tbuckley/cabot-search huggingface dataset:
Race and socoioeconomic status in pediatric allogeneic hematopoietic cell transplantation: A single-center study.
Authors: Sarah M Harney, Zhezhen Jin, Angela M Ricci, Justine Kahn, Priscilla Wong, Sarah McKetta, Prakash Satwani
Journal: Journal of Clinical Oncology (2018)

e18659 Background: Survival disparities by race/ethnicity and socioeconomic status (SES) have been observed in pediatric cancer and adult allogeneic hematopoietic cell transplant (alloHCT) patients. Data on race and SES in pediatric alloHCT are limited. We examined whether survival differed by race or SES in children receiving alloHCT at a tertiary care center with standardized treatment, supportive care, and follow-up. Methods: This study examined the impact of race and SES on survival in children with malignant and non-malignant disease undergoing first alloHCT. Median household income was determined by census tracts. Between-group comparison was done by analysis of variance for continuous measures and Chi-square or Fisher’s exact test for categorical. The Kaplan-Meier method was used to estimate overall survival (OS) with the logrank test for between-group comparisons. Cox proportional hazards models were used for adjusted analysis of OS. Results: We included 215 patients age 0-21y who underwent alloHCT between 2005-2016; 49% malignant and 51% non-malignant; 30% non-Hispanic (NH) white, 26% NH black, 37% Hispanic, 7% Asian. Mean follow up was 4.8±4.0y. Sociodemographic features varied across racial groups: 70% of NH white patients had private insurance vs. 35% NH black, 20% Hispanic, and 44% Asian (p<0.001). NH white patients had highest median household income (p<0.001). Regarding transplant indication, 67% of NH white patients had malignancy vs. 34% of NH black and 42% of Hispanic patients (p<0.001). Unadjusted models showed no significant difference in OS by race or SES in the pooled cohort nor when stratified malignant vs. non-malignant. In multivariable regression, race and SES were not significantly associated with OS (Table). Conclusions: We found no difference in OS by race or SES in a diverse cohort of pediatric alloHCT patients at a tertiary care center. These findings require validation in larger studies across multiple institutions. HR CI95% p Race NH White 1 NH Black 0.8 0.4-1.6 0.6 Hispanic 0.7 0.4-1.5 0.4 Asian 0.8 0.3-2.1 0.8 Malignant vs. non-malignant 3.3 1.8-6 <0.001 Related vs. unrelated donor 0.3 0.1-0.5 <0.001 Age 1 0.9-1 0.9 Insurance private vs. public 0.7 0.4-1.3 0.3
Trend of second primary malignancy in Hodgkin lymphoma.
Authors: Mahesh Nepal, Ranju Kunwor, Dominic Ho, Krishna Bilas Ghimire
Journal: Journal of Clinical Oncology (2018)

e18713 Background: Long term survivors of HL are at increased risk of second primary malignancy (SPM). We conducted this study to evaluate the trend of SPM after the diagnosis of HL over the last four decades using the U.S. Surveillance, Epidemiology, and End Result (SEER) registry database. Methods: We selected HL patients, age ≥ 18 yrs, diagnosed (Jan 1973- Dec 2012). We analyzed SPM at < 5, 5-10 , 10-20 , ≥20 yrs after diagnosis HL during (1973-1982), (1983-1992), (1993-2002), (2003-1012). We used SEER 9, MP-SIR session and SEER stat software to calculate observed/ expected (O/E) ratio to evaluate trend of SPM. Excess risk (ER) is per 10,000 patients. Results: Among 22,740 patients with HL during 1973-2012; 2883 patients developed 3,339 all sites SPMs with O/E : 2.03 & ER: 56.9. Highest risk of SPM was observed after 20 years of diagnosis O/E 2.43, ER: 122. Colorectal with O/E :1.35, lung: 2.97, breast: 2.2, kidney: 1.65, urinary bladder:1.26, thyroid: 2.76, non hodgkin lymphoma (NHL): 5.88, Acute lymphoid leukemia (ALL): 7.06, Acute myeloid leukemia (AML): 10.83 &, Chronic myeloid leukemia (CML): 2.35, as SPM were also significantly increased in HL during 1973-2012. There is a decrease in trend of SPM ER (80 to 59 to 34 to 32) for all site SPM during (1973-1982), (1983-1992), (1993-2002) & (2003-1012) respectively. Though lung cancer as SPM remains significantly increased, there is a decreasing trend of SPM ER (21 to 15 to 7 to 4) during four decades. Colorectal cancer and breast also show a decreasing trend. There is a steadily increasing trend of NHL as SPM with an increase in ER of (9 to 10 to 12 to 19). This increase in SPM as NHL was observed at < 5 , 5-10 , 10-20 & ≥20 yrs after diagnosis HL in last four decades . Similarly ER of AML as SPM changed from (3.9 to 4 to 2.5 to 5.6) during (1973-1982), (1983-1992), (1993-2002) & (2003-1012). Conclusions: With improvement in treatment modalities and supportive care more patients with HL are long term survivors. However, the survivors have increased risk of SPM. Our study shows that there is a decreasing trend of lung, breast, colorectal cancer as SPM whereas trend of NHL and AML is increasing. Providers who take care of HL patients need to be aware of SPM after diagnosis of HL and whether these patients benefit from more intense screening remains to be seen.
Over 1200 NHS staff have been disciplined for social media use
Authors: Abi Rimmer
Journal: BMJ (2018)

