tbuckley/cabot-search huggingface dataset:
Niclosamide a new chemotherapy agent? Pharmacokinetics of the potential anticancer drug in a patient cohort of the NIKOLO trial.
Authors: Susen Burock, Severin Daum, Hanno Tröger, Theo Daniel Kim, Sandrine Krüger, Damian Tobias Rieke, Sebastian Ochsenreither, Kerstin Welter, Pia Herrmann, Arthur Sleegers, Wolfgang Walther, Ulrich Keilholz, Ulrike Stein
Journal: Journal of Clinical Oncology (2018)

e14536 Background: Patients with metastasized colorectal cancer (mCRC) progressing under standard therapy have poor prognosis and need further treatment alternatives. The S100 calcium binding protein A4 transcriptional target of the Wnt/β-catenin signaling pathway was shown to be predictive for metastasis formation and reduced survival. The FDA and EMA-approved anti-helminthic drug niclosamide is known to intervene in the Wnt/β-catenin pathway and shows its antimetastatic efficacy via S100A4 inhibition in preclinical models. This prospective phase II, single center, one-arm open-label clinical trial evaluates safety and efficacy of drug repositioning of niclosamide in patients with mCRC progressing under standard therapy (NIKOLO). Here we report pharmacokinetic data and early signs of efficacy for this approach. Methods: Patients received 2 g of oral niclosamide (Yomesan) QD until disease progression or toxicity. We report pharmacokinetic results of the first 5 patients in whom peripheral blood samples were collected at baseline, 30, 120, 240, 720 minutes and one the day after first niclosamide intake. Further blood samples were analyzed at times of scheduled blood collection. All blood samples were analyzed for niclosamide plasma levels by HPLC to investigate the pharmacokinetic of niclosamide. Results: After oral intake niclosamide plasma levels peaked after 240 minutes in 3 out of 5 patients; in 2 patients the peak was reached after 120 or 720 minutes, respectively, with a median cmax plasma level of 0.665 µg/ml (0.429 to 0.848). During follow-up plasma levels peaked at week 5 in 3 patients. Two patients did not have blood collected at week 5, but showed a peak at week 6 with a median cmax plasma level of 0.759 µg/ml (0.485 to 1.177). No drug related toxicities were observed. The patient with the highest median plasma level (0.598 µg/ml) showed stable disease at 4 months. Conclusions: Niclosamide is well tolerated at approved dose with no dose limiting toxicities. Preliminary data suggests that patients with higher plasma levels might experience longer time to progression. However, this warrants further investigation in the next patient cohort of this currently recruiting trial. Clinical trial information: NCT02519582.
Changes of PD-1 expressing tumor infiltrating lymphocytes (TILs) in primary and metastatic tumor in renal cell carcinoma (RCC).
Authors: Axel Hegele, Mareike Kalisch, Peter Rexin, V Wischmann, Rainer Hofmann, W Nimphius
Journal: Journal of Clinical Oncology (2016)

e16128 Background: Immune checkpoint inhibitors represent a new therapeutic option in metastatic RCC (mRCC) dependent on PD-1 and PD-L1 expression. We examined the occurrence and amount of PD-1 expressing tumor infiltrating lymphocytes (TILs)in the primary tumor (kidney) as well as in synchronous/metachronous metastases of RCC. Aim of this study was to detect possible correlations for development of metastases as well as differences in PD-1 expression level between primary and metastatic RCC. Methods: IHC was performed on paraffin embedded samples from patients with localised and metastasized RCC treated at the university hospital of Marburg (2013-2014) using an antibody against PD1 (Zytomed, Cat. No. 516-18662). Samples were scored as positive if any staining was seen (Level 0/1/2). Data were analyzed using SPSS for Windows (Version 22). Examinations were approved by the local Ethical Review Board (AZ 181/13). Results: PD-1 - expressing tumor infiltrating lymphocytes (TILs) were determined in kidney RCC samples of 43 patients: n = 6 no expression, n = 25 low level expression, n = 12 high level expression. We found no correlation of the level of PD – 1 positive TILs with T-stage (0.71), tumor differentiation (0.12) and concomitance of metastases (n = 5, 0.78). During follow-up 19 patients developed RCC metastases. The PD – 1 expression level comparing metastases with primary tumor was identical in 7 patients, lower in 3 patients and higher in 9 patients without significant correlation in this small cohort (0.86). We found also no correlation to PD-1 expression level in primary tumor site and development of metastases. Conclusions: The level of PD-1 expressing tumor infiltrating lymphocytes in localized RCC shows no correlation to clinical parameters. In addition PD-1 expression level in primary tumour and metastases changed in 63% (16 % decrease and 47% increase) of our patients illustrating possible variations in biological behaviour of metastases compared to primary tumor.
Association of circulating tumor (ct)-DNA genomic alterations (GA) with outcomes in metastatic urothelial carcinoma (mUC).
Authors: Petros Grivas, Gregory Russell Pond, Rebecca J Nagy, Pedro C. Barata, Prateek Mendiratta, Dharmesh Gopalakrishnan, Alexandra Drakaki, Sumati Gupta, Neeraj Agarwal, Jue Wang, Bishoy Faltas, Ulka N. Vaishampayan, Gurudatta Naik, Bradley Alexander McGregor, Sumanta K. Pal, Lesli Ann Kiedrowski, Richard B. Lanman, Guru Sonpavde
Journal: Journal of Clinical Oncology (2018)

