PINNACLE Study Research Articles

Deep Learning–Based Clustering of OCT Images for Biomarker Discovery in Age-Related Macular Degeneration (PINNACLE Study Report 4)

PurposeWe introduce a deep-learning-based biomarker proposal system for the purpose of accelerating biomarker discovery in age-related macular degeneration (AMD). DesignRetrospective analysis of a large dataset of retinal optical coherence tomography (OCT) images. ParticipantsA total of 3,456 adults aged between 51 and 102 years of whom OCT images were collected under the PINNACLE project. MethodsOur system proposes candidates for novel AMD imaging biomarkers in OCT. It works by first training a neural network using self-supervised contrastive learning to discover, without any clinical annotations, features relating to both known and unknown AMD biomarkers present in 46,496 retinal OCT images. To interpret the learned biomarkers, we partition the images into 30 subsets, termed clusters, that contain similar features. We conduct two parallel 1.5-hour semi-structured interviews with two independent teams of retinal specialists to assign descriptions in clinical language to each cluster. Descriptions of clusters achieving consensus can potentially inform new biomarker candidates. Main Outcome MeasuresWe checked if each cluster showed clear features comprehensible to retinal specialists, if they related to AMD and how many described established biomarkers used in grading systems as opposed to recently proposed or potentially new biomarkers. We also compared their prognostic value for late stage wet and dry AMD against an established clinical grading system and a demographic baseline model. ResultsOverall, both teams independently identified clearly distinct characteristics in 27 of 30 clusters, of which 23 were related to AMD. Seven were recognised as known biomarkers used in established grading systems and 16 depicted biomarker combinations or subtypes that are either not yet used in grading systems, were only recently proposed, or were unknown. Clusters separated incomplete from complete retinal atrophy, intraretinal from subretinal fluid and thick from thin choroids, and in simulation outperformed clinically-used grading systems in prognostic value. ConclusionsUsing self-supervised deep learning we were able to automatically propose AMD biomarkers going beyond the set used in clinically established grading systems. Without any clinical annotations, contrastive learning discovered subtle differences between fine-grained biomarkers. Ultimately, we envision that equipping clinicians with discovery-oriented deep-learning tools can accelerate discovery of novel prognostic biomarkers.

Two-year long-term follow-up of treatment with the Optilume BPH catheter system in a randomized controlled trial for benign prostatic hyperplasia (The PINNACLE Study)

BackgroundPatient outcomes were assessed 2 years after treatment with the Optilume BPH Catheter System, a minimally invasive surgical therapy for the treatment of lower urinary tract symptoms (LUTS) due to benign prostatic hyperplasia (BPH).MethodsOne-hundred forty-eight adult males with symptomatic BPH were enrolled and randomized in a 2:1 fashion to Optilume BPH or Sham (100 Optilume BPH; 48 Sham). Long-term measures include International Prostate Symptom Score (IPSS), peak urinary flow rate (Qmax), Post-Void Residual Urine (PVR), quality of life measures and sexual function. Follow-up beyond one year was limited to those treated with Optilume BPH.ResultsAt 2 years, 67.5% (56/83 CI 56.3%, 77.4%) of participants in the Optilume BPH arm were symptomatic responders as defined by ≥30% improvement in IPSS without medical or surgical retreatment. IPSS significantly improved from 23.4 ± 5.5 (n = 100) to 11.0 ± 7.0 (n = 74). Qmax improved by 116.8.% (8.9 ± 2.2 (n = 97) to 19.0 ± 16.3 (n = 65)), while PVR showed a slight reduction (83.7 ± 70.3 (n = 99) to 65.9 ± 74.5 (n = 65)). Improvement in uroflowmetry measures was consistent across all prostate volumes. BPH-II improved from 7.0 ± 2.9 (n = 98) to 2.3 ± 2.5 at 1 year (n = 89) and remained consistent at 2.3 ± 2.9 at the 2-years (n = 74), representing a 53.9% improvement. IPSS QoL also improved from 4.6 ± 1.3 (n = 100) at baseline to 2.2 ± 1.5 (n = 74). The most common adverse events reported in the Optilume BPH arm were hematuria and urinary tract infection (UTI). No device and/or treatment related serious adverse events were reported occurring beyond 12 months post-procedure. There was no impact to sexual function.ConclusionsIn the PINNACLE study, participants treated with the Optilume BPH Catheter System demonstrated continued and durable results at 2 years, affirming tolerability, safety, and the enduring effectiveness. The Optilume BPH Catheter System provides lasting results that are comparable to the more invasive therapies, while preserving the advantages with being a minimally invasive therapy.RegistrationClinicalTrials.gov NCT04131907.

