tbuckley/cabot-search huggingface dataset:
RISE-HEP project part 1: Treatment sequences evaluation in hepatocellular carcinoma cell lines.
Authors: Luca Faloppi, Massimo Nabissi, Matteo Santoni, Federica Maggi, Eva Galizia, Francesca Miccini, Maristella Bianconi, Marco Puzzoni, Giorgio Astara, Nicola Battelli, Giorgio Santoni, Mario Scartozzi
Journal: Journal of Clinical Oncology (2019)

e15663 Background: For over ten years the most stimulating results in systemic therapy for advanced HCC derived from the use of sorafenib (S). But in the last two years several drugs, in particular other multikinase inhibitors like lenvatinib (L), regorafenib (R), cabozantinib (C), proved to be effective both as an alternative or a sequential therapy to sorafenib. In this widened and rapidly increased scenario, without any head-to-head trial, clinicians struggle to define the best drug and the best treatment sequence. Aim of the first part of this project is to evaluate the activity of different treatment sequences in HCC cell lines to pave the way to a future clinical trial investigating their efficacy. Methods: Compounds of S, R, L and C were dissolved in DMSO and aliquoted. HepG2 cell line, obtained from ECACC (Salisbury, UK), was seeded at the density of 3 x 104 cells/ml. After 24 h of incubation, compounds or vehicle (DMSO) were added. Treatments were performed in single administration and six replicates were carried out for each dose. At 48h post-treatment, cells were fixed and stained with acid solution. The absorbance was measured at 520 nm using an ELISA reader (BioTek Instruments, USA). The assay was also performed with the sequences of: S-R, S-C, L-R, L-C (first line treatments for 48h followed by the second compound for 48h). Higher doses than the minimum inhibiting one were tested. Results: S showed superior activity than L as first line compound. In the sequence assay S-C and S-R seems to have the best results in terms of cell viability. After L the best compound appears to be R. See table. Conclusions: Our results showed relevant variations in cell viability with different drug sequences. Already planned analyses in the RISE-HEP project in vivo and in humans are mandatory to confirm which sequence would have the highest efficacy.[Table: see text]
Clinical significance of pathogenic variants in germline <i>BRCA</i> wild type patients at risk for hereditary breast cancer.
Authors: Xiaying Kuang, Ying Lin, Nan Shao, Liang Yu, Zhen Shan, Shuyin Chen, Xinyi Shi, Hao Liu, Jing Liu
Journal: Journal of Clinical Oncology (2019)

e13127 Background: Approximately, 10% of breast cancer (BC) are related to inherited germline mutations. BRCA1/2, the most recognized and tested genes, are responsible for 50% of hereditary BC. Genetic testing for hereditary BC has changed significantly. Increasing evidence suggests parallel multigene testing. Methods: NGS-based germline BRCA status assessment was performed on 209 high risk BC patients with at least one of the following risk factors: triple negative BC, early onset ( &lt; -45), with a family history of BC, bilateral BC and male BC. Multigene-panel testing was subsequently offered to patients with at least 2 of the risk factors and WT germline BRCA. Capture-base targeted sequencing was performed on white blood cells using a panel consisting of 53 hereditary cancer-related genes, spanning 229kb of human genome. Results: Among the 209 patients screened, only 12 patients had pathogenic BRCA1/2 mutation. Next, we investigated the prevalence of non- BRCA pathogenic germline pathogenic mutations in patients with at least 2 risk factors. Thirty-seven patients met the criteria and only 23 patients had sufficient WBC DNA for sequencing. This cohort had a median age of 42, with a majority carrying infiltrating ductal carcinoma. Except for one bilateral BC patient who had stage IV disease, all other patients had early stage disease. We identified 5 pathogenic mutations from 5 patients spanning 4 genes: PALB2, PTEN, ATM and WRN, resulting in a prevalence rate of 20% for pathogenic germline mutations in high risk germline BRCA WT BC patients. Two patients carried mutations in PALB2, one with a frameshift and another with a splice mutation. Mutation types for PTEN, ATM and WRN were splice mutation, stop gain mutation and frameshift mutation, respectively. All 5 patients were diagnosed with BC before the age of 40. Three of them had bilateral BC; one had triple negative BC and another patient had a family history of BC. Conclusions: Our study confirms the clinical significance of testing non- BRCA genes, and suggests multigene panel testing for patients at risk for hereditary BC. Such approach increases the identification of hereditary BC, thus impacting clinical decision-making.
Recurrent pseudogout after therapy with immune checkpoint inhibitors: a case report with immunoprofiling of synovial fluid at each flare
Authors: Sang T. Kim, Mohamad Bittar, Hyun J. Kim, Sattva S. Neelapu, Amado J. Zurita, Roza Nurieva, Maria E. Suarez-Almazor
Journal: Journal for ImmunoTherapy of Cancer (2019)

