Intensive Treatment Regimens Research Articles

Intravitreal aflibercept for neovascular age-related macular degeneration in patients aged 90 years or older: 2-year visual acuity outcomes.

The purpose of this study was to investigate the efficacy of intravitreal aflibercept for neovascular age-related macular degeneration (nAMD) in very elderly patients aged 90 years or older at 2 years after treatment initiation. In this multicentre retrospective data analysis from electronic medical record, consecutive treatment-naive patients with nAMD treated with aflibercept with at least 2 years follow-up were stratified into those aged < 90 years (Group I) and an older cohort aged 90 and over (Group II). We compared the visual acuity (EDTRS letters) outcomes at 4 weekly intervals between the two groups over a 2-year period. The mean visual acuity of Group I at presentation was 56.3 ETDRS letters versus 52.8 letters in Group II. Maximal visual acuity was achieved in both the groups by 6 months after initiating treatment (4.7 vs. 4.0 letters gain). By 2 years, the mean visual acuity of the older cohort fell marginally below their baseline visual acuity (0.8 letter loss), while Group I presented +2.1 letters gain. The number of injections given and the retention rate of the older cohort were no different to the rest of the patients. Very old patients with nAMD benefited from aflibercept, but not to the same degree as the younger patients. The study showed that, on an average, the very elderly patients were able to adhere to the intensive anti-VEGF treatment regimens.

Challenges and needs in experimental therapies for multiple sclerosis.

Despite dramatic advances in the treatment of people with multiple sclerosis over the last decade, several unmet medical needs still remain and should be approached with new compounds in experimental clinical trials. The prerequisites for successful clinical trials in multiple sclerosis have changed considerably over time and activities have started to improve clinical development of new drugs in several aspects including trial designs, patient selection and outcome parameters. This review will address some of the challenges in early experimental trials in multiple sclerosis and recent approaches in the field. Highly intensive treatment regimens like autologous hematopoietic stem cell transplantation provide evidence for sustained long-term treatment effects in multiple sclerosis patients. Several different approaches towards neuroprotection and remyelination have entered the clinical phase and demonstrated that stabilization, even improvement of disability is achievable in short-term studies. New therapeutic strategies have entered the clinic with the prospects of long-term efficacy and enduring effects on disability progression.

Preclinical evaluation of a new ROS1 inhibitor to overcome resistance to EGFR therapy in glioblastoma

Glioblastoma Multiforme (GBM) is the most aggressive brain tumor in adults and remains incurable despite multimodal intensive treatment regimens. The majority of GBM tumors show a mutated or overexpressed Epidermal Growth Factor Receptor EGFR; however, tumors treated with EGFR inhibitors such as gefitinib or erlotinib inevitably recur. This recurrence highlights the need to identify signaling pathways involved in GBM resistance to EGFR therapy that may serve as targets for intervention. In our recently published work, we found that activation of the ROS1 pathway is a primary mechanism by which glioma cells become resistant to EGFR‐targeted therapy. ROS1 is a proto‐oncogene receptor tyrosine kinase activated by chromosomal rearrangement in several human cancers, including non‐small‐cell lung cancer (NSCLC), cholangiocarcinoma, gastric cancer, ovarian cancer, and glioblastoma. We therefore, designed, synthesized and screened a series of new ROS1 inhibitors. The lead compound, ROS‐Ic, is very potent (IC50 = 24nM) and highly specific to ROS1 protein. Treatment of gefitinib‐resistant GBM cells with ROS1‐lc sensitized the resistant cells to low concentrations of gefitinib resulting in apoptosis following a prolonged S phase cell cycle arrest. When compared to Crizotinib, an FDA‐approved small‐molecule tyrosine kinase inhibitor currently used to treat ALK‐ and ROS1+ NSCLC patients, ROS‐Ic showed superior cytotoxic activity in vitro towards ROS1‐positive GBM cells. Crizotinib resistance is thought to be due to diminished Crizotinib binding, due to ROS1 mutations in Crizotinib binding pocket. Interestingly, our initial analysis suggests that our lead compound ROS1‐Ic might not be affected by these mutations, highlighting the potential therapeutic value of this compound.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Hyperthermic isolated limb perfusion, preoperative radiotherapy, and surgery (PRS) a new limb saving treatment strategy for locally advanced sarcomas.