Automated deep learning-based AMD detection and staging in real-world OCT datasets (PINNACLE study report 5)

Real-world retinal optical coherence tomography (OCT) scans are available in abundance in primary and secondary eye care centres. They contain a wealth of information to be analyzed in retrospective studies. The associated electronic health records alone are often not enough to generate a high-quality dataset for clinical, statistical, and machine learning analysis. We have developed a deep learning-based age-related macular degeneration (AMD) stage classifier, to efficiently identify the first onset of early/intermediate (iAMD), atrophic (GA), and neovascular (nAMD) stage of AMD in retrospective data. We trained a two-stage convolutional neural network to classify macula-centered 3D volumes from Topcon OCT images into 4 classes: Normal, iAMD, GA and nAMD. In the first stage, a 2D ResNet50 is trained to identify the disease categories on the individual OCT B-scans while in the second stage, four smaller models (ResNets) use the concatenated B-scan-wise output from the first stage to classify the entire OCT volume. Classification uncertainty estimates are generated with Monte-Carlo dropout at inference time. The model was trained on a real-world OCT dataset, 3765 scans of 1849 eyes, and extensively evaluated, where it reached an average ROC-AUC of 0.94 in a real-world test set.

Abstract 14451: Switching From Warfarin to Direct Oral Anticoagulants (DOACs) in Medicine Clinic at a Safety Net Hospital in New York City: A Quality Improvement Project

Introduction: Many patients are still using warfarin for thromboembolic prevention, even though Direct-Acting Oral Anticoagulants (DOACs) have replaced it in most indications to decrease the need for frequent dose adjustments and minimize drug interactions. Methods: This study is a clinic patient-based observational quality improvement project to review warfarin use in adult patients following at the anticoagulation clinic at Metropolitan Hospital. Electronic medical records were screened, and TTR was calculated over 3 months. STATA was used for statistical analysis, including Histograms, Skewness-Kurtosis tests for normality, student-T tests for continuous variables, and χ2 tests for categorical variables. The P-value of less than 0.05 was considered statically significant. Results: A total of 45 patients were included; the mean age was 61, of whom 23 (51.1%) were males. The comorbidities observed were hypertension (HTN), diabetes mellitus (DM), chronic obstructive pulmonary disease (COPD), and obesity. The time in therapeutic range (TTR) was less than 65% in 22 patients (48.9%). Warfarin was indicated in 28 patients (62.2%) and not indicated in 17 patients (37.8%), out of which 6 patients (36.3%) agreed to switch to direct oral anticoagulants (DOACs) (Figure 1). Conclusions: Our project revealed a significant number of patients are still using warfarin despite being suitable for DOACs. 60% prefer warfarin due to perceived safety with frequent clinic visits. Socioeconomic status affects the transition. The PINNACLE Study identified practice and provider variations, Practices with high-volume clinics, more electrophysiologists, and those located in the western region are more likely to switch to DOACs. Based on our findings, we recommend the following: - Physicians should engage in shared decision-making with patients on warfarin use. - Physicians may need to discuss the available DOACs options with insurance companies due to coverage limitations.

