Post-treatment Time Points Research Articles

1744P - Mutational profiling of tumour tissue and sequential plasma illustrates emergent clones during treatment in late stage small cell lung cancer (SCLC)

BackgroundSCLC is an aggressive disease with poor prognosis. Despite initial response to chemotherapy and radiotherapy, relapse occurs in most cases. To characterize genomic changes in SCLC over the course of therapy, we explored tracking tumor mutations in cell-free DNA (cfDNA) across post-treatment blood draws and comparing them to pre-treatment plasma and tissue profiles. MethodsWe retrospectively evaluated 235 samples collected from 24 subjects with late stage SCLC treated with first-line chemotherapy or chemoradiation in a prospective observational study. Tumor tissue samples were analyzed with the AVENIO Tumor Tissue Surveillance Kit (For Research Use Only, not for use in diagnostic procedures), a 198-kb next-generation sequencing panel covering 197 cancer genes. Matched peripheral blood mononuclear cells (PBMC), pre-treatment plasma, and multiple plasma from post-treatment timepoints were analyzed with the same panel using the AVENIO ctDNA Surveillance Kit (For Research Use Only, not for use in diagnostic procedures). A median input amount of 29ng cfDNA, 129ng tumor tissue DNA, and 50ng PBMC DNA were sequenced to median deduplicated depths of 4491, 1315, and 6512, respectively. Somatic single nucleotide variants (SNVs) in tissue and plasma were identified by removing PBMC-matched germline or clonal hematopoietic mutations. ResultsWe detected a median of 4 SNVs in tissue samples and a median of 100% (range 66 - 100%) of tissue SNVs in matched pre-treatment plasma. 96% (23/24) of subjects had at least one shared SNV between tissue and plasma, most commonly a TP53 mutation. A median of 7 SNVs were detected in pre-treatment plasma, whereas across all available post-treatment plasma (range 2 - 20 time points per subject), a median of 4 SNVs were detected. 53% of these mutations were not present in pre-treatment plasma or tissue. ConclusionsSomatic mutations found in pre-treatment plasma were concordant with matched tissue, consistent with the highly metastatic nature of SCLC. ctDNA sequencing can provide additional molecular insights; in particular, detecting emergent mutations in ctDNA during treatment could advance our knowledge of SCLC. Legal entity responsible for the studyRoche Sequencing Solutions, Inc. FundingRoche Sequencing Solutions, Inc. DisclosureS. Yaung: Full / Part-time employment: Roche. C. Woestmann: Full / Part-time employment: Roche. L. Xi: Full / Part-time employment: Roche. C. Ju: Full / Part-time employment: Roche. B. Hinzmann: Shareholder / Stockholder / Stock options, Full / Part-time employment: Roche. M. Thomas: Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche. F. Lasitschka: Research grant / Funding (institution): Roche. M. Meister: Research grant / Funding (institution): Roche. M. Schneider: Research grant / Funding (institution): Roche. F.J.F. Herth: Honoraria (institution): Roche. T. Muley: Research grant / Funding (institution), Licensing / Royalties: Roche. B. Wehnl: Full / Part-time employment: Roche. J. Palma: Shareholder / Stockholder / Stock options, Full / Part-time employment: Roche. X.M. Ma: Shareholder / Stockholder / Stock options, Licensing / Royalties, Full / Part-time employment: Roche.

Improving the Workflow Efficiency of an Outpatient Pain Clinic at a Specialized Oncology Center by Implementing Lean Principles

Objective:Adult outpatient oncology pain clinics face many challenges due to the increased number of patients, the restriction of electronic appointment systems, overcrowding, waiting time, and patient dissatisfaction. This project aimed to improve clinic time efficiency, decrease clinic waiting time, and improve patient satisfaction.Methods:Lean thinking concepts and their tools, for example, value-stream mapping and value added (VA)/non-VA (NVA) analysis were used. Electronic appointment system slots were stratified based on patient visit type. A total of 187 patients were included in a time-motion survey at three different occasions: preintervention (n = 67) and two consecutive quarter postintervention time points (n = 64, n = 56). Simultaneously, patient satisfaction was reported quarterly by a quality management office.Results:The pain clinic workflow became more efficient; the mean clinic waiting time decreased from 72.5 min at preintervention to 19.5 and 21 min at the two postintervention quarters, respectively. Moreover, patient satisfaction improved from 75% at the preintervention to 100% and 96.7% at the two postintervention quarters.Conclusions:Redesigning the process of an electronic appointment system using lean thinking considerably decreases patients’ waiting time, improves patient satisfaction, improves resource utilization, allows proper scheduling based on patient visit types, eliminates unnecessary waste processes, and reallocates health-care providers’ time toward direct, individualized patient care.

