bluuebunny/crossref_metadata_2025 huggingface dataset:
Cyclooxygenase inhibitor use during checkpoint immunotherapy and effect on time to progression and overall survival for metastatic melanoma and non-small cell lung cancer patients.
Authors: Wang Shang-Jui , Khullar Karishma , Kim Sinae , Crayton Samuel H , Yegya-Raman Nikhil , Groisberg Roman , Silk Ann W. , Nosher John L , Malhotra Jyoti , Gentile Michael A. , Mehnert Janice M. , Jabbour Salma K.
Published: May 2020

e22034

Background: Immune checkpoint inhibitors (ICIs) improve survival outcomes in metastatic melanoma and non-small cell lung cancer (NSCLC). Preclinical evidence suggests that overexpression of cyclooxygenase-2 (COX2) in tumors facilitates immune evasion through prostaglandin E2 production and that COX inhibition synergizes with ICIs to promote antitumor T-cell activation. This study investigates whether concurrent COX inhibitor (COXi) use during ICI treatment is associated with improved time-to-progression (TTP), objective response rate (ORR) and overall survival (OS) in metastatic melanoma and NSCLC patients. Methods: We retrospectively reviewed 90 metastatic melanoma and 37 metastatic NSCLC patients, treated only with ICI between 2011 and 2019. Differences in TTP and OS by COXi use were compared using Kaplan-Meier and Cox regression. Interaction between COXi use and neutrophil-lymphocyte ratio (NLR) was examined. Independent radiology review per RECIST v1.1 was performed. Results: For melanoma patients, median TTP was significantly prolonged in COXi users (245 v 100.5 days, p = .0002). On multivariate analysis (MVA), COXi use associated with increased TTP (HR 0.36, 95% CI: 0.2 – 0.66, p = 0.001) when adjusted for age, pretreatment NLR, and gender. For NSCLC patients, COXi use also associated with increased TTP on MVA (HR 0.45; 95% CI: 0.21 – 0.97; p = 0.042) adjusted for age. ORR at 6-months was significantly higher in patients who received concurrent COXi compared to those that did not in both melanoma (58.6% v 19.2%, p = 0.0005) and NSCLC (73.7% v 33.3%, p = 0.036) cohorts. COXi use was associated with improved OS in NSCLC patients on MVA (HR 0.3; 95% CI: 0.12 – 0.78; p = 0.013), but not in melanoma patients. In the melanoma cohort, high pretreatment NLR of > 5 associated with decreased TTP on MVA (HR 3.21, 95% CI: 1.64 – 6.3; p = 0.0007). However, for melanoma patients with high NLR > 5, COXi use significantly associated with increased TTP (HR 0.08, 95% CI: 0.03 – 0.25); but in melanoma patients with low NLR ≤5, there was no effect on TTP (HR 0.65, 95% CI: 0.32-1.32). Similar outcomes were found in an adjusted melanoma cohort after RECIST review. Conclusions: Our study suggests that use of COXi concurrent with ICI is significantly associated with longer TTP and improved ORR at 6-months in metastatic melanoma and NSCLC patients. NSCLC patients using COXi had prolonged OS. Furthermore, COXi use appears to reverse the negative prognostic effect of a high NLR by prolonging TTP in melanoma patients.
Baseline biomarkers correlated with outcome in advanced melanoma treated with pembrolizumab monotherapy.
Authors: Awada Gil , Schwarze Julia Katharina , Gondry Odrade , Jansen Yanina , Ong SuFey , Gorman Kara M. , Warren Sarah , Kockx Mark , Seremet Teofila , Keyaerts Marleen , Everaert Hendrik , Neyns Bart
Published: May 2020

e22041

Background: Pembrolizumab (PEMBRO) improves survival in advanced melanoma (MEL). This research investigates baseline (BL) biomarkers that predict long-term benefit on PEMBRO monotherapy. Methods: Outcome data on patients (pts) with advanced cutaneous/mucosal MEL treated with PEMBRO in our institution were collected after pt consent. Responses were evaluated using the immune-related response criteria. Total metabolic tumor volume (TMTV), assessed by 18-fluorodeoxyglucose positron emission tomography/computed tomography, was calculated as the sum of all tumor-associated voxels with a standardized uptake value (SUV) above the mean SUV measured in a reference region in normal liver tissue plus 3 standard deviations using Syngo.via software (Siemens Healthcare). The NanoString PanCancer IO360 panel was used for gene expression profiling (GEP). Results: A total of 196 pts was included in this analysis (median age 60; cutaneous 86%, mucosal 3%, unknown primary 12%; stage III 14%, IV-M1a/b/c 60%, IV-M1d 26%; first-line 24%). Median progression-free survival (PFS) in the population was 20.4 w (95% CI 10.2-30.7); median overall survival (OS) was 143.6 w (95% CI NR-NR). BL WHO Performance Status (PS) > 0 (HR 1.63 [95% CI 1.13-2.37]), C-reactive protein (CRP) > ULN (HR 1.92 [95% CI 1.33-2.77]), absolute lymphocyte count (ALC) < 750/mm³ (HR 2.45 [95% CI 1.32-4.55]) and > 1 metastatic site (HR 1.84 [95% CI 1.23-2.77]) were associated (P≤0.01) with worse PFS in multivariate analysis (Cox regression); BL WHO PS > 0 (HR 2.77 [95% CI 1.82-4.24]), lactate dehydrogenase (LDH) > ULN (HR 1.80 [95% CI 1.16-2.79]) and > 1 metastatic site (HR 1.95 [95% CI 1.16-3.25]) were associated with worse OS (P≤0.011). BL TMTV data were available in 118 pts (60%): BL CRP > ULN (HR 1.83 [95% CI 1.13-2.96]), ALC < 750/mm³ (HR 2.49 [95% CI 1.02-6.08]), > 1 metastatic site (HR 1.71 [95% CI 1.04-2.82]) and BL corticosteroid use (HR 4.62 [95% CI 1.38-15.45]) were associated with worse PFS (P < 0.05). BL WHO PS > 0 (HR 2.82 [95% CI 1.57-5.08]), ALC < 750/mm³ (HR 2.62 [95% CI 1.06-6.51]), history of brain metastases (HR 2.59 [95% CI 1.37-4.91]) and TMTV > 80 mL (HR 3.56 [95% CI 1.82-6.95]) were all associated with worse OS (P≤0.038). GEP data on a representative BL tumor sample were available in 27 pts (14%). Higher apoptosis signature scores were associated with increased probability of OS (HR 0.45 [95% CI 0.33-0.73], P < 0.01). Conclusions: BL TMTV > 80 mL identifies a subgroup of advanced MEL pts with worse outcome on PEMBRO. Increased apoptosis gene signature scores in a subset of patients predict increased OS.
Phase II trial of the PARP inhibitor, niraparib, in BAP1 and other DNA damage response (DDR) pathway deficient neoplasms (NCT03207347).
Authors: ali azka , DeRemer David L. , Lee Ji-Hyun , Parekh Hiral D. , Staal Stephen , Markham Merry Jennifer , Daily Karen Colleen , Stechmiller Bruce K. , Jones Dennie V. , Close Julia Lee , Murphy Martina Cathryn , Kaye Frederic J. , Allegra Carmen Joseph , Hromas Robert A. , George Thomas J.
Published: May 2020

