Dose escalation of adalimumab as a strategy to overcome anti-drug antibodies:A case report of infantile-onset inflammatory bowel disease

BACKGROUND Treatment of infantile-onset inflammatory bowel disease(IO-IBD)is often challenging due to its aggressive disease course and failure of standard therapies with a need for biologics.Secondary loss of response is frequently caused by the production of anti-drug antibodies,a well-known problem in IBD patients on biologic treatment.We present a case of IO-IBD treated with therapeutic drug monitoring(TDM)-guided high-dose anti-tumor necrosis factor therapy,in which dose escalation monitoring was used as a strategy to overcome anti-drug antibodies.CASE SUMMARY A 5-mo-old boy presented with a history of persistent hematochezia from the 10th d of life,as well as relapsing perianal abscess and growth failure.Hypoalbuminemia,anemia,and elevated inflammatory markers were also present.Endoscopic assessment revealed skip lesions with deep colic ulcerations,inflammatory anal sub-stenosis,and deep fissures with persistent abscess.A diagnosis of IO-IBD Crohn-like was made.The patient was initially treated with oral steroids and fistulotomy.After the perianal abscess healed,adalimumab(ADA)was administered with concomitant gradual tapering of steroids.Clinical and biochemical steroid-free remission was achieved with good trough levels.After 3 mo,antibodies to ADA(ATA)were found with undetectable trough levels;therefore,we optimized the therapy schedule,first administering 10 mg weekly and subsequently up to 20 mg weekly(2.8 mg/kg/dose).After 2 mo of high-dose treatment,ATA disappeared,with concomitant high trough levels and stable clinical and biochemical remission of the disease.CONCLUSION TDM-guided high-dose ADA treatment as a monotherapy overcame ATA production.This strategy could be a good alternative to combination therapy,especially in very young patients.

Intensity modulated radiation therapy with simultaneous integrated boost based dose escalation on neoadjuvant chemoradiation therapy for locally advanced distal esophageal adenocarcinoma

AIM:To evaluate impact of radiation therapy dose escalation through intensity modulated radiation therapy with simultaneous integrated boost(IMRT-SIB).METHODS:We retrospectively reviewed the patients who underwent four-dimensional-based IMRT-SIBbased neoadjuvant chemoradiation protocol.During the concurrent chemoradiation therapy,radiation therapy was through IMRT-SIB delivered in 28 consecutive daily fractions with total radiation doses of 56 Gy to tumor and 5040 Gy dose-painted to clinical tumor volume,with a regimen at the discretion of the treating medical oncologist.This was followed by surgical tumor resection.We analyzed pathological completion response(p CR) rates its relationship with overall survival and event-freesurvival.RESULTS:Seventeen patients underwent dose escalation with the IMRT-SIB protocol between 2007 and 2014 and their records were available for analysis.Among the IMRT-SIB-treated patients,the toxicity appeared mild,the most common side effects were grade 1-3 esophagitis(46%) and pneumonitis(11.7%).There were no cardiac events.The Ro resection rate was 94%(n = 16),the p CR rate was 47%(n = 8),and the postoperative morbidity was zero.There was one mediastinal failure found,one patient had local failure at the anastomosis site,and the majority of failures were distant in the lung or bone.The 3-year diseasefree survival and overall survival rates were 41%(n = 7) and 53%(n = 9),respectively.CONCLUSION:The dose escalation through IMRT-SIB in the chemoradiation regimen seems responsible for down-staging the distal esophageal with well-tolerated complications.

Dose escalation of external beam radiotherapy for high-risk prostate cancerdImpact of multiple high-risk factor