This feasibility study presents the results of a new intensive treatment regimen for locally advanced extremity soft tissue sarcomas (ESTS), consisting of hyperthermic isolated limb perfusion (HILP), preoperative external beam radiotherapy (EBRT), and surgical resection. From 2011 to 2016, 11 high grade locally advanced ESTS patients underwent this treatment regimen. Preoperative EBRT (12 × 3 Gy) started <4 weeks following the HILP (TNF-α and melphalan) and the surgical resection was planned to take place <2 weeks following the end of the EBRT. All patients completed the treatment. After a median follow-up of 32 (23-50) months, the limb was saved in 10 patients (91%), 1 patient (9%) developed a local recurrence, 5 patients (45%) developed distant metastases, and 3 patients (27%) died of their disease. During follow-up two patients (18%) developed a pathologic fracture of the treated limb and three patients (27%) developed a major wound complication requiring surgical intervention. The median overall treatment time (OTT) was 56 (49-69) days. This intensive treatment regimen is feasible and safe in locally advanced ESTS, and it achieves oncological results that are comparable with conventional HILP treatment. In addition, the major wound complication risk is comparable and the OTT is reduced.

A Retrospective Study of Double-hit Lymphomas in Elderly Patients (Aged > 70 Years): Overall Outcomes

BackgroundDouble-hit lymphomas (DHLs) are high-grade diffuse large B-cell lymphomas with concurrent translocations involving myc and bcl-2 and/or bcl-6. A patient with DHL often has advanced disease at presentation and typically responds poorly to standard therapy with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone). More intensive treatment regimens have been studied; however, few data are available on the outcomes in elderly patients (aged > 70 years) treated with these therapies. We retrospectively studied the efficacy and tolerability of chemotherapy regimens in elderly patients within the Advocate Healthcare System. Materials and MethodsA system-wide search of patients treated from 2012 to 2017 was completed to identify patients with c-myc with bcl-2 and/or bcl-6 translocations using fluorescence in situ hybridization. The patients were reviewed for the following: age at diagnosis, stage, lactate dehydrogenase, Eastern Cooperative Oncology Group performance status, chemotherapy details, grade 3/4 toxicities, and response to therapy. Overall survival (OS) and event-free survival (EFS) were calculated. ResultsWe identified 17 patients (9 men and 8 women) with a median age of 73 years (range, 70-89 years). Six patients received R-EPOCH (rituximab, etoposide, prednisolone, vincristine, cyclophosphamide, doxorubicin), 5 received R-CHOP, 1 received bendamustine and rituximab, 1 received the MaGrath regimen, and 1 received cyclophosphamide and rituximab. Three patients were not treated and were referred to hospice care. For all patients, the median follow-up period was 25 months, the EFS and OS were 28% at 36 months, and the median survival was 7.5 months. For patients treated with R-EPOCH, the EFS was 33% at 24 months. For the R-CHOP group, the EFS was 40% at 24 months. Most common grade 3/4 toxicities were neutropenia, anemia, thrombocytopenia, and infections and were more common in the R-EPOCH group. Three patients each died in the R-EPOCH and R-CHOP groups. ConclusionAlthough the numbers are small, elderly patients with DHL can achieve durable EFS and OS. Using the comprehensive geriatric assessment can aid in decision making in the treatment options for elderly patients. Our retrospective analysis, given a small sample size, suggests that intensive treatment regimens can be offered to elderly patients with DHL.

Patient at intermediate cardiovascular risk: statins, yes! - antihypertensive therapy, maybe.

Patient at intermediate cardiovascular risk: statins, yes! - antihypertensive therapy, maybe.