e22061

Background: BRCA-associated protein-1 (BAP1) is a ubiquitin ligase associated with regulating cell cycle, cell proliferation, DNA damage pathway, and cell death. It also acts as a tumor suppressor gene as seen in hereditary cancer syndrome associated with germline mutations in BAP1. Preclinical studies have shown that PARP-inhibitor treatment of BAP1 mutant cell lines demonstrated significant synthetic lethality, independent of underlying BRCA status suggesting this mutation confers a BRCA-like phenotype. BAP1 is mutated, leading to a loss of functional protein, in up to 30% of several solid tumors including cholangiocarcinoma, mesothelioma, uveal melanoma, and clear cell renal cell carcinoma. Methods: This phase 2, open-label, single arm study aims to exploit the concept of synthetic lethality with the use of the PARP inhibitor niraparib in two biologically distinct cohorts. Eligible patients (pts) with measurable metastatic and incurable solid tumors are assigned to one of the two cohorts: Cohort A (histology-specific): tumors harboring suspected BAP1 mutations including cholangiocarcinoma, uveal melanoma, mesothelioma or clear cell renal cell carcinoma with tissue available for BAP1 mutational assessment via Next Generation Sequencing (NGS); or Cohort B (histology-agnostic): tumors with known DNA damage response (DDR) mutations (Table) confirmed by CLIA-approved NGS. Key inclusion criteria also include age ≥18 years, adequate cardiac, renal, hepatic function and ECOG PS of 0 to 1. Key exclusion criteria include known BRCA1 or BRCA2 mutations or prior PARPi exposure. Pts receive niraparib 200-300mg daily (depending on weight and/or platelet count) continuously. Primary endpoint is objective response rate (ORR), and secondary endpoints are progression free survival (PFS), overall survival (OS), toxicity and exploratory biomarker determinations. Radiographic response by RECIST criteria is measured every 8 weeks while on treatment. Cohort B enrollment is closed. Enrollment in Cohort A continues. A maximum of 47 evaluable subjects is planned with expansion cohorts allowable for histologic or molecular subtypes meeting pre-specified responses. Clinical trial information: NCT03207347. [Table: see text]
Identification of potential predictive biomarkers of rapid progression and rapid response to anti-PD1 treatment by gene profiling analysis in metastatic melanoma patients.
Authors: Mallardo Domenico , Grimaldi Antonio M , Capone Mariaelena , Bayless Nicholas , Madonna Gabriele , Festino Lucia , Vitale Maria Grazia , Trojaniello Claudia , Vanella Vito , Curvietto Marcello , Esposito Assunta , Palla Marco , Scarpato Luigi , Cavalcanti Ernesta , Caraco Corrado , Ong SuFey , Warren Sarah , Cesano Alessandra , Ascierto Paolo Antonio , Simeone Ester
Published: May 2020

e22068

Background: Anti-PD-1 agents represent a standard treatment for melanoma patients. However, most patients fail to respond, showing in some cases very rapid disease progression. At moment, there are no effective biomarkers that can predict patient's clinical benefit. The aim of this study is to retrospectively identify gene profiling biomarkers that could help to select melanoma patients who most likely respond to anti-PD-1 therapy. Methods: We defined as fast responder (FR) or fast progressor (FP) patients who got clinical response or clinical progression after two cycles of therapy. We collected data from 44 metastatic melanoma patients (21 FR and 23 FP) treated in first-line with anti-PD1 monotherapy (nivolumab or pembrolizumab) at National Cancer Institute of Naples, Italy. Gene expression profiling analysis was performed using NanoString IO 360 panels on PBMCs collected at baseline from 18 patients (10 FR and 8 FP). Patients with ECOG≥2 were excluded. They were all IV stage (5 M1a, 1 M1b, 12 M1c) of which 15 were B-RAF wild-type (83%) and 3 were B-RAF mutated (17%). Statistical associations between treatment response and gene score variables were estimated by Student’s T tests and correction for multiple comparisons by the Benjamini-Hochberg method. Results: Patterns of gene expression were assessed for correlation to response. We compared PBMCs nanostring analysis between FR and FP patients. We found a higher expression of KRas, CD39, IFI16, IL18, FCGR2A, IL1RN, MAP3K8, TLR5, TLR8, MyD88 and NF-kB in FP patients (all with p-value ≤0.005), most of them related to cell proliferation and immunosuppressive mechanism. Instead we found a higher expression of PRF1, PIK3R1, HLA-DPA1, HLA-DRB1, HLA-DOA, CD45RA, LDHB, KIR3DL2, CD2, CD28, CD7, CD27 in FR patients (all with p-value ≤0.01), most of them related to priming and cytolysis. Conclusions: These preliminary data obtained through gene profiling analysis on baseline PBMCs of melanoma patients suggest that a specific gene signature may discriminate FR or FP patients. Our study provides rationale for further investigating gene profiling signature as a potential association for response to immunotherapy.
Cost-effectiveness of nodal observation versus completion lymphadenectomy in patients with melanoma and sentinel lymph node metastases.
Authors: Parvez Elena , Dumitra Teodora , Panagiotoglou Dimitra , Meterissian Sarkis H. , Dumitra Sinziana
Published: May 2020

