tbuckley/cabot-search huggingface dataset:
CDK4/6 inhibitor and radiation therapy in malignant pleural mesothelioma.
Authors: Seiji Matsumoto, Akihiro Fukuda, Toru Nakamichi, Akifumi Nakamura, Ayumi Kuroda, Masaki Hashimoto, Teruhisa Takuwa, Nobuyuki Kondo, Seiki Hasegawa
Journal: Journal of Clinical Oncology (2018)

e24326 Background: The prognosis of malignant pleural mesothelioma (MPM) is very poor; a new drug for MPM is need. The percentage of p16 loss in MPM patients is high. We hypothesized that CDK4/6 is a potential target for the treatment of MPM. Methods: Cell viability was assayed using Cell Counting Kit-8 (CCK-8: WST-8 Dojindo). MPM cells (NCI-H28, NCI-H226, NCI-H2052, NCI-H2452, and MSTO-211H) were seeded in 96-wellplates. After treatment with a CDK4/6 inhibitor (Palbociclib and Abemaciclib), Cell Counting Kit-8 solution was added to each well of the plate, and the absorbance was measured using a microplate reader. Cell cycle was assayed with a BrdU Flow kit (BD Pharmingen BrdU Flow kit). H226 cells were treated with a CDK4/6 inhibitor, Abemaciclib. BrdU was added to H226 cells 2 h before the cell cycle assay. H226 cells were injected into the subcutaneous layer over the flank region of nude mice. Mice were randomly assigned into four groups receiving 1) vehicle control 2) Abemaciclib 3) radiation 4) Abemaciclib and radiation. Tumors were measured twice a week. Results: CDK4/6 inhibitor inhibited MPM cell lines (NCI-H28, NCI-H226, NCI-H2052, NCI-H2452, and MSTO-211H) viability in a dose-dependent manner. Abemaciclib increased the population in G0/G1 (control: 49.2% Abemaciclib: 61.6%). Abemaciclib suppressed tumor growth (p < 0.05) and completely suppressed tumor growth in conjunction with radiation in the mouse model. Conclusions: In this study, we have shown that a CDK4/6 inhibitor inhibited the proliferation of all MPM cell lines (epithelial, biphasic, and sarcomatoid). We also demonstrated that Abemaciclib completely suppressed tumor growth when used with radiation in mouse models. Furthermore, the CDK4/6 inhibitor with radiation therapy is promising in MPM treatment.
Impact of cholangiocarcinoma (CC) molecular heterogeneity on outcome during first-line chemotherapy and access to targeted therapies in early clinical trials (CT).
Authors: Helena Verdaguer, Irene Brana, Cinta Hierro, Analia Azaro, Elena Elez, Elena Garralda, Berta Laquente, Juan Francisco Grau Bejar, Fiorella Ruiz-Pace, Cristina Viaplana, Susana Aguilar, Rodrigo Dienstmann, Teresa Macarulla Mercade
Journal: Journal of Clinical Oncology (2018)

4091 Background: CC has poor prognosis and limited therapeutic options beyond first-line therapy. It is molecularly heterogeneous with several gene alterations (alt) that can be matched to targeted treatments in CT. We investigated the impact of CC molecular profiling in the clinics. Methods: From 2011 to 2017, we identified 165 patients (pts) with advanced CC - 129 intrahepatic CC (ICC) and 36 extrahepatic CC (ECC) - whose tumors were analyzed in our center with NGS tests (124 had fusion panels). We retrospectively collected outcome information and access to CT. Results: Most pts were diagnosed at stage IV (67%) and received first-line gemcitabine plus platinum (80%). Most common alt found in ICC were mutations (mt) in TP53 (19%), IDH1 (14%), CDKN2A (9%), IDH2 (7%), ATM (7%), BAP1 (6%), PIK3CA (6%), KRAS (6%), NRAS (5%), BRAF (4%) and fusions in FGFR2/3 genes (3%). In ECC, we found mt in TP53 (28%), CDKN2A (11%), PTEN (11%), PIK3CA (6%), BRCA2 (6%) and mt or amplifications (amp) in ERBB2 (11%). With a median follow up of 56 months (m), median overall survival (OS) of the overall population was 23 m, with no differences between ICC and ECC (p = 0.83). There was statistically significant difference in OS between pts with TP53 mt vs TP53 wild type (wt) tumors (28 m vs 15 m, HR 1.8, p = 0.01). During first-line therapy, median progression free survival (PFS) was 6.6 m in TP53 mt and 3.8 m in TP53 wt patients (HR 2.3, p < 0.01). 40 pts (24%) were included in a CT, with 24 pts (15%) being matched by molecular alt. Most frequent matches were FGFR inhibitor (inh) (25% of pts with targetable fusion), IDH inh in 5 (21%), PI3K inh in 3 (13%), BRAF inh in 3 (13%). Among pts treated in matched CT, median PFS was 4 m; 2 pts (8%) achieved a partial response (1 MET amp;1 BRAF mut) and 11 (46%) had stable disease as best response. We found no associations between targetable gene alt and OS or PFS during first-line therapy. Conclusions: CC is a heterogeneous tumor with a broad spectrum of molecular alt that have prognostic and treatment implications. Matched therapies may confer clinical benefit. Molecular profiling of CC is of growing interest to improve the knowledge of this disease and its therapeutic opportunities.
Abstract 15062: Elderly Laypersons Are Reluctant to Initiate Cardiopulmonary Resuscitation
Authors: Lise Q Krogh, Mette A Nebsbjerg, Stinne E Rasmussen, Katrine Bjørnshave, Kristian Krogh, Jonas A Povlsen, Bo Løfgren
Journal: Circulation (2016)