MP76-02 AT 4 YEARS, OPTILUME BPH HAS THE HIGHEST SUSTAINED IMPROVEMENT IN PEAK FLOW (QMAX) OF ANY MINIMALLY INVASIVE BPH THERAPY

You have accessJournal of UrologyCME1 Apr 2023MP76-02 AT 4 YEARS, OPTILUME BPH HAS THE HIGHEST SUSTAINED IMPROVEMENT IN PEAK FLOW (QMAX) OF ANY MINIMALLY INVASIVE BPH THERAPY Steven Kaplan, Merycarla Pichardo, Edwin Rijo, Ramon Rodriguez Lay, Gustavo Espino, and Rafael Estrella Steven KaplanSteven Kaplan More articles by this author , Merycarla PichardoMerycarla Pichardo More articles by this author , Edwin RijoEdwin Rijo More articles by this author , Ramon Rodriguez LayRamon Rodriguez Lay More articles by this author , Gustavo EspinoGustavo Espino More articles by this author , and Rafael EstrellaRafael Estrella More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003350.02AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: The EVEREST-I study is a prospective, single arm, multicenter study evaluating functional improvement in urine flow and improvement in lower urinary tract symptoms (LUTS) after treatment with the Optilume BPH System, a novel minimally-invasive treatment for Benign Prostatic Hyperplasia (BPH). Optilume BPH utilizes mechanical dilation of the prostatic urethra to achieve an anterior commissurotomy while delivering the drug paclitaxel to maintain long-term urethral patency. METHODS: A total of 80 subjects were enrolled at 6 centers. Follow up is ongoing, with 32 of 72 expected subjects with 4-year follow-up complete. Symptom improvement was measured utilizing the International Prostate Symptom Score (IPSS) and BPH Impact Index (BPH-II), functional improvement measured by peak urinary flow rate (Qmax) and post-void residual volume (PVR). RESULTS: Mean Qmax showed an immediate increase from 10.9 mL/sec at baseline to 18.8 mL/sec at 14 days, which was sustained at 18.1 mL/sec through 4 years post treatment (p<0.001 vs baseline). A paired analysis of those subjects completing the 4-year visit showed a steady Qmax compared to 3-year outcomes (18.1 vs 18.8, p=0.54). IPSS and BPH-II showed significant, immediate improvement from baseline with this improvement maintained through the 4-year follow-up (Table 1). Erectile and ejaculatory function scores were not significantly changed from baseline through 4 years. CONCLUSIONS: The Optilume BPH Catheter System combines mechanical and pharmaceutical aspects for the treatment of BPH, resulting in both an immediate functional improvement by way of creating an anterior commissurotomy and a sustained anatomic result due to the application of paclitaxel to the prostatic urethra during the initial dilation. The functional and symptomatic improvements seen after treatment with Optilume BPH have been sustained through 4 years in this early feasibility study. The sustained improvement in Qmax is superior to any minimally invasive BPH device currently approved. Results from the EVEREST study will be further verified in the ongoing randomized, sham controlled PINNACLE study. Source of Funding: This study was funded by Urotronic, Inc © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e1090 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Steven Kaplan More articles by this author Merycarla Pichardo More articles by this author Edwin Rijo More articles by this author Ramon Rodriguez Lay More articles by this author Gustavo Espino More articles by this author Rafael Estrella More articles by this author Expand All Advertisement PDF downloadLoading ...

Developing and validating a multivariable prediction model which predicts progression of intermediate to late age-related macular degeneration—the PINNACLE trial protocol