e22076

Background: The MSLT-II trial demonstrated no survival benefit of completion lymphadenectomy (CLND) compared to nodal observation (NO) and subsequent therapeutic lymphadenectomy (TLND) in the case of macroscopic nodal relapse in patients with melanoma and SLN metastases. NO avoids the upfront cost and morbidity of CLND. However, patients followed with NO must undergo intensive surveillance and if TLND is required, it is associated with a higher complication rate than CLND. The cost-effectiveness of NO versus CLND in light of data from MSLT-II has not been previously studied. Methods: A Markov model with a 10-year time horizon was constructed to simulate two hypothetical cohorts of patients with SLN metastases undergoing NO and subsequent TLND for nodal recurrence or upfront CLND. Transition probabilities between disease states were derived from the MSLT-II trial. Remaining parameters including complication rates and health state utilities were obtained from an extensive review of the literature. Direct health care system costs were obtained from published US Medicare cost data and the literature. Primary outcomes were cost and quality-adjusted life years (QALYs) saved. Incremental cost-effectiveness ratio (ICER) was used to compare treatment strategies. Sensitivity analysis was performed in order to evaluate model uncertainty. A threshold of acceptance of $100,000/QALY was used. Results: Total projected cost over the study period for CLND was $28,609.87, while that of NO was lower at $20,865.27, resulting in $7,744.60 saved for the NO treatment strategy. Ten-year utility was 4.840 for CLND compared to 5.379 for NO, resulting in a gain of 0.539 QALYs in the NO arm. The NO strategy is dominant in the model as it results in both cost-savings and a gain in health effects, with an average ICER of -$14,368.46/QALY gained. Conclusions: From the payer perspective, the strategy of NO compared to CLND in patients with melanoma and SLN metastases is associated with an improvement in health outcomes and reduction in cost. Taking into account MSLT-II trial data, this study demonstrates NO is more cost-effective than CLND.
Recurrence rates and relapse-free survival for patients with completely resected melanoma: Contemporary experience.
Authors: Amin Asim , Trufan Sally Jeanne , Neelands Brittany , Gower Nicole Lee , Pasli Melisa , White Richard L.
Published: May 2020

e22080

Background: An estimated 100,000 new diagnoses of malignant melanoma are expected in 2020. Systemic treatment with immune checkpoint inhibitors (ICIs) and targeted therapy with BRAF/MEK inhibitors have impacted the natural history for resectable and unresectable/advanced disease. ICIs and the combination of dabrafenib plus trametinib have been shown to decrease the risk of recurrence. Eligibility to receive adjuvant treatment has been based on melanoma specific survival (MSS) reported by AJCC. Romano et al. (JCO 2010) have previously reported their single institution 5yr data from 1998-2004 for stage IIIa/b/c melanoma relapse free survival (RFS) to be 63%, 32% and 11% respectively. Per the AJCC 8th edition, the 5yr MSS for stage IIIa/b/c is 93%, 83% and 69% respectively. We report our single institution data for recurrence rate (RR) and RFS. Methods: Our prospective database was queried for patients with stage IIb/c, IIIa/b/c (per AJCC 7th edition) from 2005 to 2019. Time to recurrence and relapse free survival were calculated using time from surgery date to chart review. Results: 529 patients with stage IIb/c, IIIa/b/c patients were identified. The cohort was 63% male and 98% white, with a median age of 60 (IQR 48-70). The distribution of disease stage was: IIb, 27%; IIc, 10%; IIIa, 23%; IIIb, 22%; IIIc, 17%. The median time to recurrence for all patients was 1.15yrs (IQR 0.57-2.3). The overall RR was 36%. RR by stage were: IIb, 28%; IIc, 36%; IIIa, 26%; IIIb, 47%; IIIc, 46%. Recurrence most often was associated with a primary lesion on the trunk (36%), followed by head/neck (26%), lower extremity (23%) and upper extremity (15%). Distant recurrence accounted for 54% of all first recurrences, followed by regional (34%) and local (12%). The 2yr and 5yr RFS were significantly different by stage (p < 0.0001) (Table). Conclusions: 5yr RFS for stage IIIa disease in our study is considerably higher compared to the Romano et al. data (71% vs 63%). The 5yr MSS has improved from 78% to 93% (AJCC 7th vs 8th edition). Our group has demonstrated improvement in RFS when compared to historical reports suggesting further investigation is needed into IIIa patients most likely to benefit from adjuvant therapy. [Table: see text]
Association of prior interferon-alpha treatment with the efficacy of adjuvant pembrolizumab in resected melanoma.
Authors: Jin Gu , Li Tao , Niu Yanling , Ma Tonghui
Published: May 2020