Introduction: More than half of out-of-hospital cardiac arrests are witnessed, however bystander cardiopulmonary resuscitation (CPR) rates remain low. There is significant association between willingness to initiate CPR and CPR training. Studies have shown that attitudes towards and willingness to perform CPR vary widely between different populations. The majority of out-of-hospital cardiac arrests occur in private homes and an elderly layperson are the most likely bystander. Little is known about the factors that affect the willingness of elderly laypersons to perform CPR. Aim: To examine the willingness and potential barriers towards initiating CPR among elderly laypersons. Methods: A questionnaire consisting of open answer, categorical and Likert-type questions was developed and distributed to Danish laypersons above the age of 65. Results: Response rate was 82% of which 99 responses were eligible for analysis. The median age was 72 years. If witnessing a cardiac arrest the majority (85%) would be will...
ECHO-306/KEYNOTE-715: A phase 3 study of first-line epacadostat plus pembrolizumab with or without platinum-based chemotherapy vs pembrolizumab plus platinum-based chemotherapy plus placebo for metastatic non–small cell lung cancer (mNSCLC).
Authors: Rina Hui, Mihaela Munteanu, Yufan Zhao, Yiwen Luo, Ayman Samkari, Marina Chiara Garassino
Journal: Journal of Clinical Oncology (2018)

TPS9104 Background: Novel combination treatments targeting broad immunosuppression in the tumor microenvironment may improve survival. The indoleamine 2,3-dioxygenase 1 (IDO1) intracellular enzyme and PD-1 receptor both suppress T-cell–mediated antitumor immunity, are co-expressed in multiple tumor types, and are correlated with poor prognosis. Epacadostat (E) is a potent and highly selective oral inhibitor of IDO1. Pembrolizumab (P) ± chemotherapy is a first-line treatment option for mNSCLC. Because promising efficacy and minimal additive toxicity were observed with E + P in mNSCLC in the phase 1/2 ECHO-202/KEYNOTE-037 study, this phase 3 global study (NCT03322566) was initiated to evaluate first-line E + P, E + P + chemotherapy, and E-matched placebo + P + chemotherapy in patients with mNSCLC unselected by PD-L1. Methods: Eligible patients: aged ≥18 years, stage IV NSCLC (no EGFR mutation or ROS1/ALK translocations), ECOG PS ≤1, no untreated brain metastases, no prior systemic therapy for mNSCLC, and no prior IDO1 inhibitors or immune checkpoint therapies. Patients (~1062) will be randomized 1:1:1 and stratified based on ECOG PS (0 vs 1), PD-L1 status (tumor proportion score < 50% vs ≥50%), tumor histology (squamous vs nonsquamous), and region (East Asia vs non-East Asia). Treatment includes E 100 mg BID, P 200 mg Q3W, paclitaxel 175–200 mg/m2 + carboplatin AUC 5–6 Q3W × 4 cycles (squamous), or pemetrexed 500 mg/m2 + cisplatin 75 mg/m2 or carboplatin AUC 5 Q3W × 4 cycles followed by pemetrexed 500 mg/m2 Q3W (nonsquamous). Patients receive treatment up to 2 years (35 cycles of P), or until disease progression, intolerable toxicity, or investigator/patient decision to withdraw. Primary endpoints: OS and PFS. Secondary endpoints: ORR, duration of response, safety, and tolerability. Exploratory endpoints: patient reported outcomes, E pharmacokinetics, pharmacodynamics, and potential correlations between baseline biomarkers and clinical activity (OS, PFS, ORR). Tumor response will be assessed centrally per RECIST v1.1. Adverse events will be graded per CTCAE v4.0. Clinical trial information: NCT03322566.
Impact of beta blocker medication on survival outcome of ovarian cancer: A nationwide population-based cohort study.
Authors: Jeong-Yeol Park, Min-Hyun Baek, Young-Han Park, Dae-Yeon Kim, Dae-Shik Suh, Jong-Hyeok Kim, Yong-Man Kim, Young-Tak Kim, Joo-Hyun Nam
Journal: Journal of Clinical Oncology (2017)