Transient perturbation in neuro-ophthalmologic function after repetitive subconcussive head impacts: a randomized controlled trial

ObjectiveTo examine the effect of subconcussive head impacts on neuro-ophthalmologic function tested by the King-Devick test (KDT).BackgroundSubconcussive head impacts can lead to insidious neurological impairment if sustained repetitively. The oculomotor system is sensitive to brain trauma; however, neuro-ophthalmologic response to subconcussive head impacts remain unclear.Design/MethodsSixty-eight healthy adult soccer players with at least 5 years of soccer heading experience were randomized into either a soccer heading group (n = 36) or soccer kicking-control group (n = 32). The independent variables were group (heading vs. kicking control) and assessment time points (pre-, 0 hr-, 2 hr-, and 24 hr-post-heading/kicking). At each time point, KDT performance was assessed. Between the pre and 0hr post time points, heading subjects then performed 10 soccer headers, with the ball traveled at 25 mph, over the course of 10 minutes. The control subjects kicked the soccer ball 10 times.ResultsThe heading group experienced a median linear head acceleration of 31.8g per head impact (IQR: 31.1–34.5g) and a median rotational head acceleration of 3.56 krad/sec2 per head impact (IQR: 2.93–4.04 krad/sec2). Conversely, soccer kicks did not result in a detectable level of head acceleration. The kicking control group showed a significant improvement in KDT performance over time, indicating the neuro-ophthalmologic adaptability and learning effect (pre, 42.5 ± 5.7 sec; 0 hr-post, 39.3 ± 5.9 sec; 2 h-post, 38.5 ± 5.8 sec; 24 h-post, 37.3 ± 6.1 sec). However, such improvement was blunted by repetitive soccer headings in the heading group (pre, 43.6 ± 7.8 sec; 0 hr-post, 42.7 ± 7.9 sec; 2 h-post, 42.6 ± 7.8 sec; 24 h-post, 40.7 ± 7.3 sec), as illustrated by significant time × group interactions at 0 hr (p = 0.012) and 2 hr (p = 0.002) post-heading/kicking time points in the mixed-effect regression model.ConclusionsOur data suggest that the neural circuit encompassing the brain and oculomotor system has tremendous abilities to adapt and improve its function if administered repeatedly, but subconcussive head impacts induced by soccer heading can transiently impair neuro-ophthalmologic function and its adaptive property.

Effect of a group-based acceptance and commitment therapy (ACT) intervention on illness cognition in breast cancer patients

ObjectiveIllness cognition is an important predictor of psychological adjustment among breast cancer patients; however, interventions related to illness cognition remain limited. This study aimed to determine the feasibility and effectiveness of a group-based acceptance and commitment therapy (ACT) intervention in improving illness cognition among breast cancer patients undergoing chemotherapy. MethodsA quasi-experimental “time-block” design, with two arms and four assessment time points, was used. Eighty-four patients were recruited from a breast cancer center; 42 patients were assigned to the ACT group and 42 to the health education (HE) group. The ACT group participated in four sessions of group-based ACT intervention in a clinical setting, and the HE group underwent one session of group-based HE. Psychological flexibility, illness cognition, and quality of life were assessed at a pre-intervention time point (T1, baseline), a post-intervention time point (T2, 4 weeks), and two follow-up time points (T3, 8 weeks; T4, 16 weeks). ResultsThe effects of time (p < 0.001) and the interaction of time with group (p < 0.001) on psychological flexibility, illness cognition, and quality of life were significant. The rate of improvement in the ACT group was greater than in the HE group. Significant intervention effects were observed for psychological flexibility, illness cognition, and quality of life at T2, T3, and T4. ConclusionsThe intervention was effective in improving psychological flexibility, illness cognition, and quality of life. However, a randomized controlled trial is needed to confirm the findings of this pilot study.

Using a cultural dance program to increase sustainable physical activity for breast cancer survivors—A pilot study

BackgroundStudies have shown that physical activity can reduce the risk of mortality for female breast cancer patients and improve quality of life, reduce weight, and alter circulating biomarker levels. We conducted a pilot trial to determine the feasibility of increasing physical activity through a cultural dance intervention to achieve similar benefits. MethodsConducted a pilot trial implementing a cultural dance intervention to increase and sustain physical activity for breast cancer survivors, which consisted of a six-month group-based intervention of Hula Dance. Anthropometric measures, fasting blood draws, and self-reported questionnaires to assess physical activity, mood, and quality of life, were completed at baseline, at the end of the 6-month intervention (time point month-6), and at two additional post-intervention time points (month-12 and month-24) to assess sustainability. ResultsA total of 11 women with a median age of 63 years were enrolled in the intervention trial. Eight of the 11 (73%) completed the trial to month-12 and demonstrated an overall significant increase in weekly moderate exercise. There were no significant changes in intra-individual body mass index (BMI). However, there was a sustained post-intervention reduction in waist circumference and significant changes in circulating biomarker levels. For the self-reported measures, there was a significant increase in vigor/activity (p < 0.001; Profile of Mood States-Short Form). ConclusionOur intervention pilot trial demonstrated that a cultural dance program could achieve a sustainable increase in physical activity for breast cancer survivors, with potential to improve quality of life, increase vigor, and decrease levels of circulating cytokines associated with obesity and inflammation.