4540 Background: Cell-free ctDNA profiling enables noninvasive identification of GA in mUC. We hypothesized that ctDNA GA correlate with outcomes and signify therapy targets. Methods: 477 patients (pts) with UC who underwent ctDNA analysis for potentially actionable GA via Guardant360 were identified. A 73-gene ctDNA next generation sequencing (NGS) panel from CLIA-licensed, CAP-accredited laboratory (Guardant Health, Inc.) offers complete exon sequencing in 19 cancer genes, critical exons in 54 genes, amplifications (18 genes), fusions (6 genes) & indels (23 genes) from 10 mL of peripheral blood. KM method was used to estimate overall survival (OS) and failure-free-survival (FFS) since therapy initiation. Cox proportional hazards regression was used to assess the association of ctDNA GA present in > 10% of pts and clinical factors with OS and FFS in univariable analyses. All tests were 2-sided, p ≤0.05 was significant. We also evaluated GA in serial samples to assess genomic evolution. Results: 124 pts had available clinical data, of whom 65 had received prior platinum, 21 prior taxane and 10 prior PD1/PD-L1 inhibitor; ≥1 GA was detected in 112 pts. Median age at time of ctDNA collection was 72 and median (range) number of GA per sample was 4 (0-80); 110 pts had ≥1 SNV & 39 pts ≥1 CNV. Most commonly altered genes were TP53 (55%), PIK3CA (24%) and ARID1A (23%). 1-year OS and FFS were 69% and 35%, respectively. ARID1A (HR 0.49, p = 0.052) & BRAF (HR 0.24, p = 0.048) GA were associated with longer FFS, while BRCA1 (HR: 2.36, p = 0.016) GA with shorter FFS; no GA were significantly associated with OS. After ctDNA collection, 32 pts received platinum, 43 anti-PD1/PDL1, 24 other and 25 no therapy. There was no significant effect of post-ctDNA therapy on OS (p = 0.91) or FFS (p = 0.29); post-ctDNA therapy did not interact with clinical factors. Serial samples showed new and resolution of some GA. Conclusions: ctDNA GA were detected in most pts with mUC and appeared similar to those from prior tumor tissue NGS studies. BRAF & ARID1A GA correlated with longer and BRCA1 GA with shorter FFS suggesting that synthetic lethality with DNA damage repair inhibitors may be clinically useful. Serial sample analysis revealed genomic evolution.
Multicenter phase I/IIa study using T cell receptor gene therapy in metastatic melanoma.
Authors: Maartje W. Rohaan, Joost van den Berg, Raquel Gomez-Eerland, Maaike van Zon, Renate de Boer, Eleonora A.M. Bakker, Loes M. Pronk, Bart Van De Wiel, Bastiaan Nuijen, Marnix Geukes Foppen, Johannes V. Van Thienen, Christian U. Blank, John B. A. G. Haanen
Journal: Journal of Clinical Oncology (2018)