AimsAge-related macular degeneration (AMD) is characterised by a progressive loss of central vision. Intermediate AMD is a risk factor for progression to advanced stages categorised as geographic atrophy (GA) and neovascular AMD. However, rates of progression to advanced stages vary between individuals. Recent advances in imaging and computing technologies have enabled deep phenotyping of intermediate AMD. The aim of this project is to utilise machine learning (ML) and advanced statistical modelling as an innovative approach to discover novel features and accurately quantify markers of pathological retinal ageing that can individualise progression to advanced AMD.MethodsThe PINNACLE study consists of both retrospective and prospective parts. In the retrospective part, more than 400,000 optical coherent tomography (OCT) images collected from four University Teaching Hospitals and the UK Biobank Population Study are being pooled, centrally stored and pre-processed. With this large dataset featuring eyes with AMD at various stages and healthy controls, we aim to identify imaging biomarkers for disease progression for intermediate AMD via supervised and unsupervised ML. The prospective study part will firstly characterise the progression of intermediate AMD in patients followed between one and three years; secondly, it will validate the utility of biomarkers identified in the retrospective cohort as predictors of progression towards late AMD. Patients aged 55–90 years old with intermediate AMD in at least one eye will be recruited across multiple sites in UK, Austria and Switzerland for visual function tests, multimodal retinal imaging and genotyping. Imaging will be repeated every four months to identify early focal signs of deterioration on spectral-domain optical coherence tomography (OCT) by human graders. A focal event triggers more frequent follow-up with visual function and imaging tests. The primary outcome is the sensitivity and specificity of the OCT imaging biomarkers. Secondary outcomes include sensitivity and specificity of novel multimodal imaging characteristics at predicting disease progression, ROC curves, time from development of imaging change to development of these endpoints, structure-function correlations, structure-genotype correlation and predictive risk models.ConclusionsThis is one of the first studies in intermediate AMD to combine both ML, retrospective and prospective AMD patient data with the goal of identifying biomarkers of progression and to report the natural history of progression of intermediate AMD with multimodal retinal imaging.

The double bronchodilation era: new capabilities in a new drug delivery device

A literature review presents the efficacy and safety of the new glycopyrronium bromide/formoterol fumarate (GP/FF) combination in the treatment of patients with chronic obstructive pulmonary disease according to the PINNACLE 1, 2, 3, 4 studies. There are 4 fixed LAMA/LABA combinations which used in world practice, as well as in Russia: vilanterol + umeclidinium bromide, glycopyrronium bromide + indacaterol, olodaterol + tiotropium bromide and aclidinium bromide + formoterol. The GP/FF combination also approved in Russia, is currently present in Global Initiative for Chronic Obstructive Lung Disease (GOLD). A new method of co-suspension delivery via the Aerosphere inhaler has been developed for this combination. The efficacy and safety in GP/FF MDI compared to its monocomponents and tiotropium bromide were assessed in phase III clinical trials PINNACLE 1, 2, 3, 4. The GP/FF combination showed an improvement in the morning and after 2 hours parameters of FEV1 compared to monocomponents and placebo. Data from PINNACLE studies showed an improvement in the quality of life associated with a decrease in compared with the baseline level of the overall score on the scale of the St. George’s Hospital Respiratory Questionnaire (SGRQ) in 24 weeks against those taking GP/FF in contrast to monocomponents and placebo. The use of GP/FF showed a significant reduction in theuse of salbutamol compared with placebo. A pooled analysis of PINNACLE 1, 2, 4 demonstrated that GP/FF improved lung functionand reduced the risk of COPD exacerbations compared with monocomponents and placebo. According to the results of the analysis, there was also no increase in the number of the most frequently recorded side effects.

Nilotinib in Combination with Pegylated Interferon Alfa-2b for CP-CML Leads to High Molecular Response Rates: Interim Results of the Pinnacle Study

Nilotinib in Combination with Pegylated Interferon Alfa-2b for CP-CML Leads to High Molecular Response Rates: Interim Results of the Pinnacle Study

Benefits of glycopyrrolate/formoterol fumarate metered dose inhaler (GFF MDI) in improving lung function and reducing exacerbations in patients with moderate-to-very severe COPD: a pooled analysis of the PINNACLE studies