OS9.5 Evidence that adult glioblastoma adapts to standard therapy though chromatin remodeling

Abstract BACKGROUND Glioblastoma (GBM) tumours recur following standard treatment in almost all cases. We use ‘omics technologies to simultaneously profile pairs of primary and matched recurrent GBM to specifically identify and characterise the cells that resisted treatment, with the aim of determining how to more effectively kill them. MATERIAL AND METHODS We have analysed high coverage RNAseq data from pairs of GBM tumours: primary de novo tumour and matched local recurrence from patients that underwent standard therapy. Our original cohort constituted 23 pairs and our validation cohort was an additional 22 pairs. We also cultured two plates of spheroids directly from a patient’s GBM, treating one with radiation and temozolomide. We monitored growth and captured and sequenced RNA from single cells at two time-points: one week post-treatment when the deviation between untreated and treated spheroid growth curves was most pronounced; and three weeks post-treatment when the growth rate of treated spheroids had recovered. We investigated differential gene expression between primary and recurrent pairs, and single cells pre- and post-treatment, and performed a bespoke per patient gene set enrichment analysis. RESULTS Differential gene expression analysis in 23 tumour pairs indicated a treatment-induced shift in cell states linked to normal neurogenesis and prompted us to develop a novel gene set enrichment analysis approach to identify gene regulatory factors that may orchestrate such a shift. This revealed the significant and universal dysregulation of genes, through therapy, that are targeted by a specific chromatin remodeling machinery. This finding was validated in an independent cohort of 22 further GBM pairs. To understand the therapeutic potential of this finding we must determine whether genes are dysregulated through therapy owing to a) their fixed expression in inherently treatment resistance cells in the primary tumour which get selected during therapy to increase the signal of that profile, or b) changes in expression during the process of cells acquiring treatment resistance. To inspect this, we analysed single cell gene expression data from GBM spheroids pre- and post-treatment. We found that there was significant dysregulation of the genes associated with the chromatin remodeling complex but only at the three-week post-treatment time-point. CONCLUSION Our results indicate that GBM cells are being transcriptionally reprogrammed in response to treatment; the mechanism of which may represent a therapeutic opportunity.

Kinesiology taping with exercise does not provide additional improvement in round shoulder subjects with impingement syndrome: A single-blinded randomized controlled trial

ObjectiveRound shoulder posture (RSP) may exaggerate symptoms of subacromial impingement. The effects of kinesiology taping with exercise on posture, pain, and functional performance were investigated in subjects with impingement and RSP. DesignThis study was a single-blinded randomized controlled trial. SettingAn outpatient rehabilitation clinic in a university hospital. ParticipantsThirty-four subjects with subacromial impingement and RSP. InterventionsKinesiology taping with and without tension was applied 2 times per week for 4 weeks. Both groups also performed strengthening and stretching exercises 3 times per week for 4 weeks. Main outcome measurementsThe pain level, shoulder angle and self-reported score were evaluated at pre-intervention, 2-week post-intervention and 4-week post-intervention time points. ResultsFunctional performance improved after intervention in both groups (p = 0.027). A greater decrease in pain level was related to better functional performance of the shoulder in both groups (r = −0.760 and −0.674; p < 0.010). Moderate correlations were found for posture and functional performance of the shoulder in the intervention group (0.48). ConclusionFour weeks of strengthening and stretching exercises with or without kinesiology taping improved functional performance in subjects with impingement and RSP. Improvement in clinical symptoms was related to better performance of posture.

The Effect of High Intensity Interval Training Versus Steady State Aerobic Training on Skin Microvascular Reactivity in Moderately Active Young Adults: A Pilot Study