5578 Background: In experimental studies, adrenergic hormones are involved in tumorigenesis of ovarian cancer and its progression. We investigated the impact of beta adrenergic blocker on survival outcome of ovarian cancer since few studies have investigated its relevance. Methods: Data of Korean National Health Insurance Service was analyzed (n = 866). We analyzed the impact of beta blocker on survival outcome of ovarian cancer according to the duration on medication and age groups of patients. Cox proportional hazards regression was used to analyze hazard ratios (HR) for all-cause mortality with 95% confidence intervals (CI) adjusting for confounding factors. Results: Median years of follow-up was 5.98 and 6.71 for non-users and users, respectively. Among the 866 patients, 206 (23.8%) were users and 660 (76.2%) were non-users. In total, there was no survival difference between the 2 groups. But, when patietns were grouped according to the duration of medication, patients with longer duration of medication (≥1 year) showed better survival outcome (adjusted HR 0.305 [95% CI: 0.187-0.500], P &lt; 0.001). Also, beta blocker use in patients with &gt; 60 years showed better survival compared to younger patients (adjusted HR 0.579 [95% CI: 0.408-0.822], P = 0.002). In patients with &gt; 60 years, medication longer than 720 days was associated with better survival outcome (adjusted HR 0.267 [95% CI: 0.140-0.511], P &lt; 0.001). Both selective and non-selective beta blocker showed identical survival benefit in these settings without difference between each other. Conclusions: Beta blocker medication was associated with favorable survival outcome in ovarian cancer, especially when used in older patients and in long term duration.
PTP1B expression and Gleason Score (GS) in localized prostate cancer (PC).
Authors: Mauricio Mora Pineda, Shaddai Urbina Ramírez, Juan Hinojosa, Jazmin De Anda Gonzalez, Eucario Leon Rodriguez, Maria Teresa Bourlon
Journal: Journal of Clinical Oncology (2016)

e16566 Background: The Gleason grading system has remained as the most useful parameter to evaluate PC aggressiveness and guides treatment decisions. Major limitations of GS includes lack of inter and intra observer reproducibility. Protein tyrosine phosphatase 1B (PTP1B) is a direct transcriptional target of the androgen receptor (AR) and its expression has been linked to tumor growth and androgen-induced cell migration. Its association with PC grade remains poorly studied. Methods: We evaluated prostate tumor sections. An expert molecular pathologist analyzed primary Gleason pattern (3, 4 or 5) for each tumor section according to The 2014 ISUP Conference on Gleason Grading of Prostatic Carcinoma. A second pathologist, blinded to GS, assessed PTP1B expression by immunohistochemistry using the polyclonal Rabbit Anti-Human PTP1B Antibody (H-135 Santa Cruz Biothecnology INC) in tissue microarrays (TMA). PTP1B expression was considered “absent” when no expression was identified and “present” if any cytoplasmic staining was seen. The PTP1B GS according to the cytoplasmic staining intensities was defined as follows, 0:absent, 1: weak, 2: moderate, and 3: high intensity. The Spearman chi-square test was used to assess the association among PTP1B expression and GS, a two sided p-value ≤ 0.05 was considered significant. Results: A total of 96 PC sections were evaluated. Primary Gleason Pattern was as follows: grade 3 in n = 43 samples (45%), grade 4 in n = 37 (38%), and grade 5 in n = 16 (17%). The Spearman chi-square for the expression of PTP1B in TMA and tumor grade was 0.08 with a p-value of 0.46.The Spearman chi-square test correlation coefficient for cytoplasmic staining score(0,1,2 and 3) in TMA was 0.48 with a p-value of 0.64. Conclusions: Our results do not support an association of PTP1B expression and tumor grade. A limitation of this study is that immunohistochemistry does not assess the functional state of the protein. AR transcription dysfunctions are not limited to one target. Other androgen-inducible genes can modulate downstream AR transcription targets. The final tumor phenotype may rely on complex AR pathway dysregulations, not limited to one protein phosphatase and by itself PTP1B is not a predictor of tumor grade.
ADCC and treatment outcome in colorectal cancer patients receiving cetuximab-based therapy.
Authors: Gerard A. Milano
Journal: Journal of Clinical Oncology (2016)

