Early Treatment Changes Research Articles

Low risk of early conversion to surgery in non-surgically treated proximal humeral fractures - An observational cohort study of 31,761 fractures from the Swedish Fracture Register

IntroductionThe majority of all proximal humeral fractures (PHFs) are treated non-surgically. Due to the risk of early secondary fracture displacement patients with non-surgically treated PHFs routinely undergo serial clinical and radiological evaluations. However, the value of these routine follow-up visits is unclear. This study aimed to examine the rate of early conversion to surgery in non-surgically treated PHFs. Moreover, the associations between patient and fracture characteristics and the risk of conversion to surgery were explored in order to assess the need for routine follow-ups. MethodsData on all patients aged ≥18 years with a non-surgically treated PHF registered between 2013 and 2021 were extracted from the Swedish Fracture Register. Early change of treatment from non-surgical to surgical is an optional treatment modality in the SFR. The rate of early conversion to surgery within 60 days from injury was analyzed in relation to age and sex of the patient, energy level at injury and fracture morphology according to the AO/OTA classification. ResultsA total of 31,761 primarily non-surgically treated PHFs (mean age 70 years: 76 % female) were included in the study. The overall rate of early conversion to surgery was 3.7 %. Younger age and increasing fracture severity were associated with a higher conversion rate to surgery. Patients ≥80 years and those with the three most common fracture types (A1, A2, and B1) had <2 % early conversion to surgery. In contrast, patients with C-type fractures, unstable/displaced fractures (A3, B2, and C2), or fracture dislocations (A1.3, B3, and C3) had a substantially higher risk (5.0–20 %) of early conversion. ConclusionThe overall risk of early conversion to surgery in non-surgically treated PHFs is low and can be further predicted based on patient age and fracture morphology. These results could have implications regarding which patients are in need of routine follow-ups. Level of evidenceLevel II; Retrospective design; Prognosis study

Lentigo maligna and lentigo maligna melanoma in young patients in Australian tertiary centres.

This was a retrospective study of all patients with a diagnosis of lentigo maligna or lentigo maligna melanoma at 50 years of age or younger at the time of their first diagnosis in two Australian tertiary centres. The low recurrence rate in younger patients in this study warrants further investigation. Early diagnosis in young patients is crucial to allow early treatment and lifestyle changes to reduce actinic damage and subsequent development of further melanomas.

Evaluation of pretreatment and early treatment changes in serum β-hCG with methotrexate.

Serum beta-human chorionic gonadotropin (β-hCG) is an important biomarker for the detection of ectopic pregnancies (EPs). The β-hCG levels between days 1 and 4 after methotrexate (MTX) treatment as an indicator of the success of the MTX in EP have been the focus of research. To determine whether the change in the β-hCG levels at day 1 and 4 and pretreatment at 48-hour increments can predict early treatment failure of single-dose MTX in EP. This was a retrospective study of 1120 EPs treated with a single dose of MTX. Treatment failure was defined as an obligation to proceed to surgery or the need for additional doses of MTX. A total 722 out of 1120 EPs had an increase in β-hCG on day 4 after MTX treatment. The logistic regression analysis indicated that 3 dependents were significantly associated with treatment failure: 1) a pretreatment 48-hour increase in β-hCG (odds ratio (OR): 1.249, 95% confidence interval (95% CI): 1.008-2.049, p < 0.001); 2) a change in β-hCG between day 1 and 4 (OR: 1.384, 95% CI: 1.097-2.198, p < 0.001); and 3) a history of EP (OR: 1.208, 95% CI: 1.041- 2.011, p < 0.001). The optimal cutoff point for the prediction of treatment failure was an increase of more than 19% in the 48 h before the treatment, and an increase of more than 36% between day 1 and day 4 in β-hCG concentrations. Patients with an increase in β-hCG levels of less than 36% on day 4 experienced MTX treatment failure in 4.2% (n = 25), compared to 74.5% (n = 88) of the patients with an increase above 36%. A serum β-hCG increase of more than 36% on day 4 after the administration of MTX alongside a more than 19% increase in β-hCG concentration 48 h before the MTX treatment may predict the early failure of medical treatment for an EP.

Association of sarcopenia with endocrine therapy toxicity in patients with early breast cancer.