A sedentary lifestyle is associated with endothelial dysfunction, leading to vascular pathology and impaired microvascular reactivity (MVR). Enhanced endothelial functioning has been seen in aerobically trained individuals. The purpose of this study was to determine if there was a differential training response of skin MVR in response to high intensity aerobic interval training (HIAIT) as compared to steady state aerobic training (SSAT). The study involved 16 moderately active male students (age: 20.93 &amp;plusmn; 5.05 yrs). They were randomly assigned to one of three groups; HIAIT, SSAT, and control group (CG). Baseline testing was performed to determine the VO2max, lactate threshold, blood pressure, body composition and a post-occlusive reactive hyperemia response (PORH) test was used to assess microvascular reactivity on the right palmer forearm using a moorVMS-Laser Doppler Flowmetry (LDF) These parameters were reassessed after three weeks (mid-point) and six-weeks (post intervention) weeks. Statistical significance was set at p&amp;le;0.05. There were no significant interactions between the variables measured in the three groups over time. There was a positive linear relationship in the SSAT group for PORHmax/time to peak (Tp) at baseline (r = 0.998, p = 0.039), midpoint (r = 0.992, p = 0.083), and the post intervention (r = 0.987, p = 0.103). Training in the SSAT group had improved PORHpeak at midpoint and post intervention time points (r = 0.999, p = 0.22; r = 1, p = 0.006; r = 1, p = 0.011). Training in either the HIAIT or the SSAT group had no significant effect on skin MVR in moderately active young adults. SSAT did display a positive linear relationship with PORHmax/Tp, and PORHpeak, which are variables influencing skin MVR.

Effects of dental general anaesthesia treatment on early childhood caries: a prospective cohort study in China

ObjectivesTo evaluate the success rates of dental procedures, the recurrence rates of caries and changes in oral health-related quality of life (OHRQoL) in children following treatment for early childhood caries...

Outcomes of endovascular treatment of renal arterial stenosis in transplanted kidneys.

ABSTRACTObjective To evaluate the effectiveness and outcomes of endovascular treatment of TRAS with PTA.Materials and Methods We searched our prospectively collected database looking at cases of TRAS between January 2005-December 2011. CCT was the gold-standart for diagnosis of TRAS. Parameters analysed comprised technical aspects, arterial blood pressure variation, and renal function. A minimum follow-up of 24 months was considered.Results Of the 2221 renal transplants performed in the selected period, 22 (0.9%) patients were identified with TRAS. Fourteen (63.6%) were male and mean age was 377±14.8years (12-69). Kidney graft was from deceased donnors in 20 (80%) cases. On doppler evaluation, mean blood flow speed after transplantation, at TRAS diagnosis and after TAP was 210.6±99.5, 417±122.7 and 182.5±81.6mL/sec, respectively (p<0.001). For SBP and DBP, there was a significant difference between between pre-intervention and all post-treatment time points (p<0.001). After 1 month of the procedure, there was stabilization of the Cr level with a significant difference between mean Cr levels along time (p<0.001). After a mean follow-up of 16±4.2 (3-24) months, overall success rate was 100%.Conclusions Endovascular treatment with PTA/stenting is a safe and effective option for managing TRAS, ensuring the functionality of the graft and normalization of blood pressure and renal function.

Suicide Coverage in the Digital Press Media: Adherence to World Health Organization Guidelines and Effectiveness of Different Interventions Aimed at Media Professionals

ABSTRACT This study evaluated the characteristics of suicide news articles in the digital press, their adherence to World Health Organization (WHO) recommendations, and the effectiveness of interventions. We assessed adherence, avoidability, frequency and typology of suicide news over a six-month period in the four main digital media outlets of the Canary Islands (Spain). A brief training and information package intervention to the Canary Islands media outlets was carried out. We compared the quality of media reporting at both the pre-intervention and post-intervention timepoints, and compared the quality of reporting at the post-intervention timepoint in Victoria (Australia), where media interventions have been well-resourced and running for several years. We evaluated 339 suicide news articles: 38 from the pre-intervention period, 64 from the post-intervention period, and 237 from Victoria. News articles showed a very low degree of adherence to WHO recommendations, especially to those recommendations thought to have a protective effect. Post-intervention news articles showed better adherence than pre-intervention ones, but lower than those of Victoria, where constant interventions have been developed for years. We conclude that adherence to WHO recommendations is low. Simple interventions aimed at media professionals can improve adherence. However, constant and complex interventions seem to be more effective.

A psychometric comparison of patient-reported outcome measures used in pediatric hand therapy

Study DesignRetrospective case series. IntroductionPatient-reported outcome measures are important for research and also for informing clinical practice. The Pediatric Outcomes Data Collection Instrument (PODCI) and the Canadian Occupational Performance Measure (COPM) are commonly used in pediatric hand therapy. Both are validated in research, but no data exist regarding their relative merits for clinical practice. Purpose of the StudyThis study compares the psychometric properties of the PODCI and COPM in children receiving hand therapy to examine their relative utility in clinical practice. MethodsWe assessed the psychometric properties of the PODCI and COPM in 75 children receiving hand therapy. Treatment outcomes were assessed simultaneously with the PODCI (Upper Extremity Function and Pain and Comfort scales), COPM (Performance and Satisfaction scales) at baseline and posttreatment time points. Interim scores were included for a subset of patients. Each scale was assessed for responsiveness, ceiling effect, and concurrent and discriminate validity. ResultsAll scales, except PODCI/Pain from interim to completion, were able to detect changes over the course of therapy. However, both COPM scales demonstrated greater responsiveness and less severe ceiling effects than both PODCI scales at all time points. All scales had weak concurrent validity and limited discriminate validity. ConclusionsThe COPM is more responsive to changes during treatment and less hindered by a ceiling effect than the PODCI. Weak concurrent validity between the PODCI and COPM suggests that they measure different things in this population.

