bluuebunny/crossref_metadata_2025 huggingface dataset:
A phase II study of oraxol in the treatment of unresectable cutaneous angiosarcoma.
Authors: Ravi Vinod , Wagner Michael , Chen Tom Wei-Wu , Loong Herbert H. F. , Mennel Robert Gary , Yen Chueh-Chuan , Clack Glen , Cutler David , Kwan Min-Fun Rudolf , Chan Wing Kai
Published: May 2020

11517

Background: Oraxol is a combination of oral paclitaxel and a novel oral P-glycoprotein inhibitor, HM30181A. Cutaneous angiosarcomas are highly aggressive malignant tumors with poor prognosis. Currently there is no FDA-approved treatment. Methods: This is an open label study evaluating the activity, safety and tolerability of Oraxol 205mg/m2 administered orally, once daily, for 3 consecutive days per week. Planned treatment is for 25 weeks. Subjects included in this study had not received prior therapy with a taxane and did not have metastatic disease. Tumour response was evaluated at 6 weekly intervals using RECIST and photography. A Simon two stage design was used. Results: 18 of 24 enrolled patients (pts); male/female 11/7; median age 77 years (range 56-93), were evaluable at time of analysis. Subjects were recruited during an 18 month period, from Aug-2018 to Jan-2020. Best objective response rates were: CR 22% (n = 4), PR 11% (n = 2), SD 67% (n = 12), PD 0%. 42% of pts with SD had durability > 13 weeks (range 13-25). Median PFS was 38 weeks. All pts remain alive at time of reporting. Furthermore, 5 pts (28%) who had inoperable lesions were deemed operable after Oraxol and received surgical resection. Oraxol was generally well tolerated. Most common adverse events (AEs) G>3 were: diarrhea (n = 1), fatigue (n = 3), neutropenia (n = 9), leucopenia (n = 5), lymphopenia (n = 5). Serious AEs were G3 pneumonia in 2 subjects and G4 neutropenia in 2 subjects, one of which was febrile. All events fully resolved. Neuropathy was uncommon: n = 2 (G1 = 1 @ day 10, G2 = 1 @ day 64). Dose reductions were recorded in 7 subjects. 2 subjects discontinued treatment due to AEs; both asymptomatic pneumonitis seen on CT, which recovered after discontinuation. Following the initial positive results, the protocol has been amended to change the maximum recruitment of subjects from 25 to 43. Conclusions: Oraxol provides an orally administered treatment option for angiosarcoma, with a high and durable clinical benefit rate (CR + PR+ long SD). It is generally well tolerated even in an older patient population; particularly with respect to the the low incidence of neuropathy compared to IV paclitaxel. Recruitment is ongoing. Clinical trial information: NCT03544567 . [Table: see text]
Differential genomic landscape of clinically advanced/metastatic chordomas (mChor) based on primary tumor site.
Authors: Killian Jonathan Keith , Yang Xiaohong Rose , Danziger Natalie , Elvin Julia Andrea , Vergilio Jo-Anne , Lin Douglas I. , Williams Erik Abraham , Ramkissoon Shakti H. , Severson Eric Allan , Hemmerich Amanda , Duncan Daniel , Edgerly Claire I. , Huang Richard , Hiemenz Matthew , Reddy Venkataprasanth P. , McGregor Kimberly , Venstrom Jeffrey , Schrock Alexa Betzig , Alexander Brian Michael , Ross Jeffrey S.
Published: May 2020

11521

Background: We queried whether comprehensive genomic profiling (CGP) could differentiate genomic alteration (GA) differences in mChor based on tumor site of origin Methods: 111 mChor FFPE tissues were sequenced using a hybrid-capture based CGP method to evaluate all classes of genomic alterations (GA). Tumor mutational burden (TMB) was determined on up to 1.1 Mbp of sequenced DNA and microsatellite instability (MSI) was determined on 114 loci. Results: 27 clivus (Cliv), 12 cervical (Cerv), 10 thoracic (Thor) and 44 lumbosacral (Sacr) mChor were compared (Table). A separate set of 18 mChor were submitted as metastasis biopsies with no primary tumor site available (Unk). mChor was generally more common in men with Sacr tumors. Cliv patients were significantly younger (p = 0.00002). GA/tumor was highest in Sacr at 2.9 and lowest Thor at 1.5. All (100%) mChor were MSI stable and the TMB was low ( < 5 mut/Mb) for all cases. CDKN2A and CDKN2B mutation frequencies were highest in Sacr (52% and 46%, p = 0.009 and 0.0109). Potentially actionable GA in PTEN were highest in Thor and Sacr. PTCH1 GA were seen in Cliv and Cerv and PBRM1 GA potentially associated with immune-oncology (IO) drug response were present in all groups. Additional noteworthy targets were seen in all groups but were found in less than 11% of cases throughout the study (Table). Conclusions: Genomic profiles of our mChor cohort differ based on the site of tumor origin in the axial spine. Sacr appear to have the highest frequency of GA and the greatest number of potentially targetable GA. Although MSI and TMB biomarker results do not predict responsiveness, a significant PBRM1 GA frequency in all groups raises the possibility of IO drug benefit for some patients. [Table: see text]
Characterizing the landscape of genomic variants in high-risk pediatric osteosarcoma.
Authors: Marinoff Amanda , Spurr Liam F. , Doan Duong , Corson Laura , Ward Abigail , Li Yvonne Y. , Cherniack Andrew D. , Janeway Katherine A.
Published: May 2020