Endocrine therapy reduces recurrence risk and improves survival in women with hormone receptor-positive breast cancer; however, side effects can decrease quality of life, leading to reduced treatment adherence. Sarcopenia is the loss of skeletal muscle mass that happens with age; it is associated with worse survival and reduced chemotherapy adherence in patients with breast cancer. The impact of sarcopenia on endocrine therapy tolerance has not been investigated. The current study evaluates the associations of sarcopenia with endocrine therapy toxicity and treatment tolerance. Skeletal muscle mass was measured by bioelectrical impedance spectrometry. Skeletal muscle index (SMI) was calculated to assess for sarcopenia: SMI = (SMM kg)/(patient height, m2). Patients with SMI ≤ 6.75kg/m2 were considered sarcopenic. A chart review was performed to obtain patient characteristics, endocrine therapy toxicity, and early treatment change or termination. Fisher's exact test was performed to associate patient characteristics and outcomes with sarcopenia status. Four hundred eighty-two patients with stage I-III breast cancer were prescribed endocrine therapy and had undergone sarcopenia evaluation. The median age was 61years (29-88years). Sarcopenia was identified in 35% of patients. Twelve percent of patients experienced grade 3-4 endocrine-related toxicities. On multivariable logistic analysis, sarcopenia was associated with increased odds of experiencing endocrine-related side effects (p = 0.006). In addition, patients with sarcopenia stopped or changed their medication due to side effects more often than those without sarcopenia (p = 0.03). The presence of sarcopenia in patients with EBC represents a potentially modifiable risk factor for more significant endocrine therapy side effects and reduced treatment tolerance.

Changes in mortality rate of the general population during the COVID-19 pandemic: an interrupted time series study in Korea.

Unlike other countries, South Korea did not implement a large-scale lockdown or closure of businesses to manage the coronavirus disease 2019 (COVID-19) pandemic, but relied on changes in population behaviours and early isolation and treatment of patients. It is important to evaluate the effectiveness of such alternative strategies on the mortality of the general population. Mortality and monthly population data from 2013 to 2020 were obtained. A quasi-Poisson regression model adjusting for age structure, seasonality and time was used to evaluate whether underlying trends for monthly mortality rate have changed with the pandemic. Stratification analyses based on sex and location of deaths (inside vs outside of medical facilities) were conducted. The risk estimates showed no changes in non-accidental mortality during the COVID-19 pandemic [relative risk (RR) (95% confidence interval, 95% CI), slope change: 1.00 (1.00, 1.01), step change: 0.99 (0.97, 1.01)] compared with those before the pandemic. In cause-specific analysis, there was an abrupt and sustained decrease in the mortality rate of respiratory diseases [RR (95% CI), step change: 0.81 (0.77, 0.84)]. In the analysis of deaths by location, an increase in non-accidental mortality [RR (95% CI), slope change: 1.01 (1.01, 1.02), step change: 1.16 (1.11, 1.22)] and several cause-specific mortalities was observed outside of medical facilities. The non-accidental mortality rate in South Korea for the first year of the pandemic followed the historical trends. However, there was a decrease in mortality associated with respiratory diseases, and an increase in mortality occurring outside of medical facilities. The findings may be attributed to changes in public behaviours, and availability of medical resources during the pandemic.

Multiple cArdiac seNsors for mAnaGEment of Heart Failure (MANAGE-HF) – Phase I Evaluation of the Integration and Safety of the HeartLogic Multisensor Algorithm in Patients With Heart Failure

BackgroundPatients with heart failure (HF) and reduced ejection fraction suffer from a relapsing and remitting disease course, where early treatment changes may improve outcomes. We assessed the clinical integration and safety of the HeartLogic multisensor index and alerts in HF care. MethodsThe Multiple cArdiac seNsors for mAnaGEment of Heart Failure (MANAGE-HF) study enrolled 200 patients with HF and reduced ejection fraction (<35%), New York Heart Association functional class II–III symptoms, implanted with a cardiac resynchronization therapy-defibrillator or and implantable cardioverter defibrillator, who had either a hospitalization for HF within 12 months or unscheduled visit for HF exacerbation within 90 days or an elevated natriuretic peptide concentration (brain natriuretic peptide [BNP] of ≥150 pg/mL or N-terminal pro-BNP [NT-proBNP] of ≥600 pg/mL). This phase included the development of an alert management guide and evaluated changes in medical treatment, natriuretic peptide levels, and safety. ResultsThe mean age of participants was 67 years, 68% were men, 81% were White, and 61% had a HF hospitalization in prior 12 months. During follow-up, there were 585 alert cases with an average of 1.76 alert cases per patient-year. HF medications were augmented during 74% of the alert cases. HF treatment augmentation within 2 weeks from an initial alert was associated with more rapid recovery of the HeartLogic Index. Five serious adverse events (0.015 per patient-year) occurred in relation to alert-prompted medication change. NTproBNP levels decreased from median of 1316 pg/mL at baseline to 743 pg/mL at 12 months (P < .001). ConclusionsHeartLogic alert management was safely implemented in HF care and may optimize HF management. This phase supports further evaluation in larger studies. Trial RegistrationClinicalTrials.gov (NCT03237858)