Hematological and Biochemical Evaluation of Dogs Undergoing Treatment with Veterinary Dental Gel for the Reduction of Plaque and Dental Calculus

Background: Periodontal disease affects a large proportion of dogs, causing both local and systemic symptoms. Several studies to identify alternative approaches for plaque reduction and removal have been conducted. Recently, Tropiclean Fresh Breath Clean Teeth Gel was introduced as an adjuvant to aid in plaque and calculus removal. This product is formulated using Aloe vera, green tea, and mint; however, studies on the toxic potential of this product have not been performed yet. The aim of this study was to evaluate the influence of Tropiclean Fresh Breath Clean Teeth Gel product on hematological and biochemical profiles in dogs undergoing 90-day treatment with the product.Materials, Methods &amp; Results: Per manufacturers' recommendation, the product should be used daily for 30 consecutive days, and subsequently, as maintenance at two to three times a week. In this study, 48 dogs with periodontal disease who received prolonged daily treatment for 90 consecutive days underwent hematological and biochemical evaluation. During the 90 days’ treatment duration, the animals were examined daily to identify the presence of adverse effects; and changes in halitosis were reported. At pre-treatment time-point, 5 mL of blood was collected via cephalic or jugular vein puncture in EDTA tubes for determining the complete blood count (CBC), and in tubes without EDTA for the urea, creatinine, and ALT levels; in addition, for comparison, blood was collected after 90 days’ treatment. At post-treatment time-point, the hematological and biochemical analyses showed significantly lower total leukocyte count as compared to that at pre-treatment (P &lt; 0.01); comprising lower neutrophil count as the cell type involved (P &lt; 0.05). The other parameters showed no statistically significant differences, demonstrating an absence of the products’ effect in terms of alteration of these profiles. All the dogs showed absence of apathy, vomiting, diarrhea, reduced appetite, or abnormalities in the mucosal color; in addition, all showed improvement in halitosis; of which, 39 showed improvement at 1 weeks’ treatment duration.Discussion: In the present study, the analyzed parameters were used to determine the hemolysis, leukocytes or platelet abnormalities, renal function, and liver injury. The kidneys and liver are organs that are closely linked to the metabolism and excretion of drugs; hence, their functions are often altered by the toxic effects of some substances. Despite the reported toxicity of Aloe vera, in the present study, there were no changes in the hematological and biochemical parameters in the dogs undergoing treatment for 90 days, except for the reduced total leukocyte count with differential reduction of the neutrophil population, indicating the products’ safety at 90-days’ treatment duration. The hematological and biochemical results were corroborated by the result of the absence of abnormal clinical signs at daily evaluation. In the dogs included in this study, the reduction of halitosis was associated with the reduction of the leukocyte count related to the bactericidal and bacteriostatic properties of the active ingredients of Aloe vera such as opirocatechol, cinnamic acid, ascorbic acid, and p-coumaric acid which were reported in the field of dentistry; and with regard to green tea, catechin galatoepigallocatechin (EgCG) may be responsible for the bactericidal and bacteriostatic effects. Thus, the product at 90 days’ treatment duration showed safety, without changes in the hematological and biochemical profiles in the participating dogs.

Improvements in adolescent mental health and positive affect using creative arts therapy after a school shooting: A pilot study

Mass shootings have increased in the United States in recent decades and are associated with adverse psychological outcomes. This pilot study used a pre-post design to evaluate the effectiveness of a two-week creative arts therapy camp at improving the mental health of adolescents exposed to the horrific February 14th shooting at Marjory Stoneman Douglas High School in Parkland, Florida. Participants (n = 34) were rising high school students and participated in visual art, drama, or music therapy. At baseline, a third of participants indicated clinically significant moderate-to-severe depression, a third indicated clinically significant moderate-to-severe anxiety, and nearly two thirds indicated high levels of posttraumatic stress. There were statistically significant reductions in posttraumatic stress (d = .54), depression (d = .34), and anxiety symptoms (d = .52), significant decreases in negative affect (d = .42), and significant increases in positive affect (d = .81) between pre- and post-treatment time points. When drama, music, and visual arts treatments were examined separately, drama therapy significantly improved mental health and positive affect. The vast majority of participants reported that they had fun, gained a deeper understanding of themselves, and felt safe during the treatment. Group-delivered arts therapy may be an effective treatment to improve mental health and affect in adolescents exposed to a school shooting.