e22100

Background: Adjuvant pembrolizumab or interferon-alpha has been found to prolong recurrence-free survival as adjuvant therapy for resected melanoma. Several studies have shown that interferon-alpha could modulate immune responses to melanoma. In this study, we provided clear evidence that prior treatment with interferon-alpha significantly enhanced the efficacy of adjuvant pembrolizumab for resected melanoma. Methods: 57 patients with acral or cutaneous melanoma (stage IB or II) were enrolled. After resection of the primary tumors, 25 patients received high-dose interferon-alpha as adjuvant therapy and 32 patients received observation. The patients eventually progressed to stage III or IV, with nodal, in-transit, or resectable distant recurrence. Then the patients underwent complete resection for the recurrent tumors. Next, all the patients were given 100 mg of pembrolizumab every 3 weeks. We compared progression-free survival (the time between the date of starting anti-PD-1 and the date of recurrence after anti-PD-1) between the subgroup receiving prior adjuvant interferon-alpha treatment (IFN-pembrolizumab) and the subgroup receiving observation (pembrolizumab). Results: In the pembrolizumab group, 9.4% (3 of 32) had a recurrence within two months and 38% (12 of 32) had disease progression within four months. Whereas, no patients had a recurrence within two months and the proportion of patients with less than four months PFS was 16% (4 of 25) in the IFN-pembrolizumab group. Furthermore, 44% (11 of 25) had a relapse until the date of last follow-up in the IFN-pembrolizumab group. But 56% (18 of 32) had a recurrence in the pembrolizumab group. The Kaplan-Meier curve showed that PFS was significantly improved in the IFN-pembrolizumab group as compared with the pembrolizumab group (mPFS 34.6 weeks vs. 18 weeks, HR = 0.47, 95% CI 0.23-0.99; p value = 0.0392). For stage III melanoma, mPFS was not reached in the IFN-pembrolizumab group, demonstrating increased benefit for patients with early stage. Altogether, these data suggested that prior interferon-alpha treatment could prolong PFS for adjuvant pembrolizumab. Conclusions: In this study, we for the first time demonstrated that prior treatment with adjuvant IFN-alpha exhibited significant improvement for adjuvant pembrolizumab. Meanwhile, further investigation is required to dissect how IFN-alpha enhanced the efficacy of PD-1 blockade.
Surgical wound dehiscence in dermatologic surgery.
Authors: Harding Tanner , Seyffert Jennifer , Maner Brittany , Bibliowicz Nathan , Sanghvi Asmi , Camner Shawn , Yungmann Martin , Solomon James A.
Published: May 2020

e22101

Background: Surgical wound dehiscence (SWD) describes separation of wound edges due to mechanical failure of a healing wound. The rate of SWD following dermatology office-based surgery and factors associated with its occurrence are poorly characterized in the current literature. This study aims to elucidate factors contributing to SWD following cutaneous excisions of malignant and non-malignant through a novel data mining methodology. The utility of this methodology in quality assurance and risk management applications will be concomitantly explored. Methods: An electronic query directed at the electronic medical record (EMR) database of a large national dermatology practice employing over 400 providers yielded 22,548 instances of cutaneous excision meeting inclusion criteria between 1 January 2018 and 9 September 2019. To control for confounding, procedures positive for SWD were randomly matched in 1:4 ratio with procedures negative for SWD on the basis of sex, age, and precise anatomic location. Procedures were then statistically analyzed to elucidate factors associated with SWD. Results: Of 22,548 procedures analyzed, 123 were positive for wound dehiscence, yielding an incidence of 0.54%. Age ( Χ2 ( df = 1, N = 615) = 2.49, p = 0.039), smoking history ( Χ2 ( df = 2, N = 534) = 9.97, p = 0.007), wound location on the distal extremities ( Χ2 ( df = 1, N = 615) = 9.54, p = 0.002), presence of postoperative infection ( Χ2 ( df = 1, N = 600) = 34.87, p < 0.001), and presence of postoperative bleeding ( Χ2 ( df = 1, N = 600) = 62.73, p < 0.001) are all significantly associated with SWD. A wound positive for postoperative infection or bleeding has 14.48 times the odds of being positive for SWD (95% CI: 4.62 - 45.21). A wound positive for postoperative bleeding has 20.15 times the odds of being positive for SWD (95% CI: 7.42 – 54.73). No significant relationship between SWD and sex, diabetes, or provider type is evident. Conclusions: Age, smoking history, wound location on the distal extremities, and especially other postoperative complications such as bleeding and infection are associated with SWD. There is no association between SWD and sex, diabetes, or provider type. Forthcoming multifactorial, nonlinear, non-time-dependent analysis of variables may allow for the development of a statistical model to provide greater insight into SWD following dermatologic surgery.
Methylation profiling of hypomethylating agent response and treatment failure in pediatric and young adult MDS/AML.
Authors: Jones LaQuita Marie , O'Brien Maureen Megan , Breese Erin Haag , Absalon Michael , Burns Karen Cristly , Grimley Micheal , Mizukawa Benjamin , Lee Lynn Hua , Perentesis John Peter , Phillips Christine L.
Published: May 2020