Objective:To retrospectively investigate the treatment outcomes of external beam radiotherapy with androgen deprivation therapy(ADT)in high-risk prostate cancer in three radiotherapy dose groups.Methods:Between 1998 and 2013,patients with high-risk prostate cancer underwent threedimensional conformal radiotherapy or intensity-modulated radiotherapy of 66 Gy,72 Gy,or 78 Gy with ADT.Prostate-specific antigen(PSA)relapse was defined using the Phoenix definition.PSA relapse-free survival(PRFS)was evaluated in each radiotherapy dose group.Moreover,high-risk patients were divided into H-1(patients with multiple high-risk factors)and H-2(patients with a single high-risk factor)as risk subgroups.Results:Two hundred and eighty-nine patients with a median follow-up period of 77.3 months were analyzed in this study.The median duration of ADT was 10.1 months.Age,Gleason score,T stage,and radiotherapy dose influenced PRFS with statistical significance both in univariate and multivariate analyses.The 4-year PRFS rates in Group-66 Gy,Group-72 Gy and Group-78 Gy were 72.7%,81.6%and 90.3%,respectively.PRFS rates in the H-1 subgroup differed with statistical significance with an increasing radiotherapy dose having a more favorable PRFS,while PRFS rates in H-2 subgroup did not differ with increase in radiotherapy dose.Conclusion:Dose escalation for high-risk prostate cancer in combination with ADT improved PRFS.PRFS for patients in the H-1 subgroup was poor,but dose escalation in those patients was beneficial,while dose escalation in the H-2 subgroup was not proven to be effective for improving PRFS.

Phase I trial of dose escalation of capecitabine combined with fixed docetaxel in previously treated patients with non-small cell lung cancer

Objective： Capecitabine combined with docetaxel have demonstrated antitumor synergy for non-small cell lung cancer （NSCLC）. Due to absence of phase I trial in China, we conducted this study to define the maximum-tolerated dose （MTD） of capecitabine with fixed docetaxel for Chinese patients with previously treated NSCLC. Methods： Previously treated patients with NSCLC were entered into this study. Escalating doses of capecitabine with fixed docetaxel were administered in a modified Fibonacci sequence. The initial doses were capecitabine 625 mg/m2, bid, on days d5-d 18, and docetaxe130 mg/m2 on days 1 and 8, respectively. The regimen was repeated every 21 days. If no dose-limiting toxicity （DLT） was observed, the next dose level was applied. The procedures were repeated until DLT appeared. The MTD was declared to be one dose level below the level at which DLT appeared. Results： Eighteen patients received 67 cycles at capecitabine of level I （1250 mg/m2, divided into 625 mg/m2, bid） and level II （1500 mg/m2, 750 mg/m2, bid）. The most common toxicities were neutropenia, hand and feet syndrome, fatigue and nausea. Eight DLTs occurred in 5 patients in the whole group, including 1 DLT in dose level I and 7 DLTs in dose level 2. Since 4 of 6 patients in level II experienced DLTs, we declared thus level I was MTD. Cunclusion： MTD of our phase I trial was capecitabine of 1250 mg/m2/d combined with docetaxel of 30 mg/m2/wk. This combination regimen was well tolerated for previously treated patients with NSCLC. The efficacy of this schedule is currently being further evaluated in a prospective phase II trial.

A New SDH-Based ATM Network Survivability Escalation Mechanism

This paper investigates survivability escalation strategies in multi layers transport networks such as ATM/SDH/WDM networks, and presents oriented failures and oriented traffic escalation mechanisms. Furthermore, We present a new survivability Escalation strategy for SDH Based ATM transport networks, which addresses difficult problem for resources sharing pool(RSP) among different layers restoration mechanisms. In this paper, we also present integer programming (IP) model for the resources sharing pool (RSP) design problem and the node simulation model for escalation Node. The simulation results show that the proposed ESP is very efficient. The proposed model can be easily extended for other types of multi layer networks, such as WDM based ATM networks or WDM based SDH networks.

Image-Guided Radiotherapy Dose Escalation in Intermediate and High Risk Cancer Prostate Patients and Its Effect on Treatment Toxicity

