Search

Objective: The objective of this scoping review is to map the literature on the use of diabetes technologies in the primary school environment by children with type 1 diabetes (T1D) and/or their parents., Introduction: T1D is a complex chronic disorder that is one of the fastest growing diseases in childhood. Technological advances in recent times have seen a growth in the use of diabetes technologies. Despite these advances, having T1D still creates challenges for parents' and children's school experiences. Furthermore, the literature on the use of diabetes technologies during the primary school day is under-investigated., Inclusion Criteria: This review will consider peer-reviewed primary research studies or systematic reviews that include children with T1D aged 6 to 12 years who use diabetes technologies in the primary school environment and/or their parents., Methods: This review will be conducted in accordance with JBI methodology for scoping reviews and will be reported in line with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) guidelines. Following an initial limited search, a full search strategy was developed using index terms and key text words. This strategy will be used across relevant databases, including Embase, MEDLINE (Ovid), CINAHL (EBSCOhost), and Web of Science Core Collection for the full scoping review. There will be no limitations on language or year. Two reviewers will independently screen titles, abstracts, and full-text articles and extract relevant data using the JBI data extraction instrument. Data will be presented in a descriptive manner, supported by tables and charts, and accompanied by a narrative summary., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2023 JBI.)

In 2020, Centers for Disease Control and Prevention (CDC) released guidelines recommending HCV screening in all adults 18 years and older. In the current study, we aimed to identify risk factors for HCV infection in an ED population. We performed a retrospective analysis of ED patients ≥ 18 years who were screened for HCV between 28 November 2018, and 27 November 2019, at a single urban, quaternary referral academic hospital. An HCV-antibody immunoassay (HCV-Ab) was used for screening; positive results were confirmed by measuring HCV ribonucleic acid (RNA). The outcome of interest was the number of new HCV diagnoses (presence of viremia by HCV RNA testing). Multiple logistic regression models were used to identify risk factors associated with a new HCV diagnosis. 16,722 adult patients were screened for HCV (mean age: 46 ± 15 years; 51% female). HCV seroprevalence was 5%. Independent risk factors for HCV included increasing age [10-year aOR 1.26 (95% CI 1.23, 1.30)], male sex [aOR 1.25 (95% CI 1.03, 1.51)], undomiciled housing status [aOR 2.8 (95% CI 2.3, 3.5)], history of tobacco use [aOR 3.0 (95% CI 2.3, 3.9)], history of illicit drug use [aOR 3.6 (95% CI 2.9, 4.5)], Medicaid insurance status [aOR 4.0 (95% CI 2.9, 5.5)] and Medicare insurance status [aOR 1.6 (95% CI 1.1, 2.2)].The ED services a high-risk population with regards to HCV infection. These data support universal screening of ED patients for HCV. Risk factor profiles could improve targeted screening at institutions without universal testing protocols., (© 2022 John Wiley & Sons Ltd.)

Purpose: Mutations in the RAS/RAF/MEK/ERK signaling pathway are commonly found in biliary tract cancer (BTC). Binimetinib, a selective inhibitor of MEK1/2, has single-agent activity. Preclinical data support binimetinib combination with chemotherapy, when given in an interrupted dosing schedule. Patients and Methods: A phase I/II trial evaluated binimetinib in combination with gemcitabine and cisplatin in patients with untreated advanced BTC. The primary endpoints were to determine the MTD (phase I), and PFS 6 and RR (phase II). Tumor tissue for targeted gene sequencing and blood samples for peripheral blood pERK expression were evaluated. Patients received oral binimetinib twice daily with gemcitabine and cisplatin on day 8 and 15 of a 21-day cycle. Binimetinib was held for 2 days prior to and on day of each chemotherapy treatment., Results: Twelve patients enrolled in the phase I showed the MTD of binimetinib at 45 mg orally twice daily with gemcitabine 800 and cisplatin 20 mg/m 2 . Twenty-nine patients were treated in the phase II. Six patients treated at MTD in phase I were evaluable as part of phase II. PFS 6 months was 54% and RR was 36%. Median overall survival was 13.3 months (95% CI, 9.8-16.5). MSK-IMPACT 410-gene panel showed aberrations in the RAS-RAF-MEK-ERK pathway and mutations in PIK3CA, AKT2, PIK3CG, BRAF, and MAP3K1 in responding patients., Conclusions: Binimetinib with gemcitabine and cisplatin did not show an improvement in PFS 6 and RR. Molecular profiling may help select patients who may benefit from this triplet therapy, which is not planned at this time., (©2018 American Association for Cancer Research.)

