tbuckley/cabot-search huggingface dataset:
NF-κB/c-Rel deficiency causes Parkinson’s disease-like prodromal symptoms and progressive pathology in mice
Authors: Edoardo Parrella, Arianna Bellucci, Vanessa Porrini, Marina Benarese, Annamaria Lanzillotta, Gaia Faustini, Francesca Longhena, Giulia Abate, Daniela Uberti, Marina Pizzi
Journal: Translational Neurodegeneration (2019)

Parkinson's disease (PD), the most common neurodegenerative movement disorder, is characterized by dopaminergic nigrostriatal neuron loss and brain accumulation of Lewy bodies, protein aggregates mainly composed of α-synuclein. We reported that mice deficient for NF-κB/c-Rel (c-rel-/-) develop a late-onset parkinsonism. At 18 months of age, c-rel-/- mice showed nigrostriatal degeneration and accumulation of α-synuclein aggregates associated with a motor impairment responsive to L-DOPA administration. Being c-Rel protein a transcriptional regulator for mitochondrial anti-oxidant and antiapoptotic factors, it has been inferred that its deficiency may affect the resilience of "energy demanding" nigral dopaminergic neurons to the aging process. PD patients manifest a prodromal syndrome that includes olfactory and gastrointestinal dysfunctions years before the frank degeneration of nigrostriatal neurons and appearance of motor symptoms. According to the Braak staging, the onset of non-motor and motor symptoms relates to progressive ascendant diffusion of α-synuclein pathology in the brain. The aim of this study was to identify whether c-rel-/- deficiency is associated with the onset of premotor signs of PD and spatio-temporal progression of cerebral α-synuclein deposition.Intestinal and olfactory functions, intestine and brain α-synuclein deposition as well as striatal alterations, were assessed in c-rel-/- and control mice from 2 to 18 months of age.From 2 months of age, c-rel-/- mice displayed intestinal constipation and increasing olfactory impairment. At 2 months, c-rel-/- mice exhibited a mild α-synuclein accumulation in the distal colon. Moreover, they developed an age-dependent deposition of fibrillary α-synuclein that, starting at 5 months from the olfactory bulbs, dorsal motor nucleus of vagus and locus coeruleus, reached the substantia nigra at 12 months. At this age, the α-synuclein pathology associated with a drop of dopamine transporter in the striatum that anticipated by 6 months the axonal degeneration. From 12 months onwards oxidative/nitrosative stress developed in the striatum in parallel with altered expression of mitochondrial homeostasis regulators in the substantia nigra.In c-rel-/- mice, reproducing a parkinsonian progressive pathology with non-motor and motor symptoms, a Braak-like pattern of brain ascending α-synuclein deposition occurs. The peculiar phenotype of c-rel-/- mice envisages a potential contribution of c-Rel dysregulation to the pathogenesis of PD.
Preclinical testing of ultra-rapid FLASH total abdominal irradiation demonstrates survival benefit and decreased gastrointestinal toxicity compared to conventional external beam radiation.