11530

Background: Survival rates for patients with metastatic and/or recurrent osteosarcoma are poor, and treatment strategies have remained unchanged for more than three decades. Genomic characterization can identify new treatment strategies and improve risk stratification. To date, sequencing studies of osteosarcoma have focused on newly diagnosed patients. We present one of the first reports of osteosarcoma genomics in a high-risk cohort. Methods: 92 samples from 92 patients were sequenced in a CLIA/CAP laboratory with a targeted NGS panel test. Patients were enrolled in one of two studies. The PROFILE study enrolls all patients seen at Dana-Farber Cancer Institute, and the GAIN study enrolls patients with metastatic and/or recurrent cancer at 11 institutions. Sequencing was performed using primary tumor samples at biopsy and/or from sites of metastasis when available. Results: 33 patients were enrolled on the PROFILE study, and 59 were enrolled on GAIN. Diagnostic stage was available for 65 (67%) of patients. 37% had metastatic disease at diagnosis. The 3-year overall survival (OS) was 71% for the entire study population, 56% for patients with metastatic disease at diagnosis, and 81% for patients with initially localized disease. The presence of metastases at diagnosis was significantly associated with poor outcome (p < 0.0087) and was the only independent clinical prognostic factor identified. Genomic analysis revealed frequent alterations in TP53 (37%), RB1 (15%), CDKN2A (13%), MYC (12%), CDKN1A (12%), ATRX (10%), and CCND3 (8%). Patients whose tumors had MYC amplification (defined as ≥ 6 copies) had a 3-year OS of 39% compared with a 3-year OS of 76% in the absence of MYC amplification, a difference with borderline statistical significance (p = 0.051). Conclusions: In the first study to examine genomic alterations detected by targeted gene panel sequencing in a CAP-certified laboratory in a large population of pediatric patients with higher risk osteosarcoma, the most frequently occurring events were similar to those found in prior reports. MYC amplification, reported as a possible poor prognostic factor in other studies, was present in 12% of patients and was associated with a worse OS, though this finding did not reach statistical significance.
Outcomes of patients (pts) with advanced gastro-intestinal stromal tumors (GIST) treated with multi-kinase inhibitors other than imatinib (IM) as first-line treatment.
Authors: Boileve Alice , Dufresne Armelle , Chamseddine Ali N. , Dumont Sarah Naomie , Brahmi Medhi , Adam Julien , Rouleau Etienne , Karanian Marie , Haddad Veronique , Faron Matthieu , Honoré Charles , Meeus Pierre , Le Cesne Axel , Blay Jean-Yves , Mir Olivier
Published: May 2020

11532

Background: IM is the standard first-line therapy in advanced GIST, with a median progression-free survival (PFS) of 30 months. Recent multi-kinase inhibitors (MKIs) such as nilotinib, dasatinib or masitinib have been tested as first-line therapies in phase II/III studies. This might theoretically result in increased PFS (by the addition of a new line of treatment), or in early emergence of resistance to approved MKIs. Methods: A retrospective chart review was performed in GIST pts who received investigational MKIs (in phase II/III trials) as first-line treatment, followed by IM as second line. Data on demographics, molecular profile, PFS, and overall survival (OS) were collected in two French referral centers. Results: Of 47 pts, (57% females), 22 (47%) had a KIT exon 11 mutation, one a KIT exon 9 mutation (2%), one a PDGFR D842V mutation (2%). Five patients were wild-type for KIT and PDGFR. The mutational status was unknown in 18 pts (38 %). From 2005 to 2011, 21 pts (45%) received masitinib, 18 (38%) received dasatinib and 8 pts (17%) received nilotinib. Median PFS on first-line treatment was 18.9 months [95%IC: 9.0-26.0]. Median time-to-failure (TTF) with IM was 19.7 months [95%IC: 14.8-53.4]. Median time to second relapse was 50.2 months [95%IC: 31.2-92.2]. Thirty-five patients (74.5%) were dead at the end of follow-up. The median OS from time of initial diagnosis was 5.9 years [95%IC: 4.5-8.2]. Conclusions: GIST pts who received MKIs other than IM as first-line treatment and IM as second-line had a time to second relapse longer than that observed historically with IM in first line. This suggests that using MKIs other than IM in first line does not decrease IM efficacy in second line. Further comparative studies are needed to confirm these findings, but this is encouraging to further develop studies with other MKIs in the first line setting.
Identification of SDHA germline mutations in sporadic SDHA mutant gastrointestinal stromal tumors (GIST): The need of a genetic counselling.
Authors: Nannini Margherita , Urbini Milena , Indio Valentina , Schipani Angela , Vincenzi Bruno , Silletta Marianna , Grignani Giovanni , Tolomeo Francesco , Rizzo Alessandro , Fumagalli Elena , Conca Elena , Saponara Maristella , Astolfi Annalisa , Pantaleo Maria A.
Published: May 2020