Purpose: Arginine depletion interferes with pyrimidine metabolism as well as DNA damage repair pathways. Preclinical data indicates that pairing pegylated arginine deiminase (ADI-PEG 20) with fluoropyrimidines or platinum enhances cytotoxicity in vitro and in vivo in arginine auxotrophs., Methods: This is a single-center, open-label, phase 1 trial of ADI-PEG 20 and modified FOLFOX6 (mFOLFOX6) in treatment-refractory hepatocellular carcinoma (HCC) and other advanced gastrointestinal tumors. A 3 + 3 dose escalation design was employed to assess safety, tolerability, and determine the recommended phase 2 dose (RP2D) of ADI-PEG 20. A RP2D expansion cohort for patients with HCC was employed to define the objective response rate (ORR). Secondary objectives were to estimate progression-free survival (PFS), overall survival (OS), and to explore pharmacodynamics and immunogenicity. Eligible patients were treated with mFOLFOX6 intravenously biweekly at standard doses and ADI-PEG-20 intramuscularly weekly at 18 (Cohort 1) or 36 mg/m 2 (Cohort 2 and RP2D expansion)., Results: Twenty-seven patients enrolled-23 with advanced HCC and 4 with other gastrointestinal tumors. No dose-limiting toxicities were observed in cohort 1 or 2. The RP2D for ADI-PEG 20 was 36 mg/m 2 weekly with mFOLFOX6. The most common any grade adverse events (AEs) were thrombocytopenia, neutropenia, leukopenia, anemia, and fatigue. Among the 23 HCC patients, the most frequent treatment-related Grade ≥ 3 AEs were neutropenia (47.8%), thrombocytopenia (34.7%), leukopenia (21.7%), anemia (21.7%), and lymphopenia (17.4%). The ORR for this group was 21% (95% CI 7.5-43.7). Median PFS and OS were 7.3 and 14.5 months, respectively. Arginine levels were depleted with therapy despite the emergence of low levels of anti-ADI-PEG 20 antibodies. Arginine depletion at 4 and 8 weeks and archival tumoral argininosuccinate synthetase-1 levels did not correlate with response., Conclusions: Concurrent mFOLFOX6 plus ADI-PEG-20 intramuscularly at 36 mg/m 2 weekly shows an acceptable safety profile and favorable efficacy compared to historic controls. Further evaluation of this combination is warranted in advanced HCC patients.

Background: Arginine depletion is a putative target in hepatocellular carcinoma (HCC). HCC often lacks argininosuccinate synthetase, a citrulline to arginine-repleting enzyme. ADI-PEG 20 is a cloned arginine degrading enzyme-arginine deiminase-conjugated with polyethylene glycol. The goal of this study was to evaluate this agent as a potential novel therapeutic for HCC after first line systemic therapy., Methods and Patients: Patients with histologically proven advanced HCC and Child-Pugh up to B7 with prior systemic therapy, were randomized 2 : 1 to ADI-PEG 20 18 mg/m2 versus placebo intramuscular injection weekly. The primary end point was overall survival (OS), with 93% power to detect a 4-5.6 months increase in median OS (one-sided α = 0.025). Secondary end points included progression-free survival, safety, and arginine correlatives., Results: A total of 635 patients were enrolled: median age 61, 82% male, 60% Asian, 52% hepatitis B, 26% hepatitis C, 76% stage IV, 91% Child-Pugh A, 70% progressed on sorafenib and 16% were intolerant. Median OS was 7.8 months for ADI-PEG 20 versus 7.4 for placebo (P = 0.88, HR = 1.02) and median progression-free survival 2.6 months versus 2.6 (P = 0.07, HR = 1.17). Grade 3 fatigue and decreased appetite occurred in <5% of patients. Two patients on ADI-PEG 20 had ≥grade 3 anaphylactic reaction. Death rate within 30 days of end of treatment was 15.2% on ADI-PEG 20 versus 10.4% on placebo, none related to therapy. Post hoc analyses of arginine assessment at 4, 8, 12 and 16 weeks, demonstrated a trend of improved OS for those with more prolonged arginine depletion., Conclusion: ADI-PEG 20 monotherapy did not demonstrate an OS benefit in second line setting for HCC. It was well tolerated. Strategies to enhance prolonged arginine depletion and synergize the effect of ADI-PEG 20 are underway., Clinical Trial Number: www.clinicaltrials.gov (NCT 01287585).

