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Concept: Escalation


PurposeTo analyze the incidence and clinical course of patients developing progressive ocular inflammation following anti-tubercular therapy (ATT) for presumed ocular tuberculosis (TB).MethodsRetrospective analysis of medical records of patients who received ATT for presumed ocular TB and completed at least 12 months follow-up after initiation of ATT. The diagnosis of presumed ocular TB was based on presence of ocular signs suggestive of TB, evidence of past tubercular infection, and exclusion of mimicking clinical entities. All patients received a combination of ATT and corticosteroid therapy. Primary outcome measure was progression (worsening) of ocular inflammation, defined as a two-step increase in level of inflammation (anterior chamber/ vitreous) or the appearance of new lesions following initiation of ATT.ResultsA total of 106 patients (64 male, 42 female) received ATT for presumed ocular TB. Twenty-six (24.5%) patients developed progressive intraocular inflammation following ATT. Primary diagnoses in these patients were: anterior uveitis (n=1), intermediate uveitis (n=9), retinal vasculitis (n=3), serpiginous-like choroiditis (n=7), multifocal choroiditis (n=2), and pan-uveitis (n=4). Following progressive inflammation, diagnosis was revised in two patients (7.7%)-both responded to alternative therapy. Of the rest, majority (n=16; 61.5%) resolved with escalation of corticosteroid therapy. Five patients (19.2%)-all having intermediate uveitis-required therapeutic vitrectomy for resolution. Three patients (11.5%) had persistent inflammation at end of follow-up period.ConclusionProgressive inflammation following ATT for presumed ocular TB is common. It generally resolves on escalation of corticosteroid therapy. Cases not responding to increased immunosuppression need to be re-investigated to rule out a nontubercular cause.Eye advance online publication, 1 March 2013; doi:10.1038/eye.2013.5.

Concepts: Corticosteroid, Retina, Progressive lens, Escalation, Sarcoidosis, Uveitis, Vasculitis, Ophthalmology


Abstract Objective Evaluate efficacy of infliximab with response-driven dosing in patients with active RA. Research design and methods: Patients (n=203) with active RA despite methotrexate+etanercept/adalimumab, participated in this active-infliximab-switch study. Infliximab 3mg/kg was infused at Weeks0, 2, 6, 14 and 22 with escalation to 5 or 7mg/kg depending on EULAR response at Week14 and 22. The primary endpoint was EULAR response at Week10. Safety was assessed through Week30. Infliximab levels and antibodies to infliximab (ATI) were measured at Weeks 0, 6, 14 and 26. Clinical trial registration: NCT 00714493, EudraCT 2007-003288-36 Results: Of 197 evaluable patients, 120/77 previously received etanercept/adalimumab. Baseline mean(SD) swollen and tender joint counts: 17.3(10.54) and 30.2(16.89), respectively; mean DAS28-ESR: 6.19(0.981). At Week10, 98 (49.7%; 95% CI: 42.6%, 56.9%) patients achieved EULAR response, with a significantly improved DAS28-ESR (mean[SD] change -1.1[1.15]; p<0.001). EULAR response was achieved by 41.7/62.3% of patients previously receiving etanercept/adalimumab (p=0.006). At Week26, 51.8% (95%CI: 44.6%, 58.9%) of patients achieved or maintained EULAR response. Infliximab dose was escalated in 100 patients, 52% achieved EULAR response at Week26. Median serum concentration levels at Week26 showed that dose escalation helped EULAR non-responders achieve levels similar to or higher than the levels seen in responders. ATI were associated with lower serum concentrations of infliximab, consistent with lower efficacy rates among ATI-positive patients. Conclusion: Infliximab, in treat-to-target settings with individual dose escalation, demonstrated significant efficacy at Weeks10 and 26 in patients switched to infliximab after inadequate response to etanercept/adalimumab. The observed efficacy indicated that the switch to infliximab and ability to increase dose in a targeted fashion were beneficial.

Concepts: Escalation, Ankylosing spondylitis, Psoriatic arthritis, Infliximab, Rheumatology, Etanercept, Adalimumab, Rheumatoid arthritis


