Short-term Drug Research Articles

Abstract 4012: EGFR inhibition in combination with PI3K/AKT/mTOR and/or Bcl-2 inhibition is a promising novel therapeutic approach for inverted sinonasal papillomas and associated sinonasal carcinomas

Abstract Introduction: Activating EGFR mutations are characteristic of inverted sinonasal papillomas (ISP) and ISP-associated sinonasal carcinomas (SNC). Using standard 2D culture models, our group has shown that targeting EGFR activity in ISP-associated SNC effectively inhibits cellular proliferation in vitro. Targeting EGFR in pre-clinical models that are more representative of in vivo patient responses is a critical next step. Methods: High-throughput drug screening was conducted using a 3D in vitro culture model for two ISP-associated SNC cell lines (SCCNC4 and UM-SCC-112) using a library of >800 curated small molecule inhibitors including inhibitors of EGFR, PI3K/AKT/mTOR (P/A/M), and Bcl-2. Viability was assessed and drug sensitivity scores were calculated. Dual combinations (inhibition of EGFR and P/A/M or Bcl-2) and triple combinations (inhibition of EGFR, P/A/M, and Bcl-2) for select drugs were tested for synergistic killing using the Chou-Talalay and Bliss methods. Treatment-associated transcriptomic changes were monitored using whole-transcriptome RNAseq. Finally, patient-derived organoids (PDOs) from primary sinonasal papilloma or carcinoma tissue were utilized ex vivo for short-term drug screening with EGFR, P/A/M, and/or Bcl-2 inhibitors at maximum human plasma concentration (Cmax) format. Results: Drug screening demonstrated that ISP-associated SNC cell lines are highly resistant to a diversity of standard and targeted therapeutic agents. Indeed, these cell lines demonstrated poorer responses than other highly resistant tumor types previously analyzed by our group, including triple-negative breast cancer and bladder cancer. Our data demonstrated that EGFR inhibition alone does not effectively kill ISP-associated SNC cells in 3D culture; however, dual and triple combinations of EGFR and P/A/M and/or Bcl-2 inhibitors showed synergistic killing. Finally, sinonasal papilloma and carcinoma PDOs showed partial responses to selected EGFR inhibitors in 3D ex vivo culture. Conclusions: While EGFR inhibitors effectively inhibit cellular proliferation in ISP-associated SNC cell lines in 2D culture, drug screening in 3D culture and using PDO material - more representative models of in vivo patient responses - show that EGFR inhibition alone is insufficient to completely eliminate these tumor cells, suggesting that EGFR inhibitors alone are unlikely to generate significant clinical responses for patients with ISP or associated SNCs. However, combining targeting of the P/A/M and/or Bcl-2 pathways revealed synergistic killing of ISP-associated SNC cell lines. Taken together, these data demonstrate that compensatory oncogenic and/or anti-apoptotic pathways must be targeted to potentiate EGFR inhibition for successful treatment of ISP and associated SNCs. Citation Format: Athena M. Apfel, Zhaoping Qin, Albert Liu, Matthew B. Soellner, Sofia D. Merajver, Aaron M. Udager, Nathan M. Merrill. EGFR inhibition in combination with PI3K/AKT/mTOR and/or Bcl-2 inhibition is a promising novel therapeutic approach for inverted sinonasal papillomas and associated sinonasal carcinomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4012.

256-OR: Five-Year Simulation of Diabetes-Related Complications in Individuals Treated with Once-Weekly Tirzepatide and Semaglutide vs. Once-Daily Insulin Glargine