Authors: Karen Levy, Marjan Rafat, Emil Schueler, Joshua Thomas Eggold, Jinghui Wang, Keriann Casey, Albert Koong, Peter Maxim, Billy W. Loo, Erinn Rankin
Journal: Journal of Clinical Oncology (2019)

3092 Background: Total abdominal irradiation (TAI) is not widely used in the treatment of ovarian cancer due to high abdominopelvic toxicity. Ultra-rapid FLASH irradiation has been shown to spare the lung, skin and brain from radiation toxicity in preclinical models. Conventional radiotherapy delivers a dose-rate of 3-4 Gy/minute, while our small animal FLASH system uses a linear accelerator to generate a dose-rate of 200 Gy/second. Our data demonstrates that use of FLASH-TAI in a preclinical model protects against death from irradiation and confers gastrointestinal (GI) protection when compared to conventional external beam irradiation. Ongoing studies are evaluating the potential for tumor control in an ID8 mouse model of ovarian cancer. Methods: Female C57BL/6 mice received TAI using FLASH and conventional (CONV) radiation at increasing doses: 8.5 Gy, 10.5 Gy and 12 Gy. Unirradiated controls and irradiated cohorts were analyzed at 5-days and 12 months post-irradiation. Normal tissue toxicity was determined by measuring total body weights, stool counts, laboratory analysis, histological analysis, immunohistochemistry, immunofluorescence microscopy and survival. Results: Solid stool production was preserved in FLASH mice, whereas a 50-63% decrease was observed in the CONV cohorts. Histology demonstrated that FLASH preserves small intestinal architecture. TUNEL analysis demonstrated an increase in apoptosis throughout the small intestine of only the CONV cohort. Exploratory necropsy of all surviving cohorts at 12 months post-irradiation was notable for secondary transmural proximal duodenal adenocarcinomas within the radiation field in 25% of only the aged CONV cohorts. There was no laboratory evidence of long-term hematopoietic, liver or kidney toxicity at 12 months. Survival analysis was notable for death of all 12 Gy CONV mice by 9 days post-irradiation whereas 75% of the 12 Gy FLASH mice were alive at 11 months. Conclusions: FLASH protects against death from TAI, improves small intestine epithelial integrity following TAI, protects against radiation-induced apoptosis and may protect from secondary gastrointestinal tumors in the radiation field. Our discovery that FLASH is a safe strategy to deliver effective doses of total abdominal radiation potentially identifies a new opportunity to utilize FLASH-TAI for treatment of ovarian peritoneal metastases.
Longitudinal monitoring of cell-free DNA to predict for transarterial chemo-embolization failure in hepatocellular carcinoma.
Authors: Joanne Evans, Caroline Ward, Madhava Pai, Rohini Sharma
Journal: Journal of Clinical Oncology (2019)

e14544 Background: Transarterial chemo-embolization (TACE) is the standard of care for patients with intermediate stage hepatocellular carcinoma (HCC) with adequate synthetic function, and as bridging treatment in early stage disease. Survival outcomes are heterogeneous, and improved biomarkers are needed for detection of early relapse. Current practice relies on monitoring of alpha-foetoprotein (AFP) and serial imaging. Circulating cell-free DNA (cfDNA) is a compelling emergent biomarker. Here, we describe the first study of cfDNA as prognostic biomarker in HCC following TACE. Methods: 34 patients treated with TACE (2012-2018) who had full demographic information and longitudinal stored plasma available were identified. Samples were retrieved and cfDNA extracted using the QIAamp Circulating Nucleic Acid Kit. cfDNA yields were quantified by high-sensitivity Qubit analysis. Results: 74% of patients were male, 66% had Childs Pugh A disease, and 56% of patients secreted AFP ( &gt; 10ng/mL). Aetiologies of liver diseases were varied: viral hepatitis (44%), alcoholic or non-alcoholic steatohepatitis/cirrhosis (29%), hereditary or auto-immune (12%), and unexplained (15%). 79% of patients saw a fall in cfDNA titre following TACE. Where no reduction was seen, patients had a poorer median overall survival than those who did: 20 months (range 5.13 – 66.7 months) compared to 37 months (9.9 – 79.3 months). Of note, 44% of patients were AFP non-secretors. Here, cfDNA had a clear advantage in disease monitoring, with mean cfDNA titres in this group falling post treatment: from 1605.1 (range 185.9 – 6830) ng/mL to 693.7 (range undetectable - 2300) ng/mL and rising again with subsequent progression (mean of 1329.2 - range 616 – 3341 - ng/mL). Conclusions: These findings support a cost-effective monitoring role for plasma cfDNA analysis following treatment with TACE, with an added advantage in AFP non-secretors. Prospective validation is suggested to fully assess clinical utility.