e22502

Background: Hypomethylating agents (HMAs) have favorable toxicity profiles and anti-leukemia activity in adult AML/MDS. We previously reported similar activity in eight pediatric patients (Phillips et al., British Journal of Hematology 2013), however, it remains unclear which factors influence outcome and sustainability of response. We sought to update our clinical experience and determine molecular correlates of HMA response and relapse with the goal of identifying potential biomarkers and physiologic insights. Methods: Clinical data was retrospectively collected through chart review from 2012 to 2017. Cryopreserved patient bone marrow was obtained from our institution’s biorepository under an IRB-approved protocol. Leukemic blasts were enriched by FACS, and genomic DNA was extracted and subjected to reduced representation bisulfite sequencing (RRBS). Differentially methylated regions (DMRs) were calculated using MethylKit. Results: Fourteen patients were treated with hypomethylating agents. Median age was 9.5 years (range 2-34). Two patients (14%) had germline TP53 mutations, secondary MDS/AML, and achieved complete response (CR). Four patients (29%) had monosomy 7, with 2 CR (50%) and 2 partial responses (PR). Contrarily, in the non-monosomy 7 patients, only 1 patient achieved a CR, 2 PR, and one had stable disease. DMRs were identified by comparing diagnostic and relapse samples, as well as responsive and refractory specimens. As expected, there was global DNA hypomethylation following treatment with HMAs. Pathway analysis of DMRs identified in relapse vs diagnostic samples revealed promoter hypomethylation in processes related to DNA binding, transcription factor activity, and RNA biosynthesis, as well as promoter hypomethylation of polycomb repressive complex 2 targets and gene sets classically associated with histone H3 K27 trimethylation. Gene set enrichment analysis (GSEA) of relapse versus remission marrow samples demonstrated reduced methylation of promoter regions regulating DNA repair, responses to DNA damage, and adaptive immune signaling. Conclusions: Our data suggests that HMA response and relapses after treatment may exhibit unique biological signatures reflected in methylation changes. These findings can inform further hypothesis generation and potentially combination therapies.
Finding an optimal treatment regimen for endemic Burkitt's lymphoma in a limited resource setting: A historical comparison of an INCTR-03-06 protocol for children treated at a tertiary pediatric oncology unit in Tanzania.
Authors: Kayungo Shakilu Jumanne
Published: May 2020

e22507

Background: Adoption of intensive chemotherapy for endemic Burkitt lymphoma (eBL) in low income settings such as the French LMB-protocol with survival rates over 90% is limited by unavailability of quality supportive care for treatment related toxicity. Late stage at diagnosis and comorbidities such as HIV, Malnutrition and other socioeconomic challenges complicate this quagmire. Review the nonclinical trial setting performance of a three-drug regimen previously reported by the INCTR-03-06 study among children treated for eBL from 2012 to 2017 at a National Hospital in Dar es Salaam Tanzania. Methods: Medical record review of children treated for eBL to document demographic, clinical, chemotherapy regimen and outcome was conducted followed by phone call structured interviews for current survival status. Overall survival (OS) and Event Free Survival (EFS) were determined by Kaplan-Meier method and survival differences compared using the Log-rank test. Cox regression analysis was used to relate variables with mortality. Data analysis was done by SPSS version 20 and p-value of < 0.05 considered statistically significant. Results: Out of the 123 children enrolled, male to female ratio was 1.6:1, median age 7 years (IQR 4 -10). Abdominal disease was the commonest presentation, 39% (48/123) and 25.2% (31/123) jaw mass. On phone call interviews 39.84% (49/123) of the children were in remission, 33.33%(41/123) died while 26.83% (33/123) were lost to follow up. Complete tumor response was achieved in 55.9% (62/111) of children treated on 1st line chemotherapy. Overall Survival rates (OS) at 12 and 18 months were 63.4% and 54% respectively while Event-Free Survival (EFS) were 38.8% and 36.4% respectively. HIV infected children (aHR 5.12 95% CI 1.39- 19.0; log-rank P< 0.01). and those with advanced disease at diagnosis( aHR2.34 95% CI 1.09-5.05 P < 0.03) were at high risk of death. Conclusions: Contrary to prior understanding of eBL as a predominantly jaw disease, abdominal site is increasingly reported likely due to widespread use of sensitive imaging modalities. In line with other studies in low- and middle-income countries, few children with eBL achieve complete remission using low intensity chemotherapy regimens calling for more studies for safe and feasible regimens to be used as efforts to improve supportive care continue. HIV infected children with eBL and those with advanced disease at diagnosis should be considered at high risk of mortality.
FAM120A-PTPN3 variations in neuroblastoma: Implications for poor prognosis and relapse.
Authors: Sun Lan , Stucky Andres , Tu Lingli , Chen Xuelian , Luo Jun , Zhong Jiang F.
Published: May 2020

e22512

Background: Neuroblastoma (NB), the most common tumor in infants, presents clinical unpredictability of relapse and treatment response. Staging and risk stratification depending on clinical examinations are often undertaken while molecular risk factors are less known. Relapse of high-risk NB remains the greatest clinical challenge. Thus, we conduct this study to investigate the molecular mechanism of NB relapse. Methods: Six patients with neuroblastoma who had both primary tumor and relapse samples were studied to identify key mutations in relapse. A cohort analysis of genetic profiles was then performed in order to find out gene mutations associated with the relapse samples. Mutation distribution and expression profiling in 127 patients from the national cancer institute database were used to identify relapse related gene networks. Kaplan-Meier analysis was performed for Overall survival (OS) on each mutation and Ingenuity pathway analysis (IPA) was consulted for their possible interactions. Gene manipulation in two neuroblastoma cell lines were used for verification. Results: We identified 40 potential mutations that associated with the relapse samples, including FAM120A and PTPN3. Mutation distribution in a larger NB population with 127 patients showed FAM120A mutation rate was 32.3% (41/127) and PTPN3 was 52.8% (67/127). Both had significant impact on OS. The median OS (mOS) with or without FAM120A mutation was 1527±214 days and 2300±139 days, respectively (p = 0.000). mOS with or without PTPN3 mutation was 1822±163 days and 2285±179 days, respectively (p = 0.037). Additionally, mOS in group lacking both mutations (42/127) was 2555±196 days, much higher than 1857±153 days, in those who had only one (62/127), or 1391±266 days, in those who had both (23/127). Furthermore, the prevalence of FAM120A mutation was at Chr.9:93543407 (61.0%, 25/41) and PTPN3 at Chr.9: 109457194 (61.2%, 41/67). Variant at Chr.9:93543407 had more significant impact on OS compared to other sites in FAM120A-mutation subgroup (p = 0.01). Expression of FAM120A was significantly down-regulated in the FAM120A-mutation subgroup compared to non-mutated (p = 0.01). IPA and in vitro assay showed these factors may have an additive effect possibly interacting through TRIM25, MYC and VIRMA. Conclusions: Our results suggest that variations in FAM120A and PTPN3 interact in neuroblastoma resulting in poor prognosis and cancer relapse, and may be a potential target for improvement of current treatment.
Conditional survival of patients with nonmetastatic bone osteosarcoma.
Authors: Miao Ruoyu , Wang Haotong , Choy Edwin , Cote Gregory Michael , Raskin Kevin , Schwab Joseph H. , Hornicek Francis J. , DeLaney Thomas F. , Chen Yen-Lin
Published: May 2020