We analyzed the results of previously treated patients with metastatic colorectal cancer (mCRC) who received regorafenib plus FOLFIRI with the irinotecan dose escalation on the basis of uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) genotyping. Thirteen patients with previously treated mCRC were subjected to UGT1A1 genotyping between October 2013 and June 2015 and were administered regorafenib plus FOLFIRI with irinotecan dose escalation. Patients with UGT1A1*1/*1 and *1/*28 genotypes were administered 180 mg/m2 of irinotecan, whereas those with the UGT1A1*28/*28 genotype were administered 120 mg/m2 of irinotecan. For all patients, the irinotecan dose was increased by 30 mg/m2 every two cycles until grade ≥3 adverse events or severe adverse events developed, following which the dose was reverted to and maintained at the previously tolerated level. The oral regorafenib dose was adjusted to 120 mg/day daily. The median follow-up period was 10.0 months (1.0-21.0 months). The disease control rate was 69.2%, whereas the median progression-free survival and overall survival were 9.5 and 13.0 months, respectively. Our findings indicate that regorafenib plus FOLFIRI with irinotecan dose escalation based on UGT1A1 genotyping in previously treated patients with mCRC and with UGT1A1*1/*1 and UGT1A1*1/*28 genotypes is clinically effective and yields improved oncological outcomes.

Concepts: Escalation, Genotype, Chemotherapy, Oncology, FOLFIRI, Genetics, Cancer, Colorectal cancer


Performing a therapeutic switch in MS is still a matter of debate. Objective of our study is to compare switching to another first-line therapy with switching to a second-line therapy in persons with relapsing-remitting multiple sclerosis (pwRRMS). A retrospective analysis of data prospectively collected was performed. PwRRMS experiencing on-treatment disease activity were included. No clinical relapse, no sustained disability progression by the Expanded Disability Status Scale (EDSS), and no radiological activity (new T2 and/or gadolinium-enhanced brain lesions) were used as indicators of no disease activity (NEDA 3). Time to reach the first relapse after switch and time to reach an EDSS of 4.0 were also evaluated. Ninety-one pwRRMS were enrolled. Forty-eight (52.7 %) were on lateral switch, and 43 (47.3 %) on escalation switch. At baseline, the two groups differed for T2 and T1 brain lesions number (higher in the escalation group, p < 0.005). The proportion of pwRRMS who were NEDA 3 after 24 months from the switch was similar in the two groups (20.8 % in lateral group and 18.6 % in escalation group). No difference in timing to reach the first relapse after switch and an EDSS of 4.0 were found. Therefore, in selected pwRRMS, lateral and escalation strategies showed similar efficacy in delaying MS progression.

Concepts: Retrospective, Therapy, Escalation, Expanded Disability Status Scale, Magnetic resonance imaging, Medicine, Multiple sclerosis


The article ‘Help in raising concerns about child abuse’ (features April 27) focuses on escalation processes at the expense of providing practical advice about how professionals should respond in the event of a child disclosing an allegation of abuse.

Concepts: Child abuse, Escalation


The objective of this study was to evaluate the safety and efficacy of different lenalidomide starting doses in patients with relapsed/refractory chronic lymphocytic leukemia (CLL). CLL patients were randomized to receive lenalidomide at initial doses of 5, 10, or 15 mg/d (N = 103). Doses were escalated by 5 mg every 28-d up to a maximum of 25 mg/d; dose reductions in up to 5 mg decrements were permitted. The most common grade ≥3 adverse events (AEs) were neutropenia and thrombocytopenia. Ten patients died during therapy (four deaths considered as related to lenalidomide); 12 patients experienced second primary malignancies. The most common cause for treatment discontinuation was AEs. Overall response rates were similar across arms. Progression-free survival and overall survival rates were longer in patients who escalated treatment (to 15 or 20 mg/d) versus those who did not. Lower starting doses allowed subsequent dose escalation of lenalidomide while maintaining an acceptable tolerability profile in patients with relapsed/refractory CLL.

Concepts: Escalation, Death, Dose, Chemotherapy, White blood cell, Blood disorders, Clinical trial, Leukemia


Hepatic veno-occlusive disease (VOD) is a serious complication of high-dose chemotherapy regimens, such as those utilized in hematopoietic cell transplantation recipients. Defibrotide is considered a safe and effective treatment when dosed at 25 mg/kg/day. However, patients who develop VOD still have increased mortality despite the use of defibrotide. Data are limited on the use of doses above 60 mg/kg/day for persistent VOD. In this prospective clinical trial, 34 patients received escalating doses of defibrotide. For patients with persistent VOD despite doses of 60 mg/kg/day, doses were increased to a maximum of 110 mg/kg/day. There was no observed increase in toxicity until doses rose beyond 100 mg/kg/day. Patients receiving doses between 10-100 mg/kg/day experienced an average of 3 bleeding episodes per 100 days of treatment, while those receiving doses >100 mg/kg/day experienced 13.2 bleeding episodes per 100 days (p=0.008). Moreover, dose reductions due to toxicity were needed at doses of 110 mg/kg/day more often than at lower doses. Defibrotide may be safely escalated to doses well above the current standard without an increase in bleeding risk. However, the efficacy of this dose escalation strategy remains unclear, as outcomes were similar to published cohorts of patients receiving standard doses of defibrotide for VOD.