Purpose: To study the effect of escalating radiation dose;in intermediate and high risk prostate cancer patients;via online image-guidance on acute toxicities. Patients and Methods: thirty-eight prostate cancer patients were treated by using simultaneous integrated boost-intensity modulated radiation therapy (SIB-IMRT) with online image guided correction via kilo voltage cone beam computed tomography (KV-CBCT)/electronic portal imaging device (EPID) of trans-rectal ultrasound (TRUS)-inserted intraprostatic gold fiduciary markers. High-risk patients received a median dose of 80.5 Gy to prostate and 56 Gy to pelvic nodes in 35 fractions over 7 weeks. Intermediate-risk patients received a similar prostate dose over the same overall treatment time. Acute toxicity (bladder, rectal and bowel symptoms) was reported once weekly during the radiation course and up to 3 months from the end of the radiation course. Results: The image guided (IG)-IMRT allows escalating the radiation dose delivered to the prostate through minimizing the margin of setup error to less than 0.5 cm with subsequent sparing of nearby organs at risk. Out of thirty-eight patients, no patient developed >grade 1 acute rectal toxicity, 7.9% of patients experienced grade 3 urinary toxicity and there was no reported small intestinal toxicity. Conclusion: Escalating the radiation dose more than 80 Gy in intermediate and high risk prostate cancer patients was safe and not associated with grade 3 - 4 RTOG toxicity when guided by online verification of intra-prostatic fiducial markers.

Time of infliximab therapy initiation and dose escalation in Crohn's disease

AIM: To determine if early initiation of anti-tumor necrosis factor therapy affects the need for dose escalation.

A phase I radiation dose escalation of stereotactic body radiotherapy for malignant lung tumors

Objectives: This Phase I study determines the maximum tolerated dose (MTD) of stereotactic body radiotherapy (SBRT) for lung tumors. Methods: Eli- gible patients had biopsy proven cancer with a maxi- mum tumor size ≤ 5 cm. Total doses were escalated from 40 to 48, then to 56 Gy, delivered in 4 equal fractions administered 2 to 3 times per week on an IRB approved protocol. SBRT was administered us- ing 5 to 9 fixed beam arrangements with CT loca- lization. Internal target volumes (ITV) were based on breath hold scans or 4D CT simulation. The planning target volume (PTV) was defined as the ITV with a uniform 5 mm expansion. Dose limiting toxicity (DLT) was defined as any grade 3 or higher toxicity using the Radiation Therapy Oncology Group (RTOG) common toxicity criteria (CTC). Results: Between April 2004 and February 2008, 18 patients received the prescribed treatment (40 Gy n = 6, 48 Gy n = 7, 56 Gy n = 5). Seventeen of 18 patients had non-small cell lung cancer (1 with rectal cancer), four of whom were treated for an oligometastasis. The median age of the patients was 68, while the median Karnofsky performance status was 90. The mean tumor size was 2.6 cm (range 0.9 to 4.5 cm). One grade 3 pulmonary event occurred (at 48 Gy dose level) immediately following treatment with the onset of fever and shortness of breath that responded to antibiotics. No other DLTs occurred. Conclusions: SBRT utilizing patient specific target volumes without gating appears safe. The maximum tolerated dose was not reached.

Security Operations Center: A Framework for Automated Triage, Containment and Escalation

There have been a lot of research exertions and studies to improve the safety of critical infrastructures using the Security Operations Center (SOC). As part of efforts, the purpose of this research is to propose a framework to automate the SOC’s performance of triage, containment and escalation. The research leveraged on qualitative desk review to collect data for analysis, deduced strengths and weaknesses for the current SOC implementations and used that as a basis for proposing the framework. In view of the constant evolution of SOC operations and capabilities coupled with the huge volumes of data collected for analysis, an efficient framework for SOC operations is proposed. The qualitative analysis is used to deduce strengths and weaknesses for the current SOC implementations as a premise for proposing the framework. It consists of eight interactive stages that further leverage on a proposed algorithm for baselining, remediation and escalation. The result of this research is a proposed framework that serves as a unique contribution to enhancing the SOC’s ability to automatically perform triage, containment and escalation. Supplementary to similar and earlier work reviewed, the framework is proposed as the way forward to automatically enable SOC setups with the capacity to efficiently perform triage of security threats, vulnerabilities and incidents, effectively contain identified breaches and appropriately escalate for prompt and accurate solutions.

