Escalation In Patients Research Articles

Management of children with fever and neutropenia: results of a survey in 51 pediatric cancer centers in Germany, Austria, and Switzerland

PurposeInvestigation of the current practice of diagnostics and treatment in pediatric cancer patients with febrile neutropenia.MethodsOn behalf of the German Society for Pediatric Oncology and Hematology and the German Society for Pediatric Infectious Diseases, an Internet-based survey was conducted in 2016 concerning the management of febrile neutropenia in pediatric oncology centers (POC). This survey accompanied the release of the corresponding German guideline to document current practice before its implementation in clinical practice.ResultsIn total, 51 POCs participated (response rate 73%; 43 from Germany, and 4 each from Austria and Switzerland). Identified targets for antimicrobial stewardship concerned blood culture diagnostics, documentation of the time to antibiotics, the use of empirical combination therapy, drug monitoring of aminoglycosides, the time to escalation in patients with persisting fever, minimal duration of IV treatment, sequential oral treatment in patients with persisting neutropenia, indication for and choice of empirical antifungal treatment, and the local availability of a pediatric infectious diseases consultation service.ConclusionThis survey provides useful information for local antibiotic stewardship teams to improve the current practice referring to the corresponding national and international guidelines.

More than a number; the limitations of the Clinical Frailty Scale for patient escalation decision making in COVID-19

More than a number; the limitations of the Clinical Frailty Scale for patient escalation decision making in COVID-19

Chlorella sorokiniana Extract Prevents Cisplatin-Induced Myelotoxicity In Vitro and In Vivo.

Cisplatin chemotherapy causes myelosuppression and often limits treatment duration and dose escalation in patients. Novel approaches to circumvent or lessen myelotoxicity may improve clinical outcome and quality of life in these patients. Chlorella sorokiniana (CS) is a freshwater unicellular green alga and exhibits encouraging efficacy in immunomodulation and anticancer in preclinical studies. However, the efficacy of CS on chemoprotection remains unclear. We report here, for the first time, that CS extract (CSE) could protect normal myeloid cells and PBMCs from cisplatin toxicity. Also, cisplatin-induced apoptosis in HL-60 cells was rescued through reservation of mitochondrial function, inhibition of cytochrome c release to cytosol, and suppression of caspase and PARP activation. Intriguingly, cotreatment of CSE attenuated cisplatin-evoked hypocellularity of bone marrow in mice. Furthermore, we observed the enhancement of CSF-GM activity in bone marrow and spleen in mice administered CSE and cisplatin, along with increased CD11b levels in spleen. In conclusion, we uncovered a novel mechanism of CSE on myeloprotection, whereby potentially supports the use of CSE as a chemoprotector against cisplatin-induced bone marrow toxicity. Further clinical investigation of CSE in combination with cisplatin is warranted.

P081 AN EVALUATION OF VEDOLIZUMAB “PARTIAL RESPONDERS”: QUANTIFYING BENEFIT OF SHORTENED DOSING INTEVALS IN ULCERATIVE COLITIS

Abstract Introduction Six years ago, the Gemini pharma trial reported no significant difference in response rate between Ulcerative Colitis (UC) patients randomized to q8week vedolizumab dosing vs q4weeks.1 In Gemini, patients were randomized based on response after 6 week induction, but post-hoc analysis and real world data report an average response time of 19 weeks.2 Patients in Gemini may have been dose escalated too early, which minimized potential difference between groups. Previous studies indicate dose intensification benefits patients who initially achieved remission on standard dosing but lost response.3 To our knowledge, the benefit of dose escalation in patients who achieve partial response to standard dosing has not been investigated. Methods In this single institution retrospective review, 90 patients with UC who completed vedolizumab induction between 1/2017-1/2019 were included for analysis. Collected variables included subject demographics, disease severity, location, and duration, prior anti-TNF use, corticosteroid dependence, fecal calprotectin, CRP, albumin, and hemoglobin. Primary outcomes collected were time to response (decrease in partial mayo score by ≥2), and time to remission (partial mayo score <2) for patients on standard vs escalated dosing. Results 52/90 (57.8%) patients achieved and maintained remission on q8weeks. 30/90 (33.3%) had a partial response to q8week dosing, 3/90 patients achieved remission on q8week dosing but relapsed, and 5/90 had no response. 22/33 (66.7%) patients with either partial q8week response (19 patients) or relapse after remission on q8week (3 patients) were dose escalated. Of the 19 “partial responders” who were dose escalated, 8 (42.1%) achieved remission, 8 (42.1%) achieved partial response, and 2 had no response (10.5%). Of the “partial responders” who were not dose escalated, none achieved remission. Average time to remission with standard dosing was 42.3 weeks. Average time to dose escalation in partial responders was 54 weeks. The average time to remission after dose escalation was 27.7 weeks. There were no identifiable clinical predictors of poor response, including: BMI >24.9 (p=0.22) or >30 (p=0.44), prior anti-TNF use (p= 0.53), disease location (p=0.61), or disease duration (± 5 years, p=0.85). Conclusion Our results suggest escalation to q4week is a viable treatment option for UC patients who partially respond to vedolizumab at standard dosing. This is supported not only by the high ratio of escalated patients achieving remission, but also the lack of remission in the 11 “partial responders” not dose escalated. We were not able to identify any clinical predictors that may impact response to vedolizumab prior to induction dosing, but is likely of less importance given the predictability of early trough levels. We feel that our study supports dose escalation in patients with partial response, and this knowledge can be used to bolster confidence in early dose escalation as vedolizumab trough levels move into routine practice.