BackgroundThe Phase III PINNACLE studies assessed the efficacy and safety of glycopyrrolate/formoterol fumarate metered dose inhaler (GFF MDI), a dual long-acting bronchodilator for chronic obstructive pulmonary disease (COPD). Here we present a pre-specified pooled analysis of PINNACLE-1, PINNACLE-2, and PINNACLE-4.MethodsPINNACLE-1, -2, and -4 were multicenter, double-blind, randomized controlled trials that enrolled patients with moderate-to-very severe COPD, with no requirement for exacerbation history or a high symptom burden. Patients received GFF MDI 18/9.6 μg, glycopyrrolate (GP) MDI 18 μg, formoterol fumarate (FF) MDI 9.6 μg, or placebo MDI, twice-daily for 24 weeks. The primary endpoint of the pooled analysis was the change from baseline in morning pre-dose trough forced expiratory volume in 1 s (FEV1) at week 24. Secondary endpoints included COPD exacerbations and clinically important deterioration (CID). Adverse events were also assessed.ResultsThe pooled intent-to-treat population included 4983 patients; of these, 61.9% had a COPD assessment test (CAT) score ≥15, and 25.0% had experienced ≥1 moderate/severe exacerbation in the past year. At week 24, GFF MDI improved morning pre-dose trough FEV1 versus GP MDI (least squares mean [LSM] difference [95% confidence interval (CI)]: 59 mL [43, 75]), FF MDI (65 mL [48, 81]), and placebo MDI (146 mL [125, 166]); all p < 0.0001. GFF MDI reduced the risk of a moderate/severe exacerbation by 18% (p = 0.0168), 15% (p = 0.0628), and 28% (p = 0.0012) compared with GP MDI, FF MDI, and placebo MDI, respectively. In general, exacerbation risk reduction with GFF MDI versus comparators was greater in subgroups of symptomatic patients (CAT ≥15) and those who had an exacerbation history, than in the pooled intent-to-treat population. The risk of CID was also lower with GFF MDI versus GP MDI (23% decrease), FF MDI (17%), and placebo MDI (49%); all p < 0.0001. All treatments were well tolerated, with no unexpected safety signals.ConclusionsThis pooled analysis of the PINNACLE studies demonstrated that GFF MDI improved lung function and reduced the risk of exacerbations compared with monocomponents and placebo in patients with COPD. Exacerbation reductions with GFF MDI versus comparators were generally greater in patients with higher symptom burden and those with exacerbation history.Trial registrationClinicalTrials.gov NCT01854645, NCT01854658, and NCT02343458. Registered 13 May 2013 (NCT01854645, NCT01854658) and 6 January 2015 (NCT02343458).

Glycopyrrolate/formoterol fumarate metered dose inhaler for maintenance-na\xefve patients with chronic obstructive pulmonary disease: a post-hoc analysis of the randomized PINNACLE trials

BackgroundGlycopyrrolate (GP)/formoterol fumarate (FF; GFF) metered dose inhaler is a fixed-dose combination dual bronchodilator for patients with chronic obstructive pulmonary disease (COPD); however, whether the efficacy in patients without current maintenance treatment is consistent with currently maintenance-treated patients is unclear.MethodsData from patients who were not maintenance-treated at screening (NMT) (n = 1943) and patients who were maintenance-treated at screening (MT) patients (n = 3040) receiving GFF, FF, GP, or placebo were pooled from the Phase III PINNACLE studies (NCT01854645, NCT01854658, NCT02343458) for post-hoc analysis. MT patients had received long-acting bronchodilators and/or inhaled corticosteroids in the 30 days prior to screening, and/or prior to randomization. NMT patients had received short-acting bronchodilators or no treatment. Outcomes included forced expiratory volume over 1 s (FEV1), clinically important deterioration (CID), rescue medication use, and safety.ResultsGFF provided significant lung function improvements at Week 24 versus placebo, GP, and FF for NMT patients, with pre-dose trough FEV1 treatment differences of 152 (117–188) mL, 73 (45–100) mL, and 56 (29–84) mL, respectively (least squares mean change from baseline versus comparators [95% CI]; all P < 0.0001). GFF reduced the risk of CID by 17–43% in NMT (P ≤ 0.0157) and 18–52% (P ≤ 0.0012) in MT patients compared with monotherapy and placebo, and reduced rescue medication use by 1.5 puffs/day over 24 weeks for both cohorts. Safety profiles for all cohorts were consistent with each other and the parent studies.ConclusionsNMT patients achieved better lung function with GFF versus monotherapy and placebo, without increased safety risk. Dual bronchodilator therapy may offer better outcomes than monotherapy for COPD patients when administered as first-line treatment.