Psychological Factors Associated with Episodic Chelation Adherence in Thalassemia

β-Thalassemia major (β-TM) is a life-long genetic hemoglobin (Hb) disorder requiring intensive treatment regimens, including frequent blood transfusions and daily chelation therapy. Understanding psychosocial correlates of chelation adherence is important for developing interventions to improve adherence. This study investigated within-participant correlates of oral chelation adherence on a daily (episodic) basis. Thirty-seven adult participants with β-TM were recruited from clinics at two hospitals (22 males, 9 females, mean age 34.5 years, range 19–54 years). A structured interview was used to assess behavioral and psychological situational variables related to an adherent and a nonadherent episode for each participant. Positive outcome expectancies and higher self-efficacy were both significantly associated with adherent episodes. Behavioral variables, including difficulty in accessing medication, location, and whether alone or with others, were also associated with nonadherent episodes. Findings suggested that situational psychological factors are important for chelation adherence. Adherence interventions should consider focusing on potentially modifiable situational variables (psychological and behavioral).

The Moderating Relationship of Comorbid Psychopathology and Treatment Outcome for Young Adult Offenders in Drug Court

Since its inception, the American criminal justice system has focused on punishing offenders to deter and prevent criminal activity. In 2013, about 2 million American citizens were incarcerated—approximately 716 people per 100,000. Contrary to expectations, incarceration has been consistently demonstrated as widely ineffective for preventing recidivism[3–5]. In particular, offenders with substance abuse issues have become a growing concern within the criminal justice system. Mandatory minimums on drug offenses, combined with the rigorous conviction of non-violent drug offenders, have fueled an extraordinary amount of incarcerated offenders with addictions[6]; Offenders struggling with addictions are about 82% more likely to recidivate than non-addicted offenders upon release[3]. Without adequate substance abuse and mental health services, offenders with addictions are at a higher risk of recidivism upon release into the community. Adult drug court is a problem-solving court created to divert offenders with substance abuse issues from incarceration by focusing predominately on rehabilitation. The drug court system is a collaborative effort between court personnel (e.g. judges, drug court specialists, state attorneys, and public defenders), treatment providers, independent evaluators, and offenders to eliminate addictions. Eligible drug offenders are given the option to participate in drug court; upon agreement, clients are mandated to complete a rigorous and intensive treatment regimen combined with ongoing random drug testing and scheduled court appearances. Contingent upon their completion of treatment, the drug court will dismiss their charges and oftentimes expunge their criminal record. If an offender fails to complete treatment, commits an additional crime or consistently fails drug tests, the individual is convicted and sentenced thereafter.

Abstract A141: Preclinical evaluation of a new ROS1 inhibitor to overcome resistance to EGFR therapy in glioblastoma

Abstract Glioblastoma (GBM) is the most aggressive brain tumor in adults and remains incurable despite multimodal intensive treatment regimens. The majority of GBM tumors show a mutated or overexpressed epidermal growth factor receptor (EGFR); however, tumors treated with EGFR inhibitors such as gefitinib or erlotinib inevitably recur. This recurrence highlights the need to identify signaling pathways involved in GBM resistance to EGFR therapy that may serve as targets for intervention. In our recently published work, we found that activation of the ROS1 pathway is a primary mechanism by which glioma cells become resistant to EGFR-targeted therapy. ROS1 is a proto-oncogene receptor tyrosine kinase activated by chromosomal rearrangement in several human cancers, including non-small cell lung cancer (NSCLC), cholangiocarcinoma, gastric cancer, ovarian cancer, and glioblastoma. We therefore designed, synthesized, and screened a series of new ROS1 inhibitors. The lead compound, ROS-Ic, is very potent (IC50 = 24nM) and highly specific to ROS1 protein. Treatment of gefitinib-resistant GBM cells with ROS1-lc sensitized the resistant cells to low concentrations of gefitinib, resulting in apoptosis following a prolonged S-phase cell cycle arrest. When compared to crizotinib, an FDA-approved small-molecule tyrosine kinase inhibitor currently used to treat ALK- and ROS1+ NSCLC patients, ROS-Ic showed superior cytotoxic activity in vitro towards ROS1-positive GBM cells. Crizotinib resistance is thought to be due to abolished crizotinib binding by ROS1 mutations in crizotinib binding pocket. Interestingly, the binding of our leading compound ROS1-Ic was not affected by these mutations and crizotinib-resistant cells harboring these mutations were still sensitive to ROS1-Ic, highlighting the potential therapeutic value of this compound. Citation Format: Hashim M. Aljohani, Mohamed Aittaleb, Byung Sun Park, So Ha Lee, El Mustapha Bahassi. Preclinical evaluation of a new ROS1 inhibitor to overcome resistance to EGFR therapy in glioblastoma [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A141.