e15085 Background: ADCC (Antibody Dependent Cell Cytotoxicity) is a complement of antitumor activity, mainly mediated by the presence of FC receptor on tumor infiltrated NK cells and conferred by IgG1 McAb like cetuximab.ADCC clinical importance remains to be established and faithful indicators of treatment outcome are still lacking in colorectal cancer (CRC) under cetuximab-based therapy. Methods: A multifactorial clinical-biological study was prospectively performed (n = 41 patients, tumor RAS WT, cetuximab + FOLFIRI, mean age = 65, 49-84). Circulating NK cell subpopulations, FC receptor germinal polymorphisms potentially influencing ADCC (rs1801274 for FCGR2A and rs396991 for FCGR3A) and individual ex vivo ADCC activity (LDH assay) were systematically determined before and during treatment. Median follow-up was 24 months (4-60). Results: Basal ADCC activity was widely distributed (10-99 %, median 71 %). Globally, treatment influenced ADCC with an average reduction of 36 % at 2-4 months. Response to treatment (39 % ORR) was not significantly linked to the tested variables. Basal ADCC was found to be independently related to OS (50 % survival, above median = 18 months, below = 8 months, p = 0.026). Combining basal ADCC and basal invariant NK cell count conferred higher prognostic discrimination [23 (above/above) vs 10 months (others), p = 0.0075]. Conclusions: The results highlight ADCC as a strong prognostic factor in cetuximab-based therapy with major consequences: ADCC should be taken into account as a component of the clinical activity of IgG1 McAb and individual ADCC could be integrated into precision medicine for CRC . In perspective ,immune-treatment strategies aiming at stimulating NK cells (anti-KIR, anti-NKG2A) for boosting ADCC are justified. Authors: Marco Merlano 1 , Daniela Vivenza1, Laura Lattanzio1, Vincenzo Ricci1, Emanuela Miraglio1, Alberto Comino2, Cristiana Lo Nigro1 and Gerard Milano3. 1 Oncology Dpt Santa Croce & Carle Teaching Hospital, Cuneo, Italy 2 Pathology Dpt Santa Croce & Carle Teaching Hospital, Cuneo, Italy 3 Oncopharmacology Unit, Centre Antoine-Lacassagne, Nice, France.
Microsatellite instability in prostate cancer and response to immune checkpoint blockade.
Authors: Wassim Abida, Michael L. Cheng, Joshua Armenia, Sumit Middha, Karen A. Autio, Dana E. Rathkopf, Michael J. Morris, Daniel Costin Danila, Susan F. Slovin, Emily Carbone, Melanie Hullings, Jaclyn Frances Hechtman, Victor E. Reuter, Michael F. Berger, Philip W. Kantoff, Charles L. Sawyers, Nikolaus Schultz, David B. Solit, Anuradha Gopalan, Howard I. Scher
Journal: Journal of Clinical Oncology (2018)

5020 Background: Immune checkpoint blockade has shown clinical benefit in mismatch repair deficient (dMMR) cancers, leading to accelerated FDA approval of pembrolizumab, a PD1-targeting agent, for the treatment of dMMR or microsatellite instability-high (MSI-H) advanced solid tumors. However, the frequency of MSI-H prostate cancer (PCa), as well as response to PD1/PDL1 agents in this disease subset, remain poorly defined. Methods: 839 PCa patients underwent targeted next-generation sequencing (NGS) of tumor and matched normal samples on an institutional protocol for the characterization of somatic mutations, copy number alterations and germline mutations (with specific consent). MSIsensor analysis, a computational method for detecting MSI, was performed. Tumor mutation burden (TMB) was calculated, with additional analysis for mutational signatures and immunohistochemical (IHC) staining of MMR proteins in selected cases. Results: 20/839 PCa patients (2.4%) were found to have MSI-H/dMMR tumors, defined as an MSIsensor score of ≥ 3 and TMB of ≥ 10, confirmed by IHC and mutational signature analysis. Of 13/20 MSI-H patients who consented to germline analysis, 3/13 (23%) had a germline MMR gene mutation. 3/5 MSI-H patients who underwent profiling of ≥2 matched tumors demonstrated MSI in the later tumor. In total, 10 patients with MSI-H tumors received a PD1/PDL1 targeting agent. 2/10 had radiographic PR with PSA decline of > 80%. 3/10 are early in their treatment with PSA decline of > 60%. 1/10 had stable disease for 6 months then progressed. 3/10 had no response. 1/10 was inevaluable. Conclusions: Tumor profiling for MSI status can be considered for patients with advanced PCa. MSI can develop as a later somatic event, arguing for profiling of a recent tumor when possible. Germline profiling should be recommended for patients with MSI-H PCa. While early in this dataset, responses to PD1/PDL1 therapy may occur in ~50% of patients with MSI-H/dMMR PCa. Longer follow up and additional prospective studies will be necessary to confirm responses in this patient population.
A comparison of liver cancer and lung cancer patients at two Veteran Affairs Medical Centers.
Authors: Sejal Kothadia, Zhen Wang, Sarah Lee, Victor Tsu-Shih Chang, Yucai Wang, Yeun-Hee Anna Park, Ellen Olson, David Klein, Andrea Nadine Leaf, Stephanie Hwa, Fengming Zhong
Journal: Journal of Clinical Oncology (2017)