Pretreatment Positron Emission Tomography with 18F-Fluorodeoxyglucose May Be a Useful New Predictor of Early Progressive Disease following Atezolizumab plus Bevacizumab in Patients with Unresectable Hepatocellular Carcinoma

Background and Aims: The aim of this study was to identify the utility of ¹⁸F-fluorodeoxyglucose positron emission tomography/computed tomography (¹⁸F-FDG-PET/CT) as a predictor of early progressive disease (e-PD) in patients with hepatocellular carcinoma (HCC) treated with atezolizumab plus bevacizumab (Atezo/Bev). Methods: Twenty consecutive patients with measurable intrahepatic target nodules who received Atezo/Bev treatment were reviewed. The oncological aggressiveness of tumors estimated by ¹⁸F-FDG-PET/CT was analyzed using the rate of e-PD within 12 weeks and early progression-free survival (e-PFS) and overall survival (OS). Multivariate analysis was used to identify potential confounders for PD during Atezo/Bev therapy. Results: Using the Response Evaluation Criteria in Solid Tumors version 1.1, a tumor-to-normal liver ratio (TLR) ≥2, indicating higher oncological aggressiveness in HCCs, was associated with lower objective response rates compared with TLR values <2 (18% vs. 33%, respectively). Moreover, TLR values ≥2 were significantly associated with higher e-PD rates compared with TLR values <2 (64% vs. 11%, respectively) and worse e-PFS (p = 0.021). In multivariate analysis, TLR ≥2 showed marginal significance as a predictor of e-PD (p = 0.053), and utility as a predictor for worse e-PFS (hazard ratio, 7.153; 95% confidence interval, 1.258–40.689; p = 0.027). In contrast, no significant differences in OS with/without e-PD were observed during the treatment course. In this study, 8 patients experienced e-PD and almost 40% of patients experienced acceptable disease control following subsequent lenvatinib treatment. Conclusion: Pretreatment ¹⁸F-FDG-PET/CT may be a useful new predictor of e-PD and may enable early decision-making based on early treatment changes following Atezo/Bev treatment of HCC.

Early Treatment Change in Perpetrators of Sexual Versus Non-Sexual Violence.

The purpose of this study is to assess treatment change at both a group and individual level in a sample of 81 Dutch male patients who received mandated care for either violent (non-sexual) behavior or sexual violent behavior. Psychiatric nurses rated patients' social skills, insight, hostility, physical violence with the BEST-Index every 6 months over the course of 2 years after patients were admitted to hospital. Mixed analysis of covariances and the reliable change index indicated that patients, irrespective of offense type, showed treatment change over time with exception of physical violence. This study shows that general treatment may be useful in the first 18 month for risk factors common to different types of offenses, but that specialized treatment is needed to establish further change.

192. Tolerability Outcomes of Multi-drug Antibiotic Treatment for Pulmonary Nontuberculous Mycobacterial Disease due to Mycobacterium avium Complex in U.S. Medicare Beneficiaries with Bronchiectasis