Safety,tolerability,and pharmacokinetics of BAT8001 in patients with HER2-positive breast cancer:An open-label,dose-escalation,phase I study

Background:The introductions of anti-human epidermal growth factor receptor-2(HER2)agents have significantly improved the treatment outcome of patients with HER2-positive breast cancer.BAT8001 is a novel antibodydrug conjugate targeting human epidermal growth factor receptor-2(HER2)-expressing cells composed of a trastuzumab biosimilar linked to the drug-linker Batansine.This dose-escalation,phase I study was designed to assess the safety,tolerability,pharmacokinetics,and preliminary anti-tumor activity of BAT8001 in patients with HER2-positive locally advanced or metastatic breast cancer.Methods:This trial was conducted in subjects with histologically confirmed HER2-positive breast cancer(having evaluable lesions and an Eastern Cooperative Oncology Group performance status of 0 or 1)using a 3+3 design of escalating BAT8001 doses.Patients received BAT8001 intravenously in a 21-day cycle,with dose escalation in 5 cohorts:1.2,2.4,3.6,4.8,and 6.0 mg/kg.The primary objective was to evaluate the safety and tolerability of BAT8001.Preliminary activity of BAT8001 was also assessed as a secondary objective.Results:Between March 2017 to May 2018,29 HER2-positive breast cancer patients were enrolled.The observed dose-limiting toxicities were grade 4 thrombocytopenia and grade 3 elevated transaminase.The maximum tolerated dose was determined to be 3.6 mg/kg.Grade 3 or greater adverse events(AEs)occurred in 14(48.3%)of 29 patients,including thrombocytopenia in 12(41.4%)patients,aspartate aminotransferase increased in 4(13.8%)patients,γ-glutamyl transferase increased in 2(6.9%)patients,alanine aminotransferase increased in 2(6.9%)patients,diarrhea in 2(6.9%)patients.Objective response was observed in 12(41.4%,95%confidence interval[CI]=23.5%-61.1%)and disease control(including patients achieving objective response and stable disease)was observed in 24(82.8%,95%CI=64.2%-94.2%)patients.Conclusions:BAT8001 demonstrated favorable safety profiles,with promising anti-tumor activity in patients with HER2-positive locally advanced or metastatic breast cancer.BAT8001 has the potential to provide a new therapeutic option in patients with metastatic HER2-positive breast cancer.

Dose escalation guided by^(18)F-FDG PET/CT for esophageal cancer

Objective:To assess the feasibility of dose escalation guided by ^(18)F-deoxyglucose positron emission tomography/computer tomography(^(18)F-FDG PET/CT)for esophageal cancer(EC).Methods and materials:Ten random patients treated with definitive chemoradiotherapy and pre-therapeutic ^(18)FFDG PET/CT were included in this study.Retrospectively,a threshold of 50%of SUVmax was used to define the high FDG uptake region of the GTV(GTVPET).Three intensity-modulated radiation therapy(IMRT)plans were generated,delivering three dose levels to three different planning target volumes(PTVs).50.4 Gy delivered to PTV50.4 was defined on computed tomography(CT)as Plan50.4,63 Gy was delivered to PTV63 was defined as GTV plus a uniform margin of 0.5 cm as Plan63,and 70 Gy delivered to PTV70 was defined as GTVPET plus a 0.5 cm margin as Plan70.A dosimetric comparison was performed based on normal tissue complication probability(NTCP)for the lung and heart.Results:Clinically acceptable dose escalation failed for 2 of 10 patients in Plan63 due to heart dose constraints.One patient failed heart dose constraint for Plan70.Two patients failed spinal cord constraint for Plan63.Three patients failed lung dose constraints for both Plan63 and Plan70,two of which were even not suitable for Plan50.4 for the same reason.NTCP modeling for lung showed increased risk for Plan63 and Plan70 compared to Plan50.4.The difference between Plan63 and Plan70 was insignificant.NTCP modeling for heart showed an increased risk from 6.38%of Plan50.4 to 8.88%of Plan70(P=0.009)or 9.79%of Plan63(P=0.007).The risk of heart mortality was significantly higher for Plan63 than Plan70(P=0.047).Conclusions:Selective boosting of sub-volumes based on ^(18)F-FDG PET/CT is feasible way with a modest increase in the risk of cardiac and lung toxicities.

