tbuckley/cabot-search huggingface dataset:
Incidence, patterns of progression and outcomes of melanoma brain metastasis (MBM) during programmed-death 1 inhibitor (PD1i) therapy.
Authors: Gustavo Schvartsman, Junsheng Ma, Roland L. Bassett, Lauren Elaine Haydu, Rodabe Navroze Amaria, Patrick Hwu, Wen-Jen Hwu, Adi Diab, Sapna Pradyuman Patel, Michael A. Davies, Hussein Abdul-Hassan Tawbi, Isabella Claudia Glitza
Journal: Journal of Clinical Oncology (2017)

9532 Background: MBM are common in patients (pts) with metastatic melanoma (MM) and represent a frequent site of treatment failure with current therapies. Little is known, however, about the incidence, patterns of progression and outcomes of MBM pts treated with PD1i and in conjunction with central nervous system (CNS) focused therapy. Methods: Outcomes of mm pts treated with PD1i at MD Anderson from 01/12 to 07/16 were reviewed. The association between clinical variables and development of MBM and overall survival (OS) were assessed using logistic regression and Cox regression analyses. Results: We identified 324 mm pts, including 77 pts (24%) who had MBM prior to first dose of PD1i. Median follow-up from start of therapy was 16.3 months, median OS for pts without MBM at the start of PD1i 3.37 years, as compared to 2.85 years in pts with prior MBM (p = 0.268). Of the 247 pts without prior MBM, 64 (26%) developed MBM after exposure to PD1i. Of those, 21 pts (8.5%) developed MBM during therapy or within 30 days of discontinuation, with 12 (4.5%) having CNS-only progression, while 9 (3.6%) had both systemic and CNS progression. Pts with MBM prior to PD1i (n = 77) had CNS-only progression in 22 pts (28.6%) during therapy. Progression occurred in systemic and systemic plus CNS in 12 pts (15.6%) and 19 pts (24.7%), respectively. 24 pts (31.2%) had stable disease (SD). On multivariate analysis, pts with lung metastases (OR, 2.16; 95% CI, 1.25 - 3.78; p = 0.006) and NRAS-mutated tumors (OR, 2.17; 95% CI, 1.14 - 4.18; p = 0.02) were more likely to develop MBM; pts who had liver metastases at the start of PD1i (HR, 1.77; 95% CI, 1.09 - 2.87; p = 0.002) and those who developed MBM during PD1i (HR, 4.81; 95% CI, 3.00 - 7.71; p &lt; 0.0001) had increased risk of death. Conclusions: We found a 26% incidence of MBM after PD1i exposure. Pts that develop MBM are still at higher risk of death despite advances in systemic and local CNS therapy. CNS-only progression was substantially higher in patients with MBM prior to PD1i, supporting a change in the natural history of the disease after PD1i. These findings support the use of CNS imaging to monitor disease during PD1i therapy.
P01.092 Salvage Frameless Stereotactic Radiosurgery as first treatment option for recurrent brain metastases. May durable intracranial control be achieved?
Authors: P A Jablonska, M Gimeno, L Arbea, M Moreno, D Azcona, L Ramos, B Barbés, M Santisteban, I Gil Bazo, M A Idoate, M R García de Eulate, S Tejada, R Díez Valle, J J Aristu
Journal: Neuro-Oncology (2018)

Frameless Stereotactic Radiosurgery (FL-SRS) is a feasible procedure for the management of brain metastases (BM), delivering a single large radiation dose to a well-defined target. We aimed to assess its role as a first treatment option in recurrent brain metastases (r-BM) previously treated with SRS, WBRT or metastasectomy with or without radiation. Patients (p) were immobilised with a thermoplastic mask and individualised dental mould. Radiation techniques (arch-therapy, IMRT or VMAT) were selected depending on location, shape and size of the lesion. Treatment was delivered with a linac equipped with FFF, Cone beam-CT and HEXAPOD system. PTV was defined as GTV plus 1,5-2mm margin. The total dose (18-36Gy) was prescribed to 95% of the PTV in 1–5 fractions. Between October 2014 and April 2017, 28 patients with 98 r-BM were treated. Primary tumor distribution was: NSCLC (11p, 39%), breast cancer (7p, 25%) and other tumor histologies (10p, 36%). A median of 3 r-BM were treated per patient with a median prescribed dose of 18,88 Gy. The median PTV volume was 1,00cc. Nineteen (68%) patients were previously treated with SRS, 6p (21%) received WBRT, 2p (7%) underwent metastasectomy plus irradiation of the surgical bed and 1p (4%) metastasectomy alone. Fourty-three percent of r-BM showed radiological response. Local progression was observed in 8 r-BM (8%) and the local-failure free-survival was 86% at 1-year and 73% at 2-years. Distant brain failure was recorded in 13p (46%). With a median follow up of 19 months, the median OS has not been reached, brain-PFS and OS at 1-year and 2 years were 70% - 52% and 29% - 35%, respectively. Twelve BM developed signs of radionecrosis (12%) and 2 out of 7p were symptomatic requiring an active treatment. Only one patient died due to a neurological cause. FL-SRS is a precise, feasible and effective first option treatment for r-BM. Despite the poor prognosis in this subgroup of patients, our data show excellent local control and long-term survivors with very low rates of toxicity.
Advances in the approach to treatment of bilateral retinoblastoma: 26-year experience.
Authors: Rejin Kebudi, Samuray Tuncer, Sema Bay Buyukkapu, Serra Sencer, Omer Gorgun, Fulya Yaman Agaoglu, Inci Ayan, M. Emin Darendeliler
Journal: Journal of Clinical Oncology (2017)