TPS9602 Background: Since the introduction of targeted therapy and checkpoint inhibitors, the historically poor prognosis of patients with unresectable stage IIIc/IV melanoma has greatly improved, with now known 2-year survival rates of 46-64%. However, a substantial group of patients, for example those with metastatic uveal melanoma, have poor response rates upon these therapies with no alternative approved therapy yet available. Adoptive transfer of T cell receptor (TCR) gene modified T cells is a modality to create a large pool of tumor reactive T cells. Responses of clinical significance have been seen in preclinical and clinical trials when targeting the melanocyte differentiation antigens gp100 and MART-1. The primary aim of our study is to explore the feasibility, safety and objective response rate of the adoptive transfer of autologous T cells modified with a MART-1 specific TCR, preceded by non-myeloablative (NMA) chemotherapy. Methods: In this phase I/IIa study, a total of 25 patients ≥ 18 years of age, with irresectable stage IIIc/IV melanoma (cutaneous, melanoma of unknown primary, mucosal and uveal melanoma) who have failed previous standard treatments, are HLA-A2 positive and have MART-1 and MHC class I expressing tumors, will be included. Patients will undergo leukapheresis to isolate autologous T cells, which will be transduced with a retroviral vector encoding the 1D3HMCys MART-1 TCR and expanded ex vivo. Patients will receive NMA chemotherapy and a single intravenous infusion with MART-1 TCR transduced T cells in a dose escalating regimen after evaluation of toxicity and efficacy. Primary endpoints are the feasibility of MART-1 specific TCR therapy in terms of delivery of this sequence of treatment in metastatic melanoma patients, safety according to CTCAE 4.0 and objective response rate according to RECIST 1.1. Secondary endpoints are the 1-year progression free survival, median overall survival and the efficacy of induction of tumor specific T cell responses measured in peripheral blood and tumor biopsies. Enrollment started in March 2012 in The Netherlands Cancer Institute and will be continued in a 2-stage Simon design. Clinical trial information: NCT02654821.
Comparing clonality between components of combined hepatocellular carcinoma and cholangiocarcinoma by targeted sequencing
Authors: N. Yoon, J. Jeon
Journal: Annals of Oncology (2018)

Background: Combined hepatocellular-cholangiocarcinoma (cHCC-CC) is a very rare tumor. It has two different components (hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC)) in a single mass. Although several studies have determined genetic characteristics of cHCC-CC, Next-generation sequencing (NGS) data for comparing clonality of cHCC-CC are currently unavailable. Methods: We selected four cHCC-CC cases and micro-dissected HCC, CC, and normal components separately from each case. DNA and RNA were isolated from each sample and sequenced by Oncomine Comprehensive Panel (OCP) interrogating 143 cancer genes using Ion S5 XL sequence platform. Genetic features of HCC and CC from each patient were compared. Results: All cases successfully produced NGS data. Two cases demonstrated different mutations between HCC and CC components (biclone) while two cases shared the same mutations between two components (monoclone). SNPs of TP53 (4/4) and PTEN (1/4) and gene amplifications of MET (1/4), c-MYC (1/4), and CDK6 (1/4) were found in CC component. In HCC component, SNPs of TP53 (3/4), PTEN (1/4) and CTNNB1 (1/4) and CCND1 amplification (1/4) were detected. Two biclonal cases showed histologically distinguished border between HCC and CC components with or without intermediate cell foci. Two monoclonal cases showed histologically ambiguous border between HCC and CC components with more intermingled pattern than biclonal cases. Conclusions: We compared genetic compositions of HCC and CC components and matched clonality with histologic feature in cHCC-CC using targeted sequencing. Two (50%) of four cases had different clones between HCC and CC components with more distinguished histologic features than monoclonal cases. Considering such heterogeneity, partly sequencing is recommended for cHCC-CC, especially in those who have histologically distinguished HCC and CC components regardless of the presence of intermediate component. Legal entity responsible for the study: Nara Yoon. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.
Smart vaccine delivery based on microneedle arrays decorated with ultra-pH-responsive copolymers for cancer immunotherapy
Authors: Huu Thuy Trang Duong, Yue Yin, Thavasyappan Thambi, Thanh Loc Nguyen, V.H. Giang Phan, Min Sang Lee, Jung Eun Lee, Jaeyun Kim, Ji Hoon Jeong, Doo Sung Lee
Journal: Biomaterials (2018)
Phase 1b study of selinexor, a first-in-class selective inhibitor of nuclear export (SINE) compound, in combination with doxorubicin in patients (pts) with locally advanced or metastatic soft tissue sarcoma (STS).
Authors: Eoghan Ruadh Malone, Jeremy Howard Lewin, Esmail Mutahar Al-Ezzi, Abha A. Gupta, Pernille Pedersen, Michelle Ng, Lisa Wang, Angela Rodriguez, Albiruni Ryan Abdul Razak
Journal: Journal of Clinical Oncology (2019)