P081 AN EVALUATION OF VEDOLIZUMAB “PARTIAL RESPONDERS”: QUANTIFYING BENEFIT OF SHORTENED DOSING INTEVALS IN ULCERATIVE COLITIS

Six years ago, the Gemini pharma trial reported no significant difference in response rate between Ulcerative Colitis (UC) patients randomized to q8week vedolizumab dosing vs q4weeks.1 In Gemini, patients were randomized based on response after 6 week induction, but post-hoc analysis and real world data report an average response time of 19 weeks.2 Patients in Gemini may have been dose escalated too early, which minimized potential difference between groups. Previous studies indicate dose intensification benefits patients who initially achieved remission on standard dosing but lost response.3 To our knowledge, the benefit of dose escalation in patients who achieve partial response to standard dosing has not been investigated.

P632 Vedolizumab dose escalation in patients with inflammatory bowel disease experiencing loss of response: A systematic review and meta-analysis of real-world evidence

Abstract Background Moderately to severely active inflammatory bowel disease (IBD), featured as Crohn’s disease (CD) and ulcerative colitis (UC) collectively, is commonly treated with biologic therapies. A proportion of patients experience loss of response (LOR) over time. The approved dose of vedolizumab (VDZ), 300 mg every 8-week (Q8W), is known to be safe and effective in the treatment of UC and CD. In an open-label long-term safety study (GEMINI LTS), patients who experienced LOR during maintenance benefitted from dose escalation to an every 4-week (Q4W) regimen. Clinical response and remission were regained in 41% and 28% respectively in UC patients (N=32) and 47% and 32% respectively in CD patients (N=57) through 52 weeks of escalated dosing. The aim of this study was to conduct a meta-analysis of existing real-world evidences to evaluate the effectiveness of VDZ dose escalation to Q4W in IBD patients experiencing LOR to Q8W dosing. Methods A systematic literature review was performed using PubMed and Embase databases for articles and conference abstracts from January 2014 through January 2019 for real-world studies reporting clinical outcomes to VDZ dose-escalation among adult patients with UC or CD. Relevant congresses were also screened for accepted abstracts through June 2019. Summary estimates for the proportion of regained response and remission were synthesised under a random effect model (given considerable heterogeneity as measured by I2 statistic) using the DerSimonian-Laird approach. Results The search yielded a total of 842 citations from the databases and 12 citations from hand searching. Of these, 5 full-text articles and 1 abstract were included in the meta-analysis. The 6 study cohorts included a total of 297 patients with IBD. The random-effects pooled regained response rate from the 6 studies was 56.5% (95% confidence interval [CI], 44.9%–67.5%) within 52 weeks (figure). Subgroup analysis showed a regained response rate of 62.7% (95% CI,52.8%–71.6%) when measured within 30 weeks vs. 50.2% (95% CI, 38.3%–62.2%) when measured after 30 weeks. Of the 6 studies, 2 reported remission rates that were included in the pooled analysis among 203 patients experiencing LOR. The random-effects pooled estimate of recaptured remission was 42.4% (95% CI, 25.1%–61.8%) within 52 weeks. Conclusion More than half of IBD patients who experienced LOR during maintenance phase after initial response to VDZ Q8W dosing regained response on the escalated Q4W regimen within 52 weeks. These findings and the data from the open-label clinical trial support the benefits of VDZ dose escalation among patients experiencing LOR to Q8W dosing.

