tbuckley/cabot-search huggingface dataset:
Safety of nivolumab in combination with dendritic cell vaccines in recurrent high-grade glioma.
Authors: Katherine B. Peters, Gerald E. Archer, Pamela Norberg, Weihua Xie, Stevie Threatt, Eric S Lipp, James Emmett Herndon, Patrick Healy, Kendra Congdon, Luis Sanchez-Perez, Henry S. Friedman, Annick Desjardins, Gordana Vlahovic, John H. Sampson
Journal: Journal of Clinical Oncology (2019)

e13526 Background: Recurrence of high-grade glioma (HGG) (WHO grade III-IV) is a nearly universal phenomenon and necessitates the development of new therapeutic modalities. Two possible immunotherapeutic modalities are checkpoint blockade with agents such as nivolumab, a blocking antibody against the inhibitory checkpoint programmed cell death-1 (PD-1), and dendritic cell (DC) vaccination. We have shown in phase 1 and 2 trials that DC vaccination against the glioblastoma (GBM)-associated antigen human cytomegalovirus pp65-lysosomal-associated membrane protein (CMVpp65) is safe and possesses potential benefit. We hypothesized that nivolumab-induced immune checkpoint blockade could enhance efficacy of DC vaccination. Therefore, we undertook a phase 1 study to evaluate safety of nivolumab in combination with CMVpp65 mRNA pulsed DC vaccination in subjects with first or second recurrence of resectable HGG. Methods: We performed a phase 1, single-center, randomized study of nivolumab alone versus nivolumab + DC vaccination prior to planned surgical resection for both groups. We administered nivolumab 3 mg/kg IV q2weeks for 8 weeks followed by surgery and planned continuation of nivolumab. For the group receiving nivolumab + DC vaccination, we administered 3 vaccines before surgical resection with both groups receiving 5 planned post-resection DC vaccines. Primary endpoint was safety assessment using NCI-CTCAE 4.03. Results: We enrolled 6 subjects (4: GBM, 1: anaplastic astrocytoma, 1: anaplastic oligodendroglioma) with 3 receiving nivolumab alone and 3 receiving nivolumab + DC vaccination. Age range was 45-63 years subjects. We documented similar adverse events in both groups with most common grade 1-2 toxicities being fatigue (2 subjects, nivolumab alone) and thrombocytopenia (2 subjects, nivolumab + DC vaccine). Grade 4 toxicities included wound infection (2 subjects, nivolumab + DC vaccine) and meningitis (1 subject, nivolumab + DC vaccine). While we designed the study to enroll 66 subjects, we terminated the study early in light of CheckMate 143 phase III data showing nivolumab did not improve overall survival in recurrent GBM. Conclusions: Safety of nivolumab + DC vaccination in recurrent HGG is similar to nivolumab alone. Continued evaluation of new therapeutics including immunotherapy is underway for this patient population. Clinical trial information: NCT02529072.
Impact of high-dose vitamin d supplementation on short physical performance battery and bioelectrical impedance analysis in older patients with prostate cancer on ADT.