This study compared the 5-year risk of diabetes complications of tirzepatide (TZP) and semaglutide with insulin glargine in individuals with type 2 diabetes (T2Ds) , using the BRAVO diabetes model, which has been validated to have a high degree of accuracy. We used the BRAVO model to predict 5-year complications among users of TZP (5 mg, mg, or 15 mg) , semaglutide (1 mg) , and insulin glargine, based on short-tern efficacy data from the SURPASS-2 trial and SUSTAIN-4 trial, under two scenarios: the short-term drug efficacy lasted for 5 years (optimistic) , and the drug efficacy diminished in 5 years (conservative) . We found a 5-year risk reduction in major adverse cardiovascular events (MACE) (relative risk [RR] 63.7%, 95% CI: 61.4%-66.2%) with 15 mg TZP under an optimistic scenario, and MACE (RR 87.6%, 95% CI: 86.8%-88.6%) risk reduction with 15 mg TZP under a conservative scenario, when compared with insulin glargine (Figure) . Lower doses of TZP also had similar, albeit slightly smaller, benefits. The long-term use of TZP and semaglutide may lead to a substantial reduction in diabetes-related complications among individuals with T2Ds, compared to insulin. A high dose of TZP was also superior to semaglutide in this respect. Disclosure S.Niu: None. T.Jiao: None. Y.Guo: None. J.Bian: None. L.Shi: None. V.Fonseca: Consultant; Abbott, Asahi Kasei Corporation, Bayer AG, Novo Nordisk, Sanofi, Research Support; Fractyl Health, Inc., Jaguar Gene Therapy, Stock/Shareholder; Abbott, Amgen Inc., BRAVO4Health, Mellitus Health. H.Shao: Board Member; BRAVO4HEALTH, LLC.

Effect of hydroxychloroquine or chloroquine and short wavelength light on in vivo retinal function and structure in mouse eyes

ABSTRACT Clinical relevance The use of chloroquine or hydroxychloroquine can lead to both acute and chronic changes to both retinal structure and function. Background Chloroquine (CQ) and hydroxychloroquine (HCQ) have the potential for retina toxicity. The acute impact of short-term drug exposure (2-4 weeks) on in vivo retinal structure and function and assess whether short wavelength light exposure further exacerbates any structural and functional changes was assessed in a murine model. Methods Adult C57BL/6 J mice received intraperitoneal injection of vehicle or hydroxychloroquine (10 mg/kg) 3 times per week for 2 or 4 weeks, or chloroquine for 4 weeks (10 mg/kg). Over this period, animals were exposed to room light (8 hours) or short-wavelength light 4 hours per day (4 hours of normal room light) for 5 days each week. Retinal changes were assessed using electroretinography (ERG), in vivo optical coherence tomography (OCT) imaging. Results Short-term low-dose HCQ and CQ treatment led to RPE thickening and elongation of photoreceptors. These structural changes were associated with a no dysfunction in the case of HCQ treatments and widespread functional changes (photoreceptor sensitivity, bipolar cell amplitude and oscillatory potential amplitude) in the case of CQ treatment. Exposure to low intensity short-wavelength light does not appear to alter the effect of HCQ or CQ. Conclusions HCQ and CQ treatment has acute effects on both retinal structure and function, effects that were not exacerbated by short wavelength light exposure. Whether chronic short wavelength light exposure exacerbates these changes require further study.

Influence and interaction of resting state functional magnetic resonance and tryptophan hydroxylase-2 methylation on short-term antidepressant drug response