DOP73 Efficacy and safety of escalation to tofacitinib 10 mg BID for patients with UC following loss of response on 5 mg BID maintenance therapy: Results from OCTAVE open-label, long-term extension study

Abstract Background Tofacitinib is an oral, small-molecule JAK inhibitor for the treatment of ulcerative colitis (UC). The efficacy and safety of tofacitinib have been demonstrated in patients with moderate to severe UC in three Phase 3 studies (OCTAVE Induction 1 and 2 [NCT01465763; NCT01458951]; OCTAVE Sustain [NCT01458574]) [1]. Here, we present updated efficacy and safety data of tofacitinib dose escalation in patients with UC participating in an ongoing, open-label, long-term extension (OLE) study (OCTAVE Open, NCT01470612) [2]. Methods We present updated data from the dose-escalation subpopulation of the OLE study (as of May 2019; database not locked) comprising patients who achieved clinical response (CR) following 8 weeks of tofacitinib 10 mg twice daily (BID) induction therapy, entered OCTAVE Sustain receiving tofacitinib 5 mg BID, experienced treatment failure between Week 8 and Week 52, and subsequently entered OCTAVE Open with escalation to tofacitinib 10 mg BID. Treatment failure was defined as an increase of ≥3 points from maintenance study baseline total Mayo score, plus an increase of ≥1 point in both rectal bleeding subscore and centrally read endoscopic subscore (ES), and an absolute ES of ≥2 after ≥8 weeks of maintenance therapy. CR, mucosal healing (MH) and remission (R) were evaluated at Months 2, 12, 24 and 36 of OCTAVE Open (non-responder imputation and last observation carried forward [NRI-LOCF] and observed data). Safety was evaluated throughout the study. Results Of 944 patients enrolled in the OLE study, the dose escalation subpopulation comprised 59 patients. In these patients, CR, MH and R rates 36 months after dose escalation were, respectively, 40.7%, 39.0% and 30.5% for NRI-LOCF and 95.2%, 86.4% and 66.7% for observed data (Table). Of these 59 patients, 29 had prior tumour necrosis factor inhibitor (TNFi) failure; in these patients, CR, MH and R rates at Month 36 were, respectively, 51.7%, 51.7% and 41.4% for NRI-LOCF, and 100.0%, 92,3% and 75.0% for observed data. Incidence rates for safety events and pt-years’ exposure are reported in the table. Conclusion For most patients who lost initial CR to tofacitinib 10 mg BID induction therapy while on tofacitinib 5 mg BID maintenance therapy, including those with prior TNFi failure, dose-escalation back to 10 mg BID recaptured CR by Month 2 and was generally maintained over 3 years. The safety profile with tofacitinib 10 mg BID in the dose-escalation subpopulation was generally consistent with that in the overall study population, although there was a numerically higher rate of herpes zoster. These analyses are limited by low pt numbers and the absence of a comparator arm. References

Multi-Institutional Validation of Deep Learning for Pretreatment Identification of Extranodal Extension in Head and Neck Squamous Cell Carcinoma.

Extranodal extension (ENE) is a well-established poor prognosticator and an indication for adjuvant treatment escalation in patients with head and neck squamous cell carcinoma (HNSCC). Identification of ENE on pretreatment imaging represents a diagnostic challenge that limits its clinical utility. We previously developed a deep learning algorithm that identifies ENE on pretreatment computed tomography (CT) imaging in patients with HNSCC. We sought to validate our algorithm performance for patients from a diverse set of institutions and compare its diagnostic ability to that of expert diagnosticians. We obtained preoperative, contrast-enhanced CT scans and corresponding pathology results from two external data sets of patients with HNSCC: an external institution and The Cancer Genome Atlas (TCGA) HNSCC imaging data. Lymph nodes were segmented and annotated as ENE-positive or ENE-negative on the basis of pathologic confirmation. Deep learning algorithm performance was evaluated and compared directly to two board-certified neuroradiologists. A total of 200 lymph nodes were examined in the external validation data sets. For lymph nodes from the external institution, the algorithm achieved an area under the receiver operating characteristic curve (AUC) of 0.84 (83.1% accuracy), outperforming radiologists' AUCs of 0.70 and 0.71 (P = .02 and P = .01). Similarly, for lymph nodes from the TCGA, the algorithm achieved an AUC of 0.90 (88.6% accuracy), outperforming radiologist AUCs of 0.60 and 0.82 (P < .0001 and P = .16). Radiologist diagnostic accuracy improved when receiving deep learning assistance. Deep learning successfully identified ENE on pretreatment imaging across multiple institutions, exceeding the diagnostic ability of radiologists with specialized head and neck experience. Our findings suggest that deep learning has utility in the identification of ENE in patients with HNSCC and has the potential to be integrated into clinical decision making.