BackgroundNontuberculous mycobacteria (NTM), most frequently Mycobacterium avium complex (MAC), cause increasingly common pulmonary infections. Treatment interruptions and early discontinuation are common in MAC therapy, but population-based data on treatment outcomes are severely lacking. We examined tolerability outcomes of guideline-based 3-drug therapies (GBT) targeted for pulmonary MAC infection. MethodsAmong beneficiaries with bronchiectasis (ICD-9-CM 494.0 or 494.1) in U.S. Medicare data (01/2006 – 12/2014), we identified first-time MAC GBT therapy users, excluding those with cystic fibrosis, HIV, or a history of organ transplant. MAC GBT was defined as an overlapping prescription of ≥ 28-day supply of a macrolide, ethambutol and rifamycin. Using Cox regression methods, we compared time-to-regimen change or discontinuation within 12 months of therapy start in the following groups: 1) azithromycin-ethambutol-rifamycin vs. clarithromycin-ethambutol-rifamycin; 2) macrolide-ethambutol-rifampin vs. macrolide-ethambutol-rifabutin; and 3) azithromycin-ethambutol-rifampin vs. clarithromycin-ethambutol-rifabutin.ResultsWe identified 4,626 GBT therapy users (mean 77.9 years [s.d. 6.1], female [77.7%], and non-Hispanic white [87.2%]). Overall, the rate of regimen change or discontinuation was higher in the clarithromycin-based regimens compared to azithromycin-containing regimens, and in rifabutin-containing regimens compared to rifampin-containing regimens. The rate of drug regimen change or discontinuation was 65% greater in the clarithromycin-ethambutol-rifabutin group compared to the azithromycin-ethambutol-rifampin group (adjusted hazard ratio: 1.64, 95% CI: 1.43, 1.64) (Table 1, Figure 1). ConclusionAzithromycin-based regimens and rifampin-containing regimens were less likely to be changed or discontinued within 12 months of therapy compared to clarithromycin-based regimens and rifabutin-containing regimens, respectively. More research is needed to identify factors associated with early treatment change or discontinuation. Disclosures Emily Henkle, PhD, MPH, AN2 (Consultant, Advisor or Review Panel member)Zambon (Advisor or Review Panel member) Theodore K. Marras, MD, Astra Zeneca (Speaker’s Bureau)Insmed (Scientific Research Study Investigator)Novartis (Speaker’s Bureau)RedHill (Consultant)Spero (Consultant) Kevin L. Winthrop, MD, MPH, Insmed (Consultant, Grant/Research Support)Paratek (Consultant)RedHill (Consultant)Spero (Consultant) Kevin L. Winthrop, MD, MPH, Insmed (Consultant, Research Grant or Support)Paratek (Consultant)RedHill Biopharma (Consultant)Spero (Consultant)

Effects of nutritional supplementation on glucose metabolism and insulin function among people with HIV initiating ART

BackgroundWithout high-quality nutritional support, there is a risk that people infected with human immunodeficiency virus (HIV) will replace lost muscle mass with fat mass when initiating antiretroviral therapy (ART). We have shown that lipid-based nutrient supplements (LNS) with whey or soy considerably increases lean mass among Ethiopian people with HIV starting ART. Here, we aim to assess the effects of LNS on insulin function and glucose metabolism.MethodsThis is a secondary analysis of a randomized trial testing the effect of three-month supplementation with LNS containing whey (LNS/whey) or soy (LNS/soy) among people with HIV. LNS/whey and LNS/soy groups were combined and then were compared against the non-supplemented group. The outcomes were change in fasting plasma-glucose (FPG), and 30-min glucose and 120-min glucose after oral glucose tolerance test. We further assessed effect on glycated hemoglobin (HbA1c), fasting insulin, homeostatic model assessment index for beta-cell function (HOMA-B) and insulin resistance (HOMA-IR).ResultsOf the 318 patients enrolled, 268 (84.3%) had available FPG and HbA1c and included. After 3 months of ART, HbA1c tended to be 2 mmol/mol higher in the LNS supplemented group, most pronounced among those receiving whey as the protein source. LNS led to higher 30-min glucose (0.5 mmol/L, 95% CI 0.2, 0.8) and 120-min glucose (0.4 mmol/L, 95% CI 0.03, 0.8) and a > 50% increase in fasting insulin, HOMA-B and HOMA-IR compared to the non-supplemented.ConclusionAmong Ethiopian people with HIV initiating ART, short-term LNS intake increased glucose and insulin levels, and tended to increase HbA1c, potentially leading to more insulin resistance. Higher intake of carbohydrates with LNS could influence glycemic status. Whether these metabolic changes in early HIV treatment are beneficial or increase long-term risk of metabolic disorders needs to be explored.

Earlier extracranial progression and shorter survival in ALK-rearranged lung cancer with positive liquid rebiopsies.