e22009 Background: Bilateral retinoblastomas (BRBS) comprise 25 % of all RBS. Treatment decision depends on tumor burden, potential for vision, status of the contralateral eye. As the survival rate in retinoblastoma has increased, ocular salvage and late effects has become an important issue. The aim of the study is to evaluate the demographic features, treatment modalities, and late effects in BRBS. Methods: BRBS treated in Istanbul University, Oncology Institute and Opthalmology Department between 1990-2016 were retrospectively evaluated. All patients were multidisciplinarily evaluated for chemotherapy (chemoreduction /adjuvant), local opthalmologic therapies (transpupillary thermotherapy, cryotherapy, plaque), radiotherapy, enucleation. The chemotherapy (CT) protocol used had vincristine, cisplatin, etoposide, cyclophosphamide until 2009, and vincristine, etoposide, carboplatin since then. Since 2011, intraarterial, intravitreal CT was also used. Results: 114 BRBS (228 eyes) (56 male, 58 female) with a median age of 9 months (20days-42 mo.) were evaluated. Three had extraocular disease, two trilateral RBS. Seventeen had history of retinoblastoma in their families. According to ICRB classification, there were 67 eyes in group E, 43 group D, 27 group C, 45 group B, and 19 group A. Enucleation was done in 68 (30%) eyes, mostly group E. During 1990-2000, 23/26 patients underwent enucleation, whereas 45/88 underwent enucleation after 2000. Radiotherapy was used for 30 eyes, most before 2000. Bone and soft tissue deformities and cataracts were observed in irradiated patients. Five patients had a second cancer (4 sarcomas, 1 meningioma) at a median of 11 years, four in irradiated sites. The 5 yr survival was 93.5%, 9 patients died, 4 due to second cancer. Conclusions: As the survival rate in intraocular BRBS has increased, ocular salvage and late effects have gained importance. Chemoreduction (systemic, intraarterial) and local ophtalmic therapies enable preservation of vision in most group A, B, C tumors and some D tumors. Most group E tumors require enucleation. Radiotherapy is not used in most RBS in the last decade. Intra-arterial chemotherapy is promising in maintaining ocular salvage.
P04.87 Delineating the invasive component of human brain tumors using brain organoids
Authors: W Zhou, B Klink, T R Lunavat, H Miletic, J V Joesph, M Han, M Bahador, J Wang, R Bjerkvig
Journal: Neuro-Oncology (2018)

We have previously developed a brain organoid system based on the development of fetal rat brain cells taken from fetuses at the 18th day of gestation. The purpose of the present work was to use the latest technologies to assess in detail the differentiation of various neural cell lineages into mature brain organoids and also to assess their cellular organization into mature brain structures. We also explored in detail glioma cell invasion parameters such as speed of invasion, the clonal composition of invasive cells as their transcriptional profiles. Western blot, immunohistochemistry, and immunofluorescence were used to detect the expression and distribution of mature neurons, astrocytes, oligodendrocytes, and microglia in the brain organoids at different stages of development. Transcriptomic analysis was also assessed by RNA-seq. To determine the invasive potential of the tumor cells into the organoids, we barcoded various tumor cell clones in order to establish a “rainbow” tumors where different clones were given a different color. By advanced imaging we tracked in real time the invasion of the barcoded cells. Moreover, tumor cells from the invasive areas as well as from the tumor core were analyzed by RNA-seq. Western blots showed that markers of mature neurons, astrocytes, oligodendrocytes and microglia were highly expressed at 14-21th day of brain organoid development, which was also reflected by RNA-seq. Having described in detail the mature organoid structure, we explored the invasive capacity and speed of invasion of the barcoded cells. Our results show that the average speed of glioma cell invasion is in the range of ~ 20 μm/h. We also show that that different glioma stem cell lines show different invasive capacities based on the tumor of origin. Genomic analysis of invasive cells revealed clear invasive signatures. We found that brain organoids display a highly cellular and structural organization. For the first time the speed of invasion was determined as well as their clonal composition. By a molecular identification of invasive and non-invasive cells new therapeutic strategies can be designed targeting the invasive compartment in GBMs.
Study of HPV infection in tissues of tumor and lymph nodes of patients with cervical cancer.
Authors: Galina Andreevna Nerodo, Oleg Ivanovich Kit, Tatyana A. Zykova, Victoria A. Ivanova, Vera Nikitina, Ekaterina V. Verenikina, Natalia V. Chernikova, Yuriy A. Poryvaev, Olga Selezneva, Olga A. Bogomolova
Journal: Journal of Clinical Oncology (2016)