Despite ground-breaking clinical success in the treatment of different cancers, immune checkpoint inhibitors can cause profound inflammatory and immune-related adverse events. Autoimmune inflammatory arthritis following immune checkpoint inhibitor treatment has been reported; however, to date, no cases of crystal arthritis following immune checkpoint inhibitors have been identified. We report the first case of recurrent pseudogout, an inflammatory crystal arthritis, in a patient treated with nivolumab, a PD-1 inhibitor, for renal cell carcinoma. The patient had recurrent pseudogout flares about week to 10 days after each nivolumab infusion. After treatment with prophylactic colchicine, the patient well tolerated additional nivolumab infusions without adverse events. In parallel, we characterized immune cells of synovial fluid at each flare. Immunoprofiling of synovial fluid showed that the proportion of inflammatory IL-17-producing CD4+ T cells and amount of IL-17 were notably increased in synovial fluid with every recurrent flair, and correlated with the increase in number of synovial neutrophils, suggesting a potential role of T helper 17 (Th17) cells in neutrophil-driven inflammation during pseudogout arthritis. This case suggests a potential influence of Th17 cells on the neutrophil recruitment and neutrophil-driven inflammatory events leading to pseudogout induced by immune checkpoint inhibitor therapy.
Reply to Coutrot <i>et al.</i>: Is Nitric Oxide Nephro- or Cardioprotective?
Authors: Chong Lei, Lorenzo Berra, Lize Xiong, Warren M. Zapol
Journal: American Journal of Respiratory and Critical Care Medicine (2019)

clinical studies have highlighted the role of venous congestion in the development of acute kidney injury.An association between high venous pressure (i.e., right atrial pressure or central venous pressure) and worsening renal function has been described in many different clinical settings, including patients who have undergone cardiac surgery and patients with heart failure (5).We suggest that the observed protective effect on kidney function in this study might be due to a decreased right ventricular afterload, which would decrease the right filling pressure and prevent renal venous congestion after NO inhalation (6).The population investigated in this study furthermore suggests this.Cardiopulmonary bypass was prolonged and most of the surgical procedures were for rheumatic valvular disease, including tricuspid valve surgery.These patients, approximately half of whom had pulmonary artery hypertension, had a high risk of postoperative right cardiac failure.However, data regarding the postoperative hemodynamic parameters are not presented.Unfortunately, the authors point out that transesophageal echocardiography or pulmonary artery catheterization is not the standard of care during surgery in their center-but postoperative monitoring of cardiac function, including the cardiac index and filling pressures (such as the central venous pressure), certainly is.Insights into the impact of inhaled NO on hemodynamics and right filling pressure would help us to better understand the potential mechanisms of nephroprotection and identify the patients who would most benefit from this therapy.
The efficacy and safety of exercise in metastatic solid cancer: A meta-analysis of randomized control trials.
Authors: Michelle Nadler, Ramy Saleh, Alexandra Desnoyers, Eitan Amir
Journal: Journal of Clinical Oncology (2019)