Since 2013 more than 1200 NHS staff have been disciplined for using social media or messaging apps, an investigation has found.

Of those who were disciplined at least 65 NHS staff members had lost their jobs, said the Times newspaper,1 which collected data from 194 NHS trusts in England through freedom of information requests.

It reported cases of doctors who had been disciplined for their …
P02.06 De-novo ceramide synthesis in skull base chordomas suggests a correlation with tumor proliferation
Authors: E La Corte, M Patanè, C Calatozzolo, E Maderna, A Raggi, M Dei Cas, R Paroni, R Ghidoni, P Ferroli, B Pollo
Journal: Neuro-Oncology (2018)

Skull base chordomas are rare slow-growing neoplasms that arise from notochord. Their morbidity is mainly related to highly aggressive local invasion and resistance to treatments. There isn’t bio-marker representing its heterogeneous appearance. Lipidomics is emerging as a new approach in many cancers and it has never been applied in chordomas. Our aim is to investigate chordoma biological behavior and the role of ceramides production in this context of proliferation and invasion. A prospective analysis has been performed on 15 frozen and paraffin-embedded skull base chordomas surgically treated at our Institution from 2016 to 2018. Clinical, radiological and pathological data were collected. The expression of Brachyury, cMET, PDGFR-β, cKIT, β-catenin, Filamin-A, GAB1, YKL-40, TERT was assessed by immunohistochemistry. Sphingolipids were extracted from frozen tissues and ceramides and dihydroceramides pattern was evaluated by HPLC/MS-MS. The autophagy and apoptosis pathways were also evaluated by assessing the expression of p62, bcl-2, beclin-1 and LC3-II by immunohistochemistry and western blot; transmission electronic microscopy was also performed in two cases. The histological analysis confirmed the clinical and radiological diagnosis of chordoma in all the cases. Total ceramides and dihydroceramides levels were concomitantly more elevated especially in recurrent tumors that underwent previous surgical resection and radiation therapy in comparison to the primary ones (p<0.01). Dihydroceramides elevation suggested the activation of the de-novo ceramide synthesis pathway. Total ceramides levels also correlated with MIB-1 staining (r2=0.586, β=0.765, p<0.01). Chordomas with high proliferation index and higher ceramides content showed to have also an autophagy pathway activation. A thorough lipidomics analysis has never been conducted in chordomas. De-novo ceramides synthesis seems to be higher in mostly recurrent already irradiated chordomas. Ceramide elevation could be related to both radiation stress response and autophagy pathway activation in the subgroup of high-proliferative chordomas. Cytoprotective autophagy may explain the need of chordoma cells to prolong their survival rate. Such results should be validated in future larger clinical, in-vitro and in-vivo studies to confirm such intricate link between ceramides, autophagy and tumor proliferation rate.
Hafnium oxide nanoparticle activated by radiotherapy to generate an anti-tumor immune response.
Authors: Jerome Galon, Marick Laé, Juliette Thariat, Sebastien Carrère, Zsuzsanna Papai, Martine Delannes, Paul Sargos, Philippe Rochaix, Laszlo Mangel, Fabienne Hermitte, Zoltan Sapi, Tamas Tornoczky, Isabelle Peyrottes, Raphael Tetreau, Marie-Christine Chateau, Sunyach Marie, Peter Agoston, Hervé Brisse, Axel Le Cesne, Sylvie Bonvalot
Journal: Journal of Clinical Oncology (2018)