11537

Background: SDH- deficient GIST, as defined by the loss of expression of SDHB, account up to about 10% of all gastric GIST and generally affect younger population. Germline mutations in SDHB, SDHC, and SDHD occur in about 20–30% of SDH- deficient, that may be referred to a hereditary condition known as hereditary GIST-paraganglioma syndrome (Carney-Stratakis Syndrome), whereas germline SDHA mutations have been rarely described in apparently sporadic cases. Currently, even germline testing is recommended for SDH- deficient GIST, there are no clear guidelines for genetic counselling and follow-up of SDH x mutation carriers and relatives, especially for SDHA mutant GIST not yet linked to well-defined hereditary syndrome. The aim of this work was to study the SDHA gene in the normal DNA of patients with SDHA mutant GIST. Methods: Thirteen patients carrying SDHA-mutant GIST were studied (8F/5M). Median age of diagnosis was 45,9 years (range 25-74). All GIST were located in the stomach and 3 patients out 13 presented a metastatic disease. In all cases except one, the GIST was the only cancer presentation and no personal or familial history of cancer was revealed. All cases were negative for SDHB immunohistochemistry. Germline mutations were identified through Sanger sequencing of SDHA in the normal counterpart. Results: Germline mutations were identified in all patients for which normal counterpart was available: 4 cases harboured truncating mutations (S384X, R31X and W119X); 5 cases carried pathogenic missense mutations (G233V, R171H, R589Q, G257A and R600Q) and 2 cases had splice site alterations (c.457-3_457-1 delCAG and c.456+9 C > T). In 8 cases the tumor DNA showed the loss of the corresponding wild-type allele, while in the other 3 cases compound heterozygosity for an additional somatic mutation was detected (R589W, R451C,and R171C). In 2 patients, unfortunately, normal DNA was not available, however both tumours carried two mutational hits on SDHA (one with heterozygous G419R and E564K, and one with homozygous R585Q). Of note, 5 patients presented un-usaul SDHA related clinical characteristics as were not young adult ( > 50 years-old) or no multifocal GIST. Conclusions: We demonstrated that germline SDHA mutations are highly frequent in SDHA- deficient GIST. Therefore, although a clear syndrome has not been defined, genetic counselling and follow-up of SDHA mutation carriers and relatives should be clarified.
Efficacy and safety of hypofractionated preoperative radiotherapy in treatment of patient with primary locally advanced soft tissue sarcoma of limbs/trunk wall.
Authors: Kosela Hanna , Spalek Mateusz , Borkowska Aneta , Teterycz Pawel , Morysinski Tadeusz , Wagrodzki Michal , Goryn Tomasz , Zdzienicki Marcin , Rutkowski Piotr
Published: May 2020

11555

Background: Soft tissue sarcomas (STS) are rare often malignant tumors. The primary treatment of most STS is radical resection with adjuvant radiotherapy. Our previous study showed that the use of preoperative hypofractionated radiotherapy is safe and efficient in the treatment of unselected group of patients with STS. Aim of this study was to assess the use of the treatment scheme in patients with primary STS treated in one institution. Methods: 311 patients (52% female) with primary locally advanced STS participated in this prospective trial conducted from 2010 till 2017. Median age was 55 years (range: 17-91). Median follow up is 57 months (95%CI 55-61). The most common subtypes were pleomorphic sarcoma, liposarcoma and synovial sarcoma. Median tumor size was 11cm. 258 patients (83%) had high grade tumors. The most common tumor localization were lower limbs (72%). 30% of patients received preoperative chemotherapy. For five consecutive days radiotherapy in 5 x 5Gy fraction was applied, with immediate (2-4 days) resection of the tumor. Results: In 260 patients (83.6%) clear surgical margins (R0) were obtained. 107 patients were dead at the time of the analysis.5-year overall survival is 63%. 156 (50%) had a recurrence of the disease. Local recurrence (LR) was found in 13.8% of the patients. Median time from surgery to LR was 14.7 months. In 56% of patients with LR another limb spearing radical surgery could be performed. Factors that had a significant adverse impact on LR were histological subtype (p = 0.017) and surgical margin status (p = 0.013). Factors that had a significant adverse impact on overall survival were tumor size (p < 0.0001), grade (p = 0.0047) and surgical margin status (p = 0.013). 96 patients (30.8%) had any kind of treatment toxicity, factor having negative impact on the toxicity was lower limb location of the tumor (p = 0.0012). 20 patients (6.4%) required surgery for treatment of the complications. 14.6% patients had prolonged healing of the wound ( > 1 month), 8.3% had wound dehiscence, 1.4% required prolonged punctures of the lymph fluid, 2.3% had severe fibrosis leading to contracture of limb, 11% patients prolonged edema of the operated limb. 0.9% of patients had a fracture of the treated limb. Conclusions: In this group, with a big percentage of patients with large, high grade STS use of hypofractionated preoperative radiotherapy was associated with similar local control when compared to published studies. The early toxicity is tolerable, with a small amount of late complications.
ACUFOCIN: Randomized clinical trial of ACUpuncture plus standard care versus standard care alone FOr Chemotherapy Induced peripheral Neuropathy (CIPN).
Authors: Wardley Andrew M. , Ryder David , Misra Vivek , Hall Peter S , Mackereth Peter , Stringer Jacqui
Published: May 2020