BackgroundLiquid rebiopsies can detect resistance mutations to guide therapy of anaplastic lymphoma kinase-rearranged (ALK+) non-small-cell lung cancer (NSCLC) failing tyrosine kinase inhibitors (TKI). Here, we analyze how their results relate to the anatomical pattern of disease progression and patient outcome.MethodsClinical, molecular, and radiologic characteristics of consecutive TKI-treated ALK+ NSCLC patients were analyzed using prospectively collected plasma samples and the 17-gene targeted AVENIO kit, which covers oncogenic drivers and all TP53 exons.ResultsIn 56 patients, 139 instances of radiologic changes were analyzed, of which 133 corresponded to disease progression. Circulating tumor DNA (ctDNA) alterations were identified in most instances of extracranial progression (58/94 or 62%), especially if concomitant intracranial progression was also present (89%, P<0.001), but rarely in case of isolated central nervous system (CNS) progression (8/39 or 21%, P<0.001). ctDNA detectability correlated with presence of “short” echinoderm microtubule-associated protein-like 4 (EML4)-ALK fusion variants (mainly V3, E6:A20) and/or TP53 mutations (P<0.05), and presented therapeutic opportunities in <50% of cases. Patients with extracranial progression and positive liquid biopsies had shorter survival from the start of palliative treatment (mean 52 vs. 69 months, P=0.002), regardless of previous and subsequent therapy and initial ECOG performance status. Furthermore, for patients with extracranial progression, ctDNA detectability was associated with shorter next-line progression-free survival (PFS) (3 vs. 13 months, P=0.003) if they were switched to another systemic therapy (49/86 samples), and with shorter time-to-next-treatment (TNT) (3 vs. 8 months, P=0.004) if they were continued on the same treatment due to oligoprogression (37/86). In contrast, ctDNA detectability was not associated with the outcome of patients showing CNS-only progression. In 6/6 cases with suspicion of non-neoplastic radiologic lung changes (mainly infection or pneumonitis), ctDNA results remained negative.ConclusionsPositive blood-based liquid rebiopsies in ALK+ NSCLC characterize biologically more aggressive disease and are common with extracranial, but rare with CNS-only progression or benign radiologic changes. These results reconcile the increased detection of ALK resistance mutations with other features of the high-risk EML4-ALK V3-associated phenotype. Conversely, most oligoprogressive patients with negative liquid biopsies have a more indolent course without need for early change of systemic treatment.

Early Assessment of Molecular Progression and Response by Whole-genome Circulating Tumor DNA in Advanced Solid Tumors.

Treatment response assessment for patients with advanced solid tumors is complex and existing methods require greater precision. Current guidelines rely on imaging, which has known limitations, including the time required to show a deterministic change in target lesions. Serial changes in whole-genome (WG) circulating tumor DNA (ctDNA) were used to assess response or resistance to treatment early in the treatment course. Ninety-six patients with advanced cancer were prospectively enrolled (91 analyzed and 5 excluded), and blood was collected before and after initiation of a new, systemic treatment. Plasma cell-free DNA libraries were prepared for either WG or WG bisulfite sequencing. Longitudinal changes in the fraction of ctDNA were quantified to retrospectively identify molecular progression (MP) or major molecular response (MMR). Study endpoints were concordance with first follow-up imaging (FFUI) and stratification of progression-free survival (PFS) and overall survival (OS). Patients with MP (n = 13) had significantly shorter PFS (median 62 days vs. 310 days) and OS (255 days vs. not reached). Sensitivity for MP to identify clinical progression was 54% and specificity was 100%. MP calls were from samples taken a median of 28 days into treatment and 39 days before FFUI. Patients with MMR (n = 27) had significantly longer PFS and OS compared with those with neither call (n = 51). These results demonstrated that ctDNA changes early after treatment initiation inform response to treatment and correlate with long-term clinical outcomes. Once validated, molecular response assessment can enable early treatment change minimizing side effects and costs associated with additional cycles of ineffective treatment.

Community Vs. hospital HIV testing sites in Jerusalem, Israel - who\u2019s tested and who\u2019s at risk?

BackgroundAfter decades of constant increase in HIV diagnoses among men who have sex with men (MSM), a gradual decrease has been reported in recent years. Timely detection of HIV leads to early treatment and behavioral changes which decrease further transmissions. This cross-sectional study aimed to assess demographic and behavioral characteristics of individuals who were tested for HIV in Jerusalem, Israel.MethodsThis study compared individuals who were tested at Hadassah AIDS Center (HAC) with those tested at the Jerusalem Open House (JOH) - an LGBTQ community center. Participants completed anonymous questionnaires regarding their demographic, HIV-testing history, and sexual behaviors. High-risk sexual behavior (HRSB) was defined as a diagnosis of sexually transmitted disease or condomless anal/vaginal sex during the last year.ResultsAmong 863 participants, 104 (12.1%) were tested in HAC and 759 (87.9%) in JOH. Of those, 19 (18.3%) and 227 (29.9%) were HRSB, respectively. Two MSM were tested positive in JOH. JOH received more MSM, HRSB and individuals who were previously tested for HIV, while HAC received more migrants and health-care workers. HRSB-participants were more commonly younger, males, non-Jewish, with lower income, previously tested for HIV, reported more sexual partners, payed for sex or used drugs.ConclusionsMSM and HRSB-individuals were more likely to be tested in JOH, while migrants and health-care workers in HAC, possibly due to the geographic location, reputation and specific atmosphere. In order to encourage HIV-tests among HRSB and non-Jews, additional interventions should be employed, including outreach activities, extending opening hours and reducing testing costs should be employed.