e21642 Background: Little is known about palliative care for liver cancer. In this study, we examined palliative care for liver cancer and lung cancer patients. Methods: In an IRB approved protocol, we reviewed medical records of patients diagnosed with liver cancer who were seen by the palliative care service between 2006 and 2012 at 2 VA medical centers, and matched them to patients with lung cancer by year, KPS, and stage. Veterans were compared by symptom prevalence with the CMSAS and by palliative care interventions. Statistical analyses were performed with SAS Studio Version 3.5. Results: We analyzed a total of 138 male patients at 2 VA centers; 69 with lung cancer and 69 with liver cancer. The mean age in both groups was 65 years and 60% of patients self-identified as a minority. There was a high prevalence of symptoms in both groups. Symptom prevalence differed significantly between liver and lung cancer pts for weight loss and dyspnea at one site, and for feeling drowsy, constipation, at the other site. These differences disappeared in a pooled analysis. During palliative care evaluation, more lung cancer patients received treatment for constipation (n = 44 in lung, 29 in liver, p = 0.0107) and dyspnea treatment (n = 37 in lung, 22 in liver, p = 0.0167). More patients with lung cancer were evaluated by physical therapy (n = 41 in lung, n = 28 in liver, p = 0.0276) and psychiatry (n = 31 in lung, n = 20 in liver, p = 0.032). Conclusions: Differences between lung and liver cancer patients’ symptom prevalence and treatment by palliative care can vary by site. This reinforces the importance of local surveys of symptom prevalence . Further studies should be replicated in other sites.
Correlation of expression of enhancer of zeste homolog 2 with the survival outcome in patients with metastatic breast cancer using primary and paired metastatic lesions.
Authors: Hitoshi Inari, Nobuyasu Suganuma, Kae Kawachi, Tatsuya Yoshida, Hirotaka Nakayama, Takashi Yamanaka, Ayumi Yamanaka, Takashi Oshima, Yasushi Rino, Satoru Shimizu, Yohei Miyagi, Munetaka Masuda
Journal: Journal of Clinical Oncology (2016)

e23227 Background: Enhancer of zeste homolog 2 (EZH2), a Polycomb group protein, has been linked to aggressive breast cancer. Few reports have examined EZH2 expression in metastatic lesions of breast cancer patients. Therefore, the purpose of this study was to investigate the clinicopathological significance of EZH2 expression in metastatic breast cancers (MBCs). Methods: We retrospectively studied the surgical specimens of primary breast cancer (PBC) tumors and their corresponding metastatic lesions from patients (n= 96) who underwent surgery for the PBC tumor between December 1977 and March 2013. Tissue microarrays (TMAs) and whole tissue sections were constructed, using primary and metastatic lesions, and stained with antibodies against estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), Ki-67, and EZH2. We examined the correlations between ER, PR, HER2, Ki-67, and EZH2 expression, and the clinicopathological characteristics and outcome measures of the patients. Results: Compared to primary lesions, metastatic lesions exhibited significantly higher levels of expression of Ki-67 (75.0% vs. 42.7%, P= 0.01) and EZH2 (71.9% vs. 56.3%, P< 0.0001). Ki-67 expression was significantly highly correlated with EZH2 expression in primary lesions and metastatic lesions. Patients expressing high levels of EZH2 in primary lesions were not associated with poorer overall survival (OS) outcomes after recurrence than patients expressing low levels of EZH2 in primary lesions (P = 0.096), whether patients expressing high levels of EZH2 in metastatic lesions were associated with significantly than patients expressing low levels of EZH2 (P = 0.014). High levels of EZH2 expression in metastatic lesions were independently associated with poorer OS outcomes after recurrence. Conclusions: We show that high EZH2 expression levels in metastatic lesions are independently more associated with poorer OS outcomes after recurrence than primary lesions.