e15149 Background: Radiotherapy (RT) can prime an anti-tumor immune response. Unfortunately, this response is not sufficient to allow tumor destruction and abscopal effect (effect on a distant untreated lesion) is hardly obtained. Hafnium oxide nanoparticle (HfO2-NP) is composed of high electron density material. After intratumoral injection (i.t.), HfO2-NPs are taken up by cancer cells and, when activated by RT, locally increase the radiation dose deposit, destroying more cancer cells than RT. We hypothesized that HfO2-NP + RT could enhance anti-tumor immune response, compared to RT alone, both in animal and human. Methods: Mouse CT26 cells were injected in both flanks of mice. When tumor volume is 50-120mm3, HfO2-NP (or vehicle) was injected by i.t. in the right flank tumors only, then irradiated (3x4Gy). Tumor growth was followed and animals sacrificed when a tumor reached 800mm3. Alternatively, tumors were collected 3 days after last RT fraction and immune cell infiltrates were analyzed by immunohistochemistry (IHC). Patients with locally advanced STS (NCT02379845) received either HfO2-NP + RT or RT alone. Pre- and post-treatment (biopsy and resection, respectively) tumor tissues for each patient are analyzed by immunohistochemistry and Digital Pathology for immune biomarkers and Pan-Immune gene expression profiling ( > 16 patients per arm). Results: In mouse, an abscopal effect was observed with HfO2-NP but not with RT alone. IHC analyses show that a significant increase of CD8+ cells is present in treated and untreated tumors, but no effect was observed for RT alone. IHC analysis (post- vs pre-treatment) show a marked increase of the biomarkers for patient treated with HfO2-NP + RT, particularly for CD8+ and PD1. No differences are seen for RT alone. The profile of gene expression HfO2-NP + RT differs from RT alone. Functional analysis of genes expression up-regulated in HfO2-NP + RT shows an increase of the cytokine and immune checkpoints expression, as T cell activation markers, compared to RT alone. Conclusions: HfO2-NP + RT bring marked changes to the tumor immune profile both in mouse model and in patients with STS, compared to RT. So far, these results show that HfO2-NP + RT induces a specific adaptive immune pattern. Clinical trial information: NCT02379845.
Radiographic sarcopenia measurements to predict overall survival in patients with resectable pancreatic adenocarcinoma undergoing neoadjuvant chemotherapy.
Authors: Shuang Qin Zhang, Kevin K. Roggin, Kristen Wroblewski, Hedy L. Kindler, Mary Buschmann, William Dale
Journal: Journal of Clinical Oncology (2016)