Glycopyrrolate/Formoterol Fumarate Metered Dose Inhaler Improves Lung Function versus Monotherapies in GOLD Category A Patients with COPD: Pooled Data from the Phase III PINNACLE Studies.

BackgroundThe Global Initiative for Chronic Obstructive Lung Disease (GOLD) recommends a short-acting bronchodilator or single long-acting bronchodilator as an initial pharmacological treatment for GOLD category A patients with COPD. We pooled data from the PINNACLE-1, -2, and -4 studies to evaluate the efficacy and safety of the dual bronchodilator fixed-dose combination glycopyrrolate/formoterol fumarate metered dose inhaler (GFF MDI), formulated using co-suspension delivery technology, in GOLD category A patients with moderate-to-very severe COPD.Materials and MethodsPINNACLE-1, -2, and -4 were Phase III, randomized, double-blind, parallel-group, multicenter studies (NCT01854645, NCT01854658, and NCT02343458). Patients received 24 weeks’ treatment with GFF MDI 18/9.6 µg, glycopyrrolate (GP) MDI 18 µg, formoterol fumarate (FF) MDI 9.6 µg, or placebo MDI twice daily. GOLD category A patients were identified based on a COPD Assessment Test score of <10 and exacerbation history in the previous year (none/one not requiring hospitalization). Endpoints evaluated were change from baseline in morning pre-dose trough forced expiratory volume in 1 second (FEV1), peak change from baseline in FEV1 within 2 hrs post-dose, and adverse events (AEs).ResultsThe pooled intent-to-treat population comprised 729 GOLD category A patients. GFF MDI significantly improved morning pre-dose trough FEV1 at Week 24 versus GP MDI, FF MDI, and placebo MDI (least squares mean [LSM] differences 54 mL, 62 mL, and 188 mL, respectively; all p≤0.0053), and peak FEV1 at Week 24 versus GP MDI, FF MDI, and placebo MDI (LSM differences 124 mL, 104 mL, and 307 mL, respectively; all p<0.0001). Improvements over 24 weeks were comparable to at Week 24. The AE profile of GFF MDI in GOLD category A patients was similar to monocomponents and placebo MDI.ConclusionGFF MDI significantly improved lung function versus monocomponents and placebo MDI in GOLD category A patients with moderate-to-very severe COPD, with no unexpected safety findings.

Combination of Nilotinib and Pegylated Interferon Alfa-2B Results in High Rates of MR4.5 at 24 Months - Primary Analysis of the ALLG CML 11 Pinnacle Study

Combination of Nilotinib and Pegylated Interferon Alfa-2B Results in High Rates of MR4.5 at 24 Months - Primary Analysis of the ALLG CML 11 Pinnacle Study

Combination of Nilotinib and Pegylated Interferon Alfa-2b Results in High Molecular Response Rates in Chronic Phase CML: Interim Results of the ALLG CML 11 Pinnacle Study

Combination of Nilotinib and Pegylated Interferon Alfa-2b Results in High Molecular Response Rates in Chronic Phase CML: Interim Results of the ALLG CML 11 Pinnacle Study

Quality and Safety in Health Care, Part XXXVI: Anticoagulation Therapy, Atrial Fibrillation, and Fellow Training PINNACLE Studies.

There have been numerous publications in the scientific literature based on data from the PINNACLE Registry. The current article includes PINNACLE studies on cardiology outpatients regarding anticoagulation therapy, the relationship between weight loss and atrial fibrillation, and the usefulness of the registry information for training cardiac fellows.

Epidemiology and characteristics of febrile neutropenia in oncology patients from Spanish tertiary care hospitals: PINNACLE study.