BackgroundMost antidepressants have been developed on the basis of the monoamine deficiency hypothesis of depression, in which neuronal serotonin (5-HT) plays a key role. 5-HT biosynthesis is regulated by the rate-limiting enzyme tryptophan hydroxylase-2 (TPH2). TPH2 methylation is correlated with antidepressant effects. Resting-state functional MRI (rs-fMRI) is applied for detecting abnormal brain functional activity in patients with different antidepressant effects. We will investigate the effect of the interaction between rs-fMRI and TPH2 DNA methylation on the early antidepressant effects.MethodsA total of 300 patients with major depressive disorder (MDD) and 100 healthy controls (HCs) were enrolled, of which 60 patients with MDD were subjected to rs-fMRI. Antidepressant responses was assessed by a 50% reduction in 17-item Hamilton Rating Scale for Depression (HAMD-17) scores at baseline and after two weeks of medication. The RESTPlus software in MATLAB was used to analyze the rs-fMRI data. The amplitude of low-frequency fluctuation (ALFF), regional homogeneity (ReHo), fractional ALFF (fALFF), and functional connectivity (FC) were used, and the above results were used as regions of interest (ROIs) to extract the average value of brain ROIs regions in the RESTPlus software. Generalized linear model analysis was performed to analyze the association between abnormal activity found in rs-fMRI and the effect of TPH2 DNA methylation on antidepressant responses.ResultsTwo hundred ninety-one patients with MDD and 100 HCs were included in the methylation statistical analysis, of which 57 patients were included in the further rs-fMRI analysis (3 patients were excluded due to excessive head movement). 57 patients were divided into the responder group (n = 36) and the non-responder group (n = 21). Rs-fMRI results showed that the ALFF of the left inferior frontal gyrus (IFG) was significantly different between the two groups. The results showed that TPH2–1–43 methylation interacted with ALFF of left IFG to affect the antidepressant responses (p = 0.041, false discovery rate (FDR) corrected p = 0.149).ConclusionsOur study demonstrated that the differences in the ALFF of left IFG between the two groups and its association with TPH2 methylation affect short-term antidepressant drug responses.

Short-Term Adverse Drug Reactions to Antiretroviral Therapy in Children with HIV: A Cohort Study.

To carry out an active surveillance for adverse drug reactions (ADRs) in children with HIV infection newly initiated on antiretroviral therapy (ART), determine risk factors for their occurrence, and assess their influence on adherence to ART. All children newly initiated on ART from 1st March 2014 to 30th June 2019 at a tertiary care children's hospital in New Delhi, were actively monitored for ADRs to ART for a period of 6 mo after ART initiation. The frequency, spectrum, and severity of ADRs, their influence on adherence, and risk factors for their occurrence were analyzed. Among the 174 enrolled children, ADRs were observed in 78 (44.8%) children during the first 6 mo after ART initiation. Total numbers of episodes of ADR observed were 108 (0.62 episodes of ADR/child). Sixty percent of events were of grade 1 severity, 19.4% events were of grade 2 and 3 each, while 1 (0.9%) event was of grade 4 severity. Adherence to ART was adversely affected in 21.8% of ADRs. Gastrointestinal symptoms (49.1%) were most frequent among all the events observed. Zidovudine, lopinavir/ritonavir, efavirenz and nevirapine based regimes were significantly associated with hematological, gastrointestinal, neurological, and dermatological ADRs, respectively. Children with immunological suppression were at a higher risk of developing ADRs as compared to those without it [RR 1.9 (95% CI (1.1-3.2)]. ADRs to ART are very frequent; most of them are mild and self-limiting. However, they can adversely impact adherence to ART. Anticipatory guidance, ongoing monitoring, and provision of symptomatic treatment will help tide over most ADRs and reduce their adverse impact upon ART adherence.

Association Between Short-Term PASI90 Achievement and Drug Survival of Biologics in Patients with Psoriasis.

BackgroundWith accumulating evidence that achieving a 90% improvement in the Psoriasis Area and Severity Index score (PASI90) has better correlation with improved health-related quality of life as compared to PASI75 achievement, there has been demand for establishing new treatment goals for psoriasis. We investigated whether the short-term PASI90 achievement would predict longer drug survival as compared to PASI75 achievement.ObjectiveWe investigated whether the short-term PASI90 achievement would predict longer drug survival as compared to PASI75 achievement.MethodsThis single-center retrospective cohort study reviewed 180 treatment series in 128 patients with plaque psoriasis, who were treated with tumor necrosis factor-alpha inhibitors (n=12), ustekinumab (n=88), secukinumab (n=23), guselkumab (n=45), and ixekizumab (n=12). The first effectiveness assessment, usually performed within 12 to 20 weeks, was considered a short-term treatment response to biologics.ResultsAfter adjustment for covariates, time-dependent Cox proportional hazards regression analysis showed that moderate responders (short-term achievement of ≥PASI75 but <PASI90) were more likely to discontinue therapy than the excellent responders (short-term achievement of PASI90; adjusted hazard ratio, 3.159; 95% confidence interval, 1.180~8.457; p=0.0220).ConclusionThe short-term PASI90 achievement is a better predictor of longer drug survival as compared to PASI75 achievement.