e23107 Background: The prevalence of people living with metastatic solid cancers is increasing. Such patients can experience cancer-related fatigue, decreased physical function (PF), and poor quality of life (QoL). Exercise has been shown to improve these symptoms in the curative setting, but there is uncertainty about the efficacy and safety of exercise in patients with metastatic cancer. Methods: Studies were identified from 3 prior systematic reviews and updated using a search of PubMed. Included studies were prospective randomized controlled trials of any moderate/high intensity aerobic exercise or resistance training intervention versus control in patients with metastatic solid cancers. The mean score and standard deviation (SD) for validated outcome measures (QoL, PF, and fatigue) were extracted for intervention and control groups at baseline and post-intervention. The effect of exercise was evaluated as the pooled change between baseline and post-intervention comparing exercise and control groups. Analysis was performed using the Mann Whitney test. Results: Of 21 trials which met inclusion criteria, 7 were excluded due to incomplete data. Among patients with mean baseline scores, exercise was not associated with significant change in fatigue, PF or QoL, although improvement was noted in 6-minute walk test (6-MWT) (14.7 vs 27.4 meters). QoL scores showed non-significant improvement (0.4 vs 4.9). In those with baseline scores 2SD below mean, exercise provided clinically meaningful improvement in PF using two different subscales (0.44 vs 8.5 and -1.0 vs 5.1) and avoidance of decline in 6-MWT (-29.75 vs -0.38m), although these did not meet statistical significance. There was a statistical improvement in sit-to-stand at the mean and 2 SD below the mean (2.5 vs 6.5, p = 0.029) for both groups. Only 5 papers reported adverse events in a standardized fashion in both groups. No differences in falls, fractures, or pain were reported. Conclusions: In patients with metastatic solid cancers, exercise interventions are associated with clinically meaningful improvements in PF, and statistically improved sit-to-stand scores. The effects are seen in patients with baseline score at the mean or lower.
A phase Ib study of prexasertib, a checkpoint kinase (CHK1) inhibitor, and LY3023414, a dual inhibitor of class I phosphatidylinositol 3-kinase (PI3K) and the mammalian target of rapamycin (mTOR) in patients with advanced solid tumors.
Authors: David S. Hong, Kathleen N. Moore, Johanna C. Bendell, Daniel D. Karp, Judy Sing-Zan Wang, Susanna Varkey Ulahannan, Melissa Lynne Johnson, Raid Aljumaily, Scott Hynes, Sophie Callies, Rodney Decker, Elizabeth LaBell, Michele Niland, Xuejing Aimee Wang, Aimee Bence Lin, Manish R. Patel
Journal: Journal of Clinical Oncology (2019)

3091 Background: Prexasertib inhibits CHK1, a kinase involved in DNA repair and replication. LY3023414 inhibits PI3K/mTOR signaling, implicated in the development of malignant disease. Prexasertib + LY3023414 has resulted in enhanced antitumor activity in triple negative breast cancer (TNBC) in vitro models. Methods: This Phase 1b study in patients (pts) with solid tumors assessed escalating doses of prexasertib (60-105 mg/m 2 IV every 14 days [q14d]) and LY3023414 (100-200 mg orally twice daily [BID]). Dose escalation ceased once the maximum tolerated dose of each monotherapy was reached. An initial expansion cohort (Arm E) explored prexasertib 105 mg/m 2 q14d + LY3023414 200 mg BID. Subsequent expansion cohorts evaluated prexasertib 105 mg/m 2 q14d + LY3023414 150 mg BID in pts with solid tumors with PIK3CA mutations (Arm E2) or TNBC (Arm E3). Results: Fifty pts were enrolled (escalation: n = 13; Arm E: n = 9; Arm E2: n = 15; Arm E3: n = 13). No dose-limiting toxicities (DLTs) were observed during escalation however DLT-equivalent toxicities were observed in 2 pts in Arm E (anemia, neutropenia, thrombocytopenia, oral mucositis, abdominal pain, fatigue). Due to toxicity, a reduced dose of LY3023414 (150 mg BID) was assessed in Arm E2/E3. In the 28 patients treated in Arms E2/E3, common treatment-related adverse events (any grade; grade ≥3) were: leukopenia/neutropenia (82%; 79%), thrombocytopenia (46%; 36%), nausea (46%; 0%), stomatitis (39%, 4%), vomiting (36%; 0%), and anemia (29%; 18%). Febrile neutropenia was reported in 25% of pts. Dose reductions in Arm E2/E3 were common. In escalation, 2 pts achieved a partial response (PR) and 3 pts achieved stable disease (SD). In Arm E, 78% of pts achieved SD. Of the pts evaluable at the time of data transfer, PRs were achieved in 1 pt with an unknown primary (Arm E2) and 2 pts with TNBC (Arm E3). Each agent’s pharmacokinetic profile was consistent with prior monotherapy data. Conclusions: Prexasertib + LY3023414 showed preliminary efficacy in heavily pretreated pts with solid tumors but was associated with toxicity, suggesting supportive care may be required. Clinical trial information: NCT02124148.
Eribulin ORA: A novel oral formulation of eribulin based on combination with the P-gp inhibitor HM30181A.
Authors: Laura Pitzonka, Murray Cutler, Johnson Yiu-Nam Lau, David Cutler, Rudolf Kwan, Michael Smolinski
Journal: Journal of Clinical Oncology (2019)