e15700 Background: Sarcopenia is associated with poor outcomes in pancreatic cancer (PC) patients (pts) planning surgical resection. Minimal data is available regarding the predictive value of sarcopenia in PC pts undergoing neoadjuvant (neoad) chemotherapy (chemo) prior to surgery. In an analysis of existing data, we evaluated sarcopenia in resectable PC pts at each interval of neoad therapy. We hypothesized that radiographic sarcopenia would predict poorer overall survival (OS). Methods: We reviewedCT scans for sarcopenia at each treatment interval (pre-therapy, post-neoad chemo, post-surgery, post-adjuvant chemo) in pts with resectable PC. Four cohorts were compared: resectable PC pts receiving neoad chemo, surgery, adjuvant chemo (NSA); neoad chemo, but no surgery due to progression (N); surgery and adjuvant chemo (SA); and palliative care (P). Sarcopenia was assessed at L3 by total psoas area index (TPAI) and weighted average Hounsfield units (HU), correlating with estimates of psoas muscle volume and density. Results: NSA cohort (n = 20): mean age 62; albumin 4.1; HU 50.2; TPAI 6.0. N cohort (n = 24): mean age 69; albumin 3.9; HU 42.2; TPAI 5.1. SA cohort (n = 20): mean age 62; albumin 4.0; HU 42.2; TPAI 5.5. P cohort (n = 21): mean age 74; albumin 3.5; HU 37.1; TPAI 4.1 Higher baseline TPAI was associated with improved OS, after adjusting for treatment, gender, and comorbidities (HR 0.82 [95% CI 0.68-0.99]; p = 0.04). Effect of baseline TPAI on OS did not vary between cohorts (p = 0.69). There was a decrease in TPAI, but not HU, before and after neoad chemo [mean change -0.6 (95% CI -0.8 to -0.3), p < 0.001]. Survival curves of baseline TPAI tertiles, from a Cox regression model adjusting for surgery, diabetes, renal failure, gender, age, and HU, showed a linear trend significance test of p = 0.07. There was no correlation between HU and TPAI (r = 0.14, p = 0.21). Conclusions: Higher TPAI, but not HU, was associated with better OS across cohorts. In PC patients who received neoad chemo, there was a significant decrease in TPAI during treatment. Prospective studies are warranted to assess impact of TPAI loss on clinical outcomes.
Plasma sequencing of ctDNA in early stage breast cancer as part of the screening process.
Authors: Begona Jimenez Rodriguez, Gema Diaz Córdoba, Alicia Garrido Aranda, Luis Vicioso, M Rosario Chica Parrado, Vanessa de Luque, Maria Jose Lozano, Mar Moreno Ros, Estefania Bellagarza, Cristina Hernando, Begona Bermejo, Ana Lluch Hernandez, Martina Álvarez, Frederick S. Jones, Annette Nocon, Matthew B. Ryder, Johannes Fredebohm, Daniel Mehnert, Frank Holtrup, Emilio Alba
Journal: Journal of Clinical Oncology (2018)

12073 Background: Mammography is the current standard of care for breast cancer(BC) screening. However, not all cancers are detectable on mammography and not all mammographic findings represent cancer, moreover, the confirmatory biopsy is not always 100% informative due to the intrinsic intratumor heterogeneity. The aim of this study was to investigate the power of ctDNA to both confirm and interrogate disease status beyond mammography findings by comparing ctDNA mutation results to those obtained by tissue sequencing. Methods: Matched blood and fresh tissue biopsies were collected from 56 patients with BIRADS 4c/5 mammography findings and subsequent diagnosis of primary BC. The blood draw was performed immediately before the tissue biopsy. The NGS study on fresh frozen tissue samples was performed using a customized design of TruSeq Custom Amplicon Low Input Panel (Illumina), which includes the full region of PIK3CA, TP53, CDH1, GATA3, PIK3R1 and MAP2K4 genes (most commonly mutated ganes in early stage BC according to TCGA). Plasma sequencing was performed using Plasma SafeSeq (PSS). Results: At the time of this analysis, 29 matched samples were analyzed for TP53 and PIK3CA mutations. Median age was 64y(44-92), 56% of patients has mammographic lesions greater than 2cm, 35% of patients had grade 3 tumors and % of IHQ tumor subtypes was 52% LumA, 30.5% LumB, 13% TNBC and 4.5% Her2-enriched. At least 1 mutation was detected in each patient in the tissue analysis, with 10 TP53 and 24 PIK3CA different mutations detected overall. PSS detected TP53 and PIK3CA mutations in 10 of these 29 patients. Concordance of plasma and tumor mutations was observed in 8 of 29 patients (27.6%) [3 TP53 (c.637C > T, c.398T > A,c.587G > C); 4 PIK3CA (c.3140A > G, c.1633G > A,C.1624G > A, C.3145G > C), 1 with both mutations (TP53 c.743G > T, PIK3CAC.3140A > T)]. Additionally, PSS revealed 4 plasma mutations that were not identified in the tissue (3 TP53, 1 PIK3CA). Conclusions: Mutations in ctDNA can be readily detected using a highly sensitive plasma sequencing method in early-stage breast cancer patients. These findings suggest that early ctDNA testing can provide critical clinical information that may improve patient diagnosis.
Mirvetuximab soravtansine (IMGN853), a folate receptor alpha (FRα)-targeting antibody-drug conjugate (ADC), in platinum-resistant epithelial ovarian cancer (EOC) patients (pts): Activity and safety analyses in phase I pooled expansion cohorts.
Authors: Kathleen N. Moore, Ursula A. Matulonis, David M. O'Malley, Jason A. Konner, Lainie P. Martin, Raymond P. Perez, Todd Michael Bauer, Lucy Gilbert, Shelly Marie Seward, Amit M. Oza, Rodrigo Ruiz-Soto, Michael J. Birrer
Journal: Journal of Clinical Oncology (2017)