Vincristine-induced peripheral neurotoxicity: A prospective cohort

Vincristine-induced peripheral neuropathy (VIPN) is a serious and pervasive problem, affecting 12–78% of pediatric patients, based on retrospective studies. The study objective was to prospectively collect a cohort of well-phenotyped patients receiving vincristine in order to accurately classify and grade their neurotoxicity. All children in British Columbia with leukemia or lymphoma requiring vincristine between 2013 and 2016 were approached for consent. Those recruited were assessed by occupational and physiotherapists at baseline, mid and endpoint of their treatment. Assessments included the Bruininks–Oseretsky Test of Motor Proficiency – 2nd ed. (BOT-2), strength, “Timed up and go” test and vibration sensibility. Seventy-two patients consented (age: 2.0–18.7 years). The majority were below average for age on one or more BOT-2 domains at midpoint (N = 32/45, 71%), which decreased by the endpoint (N = 19/41, 46%, p = .049). Six patients showed severe VIPN throughout treatment (N = 6/53, 11%), defined as a BOT-2 score well below average. Muscle strength for wrist extension/flexion, anterior tibialis and peronei decreased significantly between baseline (Median = 5) and midpoint (Median = 4), with no significant change noted by endpoint. Most patients had normal vibration sensibility in lower (N = 30/60, 50%) and upper limbs (N = 26/38, 68%). In conclusion, with no differences between time points. VIPN is highly prevalent among patients with pediatric cancer, causing significant morbidity and functional deficits. Identification of risk factors would allow for resource appropriation to patients at higher risk, as well as potentially permitting dose escalation in patients with low toxicity to improve survival.

Efficacy of certolizumab pegol dose escalation in patients who inadequately respond to initial treatment: Results from the CIMPACT trial

Efficacy of certolizumab pegol dose escalation in patients who inadequately respond to initial treatment: Results from the CIMPACT trial

Quality Assurance of Dose-Escalated Radiation Therapy in a Randomized Trial for Locally Advanced Oesophageal cancer

The ongoing phase 2/3 PRODIGE 26/CONCORDE trial compares chemoradiation therapy with and without dose escalation in patients with locally advanced or unresectable esophageal cancer. The results of a benchmark case procedure are reported here to evaluate the protocol compliance of participating centers as part of quality assurance for radiation therapy. Volume delineation, target coverage, and dose constraints to the organs at risk (OARs) were assessed on treatment plans of a common benchmark case performed by each participating center. The centers were classified in 3 categories: per protocol, minor acceptable deviation (MiD), or major unacceptable deviation (MaD). A plan was rejected if ≥4 MiDs or 1 MaD were found. Thirty-5 centers submitted 43 plans. Among them, 14 (32.6%) were per protocol, 19 (44.2%) presented at least 1 MiD, 2 (4.6%) presented at least 1 MaD, and 8 (18.6%) presented both MiD and MaD. Overall, 11 (25.6%) plans were rejected. Only 1 plan was rejected because gross tumor volume was not correctly delineated. The OAR delineation was respected in all cases. Dose constraints to the OARs were respected in the majority of cases except for the heart, where one-third of the plans presented a deviation. As for the target volume, 3 plans (5.8%) had a major underdosage and 1 plan (1.9%) had a major overdosage. Overall, 58% of all treatments were planned with intensity modulated radiation therapy, whereas 42% were planned with 3-dimensional chemoradiation therapy. Significantly more plans in the intensity modulated radiation therapy group were accepted compared with the 3-dimensional chemoradiation therapy group (P = .03). The high frequency of protocol deviations underlines the importance of a quality assurance program in clinical trials. Further work should assess the impact of quality assurance for radiation therapy on patient outcomes.

Dose escalation in radiotherapy for incomplete transarterial chemoembolization of hepatocellular carcinoma.

To investigate the efficacy of radiation dose escalation in patients with hepatocellular carcinoma (HCC) after incomplete transarterial chemoembolization (TACE). This study evaluated retrospective data of 323 HCC patients who received radiotherapy after incomplete TACE from 2001-2016. Radiation dose in biologically effective dose (BED) (α/β = 10) was categorized as <72 Gy (261 patients) and ≥72 Gy (62patients). Simultaneous integrated boost-intensity modulated radiation therapy (SIB-IMRT) was used significantly more frequently in the high-dose group (64.5% vs. 12.9%; P < 0.001). Local failure-free rate (LFFR), progression-free rate (PFR), and toxicities were compared between the two groups. Additionally, propensity score matching was performed. Median follow-up time for patients who were alive at the time of analysis was 47months (range 18-189months). Median overall survival after radiotherapy was 14months. In multivariate analysis, BED ≥72 Gy was an independent predictor of favorable LFFR (hazard ratio [HR] 0.32; 95% confidence interval [CI] 0.14-0.72; P = 0.006) and PFR (HR 0.67; 95% CI 0.45-0.98; P = 0.04). In the propensity score-matched cohort (62pairs), 1‑year LFFR (94% vs. 81%; P = 0.002), and 1‑year PFR (49% vs. 42%; P = 0.01) were significantly higher in the high-dose group. Treatment-related toxicities were comparable between the high-dose and low-dose groups (classic radiation-induced liver disease: 5.3% [3/57] vs. 13.8% [29/210], P = 0.08; grade2-4 gastrointestinal bleeding: 3.2% [2/62] vs. 7.3% [19/261], P = 0.39). Radiation dose with BED ≥72 Gy improved LFFR and PFR without increasing toxicity. In radiotherapy for incomplete TACE of HCC, dose escalation using SIB-IMRT should be actively considered to improve oncologic outcome.