e12577 Background: Eribulin is a potent synthetic derivative of the marine sponge natural product Halichondrin B that uniquely targets microtubule growth to induce apoptotic cell death. Eribulin is currently administered intravenously (IV) to treat patients with breast cancer and liposarcoma refractory to taxane therapy due to its superior efficacy in taxane resistant tumor types. Methods: Utilizing a proprietary Orascovery platform, Eribulin ORA, a novel orally-administered eribulin formulation has been developed, which combines the P-glycoprotein (P-gp) inhibitor, HM30181A, with oral eribulin. Results: HM30181A significantly improves the systemic exposure of oral eribulin in rodents, which enables remarkable tumor regression in murine xenografts. HM30181A improves eribulin plasma exposure &gt; 5-fold in mouse model (AUC 0-24hr = 8224 ng*hr/mL with HM30181A vs. 1516 ng*hr/mL without HM30181A) and also improves eribulin oral bioavailability in the rat (%F = 35.0 with HM30181A vs. 16.1 without HM30181A). In vitro cell viability assays of MCF-7 and MDA-MB-231 breast cancer cell lines show eribulin is synergistic with other microtubule disrupting agents, including common first-line breast cancer therapy paclitaxel. In mice bearing orthotopic MDA-MB-231 breast tumor xenografts, oral eribulin with HM30181A was administered at eribulin doses of 0.5, 1.0, and 1.5 mg/kg Q2Dx3 (M,W,F)/week for four weeks. Only mice treated with 1.5 mg/kg (highest dose) eribulin had weight loss during treatment, with the observed weight loss was &lt; 10%, (except for one mouse). All eribulin doses tested induced tumor regression, with 7/9 tumors in the 1.5 mg/kg eribulin group experiencing durable complete regression until study end, two-weeks post administration. Of the tumors in the Eribulin ORA-treated groups that resumed growth after treatment, the degree of tumor growth was minimal. Overall, Eribulin ORA was well tolerated and showed potent efficacy against breast cancer tumors, exhibiting nearly 100% growth inhibition at all dose levels tested. Conclusions: Eribulin ORA showed good oral absorption, efficacious systemic exposure, and importantly, excellent anti-cancer activity in a breast cancer model. In vitro studies demonstrated the synergistic potential of eribulin in combination with paclitaxel. Accordingly, the combination of Eribulin ORA with Oraxol (oral paclitaxel that has shown promising clinical data) may represent an excellent metronomic oral combination chemotherapy that warrants further investigation for patients with advanced breast cancer.
Validation studies for germ-free <i>Smad3<sup>-/-</sup></i> mice as a bio-assay to test the causative role of fecal microbiomes in IBD
Authors: Jisun Paik, Stacey Meeker, Charlie C. Hsu, Audrey Seamons, Olesya Pershutkina, Jessica M. Snyder, Thea Brabb, Lillian Maggio-Price
Journal: Gut Microbes (2019)

While the association between microbiomes and inflammatory bowel disease (IBD) is well known, establishing causal relationships between the two is difficult in humans. Germ-free (GF) mice genetically susceptible to IBD can address this question. Smad3-/- mice with defective transforming growth factor ß signaling are a model of IBD and colon cancer. They develop IBD upon colonization with Helicobacter under specific pathogen-free conditions, suggesting a role of the microbiome in IBD in this model. Thus, we rederived Smad3-/- mice GF to determine the potential of using these mice for testing the causative role of microbiomes in IBD. We found that fecal microbiomes from mice with IBD cause more severe gut inflammation in GF Smad3-/- and wild type mice compared to microbiomes from healthy mice and that Helicobacter induces gut inflammation within the context of other microbiomes but not by itself. Unexpectedly, GF Smad3+/+ and Smad3+/- mice given IBD microbiomes develop IBD despite their lack of disease in SPF conditions upon Helicobacter infection. This was not unique to the background strain of our Smad3 model (129); both wild type C57BL/6 and 129 strains developed IBD upon fecal transfer. However, wild type Swiss Webster stock was not susceptible, indicating that the genetic background of recipient mice influences the severity of IBD following fecal transfer. Our data suggest that the microbiome is an independent risk factor contributing to IBD development, and careful characterization of new GF models is needed to understand potential sources of confounding factors influencing microbiome studies in these mice.
Effect of neoantigen reactive T cells combined with chemotherapy and radiation on survival in advanced pancreatic cancer.
Authors: Qin Liu, Zhengyun Zou, Baorui Liu, Weiwei Kong, Fangjun Chen, Jie Shao
Journal: Journal of Clinical Oncology (2019)