5547 Background: The early clinical evaluation of mirvetuximab soravtansine (IMGN853), an ADC that comprises a FRα-binding antibody linked to the tubulin-disrupting maytansinoid DM4, has revealed encouraging signs of activity in pts with ovarian cancer. A pooled analysis of safety and efficacy was performed including individuals with platinum-resistant EOC, enrolled across three expansion cohorts of an ongoing phase I trial (NCT01609556), who met the eligibility criteria for the pivotal phase III study of IMGN853 (FORWARD I; NCT02631876). Methods: Pts were administered IMGN853 intravenously once every 3 weeks at 6 mg/kg using adjusted ideal body weight dosing. Responses were assessed according to RECIST 1.1 and adverse events (AEs) evaluated by CTCAE v4.0. Results: A total of 37 EOC pts treated as part of the three phase I expansion cohorts (pooled population; n = 113) met the FORWARD I enrollment criteria of moderate to high tumor FRα levels (≥ 50% of cells with ≥ 2+ FRα expression) and 1-3 prior lines of therapy. In this group of pts with platinum-resistant disease, confirmed objective tumor responses were observed in 17 individuals (1 complete response [CR] and 16 partial responses [PR]) for an overall response rate (ORR) of 46% (95% CI, 29.5, 63.1) and a median PFS of 6.7 months (95% CI, 4.1, 9.0). The safety profile of the pooled population was consistent with that previously reported (ASCO Annual Meeting, 2016) with the most common AEs being diarrhea, fatigue, nausea, and blurred vision; these were low grade and readily managed. Conclusions: IMGN853 continues to be characterized by favorable tolerability and encouraging activity in pts with platinum-resistant EOC. In particular, both the ORR (46%) and PFS (6.7 months) achieved in this group of pts are superior to outcomes typically seen with established single-agent chemotherapy within the setting of primary platinum resistance. Overall, these analyses provide continued, robust support for the patient eligibility strategy employed in the phase III evaluation of IMGN853. Clinical trial information: NCT01609556.
Efficacy and immune modulation of the tumor microenvironment with the combination of the PARP inhibitor rucaparib and CD122-biased agonist NKTR-214.
Authors: Andrew Simmons, Liliane Robillard, Minh Nguyen, Thomas C. Harding, Deborah H. Charych
Journal: Journal of Clinical Oncology (2018)