Purpose: BRCA-associated cancers have increased sensitivity to poly(ADP-ribose) polymerase inhibitors (PARPis). This single arm, non-randomised, multicentre phase II trial evaluated the response rate of veliparib in patients with previously treated BRCA1/2- or PALB2-mutant pancreatic adenocarcinoma (PDAC)., Methods: Patients with stage III/IV PDAC and known germline BRCA1/2 or PALB2 mutation, 1-2 lines of treatment, Eastern Cooperative Oncology Group 0-2, were enrolled. Veliparib was dosed at a volume of 300 mg twice-daily (N = 3), then 400 mg twice-daily (N = 15) days 1-28. The primary end-point was to determine the response rate of veliparib; secondary end-points included progression-free survival (PFS), duration of response, overall survival (OS) and safety., Results: Sixteen patients were enrolled; male N = 8 (50%). Median age was 52 years (range 43-77). Five (31%) had a BRCA1 and 11 (69%) had a BRCA2 mutation. Fourteen (88%) patients had received prior platinum-based therapy. No confirmed partial responses (PRs) were seen: one (6%) unconfirmed PR was observed at 4 months with disease progression (PD) at 6 months; four (25%) had stable disease (SD), whereas 11 (69%) had PD as best response including one with clinical PD. Median PFS was 1.7 months (95% confidence interval [CI] 1.57-1.83) and median OS was 3.1 months (95% CI 1.9-4.1). Six (38%) patients had grade III toxicity, including fatigue (N = 3), haematology (N = 2) and nausea (N = 1)., Conclusions: Veliparib was well tolerated, but no confirmed response was observed although four (25%) patients remained on study with SD for ≥ 4 months. Additional strategies in this population are needed, and ongoing trials are evaluating PARPis combined with chemotherapy (NCT01585805) and as a maintenance strategy (NCT02184195)., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: ADI-PEG 20 is a pegylated form of the arginine-depleting enzyme arginine deiminase. Normal cells synthesize arginine with the enzyme argininosuccinate synthetase (ASS1); ADI-PEG 20 selectively targets malignant cells, which lack ASS1., Methods: A single-arm, nonrandomized, open-label, phase 1/1B, standard 3 + 3 dose escalation with an expansion cohort of 9 patients at the recommended phase 2 dose (RP2D) was conducted. Patients who had metastatic pancreatic cancer, up to 1 line of prior treatment (the dose-escalation cohort) or no prior treatment (the expansion cohort), and an Eastern Cooperative Oncology Group performance status of 0 to 1 were included. Patients received both gemcitabine (1000 mg/m 2 ) and nab-paclitaxel (125 mg/m 2 ) for 3 of 4 weeks and intramuscular ADI-PEG 20 at 18 mg/m 2 weekly (cohort 1) or at 36 mg/m 2 weekly (cohort 2 and the expansion cohort).The primary endpoint was to determine the maximum tolerated dose and RP2D of ADI-PEG 20 in combination with nab-paclitaxel and gemcitabine., Results: Eighteen patients were enrolled. No dose-limiting toxicities (DLTs) were observed in cohort 1; cohort 2 was expanded to 6 patients because of 1 DLT occurrence (a grade 3 elevation in bilirubin, aspartate aminotransferase, and alanine aminotransferase). The most frequent adverse events (AEs) of any grade were neutropenia, thrombocytopenia, leukopenia, anemia, peripheral neuropathy, and fatigue; all 18 patients experienced grade 3/4 AEs. The most frequent grade 3/4 toxicities, regardless of the relation with any drugs, included neutropenia (12 patients or 67%), leukopenia (10 patients or 56%), anemia (8 patients or 44%), and lymphopenia (6 patients or 33%). The RP2D for ADI-PEG 20 was 36 mg/m 2 weekly in combination with standard-dose gemcitabine and nab-paclitaxel. The overall response rate among patients treated at the RP2D in the first-line setting was 45.5% (5 of 11).The median progression-free survival time for these patients treated at the RP2D was 6.1 months (95% confidence interval, 5.3-11.2 months), and the median overall survival time was 11.3 months (95% confidence interval, 6.7 months to not reached)., Conclusions: ADI-PEG 20 was well tolerated in combination with gemcitabine and nab-paclitaxel. Activity was observed in previously treated and untreated patients with advanced pancreatic cancer and in patients with ASS1-deficient and -proficient tumors. Cancer 2017;123:4556-4565. © 2017 American Cancer Society., (© 2017 American Cancer Society.)