12003

Background: CIPN is a dose limiting toxicity, and a major clinical challenge. This study aims to explore the use of acupuncture with standard care (Acu +SC) against SC alone, to reduce symptoms of CIPN. Methods: A phase II, randomised, parallel group design was used to investigate the effectiveness of a 10 week course of acupuncture to manage CIPN. Patients experiencing CIPN ≥ Grade II (CTCAE v4.03), recording a ‘Most Troublesome’ CIPN symptom score of ≥ 3 using the "Measure Yourself Medical Outcome Profile" (MYMOP 2), were randomised (1:1) to either Acu+SC or SC alone. The primary end-point was a ≥ 2 point improvement in MYMOP2 score at week 10 (logistic regression adjusted for stratification factors and baseline MYMOP2 score). The necessary sample size was 100 patients;120 were randomised to allow for attrition (90% power; 10% one-sided alpha), for a hypothesised improvement in success proportions from 30% to 55%. Results: 120 patients were randomised to ACUFOCIN; diagnosis: breast 61 (51%), multiple myeloma 9 (8%), GI 48 (40%), gynaecological 2 (2%). MYMOP2 score for most troubling CIPN symptom at baseline: 3-4 33 (28%), 5-6 87 (73%). CTCAE CIPN at baseline; grade II 103 (86%), grade III 17 (14%). Baseline characteristics were balanced between arms. Primary outcome data were available for 108 participants with 36/54 (67%) successes in the Acu+SC arm compared to 18/55 (33%) in the SC arm. Adjusted success odds ratio was 4.3 (95% CI 1.9-9.6; p < 0.001; Acu+SC vs SC). Additionally, 27/53 (51%) participants achieved a CIPN success (grade ≤ I) in the Acu+SC arm compared to 4/56 (7%) in the SC arm with adjusted odds ratio 13.1 (95% CI 4.1-41.7; p < 0.001; Acu+SC vs SC). Significant reduction in week 10 pain score; mean difference (SC+Acu – SC alone) -1.45 with 95% CI (-2.25, -0.65) after adjustment for week 1 pain, breast cancer diagnosis and treatment complete status. (note pain on a 0-10 scale). Significant increase in the EORTC QLQ-C30 summary score; mean difference (SC+Acu – SC alone) 9.51 with 95% CI (5.01, 14.02) after adjustment for the baseline score, breast cancer diagnosis and treatment complete status. (note summary score on a 0-100 scale). Significant effects seen at week 10 are also present at week 6. The week 6 effect estimates are consistently less than the week 10 effects (but not usually statistically significantly so). Conclusions: In this patient cohort, a 10 week course of acupuncture significantly improved symptoms of CIPN. These results support further investigation within a phase III trial. Clinical trial information: NCT02275403 .
Randomized trial of a perioperative geriatric intervention for older adults with cancer.
Authors: Qian Carolyn L. , Knight Helen P. , Ferrone Cristina R. , Kunitake Hiroko , Fernandez-del Castillo Carlos , Lanuti Michael , Qadan Motaz , Ricciardi Rocco , Lillemoe Keith D. , Kaslow-Zieve Emilia R. , Azoba Chinenye C. , Franco-Garcia Esteban , O'Malley Terrence A. , Jackson Vicki A. , Greer Joseph A. , El-Jawahri Areej , Temel Jennifer S. , Nipp Ryan David
Published: May 2020

12012

Background: Older adults with gastrointestinal (GI) cancers undergoing surgery often experience poor outcomes, such as prolonged postoperative (post-op) length of stay (LOS), intensive care unit (ICU) use, and readmissions. Involvement of geriatricians in the care of older adults with cancer can improve outcomes. We conducted a randomized trial of a perioperative geriatric intervention in older adults with GI cancers undergoing surgery. Methods: We randomly assigned patients age ≥65 with GI cancers planning to undergo surgical resection to receive a perioperative geriatric intervention or usual care. Intervention patients met with a geriatrician preoperatively in the outpatient setting and post-op as an inpatient consultant. The geriatrician conducted a geriatric assessment and made recommendations to the surgical/oncology teams. The primary end point was post-op LOS. Secondary end points included post-op ICU use, readmission risk, and patient-reported symptom burden (Edmonton Symptom Assessment System [ESAS]) and depression symptoms (Geriatric Depression Scale). We conducted both intention-to-treat (ITT) and per protocol (PP) analyses. Results: From 9/13/16-4/30/19, we randomized 160 patients (72.4% enrollment rate; median age = 72 [65-92]). The ITT analyses included 137/160 patients who underwent surgery (usual care = 68/78, intervention = 69/82). The PP analyses included the 68 usual care patients and the 30/69 intervention patients who received both pre- and post-op intervention components. In ITT analyses, we found no significant differences between intervention and usual care in post-op LOS (7.2 v 8.2 days, P = .37), ICU use (23.3% v 32.4%, p = .23), and readmission rates within 90 days of surgery (21.7% v 25.0%, p = .65). Intervention patients reported lower depression symptoms (B = -1.39, P < .01) at post-op day 5 and fewer moderate/severe ESAS symptoms at post-op day 60 (B = -1.09, P = .02). In PP analyses, intervention patients had significantly shorter post-op LOS (5.9 v 8.2 days, P = .02) and lower rates of post-op ICU use (13.3% v 32.4%, p < .05), but readmission rates were not significantly different (16.7% v 25.0%, p = .36). Conclusions: Although this perioperative geriatric intervention did not have a significant impact on the primary end point in ITT analysis, we found encouraging results in several secondary outcomes and for the subgroup of patients who received the planned intervention. Future studies of this perioperative geriatric intervention should include efforts, such as telehealth visits, to ensure the intervention is delivered as planned. Clinical trial information: NCT02810652 .
Impact of palliative care on end-of-life outcomes in hematologic malignancies.
Authors: Pelcovits Ari , Decker Dominic , Guyer Dana , LeBlanc Thomas William , Olszewski Adam J. , Egan Pamela
Published: May 2020

12026

Background: Patients (pts) with hematologic malignancies (HMs) receive more aggressive end-of-life (EOL) care and often die in the hospital. The impact of palliative care (PC) on EOL quality outcomes in HMs has not been well described. In 2017 we embedded a PC specialist within our inpatient malignant hematology team to facilitate the use of early PC. We sought to determine if this practice was accompanied by a shift in EOL outcomes. Methods: We conducted a retrospective review of pts diagnosed with acute myeloid leukemia (AML) at our institution in the 2 years before (Cohort A) and after (Cohort B) implementation of embedded PC. We identified pts who received PC and if it was early (during initial inpatient stay) or late (sometime after). We then examined EOL quality outcomes: hospitalizations and intensive care (ICU) admissions in the last 30 days of life, chemotherapy use in the last 14 days of life, and use of hospice and death out of hospital (DOH), using Fisher’s exact test to compare proportions. Results: Among 139 AML pts, 46 in Cohort A, 93 in Cohort B, we identified 34 and 47 decedents in each cohort respectively. The use of PC was significantly higher in Cohort B (75% vs 43%, P= 0.0006), with a significant increase in early PC (52% vs 11%, P < 0.0001). There was no significant improvement in EOL quality outcomes between Cohort A and B, or uniquely among pts receiving early PC ( P > 0.05); however, PC use in general across all cohorts was associated with significant increase in hospice use and fewer ICU admissions ( P =0.016 and 0.0043, respectively). Among pts not receiving PC, a numerical improvement was noted in EOL metrics between Cohorts A and B ( P > 0.05; see table). Conclusions: PC for pts with AML was associated with significantly better EOL quality outcomes. We also observed improvement in EOL metrics over time among pts not receiving PC, which may indicate a culture shift with the embedded PC service, whose benefit extended to pts not directly receiving PC. Embedding a PC specialist and early PC in AML, however, was not significantly associated directly with EOL care improvements. The value of these interventions in HMs may be better measured using patient-reported outcomes and quality of life measures rather than strict EOL outcomes. Further research should consider potential differential role of PC among pts with HM undergoing aggressive/curative, or non-intense/palliative therapy. [Table: see text]
Association between chronological age and geriatric assessment (GA) to identify deficits in elderly adults with cancer: Findings from the Care Registry.
Authors: Williams Grant Richard , Al Obaidi Mustafa , Weaver Alice , Kenzik Kelly , McDonald Andrew Michael , Pergolotti Mackenzi , Smith Crystal Young , Gbolahan Olumide B. , Paluri Ravi Kumar , Bhatia Smita , Giri Smith
Published: May 2020