The fossil record of durophagous predation in the James Ross Basin over the last 125 million years

We review the evidence for predation of shelly benthic prey over 125 million years of earth history in the James Ross Basin,Antarctica(~65°S).Although poor in the Early Cretaceous lower parts of the sequence,which represent essentially deeper water facies,evidence for both potential crushers and drillers becomes more apparent in the Santonian–Campanian Santa Marta Formation,and by the Maastrichtian López de Bertodano Formation there is an extensive fossil record of drill holes attributable to naticid gastropods,and some evidence of crushing by decapods crustaceans and possibly other taxa too.This continues at a similar level of intensity across the K/Pg boundary into the Danian Sobral Formation,but is less well constrained in the latest Paleocene–Early Eocene.The most extensive record of predation occurs in the Middle Eocene section of the La Meseta Formation on Seymour Island which also records the highest levels of benthic diversity within the entire basin.This key section is providing some important new evidence to suggest that the rate of acceleration of benthic predation intensity through the Late Mesozoic–Early Cenozoic in the polar regions may be similar to that seen in lower latitude regions.Predator–prey interaction was a key factor in the evolution of polar marine faunas too.

Chemo-profiling of eucalyptus and study of its hypoglycemic potential

Constant escalations in the number of diabetics worldwide and the failure of conventional therapy to restore normoglycemia without adverse effects,in spite of tremendous strides in modern medicine,calls for naturopathy and alternative medicine.Because diabetes is multi-factorial and has secondary complications,prevention of hyperglycemia is the central dogma for its management.To date,no oral hypoglycemic exists which can achieve tight glycemic control without side effects.Dietary adjuncts,lifestyle interventions and a resurgence of interest in phyto-therapy have consequently gained ground.Natural hypoglycemics have attracted attention due to ease of incorporation in everyday diet,affordability,less adverse effects,and long term safety.Ethno botanical literature reports more than 800 anti-diabetic plants species.Eucalyptus is well represented in the Aboriginal Pharmacopoeias for its various pharmacological activities.Its hot aqueous decoction has been used as a hypoglycemic in various regions of world.This editorial attempts to summarize the data on the hypoglycemic potential of the different eucalyptus species,highlight the value of its natural biomolecules for the prophylaxis and treatment of type2 diabetes,describe their mechanistic actions,shed light on the posology and safety aspects of eucalyptusand assess its applicability as a reinforcement to currently used therapy.

Is There a Future for 74 Gy Radiation Treatment of NSCLC after RTOG 0617?A Comparison of the RTOG Study Results with Our Own Department’s 74 Gy NSCLC Cohort

Background and Purpose: There have been a number of different efforts trying to improve the outcome of NSCLC patients treated with radiotherapy (RT). Contrary to most expectations, the long awaiting results of the RTOG 0617 trial didn’t show any benefit of dose escalation to 74 Gy. In this unicentric retrospective analysis we compare the RTOG 0617 result with the outcome of our own 74-Gy-NSCLC cohort. Methods and Material: Since October 2009, 80 patients with NSCLC were treated with 74 Gy in 37 fractions, of which 69 patients were eligible for a retrospective analysis of local and distant failure, survival time and treatment related toxicity. A subgroup analysis was done for patients with a possible follow-up of at least 18 month. Results: Complete local remission could be achieved in 18 patients (26.1%);26 patients (37.7%) had a partial remission and 3 patients (4.4%) a stable local disease. Local failure occurred in 12 patients (17.3%). Distant failure occurred in 27 patients (39.1%). The median survival time was 43.7 weeks (95% CI: 25.2 - 62.3 weeks). 5 patients (6.3%) developed RT induced side effects. As for the analyzed subgroup, a complete or partial local remission could be achieved in 29 patients (61.7%). Local failure occurred in 11 patients (23.4%) and 20 patients (42.6%) developed distant metastases. The 18-month overall survival was 38.3% and the median survival time was 51.7 weeks (95% CI: 27.2 - 76.3 weeks). Conclusion: The results of this retrospective analysis indicate that 74 Gy total radiation dose might not lead to results as bad as indicated by the RTOG 0617 trial. It might therefore be a suitable treatment concept for people with NSCLC.

