 58±36 U/L; 44% F2, 56% F3. Aminotransferase values were &amp;gt; ULN for ALT in 60% (7% &amp;gt; 3xULN), and for AST in 74% (9% &amp;gt; 3xULN) of patients. Rapid, progressive, and dose-dependent improvement in ALT and AST was seen across PBO, OCA 10 mg, and OCA 25 mg arms, which at Month 18 was: ALT LSM change (95% CI), respectively, -4.9% (-10.7–0.9), -23.2% (-28.9– -17.4) and -31.9% (-37.7– -26.1) and in AST, -8.7% (-12.1– -5.2), -13.4% (-16.8– -9.9), and -19.4 (-22.8– -15.9). ALT and AST LSM reductions in OCA arms vs PBO were seen regardless of patient ULN status at baseline. In all patients, ALT/AST reduction was associated with probability of fibrosis regression at Month 18, ranging from approximately 20%, 95% CI (14–27) to 45% (37–54) with any reduction in ALT (&amp;gt; 0%–100%) and between approximately 20%, 95% CI (25–38) to 43% (35–57) with any reduction in AST (&amp;gt; 0%–100%). Interestingly, even with increases of ≤ 40% in AST or ALT there was still a small probability of fibrosis regression (&amp;lt; 20%). Analysis of changes in ALT and AST in individual patients showed that more patients had improvements on OCA than PBO at Month 18 (FIG 1). Conclusions OCA resulted in consistent dose-dependent improvement of ALT and AST. Patients with reductions in ALT or AST were up to twice as likely to have fibrosis improvement than those whose ALT or AST increased. The REGENERATE study is ongoing and will continue through clinical outcomes for verification and description of clinical benefits of OCA in treatment of NASH. Funding Agencies None

Hepatitis B surface antigen and hepatitis B RNA changes in HIV/hepatitis B virus co-infected participants receiving hepatitis B virus-active antiretroviral therapy.

With advances in hepatitis B virus (HBV) therapies, there is a need to identify serum biomarkers that assess the HBV covalently closed circular DNA (cccDNA) reservoir and predict functional cure in HIV/HBV co-infection. In this retrospective study, combining samples from HIV/HBV co-infected participants enrolled in two ACTG interventional trials, proportions achieving HBsAg less than 0.05 log10 IU/ml and HBV RNA less than log10 1.65 U/ml or not detected (LLoQ/NEG) in response to DUAL [tenofovir TDF+emtricitabine (FTC)] vs. MONO [FTC or lamivudine (3TC)] HBV-active ART, were measured. Predictors of qHBsAg less than 0.05 log10 IU/ml were evaluated in logistic regression models. There were 88 participants [58% women, median age 34; 47 on DUAL vs. 41 on MONO HBV-active ART]. Twenty-one percent achieved HBsAg less than 0.05 log10 IU/ml (30% DUAL vs. 10% MONO). Time to HBsAg less than 0.05 log10 IU/ml was lower (P = 0.02) and the odds of achieving HBsAg less than 0.05 log10 IU/ml were higher (P = 0.07) in DUAL participants. HBV RNA became less than LLoQ/NEG in 47% (DUAL 60% vs. MONO 33%). qHBsAg less than 3 log10 IU/ml was the strongest predictor of HBsAg less than 0.05 log10 IU/ml. This study supports current recommendations of TDF-based DUAL-HBV active ART for initial use in HIV/HBV co-infection. HBV RNA could be a useful marker of treatment response in HIV/HBV co-infected patients on HBV-active ART.

Dysphagia Days as a Clinical Marker of EoE Treatment Response in Steroid-Refractory Patients

In HEROES (Hirano I, et al. Gastroenterology. 2019), cendakimab treatment provided histologic and endoscopic benefits for adults ≤65 years with eosinophilic esophagitis (EoE) at week 16 versus placebo; trend-level dysphagia symptom improvement (Daily Symptom Diary) was observed with cendakimab 360 mg, both overall and in steroid-refractory patients. This ad hoc analysis assessed dysphagia days (DD) as an alternative EoE clinical response measure.