12048

Background: Although ASCO and NCCN guidelines recommend that adults with cancer diagnosed at age ≥65y undergo a GA, the association between chronologic age and GA identified deficits remains understudied, and thus, the appropriate age cut-off for employing GA in clinical settings remains unknown. We addressed this gap by examining the association between chronologic age and GA deficits in older adults with cancer. Methods: The Cancer and Aging Resilience Evaluation (CARE) is an ongoing prospective registry of older adults (≥60y) with cancer at a single site. Eligible patients underwent a patient-reported GA adapted from the Cancer and Aging Research Group. The association between age categories (10y increments) and presence of GA deficits was tested using chi-squared tests of trend. Linear association between age and GA deficits was examined using Pearson correlation. Results: The median age at enrollment was 70y (60-96) for 08 participants; 58% were male. Most common cancer types were colorectal (27%), pancreatic (17%), and hepatobiliary (12%). No significant correlation was found between chronologic age and the number of GA deficits (r = 0.03). There was no association between the youngest (60-70y) vs. the oldest age groups (≥80y) with respect to the prevalence of GA deficits: frailty (33% vs. 33%, p= 0.97); impairment of activities of daily living (ADL) (20% vs. 16%, p= 0.7);impairment of instrumental ADL (50% vs 60%, p= 0.3); malnutrition (42% vs. 33%, p =0.4), cognitive impairment (8% vs. 6%, p= 0.6), falls (19% vs. 30%, p 0.1), anxiety (19% vs. 11%, p= 0.1) and depression (13.4% vs. 13.7%, p= 0.2) (Table). Prevalence of 3+ comorbidities was higher in the older patients (45% vs. 59%, p= 0.03). Conclusions: In our cohort of older adults with mostly gastrointestinal malignancies, age was not associated with GA identified deficits and the prevalence of most impairments was similar across age-groups. The use of chronologic age alone to identify which patients may benefit from GA is problematic, and adults 60yrs and above, or perhaps even younger, may derive benefits from a GA. [Table: see text]
Moving toward precision: Understanding the heterogeneity of obesity.
Authors: Hung Kin Wai (Tony) , Dong Tien , Elashoff David , Mayer Emeran , Jacobs Jonathan , Lagishetty Venu , Gupta Arpana (Annie)
Published: May 2020

12054

Background: Obesity is a global health epidemic and has been linked to detrimental impact on cancer incidence, recurrence, and mortality. Growing evidence have recognized the complex biopsychosocial relationship including microbial phenotypes that undermines the carcinogenic potential and heterogeneity of obesity. A precision understanding on obesity while at its infancy is necessary to accelerate reduction of its impact on cancer outcomes. Methods: With our aim to better understand the biopsychosocial relationship on obesity, we conducted a cross sectional study in healthy and obese individuals. Univariate and multivariate logistic regression models were used to examine obesity and its association with sociodemographic (age, gender, ethnicity, education, income, and marital status), clinical (waist to hip ratio), dietary-behavioral (daily calorie, fat, carbohydrate, protein consumption, and preference on cultural diet), and biological factors (gut microbiome). Parameters were controlled and corrected for multiple hypothesis testing. Gut microbial data using 16S rRNA sequencing were analyzed for alpha diversity, beta diversity, and association of taxa abundance. Results: Among 171 participants between July 2013 and August 2018, individuals were found to have a higher BMI if they were Hispanic [Adjusted Odds Ratio (AOR) 3.36, 95% CI 1.27-8.90], had an obese waist to hip ratio (AOR 8.51, 95% CI 3.45-21.02), and consumed an American diet (AOR 4.82, 95% CI 1.74-13.34). Multivariate permutation analysis controlling for BMI, sociodemographic, clinical, and dietary parameters found that Hispanic have a significantly different microbiome profile than non-Hispanic (p = 0.042). While microbial species richness (Chao1) were similar (p = 0.22), Hispanic had a lower microbial species evenness (Shannon) compared to non-Hispanic (p = 0.029). Differential expression of microbial species revealed a positive correlation of Firmicutes:Bacteroidetes ratio in individuals with higher BMI and consumed an American diet whereas a negative correlation to Hispanic ethnicity. Conclusions: Obesity association to Hispanic ethnicity uniquely expressed through microbial signature despite sociodemographic, clinical, and dietary differences. Microbial characterization as an emerging predictive marker for oncology therapeutics may also serve as selection biomarker in onco-obesity practices and clinical trials. Addressing ethnic disparities guided by microbial phenotypes may unlock novel understanding of obesity heterogeneity and transform its impact on cancer care.
The impact of high intensity interval training on functional performance, body composition and quality of life in a diverse group of cancer survivors.
Authors: Beebe-Dimmer Jennifer Lynn , Finlay David , Ruterbusch Julie J. , Baird Tara , Simon Michael S. , Abrams Judith , Harper Felicity W. K.
Published: May 2020