Temporal disconnection between pain relief and trigeminal nerve microstructural changes after Gamma Knife radiosurgery for trigeminal neuralgia.

Gamma Knife radiosurgery (GKRS) is a noninvasive surgical treatment option for patients with medically refractive classic trigeminal neuralgia (TN). The long-term microstructural consequences of radiosurgery and their association with pain relief remain unclear. To better understand this topic, the authors used diffusion tensor imaging (DTI) to characterize the effects of GKRS on trigeminal nerve microstructure over multiple posttreatment time points. Ninety-two sets of 3-T anatomical and diffusion-weighted MR images from 55 patients with TN treated by GKRS were divided within 6-, 12-, and 24-month posttreatment time points into responder and nonresponder subgroups (≥ 75% and < 75% reduction in posttreatment pain intensity, respectively). Within each subgroup, posttreatment pain intensity was then assessed against pretreatment levels and followed by DTI metric analyses, contrasting treated and contralateral control nerves to identify specific biomarkers of successful pain relief. GKRS resulted in successful pain relief that was accompanied by asynchronous reductions in fractional anisotropy (FA), which maximized 24 months after treatment. While GKRS responders demonstrated significantly reduced FA within the radiosurgery target 12 and 24 months posttreatment (p < 0.05 and p < 0.01, respectively), nonresponders had statistically indistinguishable DTI metrics between nerve types at each time point. Ultimately, this study serves as the first step toward an improved understanding of the long-term microstructural effect of radiosurgery on TN. Given that FA reductions remained specific to responders and were absent in nonresponders up to 24 months posttreatment, FA changes have the potential of serving as temporally consistent biomarkers of optimal pain relief following radiosurgical treatment for classic TN.

Abstract 456: Circulating tumor cells and cfDNA changes during radiotherapy in patients with head and neck cancer

Abstract Introduction: Head and neck cancer treatment response relies heavily on macroscopic clinical findings. Blood monitoring of circulating markers such as circulating tumor cell (CTC) and cell-free DNA (cfDNA) during treatment may improve earlier detection of responders versus non-responders during definitive radiotherapy. Our work prospectively describes the changes in CTC and cfDNA enumeration during definitive radiotherapy. Methods: Patients with mucosal head and neck squamous cell carcinoma and intact gross tumor were eligible for the prospective IRB-approved PREDICT-HN study. Blood samples were collected pre-treatment, after first treatment, weekly, and post-treatment (CellSave and EDTA tubes). CTC was enumerated using the FDA-approved CellSearch (Menarini Silicon Biosystems) system. Filtered plasma were collected from the EDTA tubes and stored at -80C. cfNA from pre-, mid- and post-treatment timepoints were isolated from the filtered plasma using the MagMAX Nucleic Acid Isolation Kit (Thermo Fisher Scientific) and cfDNA were quantified with Qubit high sensitivity dsDNA assay (Invitrogen). Results: 339 blood samples were collected from 45 patients; 137 had detectable CTC. Eight patients had detectable CTCs (1-3/7.5ml blood) in pre-treatment samples. After 1 fraction of radiotherapy, 16 patients had CTCs detected with 12 who had no CTC detected pre-treatment. 19 (42%) patients had detectable CTC in week 6 of treatment. All patients had detectable CTC at some point during radiotherapy except for one patient who had no CTC detected pre, during and post-treatment. There was no correlation between cancer stage, nodal status and gross tumor volume with detection of CTC. Overall circulating cfDNA levels increased during treatment, with their highest level in the final week of treatment similar to when the majority of CTC were detectable in patients, and lowest at the post-treatment time-point. Conclusions: Our interim results showed, for the 1sttime, to our knowledge, that CTCs can be detected during radiotherapy of head and neck cancer, suggesting mobilization into peripheral circulation during treatment, with as-yet-unknown viability. cfDNA kinetics during treatment correlated with CTC release, may indicate apoptotic change during radiotherapy. Combined cfDNA-CTC as an early marker of treatment response should be investigated. Citation Format: Sweet Ping Ng, Carolyn S. Hall, Salyna Meas, Vanessa N. Sarli, Houda Bahig, Baher Elgohari, Amy Moreno, Heath D. Skinner, Adam S. Garden, David I. Rosenthal, William H. Morrison, Jack Phan, G Brandon Gunn, Steven J. Frank, Clifton D. Fuller, Anthony Lucci. Circulating tumor cells and cfDNA changes during radiotherapy in patients with head and neck cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 456.

