bluuebunny/crossref_metadata_2025_split huggingface dataset:
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.