Protocol for a prospective open-label clinical trial to investigate the utility of concurrent TBS/fNIRS for antidepressant treatment optimisation

IntroductionRepetitive transcranial magnetic stimulation (rTMS) with theta burst stimulation (i.e. TBS) of the dorsolateral prefrontal cortex (DLPFC) is an innovative treatment for major depressive disorder (MDD). However, fewer than 50%...

Response Inhibition and Predicting Response to Pharmacological and Cognitive Behavioral Therapy Treatments for Major Depressive Disorder: A Canadian Biomarker Integration Network for Depression Study

BackgroundMajor depressive disorder (MDD) is associated with various cognitive impairments, including response inhibition. Deficits in response inhibition may also underlie poor antidepressant treatment response. Recent studies revealed that the neurobiological correlates of response inhibition can predict response to pharmacological treatments. However, the generalizability of this finding to first-line nonpharmacological treatments, particularly cognitive behavioral therapy, remains to be investigated. MethodsData from two independent treatment protocols were combined, one in which 65 patients with MDD underwent treatment with escitalopram, and the other in which 41 patients with MDD underwent a course of cognitive behavioral therapy. A total of 25 healthy control subjects were also recruited. Neural correlates of response inhibition were captured by participants completing a Go/NoGo task during electroencephalography recording. Response inhibition–related measures of interest included the amplitudes of the N2 and P3 event-related potentials. ResultsPretreatment P3 amplitude, which has been linked to both the motor and cognitive aspects of response inhibition, was a significant predictor of change in depressive symptoms following escitalopram and cognitive behavioral therapy treatment. A greater pretreatment P3 amplitude was associated with a greater reduction in depressive severity. In addition, the pretreatment P3 amplitude was found to be significantly greater at baseline in remitters than in nonremitters and healthy control subjects. ConclusionsThe integrity of response inhibition may be critical for a successful course of pharmacological or psychological treatment for MDD. Electrophysiological correlates of response inhibition may have utility as a general prognostic marker of treatment response in MDD. Future studies may investigate the benefit of preceding first-line treatments with interventions that improve response inhibition in MDD.

In Vivo Functional Assessment of Sodium-Glucose Cotransporters (SGLTs) Using [18F]Me4FDG PET in Rats.

Background Mediating glucose absorption in the small intestine and renal clearance, sodium glucose cotransporters (SGLTs) have emerged as an attractive therapeutic target in diabetic patients. A substantial fraction of patients, however, only achieve inadequate glycemic control. Thus, we aimed to assess the potential of the SGLT-targeting PET radiotracer alpha-methyl-4-deoxy-4-[18F]fluoro-D-glucopyranoside ([18F]Me4FDG) as a noninvasive intestinal and renal biomarker of SGLT-mediated glucose transport. Methods We investigated healthy rats using a dedicated small animal PET system. Dynamic imaging was conducted after administration of the reference radiotracer 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG), or the SGLT-targeting agent, [18F]Me4FDG either directly into the digestive tract (for assessing intestinal absorption) or via the tail vein (for evaluating kidney excretion). To confirm the specificity of [18F]Me4FDG and responsiveness to treatment, a subset of animals was also pretreated with the SGLT inhibitor phlorizin. In this regard, an intraintestinal route of administration was used to assess tracer absorption in the digestive tract, while for renal assessment, phlorizin was injected intravenously (IV). Results Serving as reference, intestinal administration of [18F]FDG led to slow absorption with retention of 89.2 ± 3.5% of administered radioactivity at 15 min. [18F]Me4FDG, however, was rapidly absorbed into the blood and cleared from the intestine within 15 min, leading to markedly lower tracer retention of 18.5 ± 1.2% (P < 0.0001). Intraintestinal phlorizin led to marked increase of [18F]Me4FDG uptake (15 min, 99.9 ± 4.7%; P < 0.0001 vs. untreated controls), supporting the notion that this PET agent can measure adequate SGLT inhibition in the digestive tract. In the kidneys, radiotracer was also sensitive to SGLT inhibition. After IV injection, [18F]Me4FDG reabsorption in the renal cortex was significantly suppressed by phlorizin when compared to untreated animals (%ID/g at 60 min, 0.42 ± 0.10 vs. untreated controls, 1.20 ± 0.03; P < 0.0001). Conclusion As a noninvasive read-out of the concurrent SGLT expression in both the digestive tract and the renal cortex, [18F]Me4FDG PET may serve as a surrogate marker for treatment response to SGLT inhibition. As such, [18F]Me4FDG may enable improvement in glycemic control in diabetes by PET-based monitoring strategies.