Authors: Julia Ellen Inglis, Eva Culakova, Richard Francis Dunne, Michelle Christine Janelsins, Po-Ju Lin, Karen Michelle Mustian, Luke Joseph Peppone
Journal: Journal of Clinical Oncology (2019)

e23106 Background: Androgen deprivation therapy (ADT) is standard treatment for prostate cancer but may cause changes in body composition that lead to decreased physical function. Low vitamin D status is also associated with decreased functionality. The Short Physical Performance Battery (SPPB) is an objective assessment tool for evaluating functionality. The bioelectrical impedance analysis (BIA) is a portable tool for assessing lean mass and phase angle, a measure of nutrition status and frailty in chronic disease. Methods: This was a secondary analysis of a randomized controlled trial to assess the impact of high dose vitamin D in older patients (≥60 yrs) with prostate cancer on ADT. Patients with prostate cancer (N = 59, age 67.6 ± 5.4) with vitamin D insufficiency ( &lt; 32 ng/ml) were randomized to high-dose vitamin D (n = 29, 600 IU/daily plus 50,000 IU/weekly) or low-dose vitamin D (n = 30, 600 IU/daily plus placebo weekly) for 24 weeks. SPPB tests and BIA were assessed at baseline, 12 weeks and 24 weeks. Phase angle values were calculated using atan(reactance/resistance) x (180°/π). A phase angle value &lt; 5.7° is a valid cutoff for frailty in older men. Results: Serum analyses showed compliance with vitamin D intake (25-OH vitamin D change: high vitamin D = +32.0 ng/ml vs low dose RDA vitamin D = +4.3 ng/ml; p &lt; .01). There were no difference at all three assessments for SPPB or lean mass between arms. The high-dose vitamin D group had wider phase angle values at 12 weeks (5.81º vs. 5.32º; p = .018) and 24 weeks (5.89º vs. 5.40º; p = .030). The low-dose group had phase angle values &lt; 5.7º over the course of the study. At baseline, over 18% of patients had phase angle values below the 10 th percentile of the general population matched on age and BMI. As vitamin D levels increased throughout the study, fewer patients fell below the 10 th percentile. Conclusions: The high-dose vitamin D group maintained wider phase angle values over 24 weeks, while phase angle for the low-dose group decreased from baseline. High-dose vitamin D supplementation may impact factors related to phase angle and frailty in patients receiving ADT. Funding: NCI UGCA189961, R21CA175793, K07CA168911, and GR501293.
Survival impact of thoracic cavity reduction during neoadjuvant chemotherapy in patients undergoing surgery for malignant pleural mesothelioma.
Authors: Ayumi Kuroda, Toru Nakamichi, Akifumi Nakamura, Masaki Hashimoto, Seiji Matsumoto, Nobuyuki Kondo, Seiki Hasegawa
Journal: Journal of Clinical Oncology (2019)

e20067 Background: It is difficult to predict prognosis for malignant pleural mesothelioma (MPM). The association of thoracic asymmetry and survival in patients with MPM was reported by Cho et al. in at the 18 th World Conference on Lung Cancer. Here we investigated the survival impact of thoracic cavity reduction during neoadjuvant chemotherapy (NAC). Methods: The subjects were patients with resectable epithelioid MPM who underwent NAC with platinum and pemetrexed followed by surgery at the Hyogo College of Medicine from Jan 2009 to Aug 2018. The length of the ant-post and med-lat extent of both hemithoraces at the level of carina was measured before and after NAC. Asymmetric ratio (ASR) was defined as the product of the ant-post and med-lat extent of affected side divided by those of healthy side. Results: One hundred thirty-three patients were enrolled: median age 66 (16-79) years, M/F 112/21, R/L 70/63, extrapleural pneumonectomy 40 and pleurectomy/decortication 93. Significantly poor prognosis was associated with ≥ 10mm reduction of the med-lat extent of affected side during NAC and ≥ 10% reduction of the product of the ant-post and med-lat extent of affected side during NAC (p = 0.0021). ASR ≤ 0.9 before or after NAC was not associated with significantly poor survival. Conclusions: This study revealed that thoracic cavity reduction during NAC was associated with significantly poor prognosis of MPM.