e17027 Background: The purpose of the study was to analyze the detection rate and viral load of HPV16 and HPV18 in tissues of cervical tumors and lymph nodes depending on the disease stage and presence of metastases. Methods: FPPE tissues of cervical tumors (histologically verified squamous cell carcinoma) and regional lymph nodes of 146 patients were studied; 68% of patients were under 50 years of age. DNA extraction was performed by sorbent method after tissue dewaxing. DNA of HPV16 and HPV18 were detected by PCR and FISH with calibrators. Results: Stage I was observed in 49% of patients, stage II in 29%, stage III in 22%. Metastases to regional lymph nodes were found in 30 patients (20.5%). HPV DNA was found in 93.2% of tumor tissue samples and in 82.4% of lymph node tissue. HPV16 in tumor tissue was found in 70.6%, HPV18 in 7.3%, HPV16+18 in 22.1%. The values for lymph nodes were 67.2%, 9.8% and 23%, respectively. Cervical tumors showed HPV16 (alone and in associations) in 86.3% of patients, HPV18 – in 29.4%; in lymph nodes - HPV16 (alone and in associations) in 90.2%, HPV18 in 32.7%. Presence of HPV16 was detected in patients with stage I – 52.4%, II – 28.6%, III – 19%, its absence - I – 30%, II – 30%, III – 40%. Metastases to lymph nodes with HPV16 – in 15.9%, without it – 50% of patients. Thus, disease prognosis was more favorable for patients with HPV16 than for patients without it. Similar but less pronounced data were found for HPV18. Mean viral load of HPV16 in tumor tissues was 5.28 lg/105 copies of β-globin gene, type 18 – 3.5 lg., in lymph nodes – 4.08 lg and 4.03 lg. Viral load of HPV16 in tumor tissues of patients with metastases was 5.85 lg, type 18 – 4.31 lg, in lymph nodes – 4.25 lg and 5.63 lg; patients without metastases: type 16 in tumor – 5.17 lg, type 18 – 3.45 lg, in lymph nodes – 4.04 lg and 3.64 lg. Conclusions: Infection with HPV DNA in patients with cervical cancer was 93.2% in tumor and 82.4% in lymph nodes. HPV 16 prevailed in all studied tissues. HPV presence in cervical cancer patients characterizes more favorable clinical course of the disease. Comparison of mean viral loads of HPV16 in the cervix and lymph nodes (with and without metastases) indicates a higher level of viral load in tissues of the cervix.
CMV gB/pp65 eVLPs formulated with GM-CSF as a therapeutic vaccine against CMV-positive tumors.
Authors: David E Anderson, Catalina Soare, Tanvir Ahmed, Julie Joseph, Abebaw Diress, Barthelemy Ontsouka, Jasminka Bozic, Francisco Diaz-Mitoma
Journal: Journal of Clinical Oncology (2018)