Optimal use of fielder XT guidewire enhances the success rate of chronic total occlusion percutaneous coronary intervention

BACKGROUND Chronic total occlusion(CTO) is found in 18-31% of patients who undergo coronary angiography. Successful recanalization of CTOs is associated with reduced recurrent angina pectoris rates and increased long-term survival.Although the success rate of CTO percutaneous coronary intervention(CTO-PCI)has improved, CTO-PCI remains technically challenging. The Fielder XT guidewire was designed for CTO lesions. To validate whether the use of the guidewire increases the success rate, we compared the results of CTO-PCI with or without the guidewire. We hypothesized that the use of Fielder XT guidewire can increase the success rate of CTO-PCI.AIM To investigate whether the use of Fielder XT guidewire increases the final procedural success of CTO-PCI via the anterograde approach.METHODS Between January 2013 and December 2015, a retrospective study was conducted on 1230 consecutive patients with CTO who received PCI via the anterograde approach at the General Hospital of Northern Theater Command. The patients were divided into an XT Group(n = 686) and a no-XT Group(n = 544) depending on whether Fielder XT guidewire was used. Both groups were compared for clinical parameters, lesion-related characteristics, procedural outcomes and inhospital complications. The data were statistically analyzed using Pearson's χ~2 test for categorical variables, and Students' t test was used to compare the quantitative data. Significant independent factors and a risk ratio with 95%confidence interval(CI) were assessed by multivariate logistic regression analysis.RESULTS In total, 1230 patients were recruited; 75.4% of the patients were male, and 55.8%of the patients were in the XT group. The overall success rate was 83.9%, with87.8% in the XT group. Based on multivariate logistic regression analysis, factors positively associated with procedural success were the use of Fielder XT guidewire(P = 0.005, 95%CI: 1.172-2.380) and systolic blood pressure(P = 0.011,95%CI: 1.003-1.022), while factors negatively associated with procedural success were blunt stump(P = 0.013, 95%CI: 1.341-11.862), male sex(P = 0.016, 95%CI:0.363-0.902), New York Heart Association(NYHA) class(P = 0.035, 95%CI: 0.553-0.979), contrast amount(P = 0.018, 95%CI: 0.983-0.998) and occlusion time(P =0.009, 95%CI: 0.994-0.999). No significant differences were found between the XT group and the no-XT group with respect to clinical parameters, lesion-related characteristics, coronary artery rupture [3(0.4%) vs 8(1.5%), P = 0.056], inhospital death [2(0.3%) vs 6(1.1%), P = 0.079] or in-hospital target lesion revascularization [3(0.4%) vs 7(1.3%), P < 0.099]. However, there were significant differences between the groups with respect to success rate [602(87.8%) vs 430(79.0%), P < 0.001], procedure time [(74 ± 23) vs(83 ± 21), P < 0.001], stent length[(32.0 ± 15.8) vs(37.3 ± 17.6), P < 0.001], contrast amount [(148 ± 46) vs(166 ± 43),P < 0.001], post-PCI myocardial infarction [43(6.3%) vs 59(10.8%), P = 0.004],major adverse cardiovascular event [44(6.4%) vs 57(10.7%), P = 0.007], side branch loss [31(4.5%) vs 44(8.1%), P = 0.009], contrast-induced nephropathy [29(4.2%) vs 40(7.4%), P = 0.018] and no reflow [8(1.2%) vs 14(2.9%), P = 0.034].CONCLUSION The use of Fielder XT guidewire shortens the Procedure and increases the success rate of CTO-PCI, and is also associated with reduced complication rates.

Has the time been reached for pseudopolyps to be re-enrolled in endoscopic inflammatory bowel disease scores?

Patients with inflammatory bowel diseases (IBD) represent heterogeneous groups with different characteristics and different clinical course. A great deal of effort is made to discover proxies for more severe disease needing more intense treatment and early intervention to gain the maximum therapeutic benefit. Endoscopy remains an invaluable method in assessment of patients with IBD. Pseudopolyps are often encountered during endoscopy and, although they are a well described entity, their presence is of unclear importance. In one of our recent studies and in conjunction with one study with a large cohort of patients with IBD and pseudopolyps, patients with pseudopolyps were found to face a higher inflammatory burden in terms of receiving more intense biological treatment. This letter comes as a comment and proposition regarding the concept of reevaluation of pseudopolyps as a promising marker in IBD scores.