Small molecule inhibitors of epithelial‐mesenchymal transition for the treatment of cancer and fibrosis
Authors: Ya‐Long Feng, Dan‐Qian Chen, Nosratola D. Vaziri, Yan Guo, Ying‐Yong Zhao
Journal: Medicinal Research Reviews (2019)

Abstract Tissue fibrosis and cancer both lead to high morbidity and mortality worldwide; thus, effective therapeutic strategies are urgently needed. Because drug resistance has been widely reported in fibrotic tissue and cancer, developing a strategy to discover novel targets for targeted drug intervention is necessary for the effective treatment of fibrosis and cancer. Although many factors lead to fibrosis and cancer, pathophysiological analysis has demonstrated that tissue fibrosis and cancer share a common process of epithelial‐mesenchymal transition (EMT). EMT is associated with many mediators, including transcription factors (Snail, zinc‐finger E‐box‐binding protein and signal transducer and activator of transcription 3), signaling pathways (transforming growth factor‐β1, RAC‐α serine/threonine‐protein kinase, Wnt, nuclear factor‐kappa B, peroxisome proliferator‐activated receptor, Notch, and RAS), RNA‐binding proteins (ESRP1 and ESRP2) and microRNAs. Therefore, drugs targeting EMT may be a promising therapy against both fibrosis and tumors. A large number of compounds that are synthesized or derived from natural products and their derivatives suppress the EMT by targeting these mediators in fibrosis and cancer. By targeting EMT, these compounds exhibited anticancer effects in multiple cancer types, and some of them also showed antifibrotic effects. Therefore, drugs targeting EMT not only have both antifibrotic and anticancer effects but also exert effective therapeutic effects on multiorgan fibrosis and cancer, which provides effective therapy against fibrosis and cancer. Taken together, the results highlighted in this review provide new concepts for discovering new antifibrotic and antitumor drugs.
Role of microRNAs, circRNAs and long noncoding RNAs in acute myeloid leukemia
Authors: Yan Liu, Zhiheng Cheng, Yifan Pang, Longzhen Cui, Tingting Qian, Liang Quan, Hongyou Zhao, Jinlong Shi, Xiaoyan Ke, Lin Fu
Journal: Journal of Hematology & Oncology (2019)

Acute myeloid leukemia (AML) is a malignant tumor of the immature myeloid hematopoietic cells in the bone marrow (BM). It is a highly heterogeneous disease, with rising morbidity and mortality in older patients. Although researches over the past decades have improved our understanding of AML, its pathogenesis has not yet been fully elucidated. Long noncoding RNAs (lncRNAs), microRNAs (miRNAs), and circular RNAs (circRNAs) are three noncoding RNA (ncRNA) molecules that regulate DNA transcription and translation. With the development of RNA-Seq technology, more and more ncRNAs that are closely related to AML leukemogenesis have been discovered. Numerous studies have found that these ncRNAs play an important role in leukemia cell proliferation, differentiation, and apoptosis. Some may potentially be used as prognostic biomarkers. In this systematic review, we briefly described the characteristics and molecular functions of three groups of ncRNAs, including lncRNAs, miRNAs, and circRNAs, and discussed their relationships with AML in detail.
Programmed cell death 1 protein and programmed death-ligand 1 inhibitors in the treatment of nonmelanoma skin cancer: A systematic review
Authors: Franchesca D. Choi, Christina N. Kraus, Ashley N. Elsensohn, Sama K. Carley, Larisa M. Lehmer, Rebecca T. Nguyen, Kenneth G. Linden, Jessica Shiu
Journal: Journal of the American Academy of Dermatology (2019)
Oral food challenge-confirmed food allergy occurs more frequently among infants with early-onset eczema than in those diagnosed after 8 months of age in HealthNuts, a population-based food allergy study
Authors: P. Martin, N. Osborne, J. Koplin, L. Gurrin, M. Robinson, L. Thiele, M. Slaa, L. Miles, D. Dawson, T. Tan, T. Dang, D. Hill, A. Lowe, M. Matheson, A. Ponsonby, M. Tang, M. Wake, S. Dharmage, K. Allen
Journal: Allergy (2010)
Is the predictive and prognostic impact of sporadic and familial microsatellite instable stage III colon cancer different? A pooled analysis of the PETACC8 and NCCTG N0147 (Alliance) trials.