Feasibility of Dose Escalation in Patients With Intracranial Pediatric Ependymoma.

Background and purpose: Pediatric ependymoma carries a dismal prognosis, mainly owing to local relapse within RT fields. The current prospective European approach is to increase the radiation dose with a sequential hypofractionated stereotactic boost. In this study, we assessed the possibility of using a simultaneous integrated boost (SIB), comparing VMAT vs. IMPT dose delivery.Material and methods: The cohort included 101 patients. The dose to planning target volume (PTV59.4) was 59.4/1.8 Gy, and the dose to SIB volume (PTV67.6) was 67.6/2.05 Gy. Gross tumor volume (GTV) was defined as the tumor bed plus residual tumor, clinical target volume (CTV59.4) was GTV + 5 mm, and PTV59.4 was CTV59.4 + 3 mm. PTV67.6 was GTV+ 3 mm. After treatment plan optimization, quality indices and doses to target volume and organs at risk (OARs) were extracted and compared with the standard radiation doses that were actually delivered (median = 59.4 Gy [50.4 59.4]).Results: In most cases, the proton treatment resulted in higher quality indices (p < 0.001). Compared with the doses that were initially delivered, mean, and maximum doses to some OARs were no higher with SIB VMAT, and significantly lower with protons (p < 0.001). In the case of posterior fossa tumor, there was a lower dose to the brainstem with protons, in terms of V59 Gy, mean, and near-maximum (D2%) doses.Conclusion: Dose escalation with intensity-modulated proton or photon SIB is feasible in some patients. This approach could be considered for children with unresectable residue or post-operative FLAIR abnormalities, particularly if they have supratentorial tumors. It should not be considered for infratentorial tumors encasing the brainstem or extending to the medulla.

PF201 THE COMBINATION OF IMGN632, A CD123-TARGETING ADC, WITH VENETOCLAX ENHANCES ANTI-LEUKEMIC ACTIVITY IN VITRO AND PROLONGS SURVIVAL IN VIVO IN PRE-CLINICAL MODELS OF HUMAN AML

Background: IMGN632 is a novel CD123-targeting antibody-drug conjugate composed of a humanized anti-CD123 antibody and a DNA-alkylating IGN payload. IMGN632 is currently in Phase I dose escalation in patients with relapsed/refractory AML or BPDCN (NCT03386513), demonstrating responses across a wide range of doses. Venetoclax, a BCL-2 inhibitor, lowers the apoptotic threshold and was recently approved for elderly AML patients in combination with azacitidine. By combining these potentially synergistic anti-leukemic mechanisms in pre-clinical AML models, the increased pro-apoptotic signaling enabled by BCL-2 inhibition would act in concert with the pro-apoptotic effects of DNA damage caused by IMGN632. Aims: The combination of IMGN632 and venetoclax was evaluated in pre-clinical AML models. Methods: The IMGN632 plus venetoclax combination was evaluated in vitro in four AML cell lines (MV4–11, MOLM-13, KG-1, EOL-1), in vivo in two subcutaneous AML xenograft models (EOL-1, KG-1), and in vivo in two AML PDX models. In subcutaneous models, tumor volume was measured, complete regressions (CRs) were noted, and endpoint was determined by either clinical observations or when tumor volume reached 1000 mm3. In PDX models, survival was measured. Results: In vitro synergy was observed in 3 of the 4 cell lines tested at doses ranging from 0.5 pM to 8 pM for IMGN632, and 0.625 nM to 20 nM for venetoclax (MV4–11, MOLM-13, EOL-1), and 1 nM to 1 μM for IMGN632, and 100 nM to 1 μM for venetoclax in the KG-1 cell line, with optimal combination indexes (CI) of 0.023 (KG-1), 0.497 (MV4–11), 0.377 (MOLM-13), and 0.67 (EOL-1), indicating strong synergy across most of the cell lines tested. In the EOL-1 model (see Figure Panel A), the combination [IMGN632 (80 μg/kg, one intravenous dose) plus venetoclax (100 mg/kg, orally, daily x28)] was highly active, resulting in 4/6 CRs and a 0% T/C (percent treatment to control of the median tumor volume, at control endpoint), compared to the corresponding inactive venetoclax (1/6 CR, 69% T/C) and active IMGN632 (2/6 CRs, 11% T/C) single agents. Importantly, the four mice treated with the combination who achieved CRs remained in remission through the end of the study at >60 days. In the IMGN632-resistant KG-1 model, the combination [IMGN632 (800 μg/kg, intravenous, weekly x3) plus venetoclax (100 mg/kg, orally, daily x28)] was active (40% T/C) while corresponding single agent IMGN632 (73% T/C) and venetoclax (81% T/C) were inactive. In a venetoclax-responsive AML PDX model (NRASm, EZH2m; see Figure Panel B), the combination [low dose IMGN632 (24 μg/kg, intravenous, weekly x3) plus venetoclax (100 mg/kg, orally, daily x28)] showed 124% ILS (% increased life span), with a median survival of 148 days. This was superior to venetoclax alone (77% ILS; median survival of 117 days) and IMGN632 alone (0% ILS; median survival of 65 days). Similarly, this same combination regimen was active (40% ILS; median survival of 108 days) in a second AML PDX model (FLT3-ITD, IDH1m), while IMGN632 (10% ILS; median survival of 85 days) and venetoclax (6% ILS; median survival of 82 days) single agents were inactive.Summary/Conclusion: The combination of IMGN632 and venetoclax demonstrated synergistic cytotoxicity in vitro and greater tumor growth inhibition and prolonged survival in vivo. Collectively, these results provide support for testing the combination of IMGN632 and venetoclax in AML patients.