Histamine food poisoning: a sudden, large outbreak linked to fresh yellowfin tuna from Reunion Island, France, April 2017
Authors: Guillaume Velut, François Delon, Jean Paul Mérigaud, Christelle Tong, Guillaume Duflos, François Boissan, Stéphanie Watier-Grillot, Mickaël Boni, Clement Derkenne, Aissata Dia, Gaëtan Texier, Philippe Vest, Jean Baptiste Meynard, Pierre Edouard Fournier, Aurélie Chesnay, Vincent Pommier de Santi
Journal: Eurosurveillance (2019)

On 20 April 2017, an outbreak of histamine food poisoning occurred in a French military unit located near Paris. A total of 40 cases were identified (attack rate: 16.6%). We conducted a case-control study on 31 cases and 63 controls. Multivariate analysis pointed to cooked yellowfin tuna fillet as the very likely source of food poisoning (odds ratio = 156.8; 95% confidence interval: 18.4-1,338.4). The fresh yellowfin tuna was from Reunion Island and was supplied vacuum-sealed and packed with ice at the principal food market of Paris. No cold chain issues could be established in the upstream and downstream supply chains. Histamine concentration was found to be 1,720 mg/kg in leftover raw tuna, and 3,720 mg/kg in control cooked tuna, well above the threshold limit values defined by European regulations (200 mg/kg). The presence of Klebsiella variicola and Pantoea agglomerans, microorganisms of the Enterobacterales order that have been reported to produce histamine, was confirmed in the leftover raw tuna. This type of food poisoning is rarely recognised and confirmed. We describe the outbreak to highlight the specific key points of this type of investigation.
Crowdfunding for lung cancer costs.
Authors: Ryan Nguyen, Nasser H. Hanna, Laura Vater
Journal: Journal of Clinical Oncology (2019)

e18340 Background: Online crowdfunding, where individuals create campaigns to solicit donations, has grown as an avenue to combat the financial toxicities of cancer. The online platform GoFundMe hosts more than 80% of the global market for crowdfunding and has raised over US $5 billion from more than 50 million donors. While medical expenses are the leading cause of crowdfunding campaigns, limited research is available on the use of crowdfunding for cancer costs. Further, no studies have evaluated the use of crowdfunding for patients with lung cancer. Methods: In January 2019, we reviewed the first 200 consecutive campaigns that resulted for “lung cancer” on GoFundMe. Campaigns were included for analysis if their description stated funds were to be used for medical costs for a patient with lung cancer in the United States. Standardized data was collected from each campaign. Descriptive statistics were used to aggregate results. Multivariable linear regression analysis were performed to examine predictors of funds raised, adjusting for campaign duration. Results: The 157 included campaigns raised a total of US $1.2 million (mean $8,364) from 11,919 donors (median 53). Compared to a similar 2018 study, our study showed lung cancer campaigns raised less than breast cancer (mean $16,026) but more than prostate cancer (mean $1,449) campaigns. Nine campaigns that were seeking funds for alternative treatment raised a total of $119,660 (mean $13,296). Narratives of financial need that were significantly associated with greater funds raised were family financial need (+$7,416), medical costs not covered by insurance (+$7,369), and the campaign stating the patient was a never-smoker (+$8,162) (all P values &lt; 0.05). Conclusions: Lung cancer has received less research funding relative to other cancer types and our study suggests a similar disparity with crowdfunding for medical costs. The “blame-the-victim” attitude that contributes to this funding disparity also exists within lung cancer crowdfunding as evidenced by the significantly greater amount of funds raised for campaigns that explicitly stated the patient was a non-smoker. Efforts to study crowdfunding for cancer costs should address the ethical implications of exacerbating funding disparities and funding for alternative treatments.
A phase II trial of olaparib and durvalumab in metastatic BRCA wild type triple-negative breast cancer.