e23511

Background: Conditional survival provides a dynamic prediction of prognosis for patients surviving a defined period of time after diagnosis. This study aimed to determine the conditional survival and prognostic factors over time among patients with non-metastatic bone osteosarcoma. Methods: We reviewed 714 bone osteosarcoma patients treated from 1985 to 2016. Patients with metastatic disease at diagnosis or limited follow up were excluded, resulting in 587 cases for analysis. Clinical and pathological variables were recorded. Predictive variables included age at diagnosis, gender, previous radiation history, tumor site, tumor size, histologic subtype, histologic grade, resection margin, chemotherapy, and radiation therapy. The multivariate Cox proportional hazards regression was used to analyze prognostic factors of conditional overall survival and progression-free survival at baseline and 5 years after diagnosis. Results: The estimated 5-year conditional overall survival increased from 71.0% (95% CI: 67.5%-75.0%) at baseline to 86.9% (95% CI: 82.6%-90.5%) at 5 years, which means if a patient with non-metastatic bone osteosarcoma survived 5 years, the chance of surviving another 5 years was 86.9%. If the patient was progression-free for 5 years, the 5-year conditional overall survival was even higher, 93.2% (95% CI: 89.5%-96.4%), and the 5-year conditional progression-free survival improved from 57.1% (95% CI: 53.3%-61.0%) at baseline to 91.2% (95% CI: 87.5%-94.6%) at 5 years. Prognostic factors for mortality and disease progression change as survival time increases. At baseline, age (p < 0.001 and p = 0.003), histologic subtype (p < 0.001 and p = 0.001), grade (p < 0.001 and p < 0.001), tumor size (p = 0.002 and p = 0.002), resection margin (p < 0.001 and p < 0.001) and chemotherapy (p = 0.001 and p = 0.001) were predictive of both overall survival and progression-free survival. However, only age (p < 0.001) and histologic subtype (p = 0.015) remained significant for mortality and resection margin (p = 0.001) for disease progression at 5 years. Conclusions: The survival probability of osteosarcoma improves as survival time increases. Estimates of conditional survival can provide useful information for individualized surveillance strategies, risk evaluation, patient counseling, and making clinical decisions.
Bone turnover markers in primary and metastatic bone tumors.
Authors: Guskova Nailya K. , Vashchenko Larisa N. , Barashev Artem A. , Danilchenko Ekaterina V. , Nozdricheva Anastasia S. , Tselishcheva Irina V. , Donskaya Aliya K. , Selyutina Olesya N. , Abakumova Svetlana V. , Belgova Svetlana V. , Zakharchenko Viktoria R. , Kit Oleg I.
Published: May 2020

e23513

Background: The purpose of the study was to reveal the levels of biochemical parameters for assessing the intensity of bone metabolism in patients with primary and metastatic bone tumors. Methods: The study included 29 patients aged 55.9±12.17 years with primary (group 1, n = 12) and metastatic (group 2, n = 17) bone tumors. Group 2 included patients with breast cancer (2a, n = 10) and renal cancer (2b, n = 7) with a history of pathological fractures. Serum levels of the bone turnover marker osteocalcin, TSH, the resorption marker β-Cross Laps (C-terminal telopeptide) (Cobas e411, Japan) and calcium (Vitros 5600, USA) were measured before and after (day 14) organ-preserving treatment. The data were compared with that in non-cancer patients of similar age (n = 15) and evaluated in the Statistika 10.0 program. Results: Osteocalcin levels in group 1 prior to surgery was 1.74 times (p < 0.05) higher than in controls (13.56±1.35 ng/mL) and decreased by 35% (p < 0.05) compared to the initial values. In group 2, changes in osteocalcin levels were multidirectional: group 2a – 24% (p < 0.05) higher than in controls both before and after surgery; group 2b – similar to control values before surgery and decreased by 19% (p < 0.05) after it. Levels of β-Cross Laps in all patients before surgery were within the control range (0.49±0.02 ng/mL). After surgery, the levels in groups 1 and 2a did not change, while group 2b showed an increase in β-Cross Laps by 1.5 times (p < 0.05) and a decrease in calcium by 20% (p < 0.05) from the initial levels (2.33±0.09 mmol/L), which, along with a decrease in osteocalcin, could be the result of specific kidney damage. TSH in groups 1 and 2b was similar to controls, but initial TSH levels in group 2a were increased by 86% (p < 0.05) and did not change after surgery, as well as osteocalcin levels, which in the absence of changes in β-Cross Laps suggested a more favorable prognosis after organ-preserving treatment. Conclusions: Bone tissue remodeling processes are determined by the nature of the initial tumor. Measuring osteocalcin and β-Cross Laps in patients with specific bone lesions may be useful in assessing the risk of fractures.
The impact of next generation sequencing on sarcoma diagnosis.
Authors: Zhao Gang , Xie Lu , Guo Wei , Xi Yanfeng , Cui Yanzhi , Yu Siying , Wan Qing , Chen Donglin , Pan Xuedong , Dong XiaoWei , Wang Kai , WANG Jian
Published: May 2020