Predicting treatment outcomes using 18F-FDG PET biomarkers in patients with non-small-cell lung cancer receiving chemoimmunotherapy.

Background:Predictive markers for treatment response and survival outcome have not been identified in patients with advanced non-small-cell lung cancer (NSCLC) receiving chemoimmunotherapy. We aimed to evaluate whether imaging biomarkers of 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) and routinely assessed clinico-laboratory values were associated with clinical outcomes in patients with advanced NSCLC receiving pembrolizumab plus platinum-doublet chemotherapy as a first-line treatment.Methods:We retrospectively enrolled 52 patients with advanced NSCLC who underwent baseline 18F-FDG PET/CT before treatment initiation. PET/CT parameters and clinico-laboratory variables, constituting the prognostic immunotherapy scoring system, were collected. Optimal cut-off values for PET/CT parameters were determined using the maximized log-rank test for progression-free survival (PFS). A multivariate prediction model was developed based on Cox models for PFS, and a scoring system was established based on hazard ratios of the predictive factors.Results:During the median follow-up period of 16.7 months (95% confidence interval: 15.7–17.7 months), 43 (82.7%) and 31 (59.6%) patients experienced disease progression and death, respectively. Objective response was observed in 23 (44.2%) patients. In the multivariate analysis, maximum standardized uptake value, metabolic tumour volume2.5, total lesion glycolysis2.5, and bone marrow-to-liver uptake ratio from the PET/CT variables and neutrophil-to-lymphocyte ratio (NLR) from the clinico-laboratory variables were independently associated with PFS. The scoring system based on these independent predictive variables significantly predicted the treatment response, PFS, and overall survival.Conclusion:PET/CT variables and NLR were useful biomarkers for predicting outcomes of patients with NSCLC receiving pembrolizumab and chemotherapy as a first-line treatment, suggesting their potential as effective markers for combined PD-1 blockade and chemotherapy.

Emerging therapeutic options in inflammatory bowel disease.

Inflammatory bowel disease (IBD) is a chronic disease that requires chronic treatment throughout the evolution of the disease, with a complex physiopathology that entails great challenges for the development of new and specific treatments for ulcerative colitis and Crohn´s disease. The anti-tumor necrosis factor alpha therapy has impacted the clinical course of IBD in those patients who do not respond to conventional treatment, so there is a need to develop new therapies and markers of treatment response. Various pathways involved in the development of the disease are known and the new therapies have focused on blocking the inflammatory process at the gastrointestinal level by oral, intravenous, subcutaneous, and topical route. All these new therapies can lead to more personalized treatments with higher success rates and fewer relapses. These treatments have not only focused on clinical remission, but also on achieving macroscopic changes at the endoscopic level and microscopic changes by achieving mucosal healing. These treatments are mainly based on modifying signaling pathways, by blocking receptors or ligands, reducing cell migration and maintaining the integrity of the epithelial barrier. Therefore, this review presents the efficacy and safety of the new treatments that are currently under study and the advances that have been made in this area in recent years.

Comprehensive Statistical Exploration of Prognostic (Bio-)Markers for Responses to Immune Checkpoint Inhibitor in Patients with Non-Small Cell Lung Cancer.