5582 Background: NKTR-214 is a biased agonist of the IL2Rbg (CD122) pathway that activates and mobilizes CD8 T and NK cells into the tumor microenvironment. The PARP inhibitor rucaparib has demonstrated activity in BRCA mutant deficient tumors through synthetic lethality. We hypothesized that PARP inhibition in a BRCA syngeneic model would lead to immunogenic cell death and synergize with NKTR-214 through antigen priming and enhanced activation of newly infiltrated intratumoral T and NK cells. Methods: Mice (n = 10/group) were inoculated with the murine ovarian tumor cells (BR5FVB1) harboring genetic alterations (TP53-/-, BRCA1-/-, myc and Akt) frequently present in human ovarian carcinomas. Tumors were grown to 125 mm3prior to treatment with vehicle, rucaparib (150 mg/kg BID x 28 days), NKTR-214 (0.8 mg/kg q9d x 3), or the combination and tumor volumes were measured. Immune modulation was evaluated by IHC and gene expression. Results: Treatment with the combination resulted in 88.5% tumor growth inhibition (day 22; p < 0.0001), and tumors were monitored for regrowth after 28 days of dosing. Tumor volume nadir was 94.5 mm3 on day 38 for rucaparib treated animals and progressed to > 1000 mm3 by day 59. In contrast, 50% of mice treated with NKTR-214 and rucaparib combination were tumor free on day 113, suggesting development of immune memory. The combination of NKTR-214 and anti-PD1 in the same model did not provide tumor-free mice. An increase in infiltrating T cells, NK cells, dendritic cells, and neutrophils, as well as the induction of interferon-gamma induced chemokines was observed with the combination of rucaparib and NKTR-214 by expression profiling. IHC staining also showed significant increases in CD3, CD4 and CD8 T cells with the combination (p < 0.05). Conclusions: The novel combination of NKTR-214 plus rucaparib results in durable complete responses in a genetically-relevant ovarian tumor model. Profiling of tumors suggested the activity of this combination is through antigen priming of infiltrating memory T cells, increased NK cell numbers, and enhanced cytotoxicity of immune infiltrates into the tumor.
Results of the first-in-human study of ABBV-075 (mivebresib), a pan-inhibitor of bromodomain (BD) and extra terminal (BET) proteins, in patients (pts) with relapsed/refractory (R/R) solid tumors.
Authors: Sarina Anne Piha-Paul, Jasgit C. Sachdev, Minal A. Barve, Patricia LoRusso, Russell Zelig Szmulewitz, Sapna Pradyuman Patel, Mark D. McKee, Johannes E. Wolff, Beibei Hu, Anjla Sood, Xiaotian Chen, Sarah C. Wilson, Bert H. O'Neil
Journal: Journal of Clinical Oncology (2018)

2510 Background: BDs are protein domains that bind to acetylated histone tails, leading to upregulation of target genes driving oncogenesis. Inhibition of the BET family prevents assembly of the macromolecular complex and its transcriptional response. ABBV-075 is a pan-BET inhibitor that induces death in cell lines and tumor growth inhibition in xenograft models. This first-in-human, phase 1, two-part study (NCT02391480) assessed the safety and pharmacokinetics of ABBV-075 in pts with advanced tumors. Results from the dose escalation part in pts with solid tumors are reported. Methods: The dose escalation part of this open-label study enrolled adult pts with R/R solid tumors in a 3+3 fashion. Endpoints included maximum tolerated dose, recommended phase 2 dose (RP2D) at different ABBV-075 dosing schedules (daily, Monday/Wednesday/Friday [MWF], or 4 days on/3 off [4/7]), safety and preliminary efficacy. Results: As of Dec 2017, 72 pts with solid tumors enrolled in the dose escalation cohort. Most common tumors were: uveal/choroidal melanoma (n = 10); breast (n = 8); pancreatic (n = 6); head and neck (n = 5); and prostate (n = 3). Median age was 61.5 years (range 23–83); median treatment duration was 7.6 weeks (range 0.9–39.6). In total, 23, 27, and 22 pts entered the daily, MWF and 4/7 schedules. Overall, 71 pts (98.6%) reported ≥1 treatment-emergent adverse events (TEAEs); thrombocytopenia (56.9%), dysgeusia (48.6%), fatigue (43.1%) and nausea (34.7%) were most common. Grade 3/4 TEAEs were reported in 52 pts (72.2%); thrombocytopenia (30.6%) and anemia (15.3%) were most common; 11 pts died (none considered study drug related). Dose-limiting toxicities included thrombocytopenia, fatigue, aspartate aminotransferase elevation, gastrointestinal bleed and hypertension. The RP2D is 1.5 mg for the daily schedule, 2.5 mg for 4/7 and 3 mg for MWF. Of 65 evaluable pts, 25 pts (38.5%) had stable disease and 40 pts (61.5%) had progressive disease. Median progression-free survival was 1.8 months (95% CI: 1.8, 1.9). Conclusions: ABBV-075 has a tolerable safety profile and led to stable disease in some pts with malignant solid tumors. Clinical trial information: NCT02391480.