Febrile neutropenia (FN) is one of the most common adverse events associated with myelosuppressive chemotherapy for cancer treatment. The objective of this study was to describe the incidence of hospitalization due to FN in Spanish tertiary care hospitals (PINNACLE study). This epidemiological, retrospective, multicenter, nationwide study involved 119 patients from oncology units of 10 Spanish tertiary care hospitals who were admitted for FN. The primary endpoint was to assess the epidemiology and characteristics of FN. The incidence of admissions due to FN in oncology patients was 2.0% (interquartile range [IQR], 1.6-3.0). In terms of fever and absolute neutrophil count (ANC), 37.0% of the patients had a temperature of ≥38.2°C and an ANC of ≤500/m3. The number of patients who received prophylactic treatment with granulocyte colony-stimulating factor (G-CSF) was significantly higher in the palliative group (32.6%) compared with that in the non-palliative group (13.5%). The hospital length of stay was significantly shorter in patients who received prophylactic G-CSF compared with those who did not (5.0 days; IQR, 4.0-9.0 vs. 7.0 days; IQR, 5.0-11.0, respectively). The hospital length of stay was also significantly shorter in patients receiving palliative treatment (5.0 days; IQR, 3.0-7.0) compared with those receiving non-palliative therapy (7.0 days; IQR, 5.0-12.0). In conclusion, the incidence of admissions due to FN in oncology patients was 2.0% and the duration of hospital stay was 7.0 days. Prophylactic G-CSF treatment was found to be associated with better outcomes and shorter hospital stays. Therefore, the use of this treatment becomes relevant for achieving better clinical outcomes and reducing hospitalization cost in the management of FN.

Subcutaneous (SQ) Bortezomib (BTZ) in Patients (Pts) with Relapsed Mantle Cell Lymphoma (MCL): Retrospective, Observational Study of Treatment Patterns and Outcomes in US Community Oncology Practices

Subcutaneous (SQ) Bortezomib (BTZ) in Patients (Pts) with Relapsed Mantle Cell Lymphoma (MCL): Retrospective, Observational Study of Treatment Patterns and Outcomes in US Community Oncology Practices

Phase 1B Trial of Anti-Notch 2/3 Antibody Omp-59R5 in Combination with Etoposide and Cisplatin (Ep) in Patients (Pts) with Untreated Extensive-Stage Small-Cell Lung Cancer (Ed-Sclc): the Pinnacle Study

ABSTRACT Aim: The Notch pathway plays a central role in embryonic development, the regulation of stem and progenitor cells, and is implicated centrally in many human cancers, including SCLC. OMP-59R5, a fully human IgG2 antibody, inhibits signaling of Notch2 and 3 receptors. Anti-tumor activity was noted in 7 of 9 pt-derived SCLC xenografts expressing Notch 2 and 3 with OMP-59R5 treatment. The maximum tolerated dose (MTD) of single agent OMP-59R5 was 7.5mg/kg IV every 3 weeks (Smith, EORTC 2012); the main dose-limiting toxicity (DLT) was Grade 3 diarrhea. This study is to determine the MTD, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary efficacy of OMP-59R5 in combination with EP in ED-SCLC. Methods: Cohorts of 3 to 6 pts were treated at each dose level of OMP-59R5. OMP-59R5 was given IV on Day 1 of each 21 day cycle along with etoposide 100 mg/m2 on Days 1, 2, and 3 and cisplatin 80 mg/m2 on Day 1. After 6 cycles, pts continued OMP-59R5 alone every 21 days in the absence of disease progression or unacceptable toxicities. Results: By April 4, 2014, 11 pts were treated. One DLT of Grade 3 nausea was reported from a subject in the 10 mg/kg dose cohort that lasted more than 48 hours despite daily IV fluids and antiemetics. Frequently reported (≥30%) adverse events (all grades) regardless of relationship were: fatigue (81.8%), nausea (72.7%), anemia (63.6%), diarrhea (63.6%), decreased appetite (54.5%), weight loss (54.4%), hypomagnesemia (45.5%), peripheral edema (45.5%), dehydration (36.4%), neutropenia (36.4%), thrombocytopenia (36.4%), vomiting (36.4%) and elevated creatinine (36.4%). Of these, fatigue (54.5%), anemia (36.4%), diarrhea (36.4%) and nausea (36.4%) were considered related to OMP-59R5. The events were mostly Grade 1 or 2, and managed with supportive care. Additional data are below: OMP-59R5 Dose (mg/kg) 5 (n=3) 7.5 (n=3) 10 (n=5) Etoposide (mg/m2) 100 Cisplatin (mg/m2) 80 DLT evaluable 3 3 5 incidence - - 1 RECIST 1.1 evaluable 3 3 4 Best Response/ Partial Response 3 2 4 Stable Disease - 1 - Progressive Disease - - - pts still on treatment - 2 4 Conclusions: OMP-59R5 with EP is well tolerated. The MTD has not been reached. Encouraging anti-tumor activity is observed. Updated safety, PK/PD, and efficacy data will be presented. The Phase 2 part of PINNACLE will start in 2014. Disclosure: A. Kapoun: Employed by OncoMed Pharmaceuticals (Sponsor), receive salary and stocks; L. Xu: Employed by OncoMed Pharmaceuticals (Sponsor), receive salary and stocks; D. Hill: Employed by OncoMed Pharmaceuticals (Sponsor), receive salary and stocks; L. Zhou: Paid consultant for OncoMed Pharmaceuticals (sponsor); J. Dupont: Employed by OncoMed Pharmaceuticals (Sponsor), receive salary and stocks. All other authors have declared no conflicts of interest.