e23528

Background: The rarity and heterogeneity of sarcoma has been complicating the diagnosis of sarcoma for years. Even expert pathologists of sarcoma could make mistakes in the diagnosis of this disease. The availability of Next Generation Sequencing (NGS) data enabled more accurate diagnosis of sarcoma. In this study, we systematically described the application of NGS on the diagnosis of sarcoma and the contribution of NGS to the diagnostic accuracy of sarcoma. Methods: A multi-center, retrospective study included 235 sarcoma patients’ tumor and paired normal samples that were sent from 56 hospitals to a College of American Pathologists (CAP) accredited and Clinical Laboratory Improvement Amendments (CLIA) certified laboratory, at Shanghai, China for Next Generation Sequencing (NGS) was performed. Using next generation sequencing based YS panel consisting 450 genes, these 235 sarcoma patients’ sample were sequenced and the NGS data was analyzed. The initial diagnosis without NGS information was reconsidered by expert pathologists. Results: Taking into consideration both the initial diagnosis and the NGS results, the final diagnosis of these 235 sarcoma cases included 8 low grade malignant fibromyxoid tumors, 11 dermatofibrosarcoma protuberans (DFSP), 38 myxoliposarcomas, 22 alveolar rhabdomyosarcomas, 11 alveolar soft tissue sarcoma, 2 desmoplastic small round cell tumors, 37 NTRK rearrangement spindle cell tumors, 40 Ewing’s sarcoma and 66 synoviosarcomas. In total, 29% initial diagnoses were changed according to NGS identified fusions, including 13% low grade malignant fibromyxoid tumors (1 FUS- CREB3L2 fusion), 27% DFSPs (3 COL1A1- PDGFB fusions), 11% myxoliposarcomas (3 FUS- DDIT3 fusions and 1 EWSR1- DDIT3 fusion), 14% alveolar rhabdomyosarcomas (2 PAX7- FOXO1 fusions and 1 FOXO1- LINC00598 fusion), 18% alveolar soft tissue sarcomas (2 ASPSCR1- TFE3 fusions), 50% desmoplastic small round cell tumor (1 EWSR1- WT1 fusion), 95% NTRK rearrangement spindle cell tumors, 13% Ewing’s sarcomas (3 EWSR1- FLI1 fusions and 2 EWSR1- ERG fusions) and 21% synoviosarcomas (9 SS18- SSX1 fusions and 5 SS18- SSX2 fusions). Conclusions: NGS would be highly recommended for accurate diagnosis of sarcoma, especially for NTRK rearrangement spindle cell tumor, the majority of which were confirmed according to NGS identified fusions.
Comprehensive genomic profiling in malignant myoepithelioma to suggest potential alternative diagnosis.
Authors: Siontis Brittany , McHugh Jonathan B. , Schrock Alexa Betzig , Pavlick Dean , Ross Jeffrey S. , Ali Siraj Mahamed , Miller Vincent A. , Robinson Dan R. , Athanikar Jyoti , Wu Yi-Mi , Chinnaiyan Arul , Baker Laurence H. , Schuetze Scott , Chugh Rashmi
Published: May 2020

e23530

Background: Malignant myoepithelioma of soft tissue (MM) is a rare tumor affecting patients (pts) of any age without sex predilection. MM has varied histopathologic findings, with epithelioid and spindle components and differentiation along osseous, chondroid or other lineages. Morphologic features suggest MM, however histologic overlap with other lesions exists. Diagnosis requires ancillary immunohistochemical &/or molecular studies; EWSR1 rearrangement with various fusion partners has been reported. Clinical behavior is varied and poorly understood due to disease rarity. Here, we undertook comprehensive genomic profiling (CGP) of MM to evaluate for potential targetable molecular alterations and report clinical outcomes. Methods: We identified pts with MM treated at University of Michigan (UM) from 2000-2017, obtained clinical data and reviewed pathology on 10 available samples and performed integrative sequencing through Michigan Oncology Sequencing Program (MI-ONCOSEQ) on 6. For 31 additional FFPE samples, hybrid capture-based DNA CGP (n = 16) or DNA+RNA CGP (n = 15) was performed (Foundation Medicine, FM). Results: 13 pts were treated at UM; median age at diagnosis was 52 (22-88) with male predominance (9/13). Primary tumor size was 3 cm (2-9.5) and most common location was trunk (4/13) and extremity (3/13). Four pts with metastatic disease (mets) underwent systemic chemotherapy with 0 responses. Median progression free and overall survival in mets was 20 (5-75) and 57 (12-91) months, respectively. CGP analyses of all samples (Table) revealed EWSR1 rearrangement in 8.1% (3/37) and presence of PHF1-TFE3 and CIC:DUX4 rearrangements in 16% (6/37). Independent blinded histopathology review of whole slides and tissue is underway. Conclusions: MM is a rare malignancy with variable clinical course. In our series, pts with mets derived little benefit from systemic therapy. CGP revealed CDKN2A/B alteration as the most prevalent with few harboring EWSR1 rearrangement. PHF1-TFE3 was recently described in ossifying fibromyxoid tumor (OFMT) that may represent a subset of OFMT not yet expressing bone markers. The presence of hypermutation and CIC:DUX4 fusions also suggests potential alternate diagnosis. These results indicate that CGP could complement histopathologic evaluation to aid in diagnoses and treatment of this entity. [Table: see text]
Development of urine metabolomic biomarkers for ifosfamide-induced encephalopathy (IIE) in soft tissue sarcoma patients.
Authors: Kinnebrew Garrett , Liebner David A. , Phillips Audra , Stets Colin W. , Tinoco Gabriel , Mathe Ewy , Chen James Lin
Published: May 2020