e14032 Background: Numerous laboratories have demonstrated cytomegalovirus (CMV) antigens in over 90% of GBM tumors, medulloblastoma and breast cancer. Memory CD4+ and CD8+ T cells are most frequently directed against the gB and pp65 antigens at frequencies that can exceed 10%. Thus, CMV gB and pp65 represent attractive, highly immunogenic “foreign” antigen components of a vaccine against CMV-positive tumors that can exploit high precursor frequencies of CD4+ and CD8+ T cells. Methods: Enveloped virus-like particles (eVLPs) are produced after transfection of HEK 293 cells with a plasmid encoding murine leukemia virus Gag plasmid fused in-frame with CMV pp65 antigen, which gives rise to particles. Co-transfected CMV gB plasmid enables particles budding from the cell surface to incorporate the gB protein into the lipid bilayer. Results: Ex vivo studies using PBMCs from GBM patients demonstrated that gB/pp65 eVLPs restimulate both CD4+ and CD8+ T cells at frequencies comparable to those observed for healthy CMV+ subjects, and formulation with GM-CSF augmented IFN-g and CCL3 secretion. Biodistribution studies demonstrated that the gB/pp65 eVLPs remain at the intradermal injection site for at least two weeks, with particles appearing in draining lymph nodes within a few hours. Mechanistic studies demonstrated that monocyte uptake of eVLP particles induces proinflammatory cytokines, which are amplified by gB expression on the surface of the gB/pp65 particles. Immunization of CMV+ rhesus macaques with a macaque-specific version of the vaccine demonstrated the safety of the vaccine and ability to boost pre-existing IFN-g-secreting T cell responses. Conclusions: A phase I/IIa multicenter study designed to demonstrate safety and determine the most immunogenic dose of vaccine in recurrent GBM patients was initiated, with the first subject dosed in January 2018. Up to 3 different antigen dose levels will be evaluated, with 6 subjects in each cohort. Comprehensive safety evaluations and immune-monitoring will be performed 2 weeks after each immunization. Ten additional subjects will be enrolled once an optimal vaccine dose regimen is identified. Subjects will be vaccinated monthly and followed until tumor progression.
Recovery of quality of life (QOL) and physical function over three years in adult survivors of acute myeloid leukemia (AML) after intensive chemotherapy (IC) compared with normative data.
Authors: Narhari Timilshina, Henriette Breunis, George A. Tomlinson, Shabbir M.H. Alibhai
Journal: Journal of Clinical Oncology (2016)

e21528 Background: The treatment of AML with IC is associated with significant toxicities. We previously showed impairments in QOL and physical function with AML at diagnosis and over 1 year. The aim of the current study to describe QOL and physical function recovery over 3 years from diagnosis compared with normative data. Methods: AdultAML patients (age 18+) undergoing IC without stem cell transplant were enrolled in a prospective, longitudinal study. Assessments were done at baseline (pre-IC) and at 11 time points over the next 3 years. At each visit, patients completed the EORTC QLQ-C30 and the FACT-Fatigue to measure global QOL and fatigue, respectively, in addition to 2 physical performance measures (PPMs; grip strength and 6-minute walk test (6MWT)). We examined recovery between 12 and 36 months after diagnosis. We compared results with gender-stratified population normative data to determine the proportion of patients whose scores were less than the minimum clinically important difference of normal on each outcome. Results: 70 one-year survivors with median age 54 years were followed for up to 3 years. Global QOL recovery was seen in 49% at 1 year, 75% at 2 years and 86% at 3 years. At 1 year, the QLQ-C30 subscales with the greatest proportion of survivors who had returned to normal were physical function (72%) and emotional function (72%), and at 3 years it was physical and social functioning (76% and 82%, respectively). For FACT-fatigue, 68% of AML survivors had similar values to population norms at 1 year and 76% at 3 years. Performance on PPMs was poorer on average, with only 39% returning to normal in grip strength at 1 year and 41% at 3 years. Also, only 53% of survivors returned to normal on the 6MWT at 3 years. Conclusions: The vast majority of survivors of AML after successful conventional IC achieve significant improvements in global QOL and its domains as well as fatigue with values similar to normative data by three years after diagnosis. These data suggest that appropriately selected patients who survive past 1 year and remain in remission generally recover most areas of QOL over the next 2 years although PPM recovery remained blunted.
Clinical observations of AML expressing mutant RUNX1 and pre-clinical studies of RUNX1-targeted novel therapy of AML.
Authors: Courtney Denton Dinardo, Christopher P Mill, Warren Fiskus, Dyana T Saenz, Agnieszka J Nowak, Baohua Sun, Keyur Patel, Tapan M. Kadia, Christopher Brent Benton, Koichi Takahashi, Hagop M. Kantarjian, Kapil N. Bhalla
Journal: Journal of Clinical Oncology (2017)