A randomized trial to examine the mechanisms of cognitive, behavioral and mindfulness-based psychosocial treatments for chronic pain: Study protocol

This randomized trial will evaluate the mechanisms of three chronic pain treatments: cognitive therapy (CT), mindfulness meditation (MM), and activation skills (AS). We will determine the extent to which late-treatment improvement in primary outcome (pain interference) is predicted by early-treatment changes in cognitive content, cognitive process, and/or activity level. The shared versus specific role of these mechanisms across the three treatments will be evaluated during treatment (Primary Aim), and immediately post-treatment to examine relapse mechanisms (Secondary Aim).We will enroll 300 individuals with chronic pain (with low back pain as a primary or secondary condition), with 240 projected to complete the study. Participants will be randomly assigned to eight, 1.5 h telehealth group sessions of CT, MM, or AS. Mechanisms and outcomes will be assessed twice daily during 2-week baseline, 4-week treatment period, and 4-week post-treatment epoch via random cue-elicited ecological momentary assessment (EMA); activity level will be monitored during these time epochs via daily monitoring with ActiGraph technology. The primary outcome will be measured by the PROMIS 5-item Pain Interference scale. Structural equation modeling (SEM) will be used to test the primary aims. This study is pre-registered on clinicaltrials.gov (Identifier: NCT03687762).This study will determine the temporal sequence of lagged mediation effects to evaluate rates of change in outcome as a function of change in mediators. The findings will provide an empirical basis for enhancing and streamlining psychosocial chronic pain interventions. Further, results will guide future efforts towards optimizing maintenance of gains to effectively reduce relapse risk.

Whole-genome cell-free DNA (cfDNA) changes as a dynamic blood-based biomarker for early response assessment of advanced tumors.

3041 Background: Liquid biopsies have potential clinical utility as dynamic biomarkers for treatment response. We analyzed serial changes in whole-genome (WG) cfDNA to identify patients with disease progression prior to routine imaging. Methods: We prospectively collected clinical data and blood from 69 advanced cancer patients (28 lung, 25 breast, 16 other). Blood was collected at baseline prior to initiation of a new treatment and at one or two additional timepoints (median 21 and 42 days). We isolated plasma cfDNA and prepared sequencing libraries for WG sequencing or WG bisulfite sequencing (median depth 20X). We quantified changes in the fraction of tumor-derived cfDNA over the initial course of treatment to predict progression vs. no progression. Treatment response at first post-treatment imaging was determined by RECIST 1.1 and clinical assessment. Study endpoints were agreement with first post-treatment imaging and progression-free survival (PFS) by cfDNA prediction. Results: Median age of patients was 70 and 59% were female. Patients were treated with the following therapies: chemotherapy (37), immunotherapy (17), endocrine (9), or targeted therapy (6). Patients with predicted progression by cfDNA (14), indicated by an increase in tumor fraction at either post-treatment blood collection, had shorter PFS (median 63 days) compared to patients without an increase (N = 55; median 255 days), with hazard ratio of 10.3 (95% confidence interval 4.6-23.4, log-rank P = 1x10-11). Positive predictive value was 100% for disease progression and negative predictive value was 78%. These findings were consistent in subset analyses of patients with lung (log-rank P = 2x10-5), breast (log-rank P = 3x10-4), and those treated with immunotherapy (log-rank P = 5x10-6). Conclusions: Our results show the ability to detect early disease progression with high fidelity using WG cfDNA prior to first imaging. These findings were consistent across multiple tumor types and treatments, including immunotherapy patients. Once validated, this dynamic, predictive, blood-based biomarker could aid in clinical decision making for early treatment change as a novel and cost-effective approach.

Efficacy Comparison of Intravitreal Anti-VEGF Therapy for Three Subtypes of Neovascular Age-Related Macular Degeneration: A Systematic Review and Meta-Analysis.