12057

Background: Given the well-documented benefits of regular exercise to cancer survivors, in 2012, an expert panel assembled by the American Cancer Society recommended that patients engage in at least 150 minutes per week of moderate-to-vigorous physical activity. However, few patients meet this goal. We have also observed racial differences in reported participation in regular exercise among cancer survivors living in Metropolitan Detroit, Michigan. Methods: The CAPABLE study is a 12- week pilot exercise intervention that introduces cancer survivors to the sport of CrossFit. We evaluated the impact of this unique, high-intensity interval training method on functional performance, cardiovascular endurance, body composition and health-related quality of life (HRQOL) as measured by the Functional Assessment of Cancer Therapy (FACT) instrument. All measures were summarized at baseline and program exit. Paired signed rank tests were used to assess change in each of these measures over time. Results: Of the 48 participants enrolled in the pilot, 37 (77%) were considered adherent to the program (attending at least 75% of sessions over the 12-week period). The mean age of participants was 58.5 years, 73% identified as African American and the majority of participants were breast cancer survivors (N = 20). The mean body mass index (BMI) at baseline was 32.8 kg/m2 decreasing to a mean of 31.7 kg/m2 at exit (BMI change -1.1, p < 0.001). Similar changes were observed in % body fat measured by bioelectrical impedance. There were significant improvements in all measures of functional performance over 12-weeks (all p < 0.001). We observed significant and meaningful improvements in reported HRQOL measured by the FACT survey, overall (FACTG total change +9.5 (p < 0.001)) and in each one of the individual domains (physical, social, emotional, and functional well-being). Conclusions: We observed significant improvements in performance, body composition and quality of life among cancer survivors introduced to a high-intensity interval training program. Understanding and eliminating barriers to programs like these are critical to improving outcomes and reducing cancer health disparities. Clinical trial information: NCT03750981 .
Effects of radiation therapy on clonal hematopoiesis.
Authors: Modlin Leslie Ann , Wijetunga N. Ari , Patel Minal , Gao Teng , Ptashkin Ryan , Sullivan Michael R , Kelly Daniel W. , Caltabellotta Nicole , Solit David B. , Berger Michael F. , Tallman Martin S. , Diaz Luis A. , Zehir Ahmet , Papaemmanuil Elli , Levine Ross L. , Bolton Kelly L , Braunstein Lior Zvi
Published: May 2020

12062

Background: Clonal hematopoiesis (CH), characterized by recurrent somatic mutations in blood, is a common age-associated condition that portends an increased risk of myeloid neoplasms and cardiac disease. Oncologic therapies appear to promote CH, including ionizing radiation therapy (RT) (OR = 1.4, p < 10−6) and systemic DNA-damaging agents (OR = 1.2, p = 8x10−4). How various RT parameters (e.g. target site, dose, fractionation, modality) may influence CH is unknown. Methods: CH mutations were identified via targeted, deep-coverage next-generation sequencing from paired peripheral blood and tumor samples (MSK-IMPACT). CH was defined as a somatic blood mutation with a minimum variant allele frequency of 2%. Putative driver mutations (CH-PD) were identified from OncoKB and other published sources. Clinical and RT characteristics were abstracted from medical records. To account for differences in RT dose and fractionation, equivalent radiation dose in 2 Gy fractions (EQD2) with an α/β ratio of 3 for late effects was calculated. Univariate and logistic regression modeling for associations between clinical and treatment parameters and CH were performed. Results: We identified 2,195 patients who received RT before blood draw and 7,832 who did not, encompassing 57 histologies. A median of 267 days elapsed between the end of RT and blood draw. After RT, 22% of patients had at least one CH-PD mutation (n = 486). The most common single anatomic sites radiated were pelvis, chest wall/breast, and head and neck. Conventional RT was used in 2% (n = 46), 3D-conformal in 14% (n = 308), intensity modulated RT in 36% (n = 787), volumetric modulated arc RT in 12% (n = 263), multiple techniques in 26% (n = 560), and unknown in 11% (n = 231). There was no association between RT modality and presence of CH-PD (p > 0.05 for all between group comparisons of modality). On multivariate regression after controlling for age, race, time from diagnosis to blood draw, smoking status, and for chemotherapy class, cytotoxic, immune, or targeted therapies in the entire cohort, EQD2 was associated with CH-PD (p = 0.012x10−3). Evaluating EQD2 by irradiated anatomic site, total pelvic dose by EQD2 in 10 Gy increments remained significantly associated with CH-PD (OR = 1.07, p = 0.0046), as was head and neck EQD2 (OR = 1.046, p = 0.032). Conclusions: CH-PD was associated with higher radiation dose for pelvic or head and neck RT, but not other anatomic sites after controlling for systemic therapies. RT modality was not associated with CH-PD. Ongoing work will directly evaluate the bone marrow dosimetry of various treatment approaches using phantom-based modeling.
Long-term cancer survival in cohorts of U.S. health professionals.
Authors: Cheng En , Lee Donghoon , Tamimi Rulla M , Hankinson Susan , Willett Walter C , Giovannucci Edward L. , Eliassen Heather , Tworoger Shelley , Meir Stampfer , Mucci Lorelei A. , Fuchs Charles S. , Spiegelman Donna
Published: May 2020