Factors associated with glycemic control in children and adolescents with type 1 diabetes mellitus at a tertiary-care center in Thailand: a retrospective observational study

Abstract Background Children and adolescents with type 1 diabetes mellitus (T1D), even those with intensive insulin treatment regimens, often have higher glycated hemoglobin (HbA1c) levels than adults. Objective To delineate the medical and psychosocial factors associated with glycemic control in an unselected pediatric population with T1D. Methods We included a cross-section of 58 adolescents (28 boys and 30 girls) aged 13.6 ± 4.0 years with T1D ≥1 year attending a well-established pediatric diabetes clinic in Thailand. Median diabetes duration was 4.1 years (range 1–18 years). Participants were divided into 2 subgroups according to their average HbA1c level over the past year. Those with good control (HbA1c &lt;8%) (n = 13) were compared with those with poor control (HbA1c ≥8%) (n = 45). Data collected from self-report standardized questionnaires and medical records were used to compare variables between groups. Results Adolescents with good control used significantly less daily insulin and had higher family income, higher scores for family support, and quality of life (QoL) than those in the group with poor control (P &lt; 0.05). Age, sex, puberty, duration of diabetes, insulin regimen, frequency of blood glucose monitoring, and self-report adherence did not differ between groups. By univariate logistic regression, the only factor associated significantly with poor glycemic control was a QoL score &lt;25. Conclusion Adolescents with T1D may be at a higher risk of poor glycemic control if they have poor QoL, impaired family functioning, poor coping skills, and lower socioeconomic status, suggesting that psychosocial interventions could potentially improve glycemic control in this population.

Predictors of Quality of Life and Other Patient-Reported Outcomes in the PANORAMA Multinational Study of People With Type 2 Diabetes.

PANORAMA, a nine-country cross-sectional type 2 diabetes study, investigated factors associated with quality of life (QoL), health status, and other patient-reported outcome measures (PROMs). Patients were randomly or consecutively selected from primary/secondary care. PROMs included the Audit of Diabetes-Dependent Quality of Life (ADDQoL) (generic QoL item and average weighted impact [AWI] scores), Diabetes Treatment Satisfaction Questionnaire (DTSQ) (patient- and physician-completed), Hypoglycemia Fear Survey-II worry subscale, and the EuroQoL-5 Dimension visual analog scale (EQ-VAS) measuring patient-reported health. Multivariable linear regression analyses determined predictors of each PROM including patient characteristics, physician-reported adherence, complications, and glycosylated hemoglobin. In 5,813 patients, mean PROM scores indicated that generic QoL approximated "good" (0.93); perceived impact of diabetes on QoL was negative (AWI -1.69). Treatment satisfaction exceeded physicians' estimates (patient-reported: 29.76; physician-estimated: 27.75), but so did patients' perceived frequency of hypo-/hyperglycemia. Worry about hypoglycemia (13.27) was apparent. Intensifying treatments to three oral agents or insulin regimens predicted worse QoL (AWI P < 0.01). Insulin alone use predicted worse QoL (generic P < 0.02; AWI P < 0.001) and hypoglycemia worry (P < 0.007). No treatment had significant associations with EQ-VAS health status. Predictors for different PROMs differed markedly and provided insights for understanding and improving these important outcomes. Intensive treatment regimens had significant negative associations with all PROMs, except the EQ-VAS health status measure. The findings demonstrate the importance of measuring QoL alongside health status and other patient-reported outcomes when evaluating diabetes treatments with a view to protecting QoL and facilitating adherence and long-term glycemic control.