Authors: Aziz Zaanan, Qian Shi, Julien Taieb, Steven R Alberts, Jeffrey P. Meyers, Thomas C. Smyrk, Catherine Julié, Ayman Zawadi, Josep Tabernero, Enrico Mini, Richard M. Goldberg, Gunnar Folprecht, Jean Luc VAN Laethem, Karine Le Malicot, Daniel J. Sargent, Pierre Laurent-Puig, Frank A. Sinicrope
Journal: Journal of Clinical Oncology (2019)

3583 Background: The Microsatellite instability (MSI) or deficient mismatch repair (dMMR) phenotype is usually taken as a single biological entity whereas no data are available concerning prognosis and response to chemotherapy between sporadic and familial dMMR cases. Methods: Resected KRAS exon 2 wild-type (WT) tumor stage III colon cancers (N = 4596) from patients (pts) randomly assigned to FOLFOX +/- cetuximab in two adjuvant large phase III trials were prospectively analyzed for MSI status and dMMR mechanism (sporadic vs familial). Stratified Cox models were used to assess prognostic and predictive values of dMMR mechanism by treatment arms, adjusting for age, gender, tumor grade, ECOG PS, pT/pN stage and primary tumor location. Results: Among dMMR patients with complete data for dMMR mechanism analysis (N = 354), there were 255 (72%) sporadic ( BRAF mutated or WT with MLH1 methylation) and 99 (28%) familial (loss of MSH2 or MSH6, or loss MLH1 with BRAF WT and unmethylated MLH1) cases. A large proportion of dMMR sporadic cases were mutated for BRAF (n = 200; 80%). In pts treated with FOLFOX, the disease-free survival (DFS) was not statistically different by dMMR mechanism, while for pts treated with FOLFOX + cetuximab, the sporadic cases did worse than familial cases (DFS; adjusted (adj) HR, 2.69; 95% CI, 1.02-7.08; P= 0.04). Considering the predictive value, a deleterious effect of adding cetuximab to FOLFOX was observed in sporadic (DFS; adjHR, 1.68; 95% CI, 1.01-2.79; P= 0.04) but not in familial dMMR pts (interaction P value regarding treatment effect = 0.03). Furthermore, a non-significant trend to a deleterious effect of adding cetuximab to FOLFOX was observed in BRAF mutant (DFS; adjHR, 1.66; 95% CI, 0.95-2.92; P= 0.07) but not in BRAF WT pts. Conclusions: The addition of cetuximab to FOLFOX was associated with reduced DFS in patients with sporadic dMMR cases. Further studies including the methylator phenotype (CIMP) analysis are needed to validate these results. Clinical trial information: NCT00265811 and NCT00079274.
Race and response to neoadjuvant chemotherapy according to MammaPrint risk.
Authors: Raquel Nunes, Femke De Snoo, Lisette Stork-Sloots, Hong-Khanh (Tina) Dinh Treece, Christa Dreezen, M. William Audeh
Journal: Journal of Clinical Oncology (2019)

578 Background: African-American (AA) women with breast cancer have a less favorable prognosis, likely due to differences in tumor biology. This is not only driven by the higher rate of triple negative/basal tumors in patients with AA ancestry, as worse outcome has also been seen in patients with luminal tumors. The Neoadjuvant BReast Cancer Symphony Trial (NBRST, NCT01479101) was a prospective trial that has shown an association of MammaPrint/BluePrint (MP/BP) with a rate of pathologic Complete Response (pCR) of 2% in Luminal A with 95% Distant Metastasis Free Interval at 3 years. Here, we determine the MP/BP risk distribution, response to therapy, and outcome in African American (AA) and Caucasian (Cau) patients. Methods: NBRST enrolled 1,072 breast cancer patients (pts) in the US (June 2011 and December 2014), median follow-up 34.9 months. The current unplanned analysis compared clinicopathological characteristics, molecular risk assignment and outcome with neoadjuvant chemotherapy (NACT) in AA and Cau pts. Molecular subtyping groups were assessed by MP/BP as follows: Luminal A (MammaPrint Low Risk), Luminal B (MammaPrint High Risk), HER2 and Basal types. Results: Out of 1,072 pts, 157 (15%) were AA, and 780 (73%) were Cau. AA patients were younger at diagnosis (52 vs 54 yrs; p = 0.016), had a higher likelihood of having higher grade (gr 3, 65% vs 53%; p = 0.005), ER-negative (45% vs 33%; p = 0.005) and lymph node positive tumors (71% vs 51; p &lt; 0.001). MP/BP classified more AA patients as Basal type, 45% compared to 33% of Cau patients (p = 0.004). Fewer AA patients were classified as Luminal A (15%) compared to Cau pts (33%; p = 0.004). In multivariate analysis race was a significant factor for higher pCR rates to NACT in AA compared to Cau pts, together with PR, HER2, T-stage and Grade (HR = 1.679, 95% CI = (1.057, 2.67), p = 0.028). The pCR rate to NACT in patients with Basal tumors was 38% and similar in AA and Cau patients. In patients with hormone receptor positive and HER2 negative tumors, patients classified by MP/BP as Luminal A had lower pCR (2%) compared to non-luminal A (13%) (p = 0.0015). MP low risk patients had higher 3 yr DMFS (97%) than MP high risk patients (86%; p = 0.010). DMFS for AA MP Low Risk patients was 100%. Conclusions: In this study, MP was able to identify patients with hormone receptor positive tumors with low sensitivity to chemotherapy and good outcome, irrespective of race, suggesting that this test can be helpful to characterize the tumor’s biology and select patients who will not benefit from chemotherapy independently of their ancestry. Clinical trial information: NCT01479101.