Concepts: Escalation, Cancer, Harshad number, Clinical trial, Hematopoietic stem cell transplantation, Effectiveness, Dose, Chemotherapy regimens


Patients who present with locally advanced inoperable non-small cell lung cancer (NSCLC) may be suitable for radical radiotherapy. A randomised trial of 563 patients compared CHART and conventional radical radiotherapy (60Gy/30f) given over 6weeks and suggested that CHART resulted in a 9% improvement in 2-year survival (Saunders et al., 1999). RT dose escalation for both conventional and CHARTWEL (CHART-WeekEndLess) - fractionation schedules is feasible with modern 3-dimensional CT-based planning techniques and we initiated a phase I CHART dose escalation study in 2009.

Concepts: Escalation, Tobacco smoking, Metastasis, Adenocarcinoma, Cancer staging, Cancer, Lung cancer, Non-small cell lung carcinoma


TIDEL-II was designed to optimise outcomes for newly-diagnosed chronic phase chronic myeloid leukemia (CP-CML) patients. Two sequential cohorts enrolled a total of 210 patients, all commencing imatinib 600 mg/day, with a planned dose escalation to 800mg/day for patients with imatinib plasma trough level <1000 ng/mL on day 22 (19%). Patients were then assessed with molecular treatment targets: BCR-ABL1 ≤10%, ≤1% and ≤0.1% at 3, 6 and 12 months, respectively. Cohort I patients who failed to achieve targets were escalated to imatinib 800 mg/day (if on 600mg/day), then subsequently switched to nilotinib 400 mg BID for failing the same target 3 months later. Cohort II patients who failed to achieve targets switched to nilotinib directly, as did patients with intolerance or loss of response in either cohort. At 2 years, 55% of study patients remained on imatinib, and 30% were on nilotinib. Only 12% were >10% BCR-ABL1 at 3 months. Confirmed MMR was achieved in 64% and 73% at 12 and 24 months, respectively. MR(4.5) at 24 months was 34%. Overall and transformation-free survival was 96% and 95% at 3 years, respectively. This trial supports the feasibility and efficacy of an imatinib-based approach with selective switching to nilotinib. Trial Registration #ACTRN12607000325404.

Concepts: Philadelphia chromosome, Privilege escalation, Imatinib, Target Corporation, Escalation, Failure, Leukemia, Chronic myelogenous leukemia


BackgroundHypoxia and increased glycolytic activity of tumors are associated with poor prognosis. The purpose of this study was to investigate differences in radiotherapy (RT) dose painting based on the uptake of 2-deoxy-2-[18¿F]-fluorodeoxyglucose (FDG) and the proposed hypoxia tracer, copper(II)diacetyl-bis(N4)-methylsemithiocarbazone (Cu-ATSM) using spontaneous clinical canine tumor models.MethodsPositron emission tomography/computed tomography scans of five spontaneous canine sarcomas and carcinomas were obtained; FDG on day 1 and 64Cu-ATSM on day 2 and 3 (approx. 3 and 24 hours pi.). Sub-volumes for dose escalation were defined by a threshold-based method for both tracers and five dose escalation levels were formed in each sub-volume. Volumetric modulated arc therapy plans were optimized based on the dose escalation regions for each scan for a total of three dose plans for each dog. The prescription dose for the GTV was 45 Gy (100%) and it was linearly escalated to a maximum of 150%. The correlations between dose painting plans were analyzed with construction of dose distribution density maps and quality volume histograms (QVH). Correlation between high-dose regions was investigated with Dice correlation coefficients.ResultsComparison of dose plans revealed varying degree of correlation between cases. Some cases displayed a separation of high-dose regions in the comparison of FDG vs. 64Cu-ATSM dose plans at both time points. Among the Dice correlation coefficients, the high dose regions showed the lowest degree of agreement, indicating potential benefit of using multiple tracers for dose painting. QVH analysis revealed that FDG-based dose painting plans adequately covered approximately 50% of the hypoxic regions.ConclusionRadiotherapy plans optimized with the current approach for cut-off values and dose region definitions based on FDG, 64Cu-ATSM 3 h and 24 h uptake in canine tumors had different localization of the regional dose escalation levels. This indicates that 64Cu-ATSM at two different time-points and FDG provide different biological information that has to be taken into account when using the dose painting strategy in radiotherapy treatment planning.

Concepts: Escalation, The UpTake, Approximation, Tumor, Correlation and dependence, Oncology, Pearson product-moment correlation coefficient, Cancer