Lessons Learned: Trebananib leveraging anti-angiogenic mechanism that is distinct from the classic sorafenib anti-vascular endothelial growth factor inhibition did not demonstrate improved progression-free survival at 4 months in patients with advanced hepatocellular carcinoma (HCC).In support of previously reported high Ang-2 levels' association with poor outcome in HCC for patients, trebananib treatment with lower baseline Ang-2 at study entry was associated with improved overall survival to 22 months and may suggest future studies to be performed within the context of low baseline Ang-2., Background: Ang-1 and Ang-2 are angiopoietins thought to promote neovascularization via activation of the Tie-2 angiopoietin receptor. Trebananib sequesters Ang-1 and Ang-2, preventing interaction with the Tie-2 receptor. Trebananib plus sorafenib combination has acceptable toxicity. Elevated Ang-2 levels are associated with poor prognosis in hepatocellular carcinoma (HCC)., Methods: Patients with HCC, Eastern Cooperative Oncology Group ≤2, and Childs-Pugh A received IV trebananib at 10 mg/kg or 15 mg/kg weekly plus sorafenib 400 mg orally twice daily. The study was planned for ≥78% progression-free survival (PFS) rate at 4 months relative to 62% for sorafenib historical control (power = 80% α = 0.20). Secondary endpoints included safety, tolerability, overall survival (OS), and multiple biomarkers, including serum Ang-2., Results: Thirty patients were enrolled sequentially in each of the two nonrandomized cohorts. Demographics were comparable between the two arms and the historical controls. PFS rates at 4 months were 57% and 54% on the 10 mg/kg and 15 mg/kg trebananib cohorts, respectively. Median OS was 17 and 11 months, respectively. Grade 3 and above events noted in ≥10% of patients included fatigue, hypertension, diarrhea, liver failure, palmar-plantar erythrodysesthesia syndrome, dyspnea, and hypophosphatemia. One death was due to hepatic failure. Serum Ang-2 dichotomized at the median was associated with improved OS in both cohorts., Conclusion: There was no improvement in PFS rate at 4 months in either cohort, when compared with sorafenib historical control., (© AlphaMedPress; the data published online to support this summary is the property of the authors.)