Safety and tolerability of donepezil 23\u2009mg with or without intermediate dose titration in patients with Alzheimer\u2019s disease taking donepezil 10\u2009mg: a multicenter, randomized, open-label, parallel-design, three-arm, prospective trial

BackgroundHigh-dose donepezil is currently prescribed for patients with Alzheimer’s disease (AD) who showed poor or waning response to a lower dose at the risk of increasing cholinergic side effects. However, the adverse events (AEs) depending on the method of dose escalation have not been clarified yet. This study aimed to find out whether dose titration before escalating to donepezil 23 mg is preferred. We investigated safety and tolerability of donepezil 23 mg during the first 12 weeks of dose escalation in patients with moderate to severe AD.MethodsThis study was a 12-week, multicenter, randomized, open-label prospective trial. We included patients with moderate to severe AD who were treated with a stable dose of donepezil 10 mg/day. Patients were randomized into 3 groups according to the dose escalation method: 15 mg of donepezil for 4 weeks before escalating to 23 mg (group 1), 10 mg and 23 mg on alternate days for 4 weeks prior to escalation (group 2), and direct escalation to 23 mg (group 3). Safety analyses included incidence, severity, timing of AEs, relationship to the study drug, and premature study discontinuation due to AEs between the groups.ResultsAmong 175 enrolled, 110 patients completed the study. Baseline characteristics were similar among the groups. Using safety population (N = 160), cholinergic gastrointestinal symptoms including anorexia and nausea were the most common AEs and titration groups showed significantly fewer cases of nausea as compared with those in no-titration group.ConclusionsIn this study, dose titration before escalating to donepezil 23 mg/day showed better safety in terms of cholinergic AEs. We suggest that dose titration during the first 4 weeks can be recommended for patients with moderate to severe AD.Trial registrationClinicaltrials.gov, NCT02550665. Retrospectively registered on 15 Sep 2015.

PD26-03 TO INVESTIGATE THE EFFECT OF VOLTAGE ESCALATION ON TREATMENT OUTCOME IN EXTRACORPOREAL SHOCKWAVE LITHOTRIPSY OF RENAL CALCULI – FINAL ANALYSIS

INTRODUCTION AND OBJECTIVES:To assess the effects of voltage escalation in patients receiving SWL for renal stones, particularly on treatment success and degree of renal injury, in term of post-SWL...

Abstract GS5-06: No survival benefit of chemotherapy escalation in patients with pCR and “high-immune” triple-negative early breast cancer in the neoadjuvant WSG-ADAPT-TN trial