12075

Background: Few studies have investigated long-term survival and causes of death among men and women diagnosed with major cancers. Methods: We estimated overall and cause-specific mortality rates for men diagnosed with prostate, lung and bronchus, colon and rectum, bladder, and melanoma cancer in the Health Professionals Follow-up Study between 1986-2010+, and women with breast, lung and bronchus, colon and rectum, uterine corpus, thyroid, and ovarian cancer in the Nurses’ Health Study (NHS) between 1976-2010+ and NHS II between 1989-2010+. Kaplan-Meier curves were used to calculate cumulative mortality rates at 5, 10, 15, 20, and 30 years and competing risk methods were used to calculate cumulative cancer-specific mortality rates of major causes at 5, 10, 15, 20, and 30 years. Additionally, among women 40-year mortality rates were calculated. Results: Except for lung and ovarian, most major cancer patients are more likely to die from other causes than the index cancer. We observed two basic patterns for cumulative cancer-specific mortality rates. The first pattern is greatly diminished risk of index cancer-specific mortality 10 years or more following diagnosis - for colorectal cancer, cancer-specific mortality rate increased by less than 3% between 10 to 30- or 40-year following diagnosis (among men, from 35.1% to 36.7%; among women, from 34.8% to 37.7%), and this pattern also applied to bladder, melanoma, or uterine corpus cancer. The second one is sustained, but nevertheless low, excess risk - prostate cancer-specific mortality rate increased gradually and almost linearly from 5.3% to 15.1% after diagnosis from 5 to 30 years, and for breast cancer, it increased likewise from 7.2% to 18.9% after diagnosis from 5 to 40 years. Conclusions: Except for lung and ovarian cancers, patients diagnosed with major cancers were more likely to die from causes other than cancer. Colorectal, bladder, melanoma or uterine corpus cancer patients surviving more than 10 years after diagnosis are unlikely to ever die from that disease. [Table: see text]
Risk of secondary hematologic malignancies in patients with ovarian cancer treated with PARP inhibitors: A combined meta-analysis of seven phase III randomized controlled trials.
Authors: Htut Thura , Ball Somedeb , Swarup Sriman , Sultan Anita , Han Myat M. , Myat Yin Mon , Hardwicke Fred L. , Tijani Lukman Aderoju , Thein Kyaw
Published: May 2020

12076

Background: Ovarian cancer (OC) is a leading cause of death from gynecologic cancers in women worldwide. Poly adenosine diphosphate ribose polymerase (PARP) inhibitors prevent the repair of single-strand breaks and generate double-strand breaks in tumor cells and have recently shown survival benefits in OC. Yet, the impact on the risk of secondary hematologic malignancies (SHM) remains uncertain. We performed a combined meta-analysis of randomized controlled trials (RCT) to determine the risk of SHM in patients with advanced OC treated with PARP inhibitors. Methods: MEDLINE, EMBASE databases and meeting abstracts from inception through January 2020 were queried. Phase III RCTs utilizing PARP inhibitors maintenance in advanced OC were eligible. Mantel-Haenszel (MH) method was used to calculate the estimated pooled risk ratio (RR) with 95% confidence interval (CI). Heterogeneity was assessed with I2 and Cochran's Q- statistic. Fixed effects model was applied. Results: A total of 4,445 patients with advanced OC from seven phase III RCTs were included. The study arm used olaparib or niraparib or rucaparib or veliparib or olaparib +bevacizumab while the control arm utilized placebo or bevacizumab. Randomization ratio was 2:1 in all studies. The I2 statistic for heterogeneity was 0, suggesting some heterogeneity among RCTs. The overall SHM incidence was 0.80% in PARP inhibitors group vs 0.47% in control group (RR 1.45; 95% CI: 0.68 – 3.07, P = 0.34). In patients with newly diagnosed OC (n = 3,044), the incidence was 0.59% vs 0.09% in control group (RR 2.7; 95% CI: 0.7—10.37, P = 0.15). In recurrent OC subset (n = 1,401), 1.28% were reported in both study and control arms (RR 0.96; 95% CI: 0.38-2.46, P = 0.94). SHM was noted in 1.3% in the olaparib subgroup compared to 1% in the control with RR of 1.24 (95% CI: 0.46 –3.31, P = 0.67). SHM occurred in 0.7% in the niraparib subgroup compared to 0.47% in the control with RR of 1.28 (95% CI: 0.30-5.45, P = 0.74). Conclusions: Our study demonstrated that the risk of SHM was not significantly increased in patients who received PARP inhibitors compared to control arm, despite attaining survival benefits. Further studies and long term follow up are necessary to define the actual relation and definitive incidence.
High flow oxygen for dyspnea in hospitalized patients with cancer: A 4x4 crossover randomized clinical trial.
Authors: Hui David , Hernandez Farley , Thomas Saji , Lu Zhanni , Elsayem Ahmed F. , Balachandran Dave , Bashoura Lara , Bruera Eduardo
Published: May 2020