Introduction: The study's aim was to establish, for children living in urban disadvantage, the nature and extent of the relationship between body mass index (BMI) and health-related quality of life (HRQoL), including the role of individual and family factors in influencing this relationship., Methods: Within the context of a longitudinal design, 255 children aged 7-12 years (50 % male) self-reported their HRQoL (Kidscreen-27) and had their height and weight measured at year one and two. One parent/guardian for each child was also assessed at year one with the OSLO Social Support Scale and Hospital Anxiety and Depression Scale. Regression analysis was also conducted., Results: BMI was weakly inversely associated with 'total HRQoL' (r = -.15, p < .05), 'physical well-being' and 'autonomy and parent relations'. Significant differences were found between normal weight and obese children on all but the latter dimension. Neither weight group, however, fell below the average European HRQoL range. BMI predicted physical well-being a year later and vice versa, whilst autonomy and parent relations also predicted BMI a year later. In terms of 'overweight' children (38 %), those approaching adolescence had poorer physical and school well-being than younger children, and those whose parents had moderate-to-severe levels of depression fared worse on school well-being than children whose parents were not depressed., Conclusion: The findings suggest that obesity programmes could aim to prevent/reduce obesity and optimise HRQoL in urban disadvantaged preadolescent children whilst also targeting parental mental health difficulties. Future research should examine mediators of the effect of BMI on HRQoL.

In childhood, burn or scald injuries are comparatively common, and the greatest risk is to infants and toddlers. The extent and severity of injuries can vary greatly, which can significantly affect recovery and outcome. To provide high quality nursing care to the child who has sustained a burn injury and the family, the children's nurse should understand the pathophysiology of the trauma and the associated physical and psychological suffering. Evidence-based nursing management of these aspects is an essential component of recovery. Children's nurses working in hospitals, schools or in the community can engage with parents, families, school staff and children to provide information, advice, and health and safety promotion for burn prevention.

Purpose: Although neoadjuvant chemoradiotherapy achieves low local recurrence rates in clinical stages II to III rectal cancer, it delays administration of optimal chemotherapy. We evaluated preoperative infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX)/bevacizumab with selective rather than consistent use of chemoradiotherapy., Patients and Methods: Thirty-two patients with clinical stages II to III rectal cancer participated in this single-center phase II trial. All were candidates for low anterior resection with total mesorectal excision (TME). Patients were to receive six cycles of FOLFOX, with bevacizumab included for cycles 1 to 4. Patients with stable/progressive disease were to have radiation before TME, whereas responders were to have immediate TME. Postoperative radiation was planned if R0 resection was not achieved. Postoperative FOLFOX × 6 was recommended, but adjuvant regimens were left to clinician discretion. The primary outcome was R0 resection rate., Results: Between April 2007 and December 2008, 32 (100%) of 32 study participants had R0 resections. Two did not complete preoperative chemotherapy secondary to cardiovascular toxicity. Both had preoperative chemoradiotherapy and then R0 resections. Of 30 patients completing preoperative chemotherapy, all had tumor regression and TME without preoperative chemoradiotherapy. The pathologic complete response rate to chemotherapy alone was 8 of 32 (25%; 95% CI, 11% to 43%). The 4-year local recurrence rate was 0% (95% CI, 0% to 11%); the 4-year disease-free survival was 84% (95% CI, 67% to 94%)., Conclusion: For selected patients with clinical stages II to III rectal cancer, neoadjuvant chemotherapy and selective radiation does not seem to compromise outcomes. Preoperative Radiation or Selective Preoperative Radiation and Evaluation Before Chemotherapy and TME (PROSPECT), a randomized phase III trial to validate this experience, is now open in the US cooperative group network.

Aim: To report on baseline outcomes of body mass index, eating habits and physical activity of a cohort of urban disadvantaged children from a longitudinal evaluation of a school based, health promoting initiative., Background: The healthy schools programme was developed for implementation in schools located in disadvantaged areas of Dublin, Ireland., Design: A prospective, cohort study design was implemented., Method: A 3-year longitudinal evaluation was conducted in five intervention and two comparison schools between 2009-2011. Data were collected on each participating child to determine their eating habits, levels of physical activity and body mass index at year 1 (baseline), year 2 and year 3. Independent t-tests were used to compare mean values, chi-square and Fishers exact tests were used to compare proportions at baseline., Results: Participation rates were over 50%. Older children reported eating on average more fruit and vegetables than younger children; breakfast was often eaten on the way to, or in school and in one age group 16.7% of intervention children reported they did not eat breakfast that day. Levels of physical activity varied with over 70% of younger children stating they never played a sport. In intervention schools over one quarter of all children were either overweight or obese. A comparison was conducted between the proportion of 9-year olds overweight and obese in our disadvantaged cohort and a national random sample of 8500 9-year olds and no important differences were observed., Conclusion: Baseline results indicate that body mass index rates particularly among pre adolescent, urban disadvantaged girls are of concern., (© 2012 Blackwell Publishing Ltd.)