Abstract 1465: Priming immunity against SCLC with oncolytic virotherapy

Abstract Small cell lung cancer (SCLC) is an aggressive subtype of lung cancer with few treatment advances over the past 3 decades and poor survival. High levels of tumor infiltrating immune cells are associated with improved SCLC patient survival Independent of tumor stage, patient performance status or treatment. Oncolytic virotherapy presents a new approach where tumor specific infection and replication stimulate host immune responses and increase infiltrating immune cells. Myxoma virus (MYXV) has been widely tested in Australia to control rabbit populations with no toxicity to humans. We have now shown that MYXV selectively infects SCLC cells with no cytotoxicity to normal tissues. In vitro studies were performed using human, murine, and cisplatin-resistant SCLC cell lines. Efficient MYXV infection, replication, and cytotoxicity was observed in all SCLC cell lines with rapid induction of immunogenic cell death (ICD), demonstrating MYXV is effective for SCLC regardless of cisplatin resistance. In contrast, we did not detect productive infection or cytotoxicity in non-tumor cells. Using an optimized conditional genetically engineered mouse (GEM) model (Ad-Cre mediated p53/Rb1/p130 null) we show untreated advanced SCLC tumors are devoid of infiltrating immune cells. Following intrapulmonary MYXV treatment, MYXV localized exclusively within lungs of tumor bearing mice and was cleared by 7 days. Despite clearance within 7 days, a robust immune response was sustained 30 days after MYXV treatment. When intrapulmonary MYXV is administered in combination with anti-PD-1 or anti-CTLA-4, both combinations show greater reduction in tumor burden throughout the lung compared to MYXV alone at the 60 day post treatment timepoint. In addition, the immune cell population localized within SCLC tumors were enhanced following combined MYXV/anti-PD-1 at 60 days post treatment. In our GEM model, MYXV alone results in a statistically significant prolongation of survival compared to both PBS and cisplatin treated animals. To determine the effect of MYXV delivered by intratumoral injection we utilized patient derived xenografts (PDX) and newly developed subcutaneous syngeneic tumor models for SCLC in immunocompetent mice. Following MYXV treatment in PDX tumors we observed extensive necrosis and persisting virus detected 10 days post treatment. In our immunocompetent subcutaneous syngeneic tumor model, MYXV is cleared by 7 days, which is consistent with clearance following intrapulmonary MYXV delivery in our GEM model. This was accompanied by extensive necrosis, reduction in tumor volume, increased infiltrating immune cells, and induction of de novo endogenous tumor specific antibody responses. In conclusion, we demonstrate the potential for MYXV as an oncolytic virotherapy for SCLC, with selective infection leading to enhanced anti-tumor immune responses. Citation Format: Patrick Kellish, Connor Hartzell, Daniil Shabashvili, Masmudur M. Rahman, Maria V. Guijarro, Akbar Nawab, Grant McFadden, Frederic J. Kaye, Maria Zajac-Kaye. Priming immunity against SCLC with oncolytic virotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1465.

An Exploration of Equine-Assisted Therapy to Improve Balance, Functional Capacity, and Cognition in Older Adults With Alzheimer Disease.

Alzheimer disease (AD) is a chronic, progressive dementia syndrome that features cognitive and behavioral symptoms, as well as physical and functional limitations that develop over the course of the disease. As an activity that involves physical and cognitive aspects, equine-assisted therapy (EAT) could be a useful therapeutic approach in conditions that involve physical and cognitive decline. However, to date, there are no reports of the use of this therapy in participants with AD. Within this context, the objective of this case series was to describe the effects of EAT on balance, functional capacity, and cognition in older adults diagnosed with AD. We enrolled 9 participants, of both sexes, with a mean age of 79.7 (7.8) years and a diagnosis of AD. The study intervention comprised 20 sessions of EAT. We evaluated participants at baseline and at the end of the intervention. Outcome measures were balance (force plate), functional capacity (Timed Up and Go test and 30-second chair stand test), and cognition (verbal fluency and Mini-Mental State Examination). Comparison between the pre- and postintervention time points (Wilcoxon test) revealed significant improvements in balance (center of pressure in the anterior-posterior direction, P = .017) and functional capacity (Timed Up and Go test, P = .036, and 30-second chair stand test, P = .012). These findings provide evidence of an association between EAT and improved balance and functional capacity in older adults with AD, with no significant impact on cognitive performance.