12077

Background: Dyspnea is common in hospitalized cancer patients and highly distressing. High flow oxygen (HFOx) is administered for oxygenation in this setting; however, its effect on dyspnea has not been well examined, particularly among non-hypoxemic patients. In this phase II trial, we assessed the effect of HFOx, high flow air (HFAir), low flow oxygen (LFOx) and low flow air (LFAir) on dyspnea. We hypothesized that HFO and HFA can alleviate dyspnea. Methods: This double-blind, 4x4 crossover clinical trial enrolled hospitalized patients with cancer who were dyspneic (NRS ≥3 at rest) and non-hypoxemic (SpO2>90% on room air). Patients were randomized to 10 minutes of HFOx, HFAir, LFOx and LFAir in different orders. The flow rate was titrated between 20-60 L/min in the high flow groups and 2 L/min in the low flow groups. The primary outcome was dyspnea 0-10 numeric rating scale (NRS) “now”, where 0=none and 10=worst. Secondary outcomes included modified Borg scale dyspnea intensity and unpleasantness, adverse effects, and overall preference. We compared among the interventions with a linear mixed model adjusting for time, treatment effect, period effect and carryover effect. Results: 17 patients completed 55 interventions in a random order. Mean age 51, 58% female, mean baseline dyspnea NRS 6.3 (SD 1.7). The absolute change of dyspnea NRS between 0 and 10 minutes was -1.8 (SD 1.7) for HFOx, -1.8 (2.0) for HFAir, -0.5 (0.8) for LFOx and -0.6 (1.2) for LFAir. In mixed model analysis, HFOx group provided greater dyspnea relief than LFOx (mean difference [95% CI] -0.80 [-1.45, -0.15], P=0.02) and LFAir (-1.24 [-1.90, -0.57], P<0.001). HFAir also provided a significantly greater dyspnea relief than LFOx (-0.95 [-1.61, -0.30], P=0.005) and LFAir (-1.39 [-2.05, -0.73], P<0.001). No difference was found between HFOx and HFAir nor between LFOx and LFAir. There was no significant carryover effect. Dyspnea Borg scale intensity and unpleasantness showed similar changes. Oxygen saturation increased in the HFOx group (97.2% to 99.7%) and LFOx group (95.5% to 98.2%) but not HFAir nor LFAir groups. HFOx was well tolerated. At the end of the study, 7 (54%), 4 (31%), 1 (8%) and 1 (8%) patients blindly preferred HFOx, HFAir, LFOx and LFAir, respectively. Conclusions: For the first time, we found that HFOx and HFAir provided a rapid and clinically significant reduction of dyspnea at rest in hospitalized cancer patients even when they were non-hypoxemic, supporting a role for high flow devices to provide palliation beyond oxygenation. Larger studies are needed to confirm these findings. Clinical trial information: NCT02932332 .
Symptom burden as a predictor of emergency room use and unplanned hospitalization in patients with head and neck cancer: A population-based study.
Authors: Noel Christopher , Sutradhar Rinku , Hallet Julie , Irish Jonathan Crawford , Coburn Natalie , Eskander Antoine
Published: May 2020

12084

Background: Symptoms are common in oncology patients, though they remain undetected and untreated by clinicians in up to 50% of cases. Integrating patient reported outcomes (PRO) within routine clinical practice has been suggested as a way to improve detection. In order to inform an effective and efficient PRO symptom screening program, we sought to determine whether outpatient symptom scores could predict emergency room use and unplanned hospitalization (ER/Hosp) in a cancer patient population. Methods: This was a population-based study of patients diagnosed with head and neck cancer who had completed at least one outpatient Edmonton Symptom Assessment System (ESAS) assessment between January 2007 and March 2018 in Ontario. Logistic regression models were used to determine the relationship between reported outpatient ESAS scores and ER/Hosp use in the 14-day period following ESAS completion. A generalized estimating equations approach was incorporated to account for possible patient-level clustering. Results: There were 11,761 unique patients identified with a total of 73,282 ESAS assessments. There were 5,203 ER/Hosp outcome events. In adjusted analysis, the odds of ER/Hosp use increased log linearly with ESAS score (1.23 per 1 unit increase in index ESAS score, [95% confidence interval (CI) 1.22 – 1.25]). This corresponds to a 9.23 (95%CI 7.22-11.33) higher odds of ER/Hosp use for the maximum index ESAS score of 10. Seven of the nine ESAS symptom scores were significantly associated with ER/Hosp use with pain, appetite and shortness of breath demonstrating the strongest association. Conclusions: ESAS scores are independently associated with 14-day ER/Hosp in head and neck cancer patients. Appropriate and timely management of symptom burden may reduce rates of ER/Hosp. [Table: see text]
Improving cancer pain control: Potential impact of CYP2D6 pharmacogenomic (PGx) testing in oncology (Onc) patients.
Authors: Reizine Natalie , Danahey Keith , Schierer Emily , Truong Tien , Ratain Mark J. , O'Donnell Peter H.
Published: May 2020

12089

Background: Several opioid analgesics have well-known germline PGx associations which may predict either inefficacy or exaggerated (toxic) responses, depending on the patient’s genotype. Despite this, germline PGx testing has not been routinely incorporated into oncology care. We hypothesized that CYP2D6 germline PGx profiling offers the potential to improve oncology patients’ pain control by identifying individuals at increased risk for inadequate analgesia with standard opioid dosing. Methods: We retrospectively analyzed the medication histories of over 81,000 adult oncology patients treated at the University of Chicago from 2012-2018 for exposure to opioids. CYP2D6 genotype (permitting assignment of metabolizer phenotype: normal metabolizer [NM], intermediate metabolizer [IM], or poor metabolizer [PM]) was determined post-hoc for 127 patients who were genotyped for other reasons unrelated to pain prescribing. The primary endpoint was the number of opioids required for pain control over the course of longitudinal care, comparing PM/IMs with NMs. The secondary endpoint was the number of hospitalizations for pain control. Results: Over 47,000 oncology patients were exposed to opioids, with an average of 2.67±1.6 different opioid medication exposures per patient. Thirteen percent of genotyped patients were IM/PM, who were at risk for inadequate analgesia. IM/PM patients demonstrated an increased number of different opioid exposures (4.5±2.1) compared to NM (2.7±2.1, P value = 0.002). IM/PM patients were also more likely to have a pain related hospitalization (OR 4.17, CI 1.3-13.2, P = 0.016). Conclusions: Based on population prevalence, we estimate that > 6000 oncology patients (1000 patients/year) who received opioids at our center were IM/PM and thus at risk for inadequate analgesia due to genetic predisposition. CYP2D6 germline PGx profiling offers the potential to improve oncology patients’ pain management.