Tuberculous Meningitis in Children and Adults: New Insights for an Ancient Foe.

Tuberculous meningitis is the most devastating manifestation of infection with Mycobacterium tuberculosis and represents a medical emergency. Approximately one half of tuberculous meningitis patients die or suffer severe neurologic disability. The goal of this review will be to review the pathogenic, clinical, and radiologic features of tuberculous meningitis and to highlight recent advancements in translational and clinical science. Pharmacologic therapy includes combination anti-tuberculosis drug regimens and adjunctive corticosteroids. It is becoming clear that a successful treatment outcome depends on an immune response that is neither too weak nor overly robust, and genetic determinants of this immune response may identify which patients will benefit from adjunctive corticosteroids. Recent clinical trials of intensified anti-tuberculosis treatment regimens conducted in Indonesia and Vietnam, motivated by the pharmacologic challenges of treating M. tuberculosis infections of the central nervous system, have yielded conflicting results regarding the survival benefit of intensified treatment regimens. More consistent findings have been observed regarding the relationship between initial anti-tuberculosis drug resistance and mortality among tuberculous meningitis patients. Prompt initiation of anti-tuberculosis treatment for all suspected cases remains a key aspect of management. Priorities for research include the improvement of diagnostic testing strategies and the optimization of host-directed and anti-tuberculosis therapies.

Predictors of Favorable Responses to Immunosuppressive Treatment in Pulmonary Arterial Hypertension Associated With Connective Tissue Disease.

The potential efficacy of immunosuppressive (IS) treatment has been reported in patients with pulmonary arterial hypertension (PAH) associated with connective tissue disease (CTD), but its positioning in the treatment algorithm remains uncertain. The aim of this study was to identify predictors of favorable responses to first-line IS treatment.Methods and Results:This single-center retrospective study included 30 patients with PAH accompanied by systemic lupus erythematosus (SLE), mixed CTD (MCTD), or primary Sjögren's syndrome (SS) who received first-line IS treatment alone or in combination with pulmonary vasodilators. When short-term treatment response was defined as an improvement in World Health Organization functional class at 3 months, 16 patients (53%) were short-term responders. Simultaneous diagnosis of PAH and CTD, and the use of immunosuppressants, especially intravenous cyclophosphamide, in addition to glucocorticoids were identified as independent predictors of a short-term response (P=0.004 and 0.0002, respectively). Cumulative rates free of PAH-related death were better in short-term responders than non-responders (P=0.04), and were best in patients with a simultaneous diagnosis of PAH and CTD who were treated initially with a combination of glucocorticoids and immunosuppressants. Patients with a simultaneous diagnosis of PAH and CTD, including SLE, MCTD, and primary SS, should receive intensive IS treatment regimens to achieve better short- and long-term outcomes.

Characteristics of people with high visit‐to‐visit glycaemic variability in Type 2 diabetes

AimsIncreased visit‐to‐visit glycaemic variability is independently associated with adverse outcomes in Type 2 diabetes. Our aim was to identify the patient characteristics associated with raised visit‐to‐visit glycaemic variability in people with Type 2 diabetes.MethodsA case–control study was conducted to establish associations between HbA1c variability and clinical covariates in 10 130 people with Type 2 diabetes. Variability was calculated by two metrics [sd and coefficient of variation (CV)] from a minimum of four HbA1c readings obtained over a 4‐year period. High and low variability groups were defined as the top and bottom tertile of the sd or CV, and used in logistic regression analyses including a number of clinical and biochemical covariates. The analyses were stratified into low mean (< 53 mmol/mol; 7%) and high mean (≥ 53 mmol/mol; 7%) HbA1c groups.ResultsFindings were consistent across both HbA1c groups and variability metrics. Treatment, independent of other factors, was the most strongly associated covariate for the risk of high HbA1c variability. A six‐fold increased risk was observed in the low HbA1c group, between the most and least intense treatment regimens (P < 0.001). Similar findings were present in the high HbA1c group with a three‐fold increase in risk (P < 0.001). In addition, male gender, younger age, reduced HDL‐cholesterol and increased BMI were all found to be independently associated with raised visit‐to‐visit glycaemic variability.ConclusionsIntensive treatment resulting in low mean HbA1c was associated with marked increase in HbA1c variability. Irrespective of diabetes control, the greatest visit‐to‐visit variability was observed in young, insulin resistant men.