Antimicrobial agents in dental restorative materials: Effect on polymerization, short-term drug release and biological impact.

With the aim to design bioactive dental restorative material, the present study investigated the influence of the antimicrobial agents chlorhexidine diacetate (CHX) and octinidine (di)hydrochloride (ODH) when incorporated in two different materials. Selected parameters were polymerization enthalpy, short-term drug release, and the effect on Streptococcus mutans as well as human gingival fibroblasts. Samples were made by mixing a nano-hybrid ormocer (O) and a methacrylate-based nano-hybrid composite (C), each with a mass fraction of 2% CHX or ODH. Release profiles and concentrations of active agents from the resins were assessed, and the cell proliferation of human gingival fibroblasts as well as Streptococcus mutans cultured with the eluates were evaluated. The influence on polymerization was assessed by means of differential scanning calorimetry. Both drugs, especially ODH, showed a decreasing effect on polymerization enthalpies associated with a lowered crosslinking degree. At the same time ODH appeared to be released more persistently than CHX. Moreover, ODH was more efficient with regard to bacteria growth inhibition but also more cytotoxic in terms of reduction of cell viability. ODH is deemed more appropriate for application in a dental resin-based drug delivery system, because of the more persistent drug release than seen for CHX.

Microneedle-mediated therapy for cardiovascular diseases

Cardiovascular diseases remain a leading cause of global disease burden. To date, the limited drug delivery efficacy confines the therapeutic effect in most conventional approaches, such as intramyocardial injections and vascular devices, due to short-term drug release and low retention within the disease sites. As a typical transdermal medical device with a minimally invasive manner and controlled/sustained drug release pattern, microneedles have gained momentum in the field of cardiovascular therapy, from which several cardiovascular diseases have been benefited to the ultimate therapeutic effects. In this concise review, strategies based on the microneedles for the treatments of cardiovascular diseases are introduced, mainly focus on hypertension, atherosclerosis, thrombus, and myocardial diseases. The limitations at the present stage and perspectives of the next-generation microneedles for cardiovascular therapy are also discussed.

PHARMACOVIGILANCE IN THE ERA OF COVID-19: A CONCISE REVIEW OF THE CURRENT SCENARIO, IMPLICATIONS, AND CHALLENGES

The pandemic of Coronavirus Disease 2019 (COVID-19) has now affected the entire globe which was first surfaced in China in December 2019. In absence of effective therapy to manage COVID-19, repurposed therapies were being used to manage the condition. In view of an urgent need for definitive therapy, multiple repurposed drugs, and investigational drug candidates are being tried in clinical trials which may lead to the emergence of unknown short term and long term adverse drug reactions (ADRs), and hence it is crucial to assess the safety of the tried therapeutic interventions. The lag in the pharmacovigilance activities in the midst of this pandemic fosters under-reporting of ADRs. Difficulty in causality assessment due to factors like wide variations in clinical presentation, concomitant use of multiple drugs, associated comorbidities, drug-drug and drug-disease interaction which forestalls the appropriate causality assessment. Hydroxychloroquine, a repurposed antimalarial drug has been a part of hue and cry at present because of its in-question safety in patients with cardiac disorders. National and International Drug monitoring centers have stressed upon reporting of ADRs and to boost up the process and come up with various recommendations. We can overcome these issues by working cohesively, motivating HCPs and patients to report ADRs electronically, and by setting up dedicated pharmacovigilance rapid response team to tackle the issues at the earliest.

A novel drug response score more accurately predicts renoprotective drug effects than existing renal risk scores.