Background: In 2008, the Irish Government initiated a pilot Healthy Schools Programme based on the World Health Organization Health Promoting Schools Model among children attending schools officially designated as urban and disadvantaged. We present here the first results on physical and emotional health and the relationship between childhood depression and demographic and socioeconomic factors., Methods: The Healthy Schools Programme evaluation was a 3-year longitudinal outcome study among urban disadvantaged children aged 4 to 12 years. Physical and psychological health outcomes were measured using validated, international instruments at baseline. Outcomes at baseline were compared with international norms and where differences were found, results were statistically modeled to determine factors predicting poor outcomes., Results: A total of 552 children responded at baseline, representing over 50% of all eligible children available to participate from 7 schools. Findings at baseline revealed that in general, children did not differ significantly from international norms. However, detailed analysis of the childhood depression scores revealed that in order of importance, psychological well-being, the school environment, social support, and peer relations and age were statistically significant predictors of increased childhood depression in children under 12 years of age., Conclusion: Future health and well-being studies in schools among urban disadvantaged children need to broaden their scope to include measures of depression in children under 12 years of age and be cognisant of the impact of the school environment on the mental and emotional health of the very young., (© 2012, American School Health Association.)

Nurse education curricula have to be continually reviewed to ensure that content remains applicable to contemporary healthcare developments. In this article, the authors report the findings of a research study that investigated the children's nursing component taught in all non-children's BSc Nursing degree programmes in Irish colleges. The aim of the study was to identify how European Union directives and national curriculum guidelines are interpreted in colleges, and to clarify the preparation that non-children's pre-registration nursing students receive with respect to caring for children. The authors explored aspects related to children's nursing in all non-children's undergraduate pre-registration programmes, including curriculum content and its delivery, assessments and practice experiences. Data were collected by a specifically designed questionnaire based on the Requirements and Standards for Nurse Education Programmes (An Bord Altranais, 2005a; b). A university ethics committee provided ethical approval. The response rate was 54% (n=7), and data were analysed using SPSS 16 and content analysis. The authors' findings illustrated that the requirements and standards of all nursing programmes are interpreted in a variety of ways regarding children's nursing. Nationally, nursing content related to children needs to be reviewed in all nursing programmes to ensure consistency among providers. Healthcare requirements for children and families need to be heightened within curricula for all disciplines.

Aim: This paper reports a study that explored the lived experiences of newly qualified registered children's nurses (RCN) in their transition from postgraduate student nurse to staff nurse., Research Question: What are the experiences of newly qualified RCNs in their transition from postgraduate student nurse to staff nurse?, Methods: A qualitative phenomenological approach was chosen for the study and six newly qualified RCNs were interviewed. Data analysis was based on the work of Coliazzi (1978) who devised a seven-step approach to assist the analysis within phenomenological inquiry., Results: Findings indicate that support is the most important aspect of the transition experience for these nurses. Mentorship and preceptorship programmes facilitate support during the transition period and previous experience prescribes the amount of support required by the newly qualified RCN., Conclusion: In highlighting the experiences of newly qualified RCNs in their transition from postgraduate student nurse to staff nurse, this study raises awareness among children's nurses, children's nurse educators and children's nursing managers about this unique group of nurses.