Retrospective analysis of treatment patterns and outcomes with subcutaneous (SQ) bortezomib (BTZ) in patients (pts) with relapsed mantle cell lymphoma (MCL).

8554 Background: Intravenous (IV) BTZ was approved in the US for the treatment of relapsed MCL in 2006 based on the phase 2 PINNACLE study (Fisher, JCO 2006). In 2012, SQ BTZ was approved based on ...

Potential biomarkers of bortezomib activity in mantle cell lymphoma from the phase 2 PINNACLE trial

Immunohistochemical analyses of archival tumor specimens were used for pre-planned exploratory analyses of protocol-specified candidate biomarkers of bortezomib activity in 73 patients with relapsed/refractory mantle cell lymphoma in the phase 2 PINNACLE study. Consistent with other studies, elevated Ki-67 was a marker of poor prognosis, demonstrating significant associations with shorter time to progression and overall survival. Elevated NF-κB p65 and low PSMA5 expression demonstrated a trend for better response and were significantly associated with longer time to progression; elevated NF-κB p65 demonstrated a trend toward longer overall survival. This is consistent with myeloma clinical genomics research, suggesting biomarker relevance across tumor types. Elevated p27 was significantly associated with longer overall survival. Overall survival analyses by International Prognostic Index and Mantle Cell Lymphoma International Prognostic Index confirmed differential prognosis by both scores. These biomarkers data begin to illuminate bortezomib's mechanism of action in lymphoma.

Is Left Ventricular Hypertrophy Regression Important? Does the Tool Used to Detect It Matter?

Left ventricular hypertrophy (LVH) has been demonstrated to define an adverse cardiovascular prognosis. However, due to poor noninvasive tools in which to accurately define LVH, the clinical manifestations dictate an inexact manner in which to either initiate therapy or to gauge the success of LVH regression. Herein, the authors define the current state of imaging modalities available to interrogate LVH and its regression, but concentrating chiefly on the "gold standard" of cardiovascular magnetic resonance imaging (CMR). The authors review the data demonstrating the importance of LVH regression. Additionally, they highlight the strengths and weaknesses of CMR via several pinnacle studies that demonstrate the ease, efficiency, and accuracy of this new noninvasive reproducible and available tool to relatively inexpensively delineate LVH. Finally, upon pharmacologic administration of an antihypertensive regimen, the authors, for the first time, define a goal of left ventricular mass reduction (in grams) for echocardiography and CMR based in part on Framingham data aiming at improving cardiovascular risk.