Abstract Background:Immune markers such as tumor infiltrating lymphocytes (TILs), CD8, PDL1, PD1 and other protein or mRNA-based genomic markers have been identified as prognostic / predictive in TNBC regarding survival / chemotherapy (CTx) efficacy. In the adjuvant WSG-PlanB trial, patients with high TILs and/or CD8 by mRNA had excellent outcome, irrespective of anthracycline use; in the neoadjuvant ADAPT-TN trial, high PDL1, PD1 and CD8 and/or TILs were predictive for pCR. Still, optimal markers for potential treatment de-escalation have yet to be determined. Here, we analyse for the first time impact of immune mRNA-based markers and TIL's as prognostic and predictive survival markers. Methods: TNBC patients (ER/PR&amp;lt;1%, HER2-,) were randomized to neoadjuvant 4x nab-paclitaxel 125 mg/m2/gemcitabine 1000 mg/m2 d1/8 q3w (gem arm) or 4x nab-paclitaxel 125 mg/m2/carboplatin AUC2 day 1/8 3-weekly (q3w) (carbo arm). Primary endpoint of WSG-ADAPT-TN was pCR (ypT0/is/ypN0); secondary endpoints included translational analyses, e.g., TILs or expression of 119 genes by nCounter platform. Standard adjuvant chemotherapy (4xEC) was optional (not randomized) in patients achieving pCR after 12 weeks. According to protocol, 1st safety survival analysis was performed after 3y median follow-up. Results: Present translational analysis included 306 of 336 TNBC patients (36 months median FU). pCR was associated with significantly better survival (3y EFS: 92% vs. 71%, p&amp;lt;.001), but despite substantially higher pCR in the carbo arm (46% vs. 29%), no significant EFS advantage was seen (p=.6) (gem: 78%; carbo: 80%; 3y-EFS). Bivariate Spearman correlations among CD8, PD1, and PDL1 were strongly positive; their correlations with TILs were moderately positive. Preliminary Cox analysis of EFS was performed with clinical variables (cN, cT, menopausal status); neoadjuvant study arm; pCR; TILs; proliferation markers (baseline Ki67 by IHC, scores derived from PAM50); baseline immune markers; risk scores; and individual gene expression scores previously identified as prognostic for pCR in one or both neoadjuvant arms. Independent prognostic factors included pCR, cN, Ki67, PD1, and CD8; these were entered into (prognostic) interaction analysis. The resulting model contained cN, high Ki67 and low TILs as (unfavorable) main effects and the interaction of (higher) PD1*pCR (favorable). Among pCR patients, the groups with/without additional adjuvant CTX were similar with respect to explanatory factors. Baseline TILs, Ki67, cN, and PD1 were entered into exploratory predictive analysis; the model retained only the interaction [adjuvant CTx * (fractionally ranked) PD1]. In patients with pCR, those with low PD1 benefited from standard anthracycline-containing adjuvant CTx, whereas patients high PD1 did not with an 98% 3y-EFS. Conclusions: Our exploratory results suggest independent prognostic impact of mRNA markers and TIL's in early TNBC. Patients with both pCR (after 12 weeks) and “high-immune” signature (defined here by PD1) had excellent 3y-EFS and may be candidates for treatment de-escalation (e.g. omission of anthracyclines), whereas “low-immune” pCR patients may benefit from standard adjuvant poly-chemotherapy. Citation Format: Gluz O, Nitz U, Liedtke C, Prat A, Christgen M, Feuerhake F, Garke M, Grischke E-M, Forstbauer H, Braun M, Warm M, Hackmann J, Uleer C, Aktas B, Schumacher C, Kuemmel S, Pelz E, Gebauer D, Paré L, Kates R, Wuerstlein R, Kreipe HH, Harbeck N. No survival benefit of chemotherapy escalation in patients with pCR and “high-immune” triple-negative early breast cancer in the neoadjuvant WSG-ADAPT-TN trial [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr GS5-06.

Facilitating Resolution of Life-Threatening Acute Graft-Versus-Host Disease By Supplementation of Human Chorionic Gonadotropin and Epidermal Growth Factor (Pregnyl®): A Phase I Study

Introduction Severe acute graft-versus-host disease (aGVHD) is characterized by an imbalance of circulating tissue repair factors, with elevated amphiregulin (AREG) and very low ( Patients and Methods Twenty-six patients received hCG/EGF in addition to standard aGVHD therapy (13 with Minnesota high risk aGVHD and 13 receiving 2nd line therapy). In both cohorts, patients with a complete or partial response (CR/PR) at the end of the initial dosing period were eligible to receive maintenance hCG/EGF SQ twice weekly for up to 5 weeks. Initial hCG dosing was at 500 units hCG/m2 SQ, escalating to 2,000 units hCG/m2 in cohorts of 2, with dose assignment by the continual reassessment method. We analyzed GVHD-associated plasma biomarkers during therapy. Results HCG/EGF was well tolerated, with no dose-limiting toxicities. At day 28 of study, responses for initial therapy were 8/13 CR (62%), 0/13 PR (0%), and 5/13 NR (38%), higher than institutional historical (n=269) 26% CR, 16% PR, 57% NR (Figure 1A). Responses for 2nd line therapy were 7/13 CR (54%), 1/13 PR (8%), 5/13 NR (38%), 4 of which were deaths (31%), improved relative to historical outcomes (n=85) of 18% CR, 19% PR, 63% NR (including 16% deaths, Figure 1A). In initial therapy patients, plasma EGF rose from baseline 3 pg/ml to 25.4 pg/ml at 6 hours post-hCG/EGF dose (p=0.02), while in 2nd line patients, plasma EGF never rose from baseline 5 pg/ml. Patients with a day 28 CR/PR had a 4.6-fold reduction in plasma AREG over time (Figure 1B). Conclusions HCG/EGF is a novel adjunct therapy in life-threatening aGVHD. The mechanisms of benefit may include facilitation of tissue repair with detectable increases in circulating EGF. The optimal dose and duration of hCG/EGF are under investigation, with ongoing dose escalation in patients with steroid-refractory aGVHD based upon these results. Decreasing plasma AREG may reflect successful treatment of severe aGVHD.