Background: S-1 is a novel oral agent combining the 5-fluorouracil (FU) prodrug tegafur with gimeracil and oteracil, which inhibit 5-FU degradation by dihydropyrimidine dehydrogenase and phosphorylation within the gastrointestinal tract, respectively. The study was designed to identify the maximum tolerable dose and the dose-limiting toxicities of two schedules of S-1 combined with oxaliplatin and bevacizumab, in advanced solid tumor patients., Methods: Schedule A: S-1 was administered orally at 20 mg/m(2) twice daily for 14 consecutive days, escalated by 5 mg/m(2), with fixed-dose intravenous bevacizumab 7.5 mg/kg and oxaliplatin 130 mg/m(2) on day 1 of each 3-week cycle. Schedule B: S-1 was administered at 25 mg/m(2) twice daily for 7 consecutive days, escalated by 5 mg/m(2), with fixed-dose intravenous bevacizumab 5 mg/kg and oxaliplatin 85 mg/m(2) on day 1 of each 2-week cycle., Results: The maximum tolerated dose and recommended phase II dose of S-1 was 25 mg/m(2) twice daily for 14 days for schedule A and 35 mg/m(2) twice daily for 7 days for schedule B. The most common dose-limiting toxicities were grade 3 diarrhea. Both regimens were well tolerated. No pharmacokinetic interactions between oxaliplatin and S-1 components were observed., Conclusions: S-1, oxaliplatin and bevacizumab can be administered with acceptable safety and tolerability and without evidence of pharmacokinetic interactions., (Copyright © 2011 S. Karger AG, Basel.)

Background: To test whether intratumoral gene expression levels and germline polymorphisms predict clinical outcome in metastatic colorectal cancer (mCRC) patients treated with cetuximab and bevacizumab plus irinotecan (CBI) vs. cetuximab and bevacizumab (CB)(BOND2)., Patients and Methods: Genomic DNA was extracted for genotyping from 65 patients (31: CBI arm and 34: CB arm). Thirty five patients had tissue samples available for the gene expression assay (18: CBI arm and 17: CB arm)., Results: High intratumoral gene expression levels of EGFR, VEGFR2 and NRP1 were associated with longer overall survival (OS) in patients receiving combined monoclonal antibodies with or without irinotecan. FCGR3A V158F, CyclinD1 A870G and EGFR R497K polymorphisms are associated with clinical outcome in patients received combined cetuximab and bevacizumab., Conclusions: Intratumoral gene expression levels of EGFR, VEGFR2 and NRP as well as polymorphisms in FCGR3A, CyclinD1 and EGFR could predict clinical outcome in mCRC patients enrolled in BOND2, independent of KRAS mutation status.

Purpose: To evaluate the safety and efficacy of IMC-A12, a human monoclonal antibody (mAb) that blocks insulin-like growth factor receptor-1 (IGF-1R), as monotherapy or in combination with cetuximab in patients with metastatic refractory anti-epidermal growth factor receptor (EGFR) mAb colorectal cancer., Methods: A randomized, phase II study was performed in which patients in arm A received IMC-A12 10 mg/kg intravenously (IV) every 2 weeks, while patients in arm B received this same dose of IMC-A12 plus cetuximab 500 mg/m(2) IV every 2 weeks. Subsequently, arm C (same combination treatment as arm B) was added to include patients who had disease control on a prior anti-EGFR mAb and wild-type KRAS tumors. Archived pretreatment tumor tissue was obtained when possible for KRAS, PIK3CA, and BRAF genotyping, and immunohistochemistry was obtained for pAKT as well as IGF-1R., Results: Overall, 64 patients were treated (median age, 61 years; range, 40 to 84 years): 23 patients in arm A, 21 in arm B, and 20 in arm C. No antitumor activity was seen in the 23 patients treated with IMC-A12 monotherapy. Of the 21 patients randomly assigned to IMC-A12 plus cetuximab, one patient (with KRAS wild type) achieved a partial response, with disease control lasting 6.5 months. Arm C (all patients with KRAS wild type), however, showed no additional antitumor activity. Serious adverse events thought possibly related to IMC-A12 included a grade 2 infusion-related reaction (2%; one of 64 patients), thrombocytopenia (2%; one of 64 patients), grade 3 hyperglycemia (2%; one of 64 patients), and grade 1 pyrexia (2%, one of 64 patients)., Conclusion: IMC-A12 alone or in combination with cetuximab was insufficient to warrant additional study in patients with colorectal cancer refractory to EGFR inhibitors.