e23534

Background: In the treatment of sarcomas, high doses of ifosfamide in combination with other chemotherapeutic agents remains a backbone of cytoreductive therapy. Unfortunately, IIE remains a prevalent treatment side effect with a reported prevalence of 10-20%. Although mild hypoalbuminemia has previously been implicated as a risk factor, its risk contribution is modest. There are no clinically significant biomarkers which may help identify IIE patents. Given the correlation with hypoalbuminemia to renal function, we hypothesized that urinary metabolites may serve as potential early biomarkers for IIE. Here we report our interim biomarker findings as part of our sarcoma metabolomic biocollection protocol. Methods: All sarcoma patients that received ifosfamide were identified (2011-2020) through a sarcoma registry (OSU-14242). Development of IIE was obtained through chart review. For consented patients undergoing adriamycin and ifosfamide treatment, urine samples were obtained over the course of 5 days and two treatment cycles (OSU IRB: 2014C0181). Urine samples were subjected to targeted metabolomic analysis for known ifosfamide metabolites and untargeted metabolomic profiling. LC-MS was performed on a Sciex TripleTOF 5600 and data preprocessing with XCMS. For each metabolite, mean abundance and slope, as determined by linear regression across all time points, was compared to development of IIE coded as a binary variable. Results: A total of 70 sarcoma patients were identified, of whom 11 developed IIE for a prevalence of 15.7%. Baseline values at the start of ifosfamide treatment were a mean albumin of 3.7 g/dL (+/- 0.38) and a mean serum creatinine of 0.79 mg/dL (+/- 0.26). Both values are within our “normal range”. For seven of these patients, of whom one developed IIE, we successfully collected additional metabolomic profiling. From these data, 6,030 features (representing metabolites or metabolite fragments) were measured. Time course plots of drug metabolites for which pure standards were run showed an increase of expected chemotherapy-related metabolites at the beginning of each cycle, with inter- and intra-patient variability. IIE was associated with 70 metabolite features (by mean abundance, FDR < 5%). Metabolite identification of putative features based on tandem mass spectrometry is in process. Conclusions: This pilot study indicates that urine metabolomic analysis is feasible and may identify IIE biomarkers. We expect to confirm these results once ongoing specimen analysis is complete.
Prognostic role of pre-treatment neutrophil-to-lymphocyte ratio in patients with soft tissue sarcoma.
Authors: Park Se Jun , Lee Jinsoo , Shin Kabsoo , Kim Hyunho , Kim In-Ho , Lee Ji Eun
Published: May 2020

e23537

Background: Recent studies suggest that the neutrophil-to-lymphocyte ratio (NLR) may be associated with prognosis in several cancers. However, it has not been widely accepted in a clinical situation. In this study, we investigated the clinical significance of NLR as prognostic marker in patients with soft tissue sarcoma. Methods: Between January 2008 to December 2018, 168 patients with STS who had available blood counts at the time of diagnosis were retrospectively evaluated. Receiver operator characteristic (ROC) curve analysis was used to identify the optimal cut-off value for NLR in predicting overall survival. The association between NLR and overall survival (OS) and disease-free survival (DFS) was analyzed with Kaplan-meier method and multivariate Cox proportional models. Results: A total of 168 patients were analyzed, 116 (69.0%) patients were initially resectable disease. Based on the results of ROC curve analysis, patients were classified into two groups as; high-NLR ( > 1.8) and low-NLR (≤1.8). High-NLR was presented in 107 (63.7%) patients which was significantly associated initial disease status (HR 3.30; 95% CI 1.51-7.20, p= 0.002), but not with age at diagnosis ( p= 0.167). High-NLR was significantly correlated with worse OS (HR 3.14; 95% CI 1.62-6.10, p < 0.001). 3-year DFS was 26.2% for high-NLR group versus 37.3% for low-NLR group. DFS tended to be better in low-NLR group, though not statistically significant (HR 1.65; 95% CI 0.95-2.87, p= 0.078). Conclusions: Pre-treatment NLR is a useful predictive factor for prognosis in patients with soft tissue sarcoma. Further studies are needed to evaluate the association between factors representing of host inflammatory status and cancer prognosis.
Patient-reported global health predicts adverse health outcomes in a cohort of patients with advanced sarcoma.
Authors: Husain Marium , Phillips Audra , Tinoco Gabriel , Chen James Lin , Liebner David A.
Published: May 2020

e23547

Background: Given the rare nature of sarcoma cancers and the sometimes severe treatment-related effects of chemotherapy, many patients with sarcoma face quality of life issues during treatment. Unplanned hospital admission and emergency room (ER) visits can occur from uncontrolled symptoms and ultimately delay treatment regimens and negatively impact quality of life. The PROMIS Global Health v1.2 (PROMIS-10) surveys are validated tools to assess patients’ physical and mental well-being at the time of the survey. We sought to evaluate the correlation between PROMIS-10 scores and adverse outcomes of interest, including unplanned admissions/ED visits and patient mortality. Methods: All patients currently seen in the Sarcoma Clinics at Ohio State University routinely complete the PROMIS-10 survey at each clinic visit. For this pilot study, we collected the raw and normalized t-scores for PROMIS-10 surveys for all patients consented to The Ohio State University Sarcoma Registry (OSU-14242) from 6/1/2018 to 11/20/2019. We also collected data on unplanned hospital admission/ED visits and mortality data for each patient. Results: A total of 864 surveys for 112 patients were collected for the study period. The median number of surveys answered per patient was 6. Mean global physical t-scores (43.7 ± 8.5) and mental t-scores (47.9 ± 9.2) were lower than reference scores for the general US population (p < 0.001). 109 of 112 patients experienced an unplanned admission or ED visit during the study, with a total of 270 such encounters during the study period. PROMIS-10 scores were slightly but significantly lower for patients experiencing an admission or ED visit within 30 days of taking the survey (physical: 41.9 vs 44.1, p = 0.006; mental: 46.4 vs 48.2, p = 0.035). A total of 26 patients died during the study period; surveys completed prior to death were consistent with a greater level of physical and mental distress, with the median physical t-score = 34.9 (range: 23.5 – 50.8) and mental t-score = 43.5 (range: 33.8 – 67.6). Conclusions: We showed that we are able to obtain worthwhile data to objectively evaluate patients’ physical and mental well-being through survey data during cancer treatment. We are currently performing additional confirmatory analysis of the predictive value of the PROMIS-10 survey for adverse events and for treatment-related complications.