Authors: Zahi Ibrahim Mitri, Jacqueline Vuky, Kathleen A. Kemmer, Michael A. Savin, Swapnil Parmar, Annette Kolodzie Kolodzie, Brett Johnson, Rochelle Williams-Belizaire, Joe W. Gray, Gordon B. Mills
Journal: Journal of Clinical Oncology (2019)

TPS1111 Background: There is an urgent need to develop novel non chemotherapy treatments for metastatic triple negative breast cancer (mTNBC) patients who otherwise have a poor prognosis. Immune checkpoint blockade (ICB) and PARP inhibitors (PARPi) have independently shown promise for the treatment of mTNBC, and the combination has shown early benefit in the MEDIOLA and TOPACIO trials. This trial looks to 1) evaluate the efficacy of the combination of the PARPi olaparib and the PD-L1 inhibitor durvalumab, and 2) perform extensive multi-omics including protein based image analytics (multiplex IHC, cyclic immunofluorescence) on serial biopsies to identify predictive biomarkers and resistance mechanisms. Methods: Trial Design: This is a single-arm phase II study to assess the efficacy of the combination of olaparib and durvalumab in BRCA-wildtype mTNBC. mTNBC participants will undergo a pre-treatment biopsy, then will start a 4 week induction treatment with olaparib (300 mg PO BID). At the end of 4 weeks of single agent therapy, participants will undergo a repeat on-treatment biopsy, following which durvalumab (1500 mg IV every 4 weeks) will be added to olaparib. Participants will also be offered an optional biopsy on progression. Endpoints: The primary endpoint of this study is overall response rate (ORR) to olaparib and durvalumab therapy. Secondary efficacy endpoints include clinical benefit rate, duration of response, progression-free, and overall survival. The incidence and severity of on-treatment adverse events will be collected per CTCAE 5.0. Statistical Methods: 28 participants are planned for enrollment to this study. A 2-stage analysis will be performed using a Simon 2-stage Minimax design. The null (ICB alone) and alternative (ICB + PARPi) hypotheses are: H 0 : π = 0.15 and H a : π = 0.35. For the primary endpoint, a total sample size of 28 participants will achieve 80% power to detect the ORR difference of 0.20 with one-sided type I error =0.05. The trial will be terminated in stage I if 2 or less out of the first 15 participants respond. If the trial goes on to the stage II, a total of 28 participants will be studied. If the total number responding is less than or equal to 7, the combination is rejected. Current Enrollment: The study was activated on 1/7/2019. To date, 3 out of 15 patients have been accrued to stage I of the study Clinical trial information: NCT03801369.
Economic evaluation crizotinib, alectinib and brigatinib in anaplastic lymphoma kinase positive (ALK+) non-small cell lung cancer (NSCLC).
Authors: Briana Choi, Nimer S Alkhatib, Elizabeth Pae, Hani M. Babiker, Linda L. Garland, Alyssa Henglefelt, Ali McBride, Ivo Abraham
Journal: Journal of Clinical Oncology (2019)

e20714 Background: Crizotinib and alectinib are approved as 1st and brigatinib as 2nd line (post crizotinib) therapy for ALK+ NSCLC. Alectinib and brigatinib are more expensive but potentially clinically more beneficial in terms of progression free survival (PFS). We performed cost-effectiveness/utility analyses based on published PFS data. Methods: The Bücher method was used to indirectly estimate comparative PFS hazard ratios (HR) for PFS between the 3 agents. A 2-state Markov model (progression, death) was specified, PFS survival curves were digitized, and Weibull distributions fitted with life time horizon. Drug costs were per RedBook (US$ 2018). Cost of adverse event management, disease progression and follow up were per published data. Outcomes included PFS life years (PFSLY) and quality adjusted life years (PFSQALY). Incremental cost effectiveness/utility ratios (ICER/ICUR) of PFSLY and PFSQALY gained were estimated. Deterministic results were verified by probabilistic sensitivity analyses (PSA). Analyses were from the US payer perspective. Results: In indirect comparisons, alectinib (HR 0.47, 95%CI 0.34-0.65) and brigatinib (HR 0.49, 95%CI 0.33-0.74) were superior, but equivalent to each other (HR 1.04, 95%CI 0.62-1.75), in PFS over crizotinib in their respective lines. Deterministic (probabilistic) PFSLY, PFSQALY and cost estimates were 0.86 (0.91), 0.54 (0.57) and $193,544 ($203,881) for crizotinib; 1.27 (1.36), 0.80 (0.85) and $236,279 ($251,183) for alectinib; 1.25 (1.33), 0.79 (0.83) and $492,681 ($522,533) for brigatinib. See Table for deterministic (probabilistic) ICER/ICUR results ($ in parentheses denote savings). Conclusions: In this independent economic evaluation not considering intracranial metastasis, brigatinib had the highest life time cost compared to alectinib and crizotinib (all drugs as approved). Comparable gains in PFSLY and PFSQALY for brigatinib can be achieved with alectinib at lower cost, making alectinib the most cost-effective treatment option for ALK+ NSCLC. [Table: see text]
Racial and insurance disparities in multiple myeloma management in a referral center.