Purpose Intravitreal antivascular endothelial growth factor (anti-VEGF) therapy has been widely used for the treatment of neovascularization (NV) secondary to age-related macular degeneration (AMD). This study aimed to compare the efficacy among different subtypes of neovascular age-related macular degeneration (nAMD). Methods PubMed, Embase, and the Cochrane Library were searched for eligible studies. We performed meta-analysis using Review Manager 5.3 and Stata/SE 12.0. Results A total of 24 studies met our inclusion criteria and were included in the systematic review. At 3 months, the mean logarithm of the minimum angle of resolution (logMAR) improvements were −0.09, −0.18, and −0.23 for type 1, 2, and 3, respectively, while the mean macular thickness (MT) changes were −104.83, −130.76, and −196.29 μm. At 12 months, the mean changes in Early Treatment of Diabetic Retinopathy Study (ETDRS) letters were 6.38, 8.12, and 9.37, while the MT decrease was 126.51, 126.52, and 139.85 μm, respectively. However, statistically significant difference was only found between type 1 and 3 in vision improvement, both in the short term (p=0.0002) and long term (p=0.01). Conclusions The reactivity to VEGF inhibitors varied among different subtypes of nAMD. The efficacy of intravitreal anti-VEGF therapy in type 3 nAMD was statistically better than type 1 when considering vision improvement at 3 and 12 months. Thus, the lesion subtype is a predictor for the treatment outcome which can help guide prognosis.

A UK nationwide prospective study of treatment change in MODY: genetic subtype and clinical characteristics predict optimal glycaemic control after discontinuing insulin and metformin

Aims/hypothesisTreatment change following a genetic diagnosis of MODY is frequently indicated, but little is known about the factors predicting future treatment success. We therefore conducted the first prospective study to determine the impact of a genetic diagnosis on individuals with GCK-, HNF1A- or HNF4A-MODY in the UK, and to identify clinical characteristics predicting treatment success (i.e. HbA1c ≤58 mmol/mol [≤7.5%]) with the recommended treatment at 2 years.MethodsThis was an observational, prospective, non-selective study of individuals referred to the Exeter Molecular Genetic Laboratory for genetic testing from December 2010 to December 2012. Individuals from the UK with GCK- or HNF1A/HNF4A-MODY who were not on recommended treatment at the time of genetic diagnosis, and who were diagnosed below the age of 30 years and were currently aged less than 50 years, were eligible to participate.ResultsA total of 44 of 58 individuals (75.9%) changed treatment following their genetic diagnosis. Eight individuals diagnosed with GCK-MODY stopped all diabetes medication without experiencing any change in HbA1c (49.5 mmol/mol [6.6%] both before the genetic diagnosis and at a median of 1.25 years’ follow-up without treatment, p = 0.88). A total of 36 of 49 individuals (73.5%) diagnosed with HNF1A/HNF4A-MODY changed treatment; however, of the 21 of these individuals who were being managed with diet or sulfonylurea alone at 2 years, only 13 (36.1% of the population that changed treatment) had an HbA1c ≤58 mmol/mol (≤7.5%). These individuals had a shorter diabetes duration (median 4.6 vs 18.1 years), lower HbA1c (58 vs 73 mmol/mol [7.5% vs 8.8%]) and lower BMI (median 24.2 vs 26.0 kg/m2) at the time of genetic diagnosis, compared with individuals (n = 23/36) with an HbA1c >58 mmol/mol (>7.5%) (or <58 mmol/mol [<7.5%] on additional treatment) at the 2 year follow-up. Overall, 64% (7/11) individuals with a diabetes duration of ≤11 years and an HbA1c of ≤69 mmol/mol (≤8.5%) at time of the genetic test achieved good glycaemic control (HbA1c ≤58 mmol/mol [≤7.5%]) with diet or sulfonylurea alone at 2 years, compared with no participants with a diabetes duration of >11 years and an HbA1c of >69 mmol/mol (>8.5%) at the time of genetic diagnosis.Conclusions/interpretationIn participants with GCK-MODY, treatment cessation was universally successful, with no change in HbA1c at follow-up. In those with HNF1A/HNF4A-MODY, a shorter diabetes duration, lower HbA1c and lower BMI at genetic diagnosis predicted successful treatment with sulfonylurea/diet alone, supporting the need for early genetic diagnosis and treatment change. Our study suggests that, in individuals with HNF1A/HNF4A-MODY with a longer duration of diabetes (>11 years) at time of genetic test, rather than ceasing current treatment, a sulfonylurea should be added to existing therapy, particularly in those who are overweight or obese and have a high HbA1c.