FOXO1, an AKT downstream substrate, plays a role as tumor suppressor in HCC pathogenesis.
Authors: Shu Zhang, Xin Chen
Journal: Journal of Clinical Oncology (2019)

e15627 Background: Hepatocellular carcinoma (HCC) represents the fifth most common tumor types in the world. However, the signaling pathways underlying hepatic pathogenesis are still poorly understood. Activation of PI3K/AKT signaling cascade has been implicated in HCC development. It has been well-established that the mammalian target of rapamycin complex 1 (mTORC1), is a major downstream effector of AKT. The reason why mTORC1 can be consistently activated is partly due to inactive mutations of a negative element regulating mTORC1, tuberous sclerosis 2 (TSC2), found in 10% human HCCs. Beyond TSC2, forkhead Box O transcription factor 1 (FOXO1), is another AKT substrate. It has been proved that FOXO1 plays a crucial role in the insulin signal pathway and liver regenerationrelying on AKT isoforms. However, the role of FOXO1 in HCC development has not been well established. Methods: FOXO1 expression was analyzed in human liver cancer from TCGA database and multiple HCC cell lines were used to verify the mechanism of how FOXO1 regulate HCC cell growth downstream of AKT activation and we further confirmed the role of FOXO1 in HCC development in vivo. Results: By using TCGA database the mRNA level of FOXO1 significantly decreases among the FOXO family, comparing tumor tissue to the surrounding tissue. The overall survival rate favors patients with high FOXO1 expression. The inhibition efficacies of MK2206, a pan-AKT inhibitor, in both TSC2 wide type cells and TSC2-null ones are not significantly different, indicating TSC2 is not the only target downstream of AKT. As FOXO1 is another major target, we knockdown endogenous FOXO1 in the same HCC cell lines, the activation of mTORC1 was no longer inhibited. Furthermore, we overexpress the activated FOXO1 (FOXO1 AAA) in TSC2-null HCC cell lines. Cell growth are significantly prohibited, implicating FOXO1 is a tumor suppressor in HCC cells. Overexpression of activated FOXO1 can also delay AKT depended HCC in met/β-catenin FVB mice model. Conclusions: AKT/mTORC1 can be a classic molecular pathway for HCC pathogenesis. Nevertheless, the parallel substrate of AKT, FOXO1, may also be an important factor in the TSC2 independent way.
Interim results from the full population of the phase 3b CompLEEment-1 study of ribociclib (RIBO) plus letrozole (LET) in the treatment of HR+/HER2– advanced breast cancer (ABC).