Background:Risk factor-based equations are used to predict risk of kidney disease progression in patients with type 2 diabetes order to guide treatment decisions. It is, however, unknown whether these models can also be used to predict the effects of drugs on clinical outcomes.Methods:The previously developed Parameter Response Efficacy (PRE) score, which integrates multiple short-term drug effects, was first compared with the existing risk scores, Kidney Failure Risk Equation (KFRE) and The Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) renal risk score, in its performance to predict end-stage renal disease (ESRD; KFRE) and doubling of serum creatinine or ESRD (ADVANCE). Second, changes in the risk scores were compared after 6 months’ treatment to predict the long-term effects of losartan on these renal outcomes in patients with type 2 diabetes and chronic kidney disease.Results:The KFRE, ADVANCE and PRE scores showed similarly good performance in predicting renal risk. However, for prediction of the effect of losartan, the KFRE risk score predicted a relative risk change in the occurrence of ESRD of 3.1% [95% confidence interval (CI) −5 to 12], whereas the observed risk change was −28.8% (95% CI −42.0 to −11.5). For the composite endpoint of doubling of serum creatinine or ESRD, the ADVANCE score predicted a risk change of −12.4% (95% CI −17 to −7), which underestimated the observed risk change −21.8% (95% CI −34 to −6). The PRE score predicted renal risk changes that were close to the observed risk changes with losartan treatment [−24.0% (95% CI −30 to −17) and −22.6% (95% CI −23 to −16) for ESRD and the composite renal outcome, respectively].Conclusion:A drug response score such as the PRE score may assist in improving clinical decision making and implement precision medicine strategies.

Journal Digest: Sertraline &amp; Depression; Cognitive Therapy &amp; Pregnancy; Clozaphine &amp; Schizofrenia; Despair &amp; Negative outcome; LGBTQ Teens &amp; Bullying; Exposure Therapy &amp; Drug Craving

Journal Digest: Sertraline &amp; Depression; Cognitive Therapy &amp; Pregnancy; Clozaphine &amp; Schizofrenia; Despair &amp; Negative outcome; LGBTQ Teens &amp; Bullying; Exposure Therapy &amp; Drug Craving

IBCL-386: Rituximab-Vemurafenib Combination for the Treatment of Relapsed/Refractory Hairy Cell Leukemia

Objective: The management of R/R-HCL is not standardized yet. Patients with HCL universally harbor BRAF mutations, which makes BRAF inhibitors a potential treatment approach. The efficacy and safety of the BRAF inhibitor Vemurafenib were evaluated both as a single-agent option in two phase 2 trials and also combined with Rituximab in another phase 2 trial. Patients: We have decided to present the first two consecutive patients who achieved a rapid and prolonged response, relapsing after treatment with purine analogues. The first two patients who received a combination of R-V for R/R HCL from the records of our institutional CLPD registry were reported. Interventions: Rituximab was given intravenously for a total of four injections every two weeks starting simultaneously with Vemurafenib, which was initially started with a total daily dose of 960 and decreased after 2 months up to a minimum of 240 mg/day. Main outcome measures: The efficacy of the combination treatment of R-V was assessed according to the count recovery in first 2 months and bone marrow findings at the end of 6th month. Results: The first patient was a 56-year-old male who had experienced three relapses, all treated with purine analogues. The second patient was a 33-year-old male who had a refractory disorder after administration of Cladribine. Both patients have achieved a complete count recovery in the first two months and were free of the disease regarding the bone marrow findings achieved at the end of the sixth month. Rituximab and Vemurafenib were all tolerated well with no documented infectious complications. The only dose-limiting complication reported was grade 2 maculo-papular skin rash, which could be managed with a short-term drug holiday and re-institution of Vemurafenib with a reduced dose of 240 mg per event. Conclusions: According to our experience, Rituximab and Vemurafenib combination offers a safe and possibly cost-effective therapeutic option with easily managed treatment emergent adverse events.

Research progress on repositioning drugs and specific therapeutic drugs for SARS-CoV-2.