Reduced-Intensity Haploidentical Bone Marrow Transplantation with Post-Transplant Cyclophosphamide for Solid Tumors in Pediatric and Young Adult Patients

High-risk, recurrent, or refractory solid tumors in pediatric, adolescent, and young adult (AYA) patients have an extremely poor prognosis despite current intensive treatment regimens. We piloted an allogeneic bone marrow transplant platform using reduced-intensity conditioning (RIC) and partially HLA-mismatched (haploidentical) related donors for this population of pediatric and AYA solid tumor patients. Sixteen patients received fludarabine, cyclophosphamide, melphalan, and low-dose total body irradiation RIC haploidentical BMT (haploBMT) followed by post-transplantation cyclophosphamide (PTCy), mycophenolate mofetil, and sirolimus. All assessable patients were full donor chimeras on day 30 with a median neutrophil recovery of 19 days and platelet recovery of 21 days. One patient (7%) exhibited secondary graft failure associated with concomitant infection. The median follow-up time was 15 months. Overall survival was 88%, 56%, and 21% at 6, 12, and 24 months, respectively. Median survival from transplant date was 14 months with a median progression-free survival 7 months. We observed limited graft-versus-host disease in 3 patients and nonrelapse mortality in 1 patient. We demonstrated that RIC haploBMT with PTCy is feasible and has acceptable toxicities in patients with incurable pediatric and AYA solid tumors; thus, this approach serves as a platform for post-transplant strategies to prevent relapse and optimize progression-free survival.

Abstract 1597: Inhibition of the novel therapeutic target pregnancy associated plasma protein A (PAPP-A) in Ewing sarcoma enhances efficacy of IGF1R targeting in vivo

Abstract Background: Despite intensive treatment regimens, Ewing sarcoma (EWS) patients with metastatic or relapsed disease still face a 5-year overall survival of less than 20%, indicating a clear need for novel targeted therapies. Utilizing ribosomal depleted RNA sequencing of 122 EWS samples (49 cell lines and 73 tumor samples) and 96 normal samples of variable tissues, we previously reported PAPP-A as one of the top 5 genes overexpressed in EWS (&amp;gt; than 4-fold) compared to normal tissue. Notably, PAPP-A showed substantial expression in tumors (median log2FPKM = 3.933, n=122) and minimal expression in normal tissue (median log2FPKM = -1.564, n=96). Pregnancy Associated Plasma Protein A (PAPP-A) is a secreted zinc metalloproteinase, that anchors to cell surface of heparan sulfate proteoglycans and enhances local IGF signaling. Through the release of IGFs from IGFBP-4, IGFBP-2 and IGFBP-5, free, bioactive IGF is being increased in close proximity to its receptors. In pregnancy PAPP-A is highly expressed by placental trophoblasts and represents a key regulator of fetal growth. The impact of IGF signaling in EWS is illustrated by the modest activity of IGF-1R inhibition as a single agent treatment in clinical trials, an approach that is limited by the rapid development of resistance. Methods: In an attempt to investigate the role of PAPP-A in Ewing sarcoma, we used CRISPR/Cas9 technology to target the PAPP-A locus in EWS cell lines and generated PAPP-A knockout clones (EW8, TC32) for further investigation in vitro and in vivo. Additionally, we tested inhibition of PAPP-A proteolytic function in a xenograft NSG mouse model, as a single agent treatment as well as in conjunction with IGF1R inhibition. Results: Knockout of PAPP-A in EWS cell lines utilizing CRISPR/Cas9 technology completely abrogated PAPP-A secretion and metalloproteinase activity in single cell clones, resulting in significantly increased complexed IGFBP-4 and diminished bioactive IGF-1, together with decreased cell growth in vitro. This phenotype could be rescued by recombinant, soluble PAPP-A. In vivo experiments showed that treatment with a monoclonal PAPP-A neutralizing antibody that inhibits the IGFBP-4 proteolytic activity of PAPP-A delays tumor growth of xenografted EWS tumor cells (EW8) in NSG mice. Furthermore, in conjunction with IGF1R inhibition (mAB h7C10), PAPP-A neutralization significantly decreased tumor growth and resulted in prolonged survival of mice (p=0.021).Conclusions: PAPP-A is a novel biologically relevant and highly tumor specific cell surface target in Ewing sarcoma. Our data suggest that neutralization of PAPP-A is a new therapeutic option that merits further evaluation for the treatment of Ewing's Sarcoma. Citation Format: Sabine Heitzeneder, John F. Shern, Lee J. Helman, Javed Khan, Crystal L. Mackall. Inhibition of the novel therapeutic target pregnancy associated plasma protein A (PAPP-A) in Ewing sarcoma enhances efficacy of IGF1R targeting in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1597. doi:10.1158/1538-7445.AM2017-1597