e15756 Background: Pancreatic cancer (PC) is one of the most aggressive and death-relating malignancy. Gemcitabine (GEM) is the key agent in the first-line standard regimen for advanced PC, which is mostly diagnosed at advanced stage and unsuitable for curative resection. The objective responsive rate (ORR) and medium progression free survival (PFS) of various GEM-based regimens are still unsatisfied. Therefore, development of new therapeutic modalities, including immunotherapy, is needed. This study is to investigate the efficacy, safety and clinical beneficial of combination neoantigen based immunotherapy with GEM and radiotherapy in locally advanced and metastatic PC patients. Methods: Three locally advanced unresectable and seven metastatic PC patients received at least two cycles of GEM (1000mg/m 2 on day 1 and day 6), radiotherapy combing with neoantigen induced DC vaccination on day 7 and cytotoxic T lymphocyte transfer from day 12 to 15 (repeated every 21 days). The locally advanced unresectable PC patients received stereotactic body radiotherapy (SBRT) with a total amount of 50-66Gy during the first cycle. For metastatic patients, their partial lesions received a low dose radiation (0.5Gy bid*2days ) on day 10 and 11 in each cycle. Results: Two cases were observed with partial remission (PR), five with stable disease (sd), and three with progressive disease (PD). The disease control rate (DCR) was 70%. Median progression free survival (PFS) was 6.4 months. After the first treatment cycle, the total effectiveness for pain easement and increasing appetite are 100% (8/8)and 66.7%, respectively. Haematotoxicities with a 40% incidence rate were the most common adverse drug reactions. Two patients had grade 1 to 2 neutropenia, two with grade 3 to 4 thrombocytopenia. Three patients suffered grade 1 to 2 gemcitabine-induced skin rash. No treatment-related mortality occurred. Conclusions: Neoantigen reactive T cells combined chemoradiotherapy demonstrated an acceptable response and safety in advanced pancreatic cancer patients.
Genomic profiling of residual tumor after neoadjuvant chemotherapy for breast cancer.
Authors: Masaya Hattori, Padma Sheila Rajagopal, Lise Sveen, Galina Khramtsova, Toshio Yoshimatsu, Nike Beaubier, Mathew Barber, Taylor Abboushi, Liu Fang, Yonglan Zheng, Kevin White, Dezheng Huo, Olufunmilayo I. Olopade
Journal: Journal of Clinical Oncology (2019)

e12106 Background: Patients who have residual disease after neoadjuvant chemotherapy (NAC) have a higher risk of metastatic recurrence. Residual disease likely includes therapy-resistant subclones of breast cancer cells, which untreated lead to metastases. The aim of this study was to identify additional adjuvant therapies based on genomic profiling of residual disease post NAC therapy. Methods: Next-generation sequencing of tumor samples from patients (pts) with residual invasive breast cancer after NAC was performed using a Tempus xT, 595 gene panel on matched tumor-normal samples. All samples were obtained from the University of Chicago Breast Cancer tissue bank. Clinical information was obtained from electronic health records and the cancer registry. Results: Of 23 evaluable patients enriched for African Americans, 65% were HER2-positive, 22% TNBC and 13% ER+/HER2-. At a median follow up of 2.9 years, 8 pts (35%) have recurred and 8 were dead. We identified 119 clinically actionable variants in 22 tumors, and the most commonly altered genes were TP53 (18 alterations, 74% of cases), ERBB2 (8, 26%), PIK3CA (7, 30%), CDK4 (4, 17%), MCL1 (4, 17%), and MDM2 (4, 17%). Of significance, 67% of HER2-positive pts had no detectable ERBB2 copy number gain in the residual tumor. 78% of pts had at least one potential druggable target according to CIViC and/or OncoKB: 19 variants in HER2-positive, 8 in HER2-negative. The mean estimated tumor mutation burden (TMB) was 4.34 m/MB (range: 0-26.7), and 13% were considered TMB-high ( &gt; 9 m/MB). No patients had high-microsatellite instability type residual tumors. Conclusions: Many potentially targetable alterations reside in residual disease of both HER2-positive and -negative breast cancer after NAC. Post-NAC treatment targeting these harbored alterations and post-NAC immunotherapy could have impact on the prognosis of breast cancer patients who have residual disease after NAC. [Table: see text]