SARS-CoV-2 has been widely spread around the world and COVID-19 was declared a global pandemic by the World Health Organization. Limited clinically effective antiviral drugs are available now. The development of anti-SARS-CoV-2 drugs has become an urgent work worldwide. At present, potential therapeutic targets and drugs for SARS-CoV-2 are continuously reported, and many repositioning drugs are undergoing extensive clinical research, including remdesivir and chloroquine. On the other hand, structures of many important viral target proteins and host target proteins, including that of RdRp and Mpro were constantly reported, which greatly promoted structure-based drug design. This paper summarizes the current research progress and challenges in the development of anti-SARS-CoV-2 drugs, and proposes novel short-term and long-term drug research strategies.

Cancer cells undergoing epigenetic transition show short-term resistance and are transformed into cells with medium-term resistance by drug treatment

To elucidate the epigenetic mechanisms of drug resistance, epigenetically reprogrammed H460 cancer cells (R-H460) were established by the transient introduction of reprogramming factors. Then, the R-H460 cells were induced to differentiate by the withdrawal of stem cell media for various durations, which resulted in differentiated R-H460 cells (dR-H460). Notably, dR-H460 cells differentiated for 13 days (13dR-H460 cells) formed a significantly greater number of colonies showing drug resistance to both cisplatin and paclitaxel, whereas the dR-H460 cells differentiated for 40 days (40dR-H460 cells) lost drug resistance; this suggests that 13dR-cancer cells present short-term resistance (less than a month). Similarly, increased drug resistance to both cisplatin and paclitaxel was observed in another R-cancer cell model prepared from N87 cells. The resistant phenotype of the cisplatin-resistant (CR) colonies obtained through cisplatin treatment was maintained for 2–3 months after drug treatment, suggesting that drug treatment transforms cells with short-term resistance into cells with medium-term resistance. In single-cell analyses, heterogeneity was not found to increase in 13dR-H460 cells, suggesting that cancer cells with short-term resistance, rather than heterogeneous cells, may confer epigenetically driven drug resistance in our reprogrammed cancer model. The epigenetically driven short-term and medium-term drug resistance mechanisms could provide new cancer-fighting strategies involving the control of cancer cells during epigenetic transition.

Multidrug-resistant HIV viral rebound during early syphilis: a case report

BackgroundSyphilis has been associated with an increase in HIV RNA and a temporary decline in CD4 T cell counts in people living with HIV who are not receiving antiretroviral treatment (ART), and may be associated with a transient HIV RNA rebound in those who are receiving ART. Our case is the first to highlight the risk of a multidrug-resistant HIV viral rebound during the course of early syphilis even if antiretroviral drug concentrations are within the therapeutic range.Case presentationThis 50-year-old HIV-1-positive male patient with concomitant early syphilis presented with an HIV RNA rebound (8908 copies/mL) during a scheduled visit to our clinic. He was receiving a stable ART regimen consisting of darunavir/cobicistat plus dolutegravir, and had a 15-year history of viral suppression. Good short-term drug adherence could be inferred as liquid chromatography tandem mass spectrometry showed that his trough antiretroviral drug concentrations were within the therapeutic range: darunavir 2353 ng/mL (minimum effective concentration > 500 ng/mL) and dolutegravir 986 ng/mL (minimum effective concentration > 100 ng/mL). A plasma RNA genotype resistance test revealed wild-type virus in the integrase region and protease region (PR), but extensive resistance in the reverse transcriptase (RT) region (M41L, E44D, D67N, K70R, M184V, L210W and T215Y). Phylogenetic analysis of next-generation sequences (used to investigate the presence of minor viral variants), the PR and RT sequences from plasma HIV RNA and pro-viral DNA extracted from peripheral blood mononuclear cells during the viral rebound, and a Sanger sequence obtained during a previous virological failure suggested clonal viral expression because the previous PR resistance mutations had been lost or had not been archived in pro-viral DNA.ConclusionsThis case shows that early syphilis may cause an HIV RNA rebound in patients under stable virological control with the potential of transmitting an extensively drug-resistant virus.

Use of Biomarker Modulation in Normal Mammary Epithelium as a Correlate for Efficacy of Chemopreventive Agents Against Chemically Induced Cancers.