Authors: Anne Renteria, Sundar Jagannath, Kezhen Fei, Sylvia Lin, Radhi Yagnik, Lisa La, Jenny J. Lin, Nina A. Bickell
Journal: Journal of Clinical Oncology (2019)

e18140 Background: Multiple Myeloma (MM) management has significantly improved disease-free and overall (OS) survival but disparities among racial groups still exist. After the Affordable Care Act, the extent to which induction, autologous stem cell transplant (ASCT), and maintenance therapies are used are uncertain. We sought to describe underuse of induction, ASCT and maintenance in a large referral center. Methods: Between 2010 and 2014, 3101 patients were diagnosed with MM via ICD-9 code from the Data Warehouse and certified hospital tumor registry. NCCN 2014 and CMS guidelines were used to define the categories of treatment underuse, and define transplant eligibility. Demographics including insurance, Charlson Comorbidity Index and treatments received were determined via chart abstraction. To date, 393 confirmed MM from 697 charts were abstracted. Comparison by groups used Chi-square for categorical variables, t-test and ANOVA for continuous variables. Multivariate logistic regression models were applied to predict underuse of induction, harvest, ASCT, and maintenance. Results: Patients were 62 ±11.3 years-old, with no racial differences in age and insurance coverage. More minorities had Medicaid (Black [B] 13%, White [W] 7%, Hispanic [H] 25%; p = 0.001). Almost all patients (97%) received induction (B 99%, W 96%, H 100%; p = 0.3), with no difference by insurance. Among transplant eligible patients, 93% underwent harvest, 87% underwent ASCT, with no racial differences. Patients with Medicare or self-pay were less likely to undergo harvest compared to patients with Medicaid or private insurance (p = 0.01). No difference in ASCT rates by insurance were noted. B patients were less likely to receive maintenance than non-B (73% vs 86%; p = 0.03), with no difference by insurance. OS was 73%, with no racial differences. In multivariate model, older age predicted induction underuse (aOR = 1.15, 95% CI: 1.06-1.25) (c = 0.9, p = 0.005), and B patients experienced more maintenance underuse (aOR = 2.22, 95% CI: 1.09-4.54) (c = 0.61, p = 0.1), controlling for age and comorbidity. Conclusions: While there were no racial or insurance differences in access to induction therapy, fewer Black patients received maintenance therapy. Interviews are underway to understand reasons for observed differences.
A phase Ib/IIa study of rucaparib (PARP inhibitor) combined with nivolumab in metastatic castrate-resistant prostate cancer and advanced/recurrent endometrial cancer.