7030 Background: Runt-related transcription factor 1 ( RUNX1) is critically involved in normal and malignant hematopoiesis. Somatic mutations in RUNX1 occur in ~10% of AML, especially in older patients with history of radiation or antecedent hematologic disorder. Presence of mRUNX1 is reported to confer relative resistance to therapy and poorer prognosis in AML, and there are no mRUNX1-targeted or specific therapies available. Methods: We retrospectively analyzed outcomes of 94 mRUNX1 and 444 wild-type RUNX1 AML patients treated at our institution from 9/2013 to 12/2016. We also determined the pre-clinical efficacy of a targeted therapy against cultured and primary AML cells expressing mRUNX1. Results: 67% of mRUNX1 patients were &gt; 65 years of age. Co-occurring mutations with mRUNX1 were ASXL1 (33%), N/KRAS (20%), FLT3 (20%), IDH2 (18%), IDH1 (13%) and TET2 (10%). In patients &gt; 65 years treated with hypomethylating agent-based therapy, the presence or absence of mRUNX1 did not impact response rate (42% vs 46% CR/CRp, p = 0.67), median event-free survival (3.4 vs 4.7 mo, p = 0.82) or overall survival (11.5 vs 9.3 mo, p = 0.97). In mRUNX1 expressing AML OCI-AML5 and MonoMac1 cells, knockdown of RUNX1 by shRNA repressed its targets, e.g., MYC and PU.1, inhibited growth and induced apoptosis. Ex vivo knockdown of RUNX1 abrogated in vivo leukemia initiation by OCI-AML5 cells. After engraftment, inducible shRNA-mediated in vivo knockdown of RUNX1 restored survival of immune-depleted NSG mice engrafted with OCI-AML5 cells. RUNX1 transcription is driven by a super enhancer occupied by the bromodomain extraterminal protein (BETP), BRD4. Accordingly, BRD4 knockdown by shRNA or treatment with the BRD4-inhibitor OTX015 depleted RUNX1 and its targets, and induced apoptosis of AML cells. Treatment of OCI-AML5 cell-engrafted NSG mice with OTX015 (50 mg/Kg/day X 5, for 3 wks) reduced AML burden and improved survival (p &lt; 0.01). Co-treatment with the BETi and BCL2 inhibitor venetoclax or CDK4/6 antagonist palbociclib or decitabine synergistically induced apoptosis of OCI-AML5 and primary AML blasts. Conclusions: These findings highlight a novel, promising, BETP antagonist-based therapy of AML expressing mtRUNX1.
Association of changes in the B-cell receptor (BCR) repertoire with overall survival after sipuleucel-T (sip-T) treatment for prostate cancer.
Authors: Li Zhang, Harini Kandadi, Alan Paciorek, Nancy N. Chang, Nadeem Anwar Sheikh, Lawrence Fong
Journal: Journal of Clinical Oncology (2018)

5072 Background: Sip-T, an autologous cellular immunotherapy for asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer (mCRPC), induces antibody responses to prostatic acid phosphatase and secondary antigens (antigen spread) that correlate with improved survival (Sheikh 2013, GuhaThakurta 2015); however, little is known about cancer immunotherapy-induced changes to the BCR repertoire. We evaluated the correlation between BCR diversity/dynamics and overall survival (OS) after sip-T. Methods: mCRPC pts (N = 52) received sip-T (wk 0, 2, 4) with enzalutamide (NCT01981122; Petrylak 2018). Blood samples were collected at wk 0, 2, 4, 6, 26, and 52. BCR diversity was assessed by clonality in samples from 19 pts. Dynamics of BCR repertoire changes were evaluated by the proportion of overlapping clones at two time points (Zhang 2017). Correlations between OS and BCR diversity/dynamics were analyzed by logrank test and Cox proportional hazards models. Results: There was minimal overlap of BCR clones from wk 0 to later time points suggesting clonal shuffling in BCR repertoire. BCR clonality peaked at wk 6 (wk 6 vs wk 0, p = 0.039; wk 6 vs wk 2, p = 0.030), indicating focusing of the BCR repertoire during and soon after sip-T. Clonality decreased from wk 6 to wk 26 and wk 52 (p = 0.049 and 0.037, respectively), reflecting long-term increase in diversity after sip-T. The proportion of overlapping clones from wk 0 to wk 2 and wk 0 to wk 4 were inversely correlated with OS during sip-T (p = 0.048 and p = 0.043, respectively) showing that a lower proportion of overlapping clones predicted better OS. Thus, greater changes in BCR repertoire during treatment, including creation of new clones and disappearance or reduction in frequency of preexisting clones, were associated with an OS benefit. Conclusions: Sip-T led to focusing of BCR repertoire during and soon after treatment, which may signify the magnification of relevant clones and transition of clones out of the periphery. Greater dynamic change in the BCR repertoire induced by sip-T correlated with longer survival. These findings corroborate the prior association between the breadth of antigen spread and OS after sip-T. Clinical trial information: NCT01981122.