In both estrogen receptor/progesterone receptor-positive (ER+/PR+) human breast cancer and in ER+/PR+ cancers in the methylnitrosourea (MNU)-induced rat model, short-term modulation of proliferation in early cancers predicts preventive/therapeutic efficacy. We determined the effects of known effective/ineffective chemopreventive agents on proliferative index (PI) in both rat mammary epithelium and small cancers. Female Sprague-Dawley rats were treated with MNU at 50 days of age. Five days later, the rats were treated with the individual compounds for a period of 14 days. At that time, normal mammary tissue from the inguinal gland area was surgically removed. After removal, the rats remained on the agents for an additional 5 months. This cancer prevention study confirmed our prior results of striking efficacy with tamoxifen, vorozole, Targretin, and gefitinib, and no efficacy with metformin, naproxen, and Lipitor. Employing a separate group of rats, the effects of short-term (7 days) drug exposure on small palpable cancers were examined. The PI in both small mammary cancers and in normal epithelium from control rats was >12%. In agreement with the cancer multiplicity data, tamoxifen, vorozole, gefitinib, and Targretin all strongly inhibited proliferation (>65%; P < 0.025) in the normal mammary epithelium. The ineffective agents metformin, naproxen, and Lipitor minimally affected PI. In the small cancers, tamoxifen, vorozole, and Targretin all reduced the PI, while metformin and Lipitor failed to do so. Thus, short-term changes in the PI in either normal mammary epithelium or small cancers correlated with long-term preventive efficacy in the MNU-induced rat model.

Phenotype-based probabilistic analysis of heterogeneous responses to cancer drugs and their combination efficacy

Cell-to-cell variability generates subpopulations of drug-tolerant cells that diminish the efficacy of cancer drugs. Efficacious combination therapies are thus needed to block drug-tolerant cells via minimizing the impact of heterogeneity. Probabilistic models such as Bliss independence have been developed to evaluate drug interactions and their combination efficacy based on probabilities of specific actions mediated by drugs individually and in combination. In practice, however, these models are often applied to conventional dose-response curves in which a normalized parameter with a value between zero and one, generally referred to as fraction of cells affected (fa), is used to evaluate the efficacy of drugs and their combined interactions. We use basic probability theory, computer simulations, time-lapse live cell microscopy, and single-cell analysis to show that fa metrics may bias our assessment of drug efficacy and combination effectiveness. This bias may be corrected when dynamic probabilities of drug-induced phenotypic events, i.e. induction of cell death and inhibition of division, at a single-cell level are used as metrics to assess drug efficacy. Probabilistic phenotype metrics offer the following three benefits. First, in contrast to the commonly used fa metrics, they directly represent probabilities of drug action in a cell population. Therefore, they deconvolve differential degrees of drug effect on tumor cell killing versus inhibition of cell division, which may not be correlated for many drugs. Second, they increase the sensitivity of short-term drug response assays to cell-to-cell heterogeneities and the presence of drug-tolerant subpopulations. Third, their probabilistic nature allows them to be used directly in unbiased evaluation of synergistic efficacy in drug combinations using probabilistic models such as Bliss independence. Altogether, we envision that probabilistic analysis of single-cell phenotypes complements currently available assays via improving our understanding of heterogeneity in drug response, thereby facilitating the discovery of more efficacious combination therapies to block drug-tolerant cells.

Peri-procedural management, implantation feasibility, and short-term outcomes in patients undergoing implantation of leadless pacemakers: European Snapshot Survey.