Abstract 4461: Analysis of circulating tumor DNA (ctDNA) identifies on-treatment genomic alterations in a phase 2 study of veliparib plus FOLFIRI ± bevacizumab vs. placebo plus FOLFIRI ± bevacizumab in metastatic colorectal cancer (mCRC)

Abstract Changes in plasma ctDNA are used as a surrogate molecular marker of response to determine clinical efficacy and provide insights into potential resistance mechanisms to targeted therapeutics. Detection of genomic alterations in circulating tumor DNA (ctDNA) in colorectal cancer has been widely employed as an approach to measure real-time changes in the tumor genome. In order to understand mechanisms of resistance to the PARP inhibitor, Veliparib (ABT-888), pathogenic alterations in oncogenes and DNA Damage Response (DDR) genes were profiled longitudinally in plasma ctDNA and associated to clinical response to Veliparib concurrent to FOLFIRI +/- Bevacizumab. Methods: 215 serial plasma samples collected at Baseline, Cycle 2 (28 days post-treatment) and at disease progression (Final Visit) from 78 patients (pts) with mCRC in the NCT02305758 clinical trial were selected for the current study, consisting of ~50% partial responders (PR), ~30% stable disease (SD) pts and 5% Non-responders (PD). Detection of ctDNA mutations was accomplished using a targeted, error-correctible NGS assay encompassing 63 cancer driver genes, tumor suppressors &amp; DDR genes. Paired pre- and on-treatment plasma samples were evaluable from 81% pts selected. Results: Veliparib (VPRB) pts with longest PFS experienced the largest fold change reductions in total cfDNA concentration by end of treatment (EOT). Interestingly, in both treatment arms, the ctDNA mutant fraction per pt decreased by EOT (median = -41%). In support of this correlation, the ctDNA mutational burden also decreased by 28% in VPRB pts and 39% in PLAC pts, largely driven by PR pts with longer PFS. Overall, tumor-specific mutations detected in ctDNA had 88% concordance with tissue, particularly in common mCRC driver mutations. Baseline KRAS mutations were detected in 46% pts (mostly PR &amp; PD) and are eliminated or diminished in 28% pts (14% VPRB, 14% Placebo) by EOT. 30 DDR &amp; MMR genes were found to be frequently altered in all pts, notably APC &amp; MSH3, at both baseline and EOT. However, by EOT, RAD1, XRCC3, BRCA1 and CHEK1 mutations were acquired or increased, while TP53BP1, POLD1 and ERCC5 mutations were eliminated or reduced, prominently in VPRB PR pts. Conclusions: Broadly, a reduction in ctDNA fraction and pathogenic mutation burden, notably in KRAS, is evidenced in both treatment arms and appears to trend with longer PFS at least in Veliparib-treated pts. Despite these prognostic ctDNA changes, VPRB-specific DDR mutation changes may provide insight into VPRB mechanism of action and resistance in mCRC and is under further exploration at earlier post-treatment timepoints and in SD pts. These data could add insights into alterations acquired earlier in the treatment regimen and the relationship of these alterations with resistance to PARPi in mCRC. Citation Format: Cyril Y. Ramathal, Erin Murphy, Elizabeth Asque, Arne Jason Grundstad, Peter Ansell, Lei He, Yan Luo, Jordan Berlin, Jeff Waring. Analysis of circulating tumor DNA (ctDNA) identifies on-treatment genomic alterations in a phase 2 study of veliparib plus FOLFIRI ± bevacizumab vs. placebo plus FOLFIRI ± bevacizumab in metastatic colorectal cancer (mCRC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4461.

Patient-reported sexual quality of life after different types of radical prostatectomy and radiotherapy: Analysis of a population-based prospective cohort.

Although patients with prostate cancer face many treatment options, to the authors' knowledge the comparative effects of different surgical and radiotherapy (RT) options on sexual function are unclear. In the current study, a population-based cohort of 835 men with newly diagnosed prostate cancer from 2011 through 2013 was recruited throughout North Carolina in collaboration with the Rapid Case Ascertainment system of the North Carolina Central Cancer Registry. All men were enrolled prior to treatment and followed prospectively using the validated Prostate Cancer Symptom Indices (PCSI) instrument. This analysis compares the sexual dysfunction scores of the PCSI among patients who received external-beam RT (EBRT), EBRT with androgen deprivation therapy (ADT), brachytherapy, nerve-sparing radical prostatectomy (RP), and non-nerve-sparing RP. Propensity scores were used to balance patient characteristics across groups, and multiple imputation was used for missing data. EBRT and brachytherapy resulted in similar PCSI scores through 24months. Compared with those receiving EBRT, patients treated with EBRT with ADT and RP with or without nerve sparing were found to have worse PCSI scores at all posttreatment time points. Preservation of useful sexual function at 24months was associated with treatment type, baseline score, and age. Predicted preservation rates were 14.1% to 70.7% for EBRT, 8.4% to 52.3% for EBRT with ADT, 4.7% to 45.3% for nerve-sparing RP, and 4.8% to 34.5% for non-nerve-sparing RP. The findings of the current study indicate that RT alone results in the best preservation of sexual function, and brachytherapy provides similar outcomes. RT with ADT and nerve-sparing RP yielded similar outcomes, whereas patients treated with non-nerve-sparing RP experienced the worst sexual function. These results help patients to make decisions among the specific types of surgery and RT they face based on each individual's diagnosis.