Simple SummaryMetastatic non-small cell lung cancer (NSCLC) patients treated with immune checkpoint inhibitors (ICIs) may suffer from heavy side effects, and not all patients benefit from the treatment. Therefore, it is crucial to gain knowledge about possible (bio-)markers for response to ICIs. We used retrospective data acquired from NSCLC patients treated with ICIs in first- or further-line therapy settings, including 16 possible markers. We conducted a comprehensive statistical analysis study to find markers for response to treatment, assessed the robustness of our results, and discussed often encountered statistical pitfalls. Our study yielded hypotheses for various predictive and prognostic (bio-)markers for response to ICIs in NSCLC patients. In particular, we found that high basophil counts may be predictive for treatment response in patients in further-line therapy settings.Metastatic non-small cell lung cancer (NSCLC) patients treated with immune checkpoint inhibitors (ICIs) may suffer from heavy side effects and not all patients benefit from the treatment. We conducted a comprehensive statistical analysis to identify promising (bio-)markers for treatment response. We analyzed retrospective data from NSCLC patients treated with ICIs in first- or further-line therapy settings at the University Hospital Zurich. We investigated 16 possible prognostic markers with respect to overall survival, tumor size reduction, and the development of an immune-related adverse event (irAE) and assessed the robustness of our results. For the further-line patient group, the most significant result was that increased basophil counts were associated with increased odds of tumor size reduction within three months and with the development of an irAE. For the first-line patient group, the most significant results were that increased lymphocyte counts, the histology of adenocarcinoma, and the intake of non-steroidal anti-rheumatic drugs (NSAR) were associated with decreased hazards of dying. Our study yielded new hypotheses for predictive (bio-)markers for response to ICIs in NSCLC patients. The possibly beneficial role of high basophil counts is a particularly interesting finding. Our results should be tested on independent data in a prospective fashion.

Emergence of resistance against direct acting antivirals in chronic HCV patients: A real-world study

Interferon/Ribavirin therapy has been replaced by Direct Acting Antivirals (DAAs) due to emergence of Resistance Associated Variants (RAVs) and decrease Sustain Virologic Response (SVR). Current study investigated treatment response of Sofosbuvir and Ribavirin in chronic HCV patients. Total 256 HCV patients with genotype 1a, 2 and 3a received sofosbuvir/ribavirin according to international standards. HCV RNA presence in serum was used as marker for end treatment response (ETR) and sustain virologic response after 24 weeks of treatment (SVR24) in each case. Response to treatment with SOF + RBV was found statistically significant among different HCV genotypes (GT) as out of 47 HCV GT1 patients 42(89.36%) resulted into good ETR but 4(9.52%) of these relapsed and 5(10.63%) led into virologic failure. 5(100%) HCV GT2 patients resulted into SVR24 whereas, out of 204 HCV GT3 patients 194(95.69%) achieved good ETR however, 8(4.12%) of these relapsed and 10(4.90%) resulted in to virologic failure. Efficacy of therapy was found non-significant in treatment naïve and treatment experienced patients as in this study out of 145 treatment naïve patients 139(95.86%) achieved good ETR where 4(2.87%) relapsed while 6(4.13%) led into virologic break through on the other hand among 111 treatment experienced patients 102(91.89%) resulted into good ETR but 8(7.84%) relapsed whereas 9(8.10%) lead into virologic failure. Current study also propose that various liver and spleen complications/liver cirrhosis are related to response of HCV patients to SOF + RBV therapy whereas, variables like old age, gender is not compromising treatment response to DAAs therapy. Various mild side effects encountered by patients during treatment were fatigue, insomnia, headache, nausea, burning body, diarrhea, cough. Overall, this study reported 89.45% efficacy of SOF + RBV regime in chronic HCV Pakistani patients. Current study suggests hunting for possible reasons of resistance so that SOF + RBV therapy may not share the same fortune as previous therapies in near future.