The aim of this European Heart Rhythm Association (EHRA) prospective snapshot survey is to assess procedural settings, safety measures, and short-term outcomes associated with implantation of leadless pacemakers (LLPM), across a broad range of tertiary European electrophysiology centres. An internet-based electronic questionnaire (30 questions) concerning implantation settings, peri-procedural routines, complications, and in-hospital patient outcomes was circulated to centres routinely implanting both LLPMs and transvenous pacemakers (TV-PM). The centres were requested to prospectively include consecutive patients implanted with either LLPMs or TV-PMs during the 10-week enrolment period. Overall, 21 centres from four countries enrolled 825 consecutive patients between November 2018 and January 2019, including 69 (9%) implanted with LLPMs. Leadless pacemakers were implanted mainly under local anaesthesia (69%), by an electrophysiologist (60%), in the electrophysiology laboratory (71%); 95% of patients received prophylactic antibiotics prior to implantation. Most patients on chronic oral anticoagulation were operated on-drug (35%), or during short-term (to 48 h) drug withdrawal (54%). Implantation was successful in 98% of patients and the only in-hospital procedure-related complication was groyne haematoma in one patient. This EHRA snapshot survey provides important insights into LLPM implantation routines and patient outcomes. These findings suggest that despite the unfavourable clinical profile of pacemaker recipients, LLPM implantation is associated with relatively low risk of complications and good short-term outcomes.

Contribution of Immune-Mediated Paraneoplastic Syndromes to Neurological Manifestations of Neuroendocrine Tumours: A Retrospective Study

Introduction: Neurological symptoms associated with neuroendocrine tumours (NETs) may be related to metastatic disease or paraneoplastic syndromes (PNSs); these last are often associated with autoantibodies targeting various onconeural antigens. To better characterize neurological PNSs related to NETs, we report the largest case-series study to date. Methods: We retrospectively reviewed the charts of all patients diagnosed with NETs of the gastrointestinal tract who presented with neurological symptoms at either of 2 tertiary academic hospitals (Henri Mondor and Beaujon, France) between 1994 and 2016. All patients underwent extensive neurological tests including clinical, laboratory, and radiological investigations. The clinical response to immunomodulating agents was recorded. Results: In the 13 identified patients, the most common presentations were peripheral neuropathy (46.2%) and encephalopathy (26.6%). Of the 6 (53.3%) patients whose serum anti-neuronal antibodies were assayed, 5 had high titres. Short-term oral corticosteroid and immunosuppressant drug therapy was given to 4 of these patients, of whom 3 had a clinical response and 1 no response. Repeated high-dose intravenous immunoglobulin therapy induced a complete clinical response in 1 patient. Encephalopathy resolved fully after hepatectomy or intrahepatic chemoembolization for liver metastases in another 2 patients. Discussion: The neurological symptoms associated with NETs may be due in part to autoimmune PNS. Based on experience at our 2 centres, we estimate that autoimmune PNS occurs in about 1% of patients with NETs. Early symptom recognition allows the initiation of effective treatments including corticosteroids, immunosuppressive drugs, and/or intravenous immunoglobulins.

Short and long-term efficacy of adalimumab in ulcerative colitis: a real-life study

Objective: Randomized controlled trials have shown the effectiveness of Adalimumab in ulcerative colitis. However, real-life data is scarce. We aimed to assess the effectiveness and predictive factors of effectiveness in a large Swedish cohort.Methods: Retrospective capture of data from local registries at five Swedish IBD centers. Clinical response and remission rates were assessed at three months after starting adalimumab treatment and patients were followed until colectomy or need for another biological. Bio-naive patients were compared to bio experienced patients. Factors associated with short term responses were assessed using logistic regression model. Failure on drug was assessed using a Cox proportional hazards regression model.Results: 118 patients (59 males, 59 females) with median age 34.4 years (IQR 27.0–51.4) were included. Median disease duration was 4.3 years (IQR 2.0–9.0) and follow-up 1.27 years (IQR 0.33–4.1). A clinical corticosteroid-free remission was achieved by 38/118 (32.2%) and response by 91/118 (77%) after three months. CRP >3 mg/l at baseline was predictive of short-term failure to reach corticosteroid-free remission. Factors associated with survival on the drug were male gender, CRP <3 mg/l and absence of primary sclerosing cholangitis. Patients >42 years of age at diagnosis were more likely to respond to adalimumab and remain on treatment compared to patients <20 years.Conclusions: An elevated CRP-level, primary sclerosing cholangitis and female gender were predictors of treatment failure. In contrast older age at diagnosis was a predictor of short-term clinical response and drug survival. Prior infliximab failure, regardless of cause, did not influence the outcome of adalimumab treatment.