Predictive value of interim positron emission tomography in diffuse large B-cell lymphoma: a systematic review and meta-analysis

PurposeDiffuse large B-cell lymphoma (DLBCL) represents the most common subtype of non-Hodgkin lymphoma. Most relapses occur in the first 2 years after diagnosis. Early response assessment with 18F-fluoro-2-deoxy-D-glucose (18F-FDG) positron emission tomography (PET) may facilitate early change of treatment, thereby preventing ineffective treatment and unnecessary side effects. We aimed to assess the predictive value of visually-assessed interim 18F-FDG PET on progression-free survival (PFS) or event-free survival (EFS) in DLBCL patients treated with first-line immuno-chemotherapy regimens.MethodsFor this systematic review and meta-analysis Pubmed, Embase, and the Cochrane Library were searched until July 11, 2017. Prospective and retrospective studies investigating qualitative interim PET response assessment without treatment adaptation based on the interim PET result were eligible. The primary outcome was two-year PFS or EFS. Prognostic and diagnostic measures were extracted and analysed with pooled hazard ratios and Hierarchical Summary Receiver Operator Characteristic Curves, respectively. Meta-regression was used to study covariate effects.ResultsThe pooled hazard ratio for 18 studies comprising 2,255 patients was 3.13 (95%CI 2.52–3.89) with a 95% prediction interval of 1.68–5.83. In 19 studies with 2,366 patients, the negative predictive value for progression generally exceeded 80% (64–95), but sensitivity (33–87), specificity (49–94), and positive predictive values (20–74) ranged widely.ConclusionsThese findings showed that interim 18F-FDG PET has predictive value in DLBCL patients. However, (subgroup) analyses were limited by lack of information and small sample sizes. Some diagnostic test characteristics were not satisfactory, especially the positive predictive value should be improved, before a successful risk stratified treatment approach can be implemented in clinical practice.

Pretreatment and early-treatment cortical thickness is associated with SSRI treatment response in major depressive disorder.

To date, there are no biomarkers for major depressive disorder (MDD) treatment response in clinical use. Such biomarkers could allow for individualized treatment selection, reducing time spent on ineffective treatments and the burden of MDD. In search of such a biomarker, multisite pretreatment and early-treatment (1 week into treatment) structural magnetic resonance (MR) images were acquired from 184 patients with MDD randomized to an 8-week trial of the selective serotonin reuptake inhibitor (SSRI) sertraline or placebo. This study represents a large, multisite, placebo-controlled effort to examine the association between pretreatment differences or early-treatment changes in cortical thickness and treatment-specific outcomes. For standardization, a novel, robust site harmonization procedure was applied to structural measures in a priori regions (rostral and caudal anterior cingulate, lateral orbitofrontal, rostral middle frontal, and hippocampus), chosen based on previously published reports. Pretreatment cortical thickness or volume did not significantly associate with SSRI response. Thickening of the rostral anterior cingulate cortex in the first week of treatment was associated with better 8-week responses to SSRI (p = 0.010). These findings indicate that frontal lobe structural alterations in the first week of treatment may be associated with long-term treatment efficacy. While these associational findings may help to elucidate the specific neural targets of SSRIs, the predictive accuracy of pretreatment or early-treatment structural alterations in classifying treatment remitters from nonremitters was limited to 63.9%. Therefore, in this large sample of adults with MDD, structural MR imaging measures were not found to be clinically translatable biomarkers of treatment response to SSRI or placebo.

A data-driven statistical model that estimates measurement uncertainty improves interpretation of ADC reproducibility: a multi-site study of liver metastases

Apparent Diffusion Coefficient (ADC) is a potential quantitative imaging biomarker for tumour cell density and is widely used to detect early treatment changes in cancer therapy. We propose a strategy to improve confidence in the interpretation of measured changes in ADC using a data-driven model that describes sources of measurement error. Observed ADC is then standardised against this estimation of uncertainty for any given measurement. 20 patients were recruited prospectively and equitably across 4 sites, and scanned twice (test-retest) within 7 days. Repeatability measurements of defined regions (ROIs) of tumour and normal tissue were quantified as percentage change in mean ADC (test vs. re-test) and then standardised against an estimation of uncertainty. Multi-site reproducibility, (quantified as width of the 95% confidence bound between the lower confidence interval and higher confidence interval for all repeatability measurements), was compared before and after standardisation to the model. The 95% confidence interval width used to determine a statistically significant change reduced from 21.1 to 2.7% after standardisation. Small tumour volumes and respiratory motion were found to be important contributors to poor reproducibility. A look up chart has been provided for investigators who would like to estimate uncertainty from statistical error on individual ADC measurements.