Authors: Raanan Alter, Gini F. Fleming, Walter Michael Stadler, Akash Patnaik
Journal: Journal of Clinical Oncology (2019)

TPS2663 Background: Immune checkpoint blockade (ICB) antibodies have made a major impact in a wide range of cancers. However, only subsets of patients across all malignancies benefit from ICB. In particular, metastatic castrate-resistant prostate cancer (mCRPC) and advanced endometrial cancers (EC) have shown very limited responses to ICB. The central hypothesis of this trial is that the combination of PARP inhibitor (rucaparib) with PD-1 inhibitor (nivolumab) will enhance ICB efficacy in mCRPC and mEC patients. Given that PTEN loss has also been associated with poor response to ICB, a secondary hypothesis of this study is that the combination therapy will have differing efficacy based on the PTEN mutation status of the tumor. Methods: This is an investigator-initiated Phase 1b/IIa clinical trial of rucaparib and nivolumab singly and in combination, in mCRPC and mEC patients. Patients are randomized to one of three arms – rucaparib, nivolumab, or both drugs in combination for 4 weeks. Metastatic biopsy samples are collected at baseline and after 4 weeks on treatment, after which all arms will switch to combination therapy. The primary objective is to assess feasibility of the combination, and to elucidate changes in immune infiltrates by Nanostring RNA sequencing, multiplex immunofluorescence, 3D mapping, IHC, and flow cytometry. Secondary objectives are to assess clinical response, and correlate changes in TME with PTEN status. We have currently enrolled 4 patients to the study, and collected pre- and 4 week on-treatment biopsies. This study presents an opportunity for in-depth TME analysis that will enable the delineation of the effects of PARP inhibition singly and in combination with PD-1 blockade, on immune subsets within the TME. The correlative analyses will also lead to the discovery of novel biomarkers of response/resistance, and suggest additional immunooncology combinations for specific molecular subsets of prostate and endometrial cancers. Clinical trial information: NCT03572478.
Comparison of preoperative and prechemotherapy lymphocyte counts to predict outcome of non-small cell lung cancer patients treated with adjuvant chemotherapy.
Authors: Hyun Woo Lee, Yong Won Choi, Mi Sun Ahn, Seok Yun Kang, Jin-Hyuk Choi
Journal: Journal of Clinical Oncology (2019)

e20002 Background: Several systemic inflammatory markers in blood have been suggested as prognostic factors in various cancers. We investigated the prognostic significance of neutrophil-to-lymphocyte ratio (NLR) and absolute lymphocyte count (ALC) in patients (pts) with non-small cell lung cancer (NSCLC) treated with adjuvant chemotherapy. Methods: A retrospective review was conducted on 108 pts who received adjuvant chemotherapy after surgical resection of NSCLC. Disease-free survival (DFS) and overall survival (OS) of pts with high NLR and ALC ( &gt; median value) before surgery or chemotherapy were compared to those of pts with low NLR and ALC (≤median value). Results: The number of pts at AJCC stage IB, IIA, IIB, IIIA, and IIIB were 1, 38, 9, 58, and 2, respectively. Adenocarcinoma, squamous cell carcinoma, and other histologic types were present in 66 (61.1%), 32 (29.6%), and 10 (9.3%) pts, respectively. The most frequently used chemotherapy regimen was vinorelbine/cisplatin (81 pts), followed by paclitaxel/carboplatin (22 pts), and others (5 pts). A total of 61 (56.5%) pts received adjuvant radiotherapy (before adjuvant chemotherapy: 53 pts). Preoperative NLR and ALC were not associated with clinicopathologic characteristics including stage and histologic types. High prechemotherapy NLR and low ALC were more frequently observed in pts who underwent radiotherapy before chemotherapy (p &lt; 0.0001). The median follow-up duration was 70 (38-162) months for survivors. Pts with stage III demonstrated poor DFS (p = 0.019) and OS (p = 0.028) compared to those with stage IB or II. The shorter median DFS was observed in pts with low prechemotherapy ALC (20 vs. 65 months, p = 0.021), without significant difference in OS (p = 0.088). On the other hand, NLR and preoperative ALC were not associated with outcome of pts. Conclusions: The present study suggests that high prechemotherapy ALC is associated with poor outcome in stage IB-III NSCLC pts who received adjuvant chemotherapy after surgical resection.