Azacitidine in adult patients with acute myeloid leukemia.

Azacitidine is recommended front-line treatment for older patients with acute myeloid leukemia (AML) who are not candidates for intensive treatment regimens, and was recently granted approval in the European Union for treatment of adult AML. Reviewed here is azacitidine experience in AML, including: mechanistic and pharmacokinetic data; safety and efficacy in controlled trials; treatment effects in AML subpopulations defined by disease characteristics; experience in unselected patients treated in the community setting; clinical outcomes relative to other approved AML therapies; and experience with azacitidine-based combination treatment regimens. Collectively, these data suggest that (a) azacitidine may prolong overall survival to a similar or greater extent than do other approved AML treatments, but with less toxicity, (b) azacitidine may be the preferred treatment option for older patients with unfavorable cytogenetics, and (c) experience and outcomes with azacitidine in the clinic are similar to those seen in clinical trials. Continued investigation of combination regimens on an azacitidine backbone is warranted.

Glut-1 expression in small cervical biopsies is prognostic in cervical cancers treated with chemoradiation

Background/purposeChemoradiation (CRT) is standard therapy for locally advanced cervical cancer (LACC). However, there is a lack of biomarkers to identify patients at high relapse-risk. We examine metabolic (glucose transporter-1 [Glut-1]), hypoxic (hypoxia inducible factor [HIF-1α]; carbonic anhydrase [CA-9]) and proliferative (Ki-67) markers for prognostic utility in LACC. Materials/methods60 LACC patients treated with CRT had pre-treatment biopsies. Immunohistochemistry was performed for Glut-1, HIF-1a and CA-9, to generate a histoscore from intensity and percentage staining; and Ki-67 scored by percentage of positive cells. For each biomarker, treatment response and survival was compared between low and high-staining groups by logrank testing and multivariate analyses. ResultsHigh Glut-1 expression was associated with inferior progression-free survival (PFS), (hazard ratio [HR] 2.8, p=0.049) and overall survival (OS), (HR 5.0, p=0.011) on multifactor analysis adjusting for stage, node positivity, tumour volume and uterine corpus invasion. High Glut-1 correlated with increased risk of distant failure (HR 14.6, p=0.001) but not local failure. Low Glut-1 was associated with higher complete metabolic response rate on post-therapy positron emission tomography scan (odds ratio 3.4, p=0.048). Ki-67 was significantly associated with PFS only (HR 1.19 per 10 units increase, p=0.033). Biomarkers for hypoxia were not associated with outcome. ConclusionsHigh Glut-1 in LACC is associated with poor outcome post CRT. If prospectively validated, Glut-1 may help select patients for more intensive treatment regimens.