Authors: Michelino DeLaurentiis, Simona Borstnar, Mario Campone, Ellen Warner, Salvador Bofill, William Jacot, Susan Faye Dent, Miguel Martin, Alistair E. Ring, Paul H. Cottu, Janice M. Lu, Eva Ciruelos, Hamdy A. Azim, Sanjoy Chatterjee, Katie Zhou, Jiwen Wu, Nii Ankrah, Claudio Zamagni
Journal: Journal of Clinical Oncology (2019)

1041 Background: RIBO, an oral, selective inhibitor of CDK4/6 (CDK4/6i), is approved for use in combination with endocrine therapy (ET) in women with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2–) ABC in multiple countries worldwide. Here we report interim safety and efficacy results from CompLEEment-1, a phase 3b trial evaluating RIBO+LET in an expanded patient (pt) population and the largest CDK4/6i trial in ABC to date. Methods: Pts with HR+, HER2– ABC, ≤1 line of prior chemotherapy (CT), and no prior ET for ABC received RIBO+LET. Treatment regimens and study endpoints have been reported previously (De Laurentiis, et al. ASCO 2018. Poster 1056). Results: Overall, 3,246 pts, who received ≥1 dose of study treatment, were evaluated (cut-off date, August 8, 2018). Median duration of RIBO exposure was 8.1 months (min, 0.0; max, 22.4). Demographic and baseline characteristics indicated a diverse population including men (1.2%), premenopausal women (22.2%), and patients aged ≥70 years (19.5%). Pts were well represented in terms of age, race, and disease history; 5.9% of pts received prior CT for ABC. The only non-hematologic any-cause grade ≥3 AEs ≥5% were increased alanine (7.3%) and aspartate (5.3%) aminotransferase. Treatment-related AEs (any grade) led to discontinuation in 11.4% of pts. Of the 51 (1.6%) on-treatment deaths, 26 were due to study indication and 25 to other reasons. The median time to progression was not estimable (NE) (95% confidence interval [CI], 17.1-NE). Overall response rate was 20.5% (95% CI, 19.1%-21.9%) and clinical benefit rate was 66.1% (95% CI, 64.4%-67.7%). Consistent mean change from baseline in Functional Assessment of Cancer Therapy – Breast Cancer questionnaire scores indicated that pts maintained their quality of life throughout treatment. Conclusions: This interim analysis demonstrates the safety, tolerability, and efficacy of RIBO+LET in a large, diverse cohort of pts with HR+, HER2– ABC who had not previously received ET for ABC. Safety results were consistent with those observed in RIBO pivotal studies and no new safety signals were observed. Clinical trial information: NCT02941926.
Implication of DYRK1B kinase in dormant glioblastoma cancers and utilization of DYRK1B inhibitors as a novel therapeutic strategy for glioblastoma.
Authors: Maria Vilenchik, Alexandra Kuznetsova, Michael Frid, Menelik Duey, Arianna Damiani, Lita De Leon, Jason Law, Denis A. Golbin, Ludmila V. Shishkina, Olga Potapova
Journal: Journal of Clinical Oncology (2019)

e14670 Background: A major determinant of cancer resistance and recurrence is the presence of quiescent cancer cells. It has long been known that quiescent cancers are resistant to a wide variety of anti-cancer therapeutics relative to actively proliferating cells. However, the presence and relative size of the quiescent compartment is not revealed by standard H&amp;E staining and morphological tumor analysis and, therefore, the data demonstrating its importance and prevalence by tumor type are lacking. DYRK1B kinase (serine/threonine-protein kinase dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1B) is associated with growth and survival of many types of cancer cells and was shown to play a key role in maintaining the cancer cells in reversible quiescent state by stabilizing the CDK inhibitor p27 and by inducing the breakdown of cyclin D isoforms. Methods: We conducted an immunohistochemical study of 80 human glioblastoma (GBM) tumors (primary / treatment-naive, Grade IV) and 10 cases of normal postmortem brain tissues for expression of DYRK1B, and quiescence and proliferation markers p27 and Ki-67, respectively. For subsection of these tissues, high levels of DYRK1B and p27 expression were observed. Results: In this study, we investigated the functional and therapeutic relevance of DYRK1B expression in glioblastomas, the most common brain cancer in adults. It is an aggressive, highly resistant to treatment tumor type with median survival time of less than 16 months following surgery and treatment. Conclusions: There was a statistically significant correlation between immunostaining of DYRK1B and p27, indicating the presence of dormant cancer cells mixed with the proliferating cancer cells within the patients' tumors. We suggest that DYRK1B inhibitors in combination with chemotherapeutics agents have a potential to improve patient treatment outcome and prolong survival.