Strategies for overcoming anti-tumor necrosis factor drug antibodies in inflammatory bowel disease:Case series and review of literature

Anti-tumor necrosis factor(TNF) biologics are currentlyamongst the most widely used and efficacious therapies for inflammatory bowel disease(IBD). The development of therapeutic drug monitoring for infliximab and ada-limumab has allowed for measurement of drug levels and antidrug antibodies. This information can allow for manipulation of drug therapy and prediction of response. It has been shown that therapeutic anti-TNF drug levels are associated with maintenance of remission, and development of antidrug antibodies is predictive of loss of response. Studies suggest that a low level of drug antibodies, however, can at times be overcome by dose escalation of anti-TNF therapy or addition of an immunomodulator. We describe a retrospective case series of twelve IBD patients treated at the University of California-Irvine, who were on infliximab or adalimumab therapy and were found to have detectable but low-level antidrug antibodies. These patients underwent dose escalation of the drug or addition of an immunomodulator, with subsequent follow-up drug levels obtained. Eight of the twelve patients(75%) demonstrated resolution of antidrug antibodies, and were noted to have improvement in disease activity. Though data regarding overcoming low-level anti-TNF drug antibodies remains somewhat limited, cases described in the literature as well as our own experience suggest that this may be a viable strategy for preserving the use of an anti-TNF drug. Low-level anti-TNF drug antibodies may be overcome by dose escalation and/or addition of an immunomodulator, and can allow for clinical improvement in disease status. Therapeutic drug monitoring is an important tool to guide this strategy.

Multiple Criteria Games-Theory and Applications

After a reivew of basic concepts in multiple criteria optimization, the paper presents a characterization of noncooperative equilibria in multiple criteria games in normal form either by weighted sums or by. order-consistent achievement scalarizing functions, for convex and nonconvex cases. Possible applications of multiple criteria games and such characterizations of their equilibria are indicated. The analysis of multiple criteria games might be especially useful when studying reasons of possible conflict escalation processes and ways of preventing them.

Rationality of escalating commitment in information systems project management： An inter-disciplinary perspective

Escalation of commitment has been linked to losses in information systems （IS） projects. Understanding the nature and the rationality of escalation allows the firm to promote optimal project management practices. This study takes an inter-disciplinary approach and draws on research from economics and management to create a model of irrational escalation and a model of rational escalation. The forces that contribute to irrational escalation include the responsibility of the same manager for both the project selection and project continuation decisions that create proneness to self-justification, the potential for negative framing of decision options due to large sunk costs, the proximity of project completion and the presence of organizational inertia. Identifying these irrational escalation factors helps design appropriate de-escalation techniques. The rational escalation model draws on the real option theory and the bandit process theory to identify conditions when project continuation is justified by the value of information and the value of flexibility that the firm receives from continuing the project.

Evaluation of Acute Toxicity and Dosimetric Parameters in High Risk Prostate Cancer Patients Treated by High Radiation Doses

For high risk prostate cancer, the treatment volumes and even dose levels are still a controversial issue. The aim of this study is to evaluate the dosemetric parameters and acute toxicity of dose-escalated whole pelvis (WP) Intensity Modulated Radiation Therapy (IMRT) and volumetric modulated arc therapy (VMAT) prostate boost following neoadjuvant and concomitant with androgen deprivation therapy in high-risk prostate cancer patients. This analysis included 73 high-risk prostate cancer patients treated with WP-IMRT followed by boost to the prostate by VMAT to total dose of 80 Gy;between January 2014 and October 2016. Androgen deprivation therapy (ADT) was given for all patients before and during radiation therapy. Drawing the dose volume histograms (DVHs) was done for planning target volumes (PTVs), including Prostate PTV & nodal PTV, and organs at risk including rectum, bladder, femoral heads, and bowel bag for the plans. Acute radiation toxicities were reported during the radiation course and the following 3 months. The DVH analysis showed good coverage of PTVs and organs at risk doses were acceptable. No recorded acute Grade ≥ 3 toxicity. Acute grade 1 toxicity for Gastrointestinal (GI) and Genitourinary (GU) were 65% and 35% respectively, while Grade 2 toxicity was 30% for both. The Proctitis and frequency were the commonest acute toxicity and were maximal during the 5th week of radiation therapy. Dose escalation in two phases utilizing Simultaneous integrated boost (SIB) combined with ADT in high risk prostate cancer patient is feasible and associated with acceptable acute GI and GU toxicity.