Abstract B24: Health related quality of life during cancer treatment: Perspectives of adolescent and young adult cancer patients and caregivers

Abstract BACKGROUND Cancer incidence among adolescent and young adults (AYAs) ages 15-39 has steadily increased over the past 25 years. Moreover, 5-year survival rates for AYAs has not improved in almost 30 years. AYAs with cancer often require an intensive treatment regimen, comprising surgery, chemotherapy, radiotherapy, or a combination. Cancer and its active treatment result in adverse effects, including physical and emotional effects and risk for additional cancers. These have a detrimental impact on health related quality of life (HRQoL) of AYAs with cancer. With a dearth of data to translate into evidence-guided interventions promoting HRQoL, we characterized patients' and caregivers' perspectives regarding cancer and its treatments' impact on HRQoL and strategies to enhance HRQoL. METHODS We conducted qualitative, in-depth semi-structured interviews with AYAs with cancer receiving care at the University of New Mexico (UNM) Pediatrics Hematology/Oncology Clinic and the UNM Comprehensive Cancer Center and caregivers. New Mexico is one of the four “minority-majority” states, with a multiethnic, multicultural, and geographically dispersed population with striking patterns of cancer health disparities. We used community engaged research methods and a purposeful sampling approach, to recruit eligible participants from diverse racial/ethnic and socio-economic backgrounds. We conducted audio-recorded interviews (September through December 2015) focusing on patients' and caregivers' perspectives on the impact of cancer, stressors, coping mechanisms, meaning of life, and strategies to enhance HRQoL. Investigators iteratively reviewed transcripts to create an initial coding structure and transcripts were imported into NVivo 10, a qualitative data analysis program, for final coding. We used the social determinants of health framework to categorize and interpret the data. RESULTS We reached thematic saturation after interviewing 10 AYAs and 10 caregivers, among which there were eight patient-caregiver dyads. AYAs and caregivers expressed acute stress, frustration, anger, and sadness as a result of the cancer diagnosis. AYAs felt a loss of sense of self-worth and self-esteem. Moreover, AYAs and caregivers experienced financial difficulties due to loss of work, reduced work hours, and expenses related to medical care and accommodations; some had to make hard decisions by choosing between basic necessities and medical treatment. AYAs felt stigmatized due to their treatment-related physical appearance and limitation. On a positive note, there were references to inner strength and resolve and discovering the true nature of friendships. When undergoing treatment, a “good day” would be doing “normal” things, spending time with loved ones. There was also the realization that life with cancer meant “live life to the fullest” and “make a difference and help as many people”. Strategies to cope with cancer included maintaining a positive outlook, family support, being engaged, finding distractions, faith, and spirituality. CONCLUSIONS Cancer and its treatment poses a tremendous emotional and financial burden on both patients and caregivers, which they addressed through reframing the meaning of life and positive active coping strategies. Effective interventions to enhance HRQoL among AYAs with cancer and caregivers need to focus on behavioral and lifestyle support coupled with education. Citation Format: Shiraz I. Mishra, Heidi Rishel Brakey, Miria Kano, Andrew Sussman. Health related quality of life during cancer treatment: Perspectives of adolescent and young adult cancer patients and caregivers. [abstract]. In: Proceedings of the Ninth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2016 Sep 25-28; Fort Lauderdale, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2017;26(2 Suppl):Abstract nr B24.

Local ablative radiotherapy of oligometastatic colorectal cancer

Colorectal cancer (CRC) often presents as oligometastatic disease. Currently available intensive systemic treatment regimens, including combination chemotherapy and molecular targeted agents, result in tumor response and transient to long-term disease control in a high percentage of patients, thus raising the question of further management. Secondary resection and ablation, e.g. by surgery or radiofrequency may contribute to long-term survival and even be curative or at least allow a relevant chemotherapy-free interval. These approaches are often limited by the anatomical site, invasiveness and morbidity of the respective procedure. With stereotactic body radiotherapy (SBRT) metastases can be treated with very high efficiency in only a few sessions and achieving long-term control. Identification of clinical studies investigating the use of SBRT for treatment of oligometastases in CRC patients. Control rates in liver and lung metastases and survival after SBRT. Toxicity and side effects of the treatment. A literature search was carried out for prospective and retrospective studies on local SBRT. The SBRT procedure has become a valid treatment option for patients with oligometastatic CRC and should also be considered in clinical practice as an alternative to surgical treatment of metastases or other local ablative techniques.