The efficacy and safety of sunitinib given on an individualised schedule as first-line therapy for metastatic renal cell carcinoma: A phase 2 clinical trial

BackgroundSunitinib is administered on a rigid schedule that may not be optimal for all patients. We hypothesised that toxicity-driven dose and schedule changes would optimise drug exposure and outcome for each patient. Materials and methodsIn a phase 2 trial, 117 patients with metastatic clear cell renal cell cancer were started on sunitinib 50 mg/day with the aim to treat for 28 days. Treatment breaks were reduced to 7 days. Sunitinib dose and the number of days on therapy were individualised based on toxicity aiming for ≤ grade II toxicity with dose escalation in patients with minimal toxicity. The null hypothesis for the primary end-point was a progression-free survival (PFS) of 8.5 months based on a study with similar eligibility criteria. ResultsThe null hypothesis was rejected (p < 0.001) with a median PFS of 12.5 months (95% confidence interval [CI]: 9.6–16.5). The median overall survival was 38.5 months (95% CI: 28.3-not reached). The objective response rate (46.1%) and stable disease rate (38.5%) translated into a clinical benefit for 84.6% of patients with no decline in quality of life scores during therapy. Fewer patients were dose reduced (26.5% vs. 50%) or discontinued due to toxicity (7.7 vs. 18–20%) compared to standard sunitinib dosing, and 20 (18.4%) patients were dose escalated to 62.5 mg (12) and 75 mg (8) with a wide individual variation in the optimal dose and treatment duration. Conclusions: Individualised sunitinib therapy is feasible, safe and an effective method to manage toxicity with one of the best efficacy seen for oral vascular endothelial growth factor inhibitors in metastatic renal cell carcinoma. Clinicaltrials.gov identifierNCT01499121.

Assessment of diabetic retinopathy using two ultra-wide-field fundus imaging systems, the Clarus\xae and Optos\u2122 systems

BackgroundThe ability to image wide fundus fields and to conduct swift, non-invasive examinations is increasingly important with the escalation in patients with diabetic retinopathy (DR).MethodsFifty eyes of 28 consecutive patients with DR were examined in this prospective observational study. A total of 46 eyes, 25 right and 21 left eyes, of 27 patients (male, 19; female, 8) were ultimately included in the analysis. All patients underwent comprehensive ophthalmological examination. A single image each was obtained using two ultra-wide-field (UWF) imaging systems: Optos® (Optos Carfornia®, Optos PLC, Dunfermline, United Kingdom) and Clarus™ (CLARUS 500™, Carl Zeiss Meditec Inc., Californea, USA), without mydriasis. The total retinal area captured and the obscured retinal area were compared between the two systems using nonparametric Wilcoxon matched-pairs signed-rank analysis. Early Treatment of Diabetic Retinopathy Study (ETDRS) and International Clinical DR severity were analyzed by κ statistics.ResultsThe Optos® allowed capture of larger areas of the fundus than the Clarus™ (465 ± 117 vs. 243 ± 39 disc areas, P < 0.0001). In 85% (39/46) of Optos® images and 7% (3/46) of Clarus™ images, a slightly obscured area was observed within the ETDRS-7 field area. κ values for ETDRS DR severity and International Clinical DR severity between the Optos® and Clarus™ images were 0.88 and 0.79, respectively. Severity was higher according to Clarus™ images in two eyes in which the ETDRS DR severity grading differed between the systems. Severity was higher in four Clarus™ images and in a single Optos® image in five eyes in which the International Clinical DR severity grading differed between the systems.ConclusionThe Optos® and Clarus™ UWF retinal imaging systems were useful for examining eyes with DR, using single images obtained without mydriasis. The systems were both generally consistent in assessing DR severity, with some partial discrepancies. It is important to understand the characteristics of each respective UWF retinal imaging system when using them to assess DR.