3123 Background: Selinexor is a first-in-class SINE compound with single-agent activity in STS. We undertook this study to determine the safety, tolerability and efficacy of selinexor in combination with doxorubicin in pts with incurable STS. Methods: This phase 1b study was conducted using a bayesian model (modified toxicity probability index). Patients with locally advanced or metastatic STS received selinexor at either 60 or 80mg weekly PO plus doxorubicin (75mg/m 2 IV q21 days, max 6 cycles). Pts with stable disease (SD) or better (per RECIST 1.1 criteria) after 6 cycles of combination treatment received selinexor monotherapy until disease progression or unacceptable toxicity. Disease assessments were made with standard imaging after every 2 cycles. Results: 24 pts (19F/5M, ECOG 0/1: 12/12, median age 58.5 years [range 34-74]) were enrolled. Disease subtypes included leiomyosarcoma (n = 6), malignant peripheral nerve sheath tumor (n = 3) and other sarcomas (n = 15). Three pts at 60mg selinexor and 21 pts at 80mg selinexor were treated. The most common G3 drug related adverse events were hematological, neutropenia n = 13 (54%), anemia n = 6 (25%). There were 4 dose-limiting toxicities (2 febrile neutropenia, 1 vomiting and 1 unresolved fatigue) all at the 80mg dose level, but does not satisfy criteria for maximum tolerated dose. Two patients had clinically significant and relevant drop in ejection fraction, presenting with cardiac symptoms. Of the 24 evaluable pts 4 (17%) had a partial response, 16 (67%) had SD as best response and SD &gt; 16 weeks was seen in 13 pts (54%). PK analysis of selinexor did not demonstrate changes compared to single agent profile. The estimated median PFS and OS are 5.5 (95% CI:4.1-7.0) and 9.4 (6.6-13.8) months. Conclusions: Our initial data demonstrate that the combination of selinexor at 80mg with doxorubicin is tolerable and is associated with clinical benefit. Longer term follow up of available patients will be needed to understand toxicity profile. Clinical trial information: NCT03042819.
Photodynamic inactivation of bacteria to decolonize meticillin-resistant <i>Staphylococcus aureus</i> from human skin
Authors: M. Schreiner, W. Bäumler, D.B. Eckl, A. Späth, B. König, A. Eichner
Journal: British Journal of Dermatology (2018)

To prevent infections that arise from the skin surface it is necessary to decolonize human skin prior to any proposed treatment or surgical intervention. Photodynamic inactivation of bacteria (PIB) uses cationic photosensitizers that attach to the surface of bacteria, generate reactive oxygen species on light irradiation and thereby kill bacteria via oxidative mechanisms.To evaluate the potential and the safety of PIB for decolonization of bacteria from skin.PIB with the new photosensitizer SAPYR [2-((4-pyridinyl)methyl)-1H-phenalen-1-one chloride] was initially tested against different bacterial species in vitro. Then, ex vivo porcine skin samples were used as a model for decolonization of different bacteria species. The numbers of viable bacteria were quantified and the mitochondrial activity of skin cells was histologically analysed (using nitroblue tetrazolium chloride, NBTC). The same procedure was performed for human skin and meticillin-resistant Staphylococcus aureus (MRSA).The in vitro studies showed a 5 log10 reduction of all tested bacterial species. On ex vivo porcine skin samples, PIB reduced the viability of all tested bacterial species by at least 3 log10 steps. On human skin samples ex vivo, PIB reduced the number of viable MRSA by maximal 4·4 log10 steps (1000 μmol L-1 SAPYR, incubation time 10 min, 60 J cm-2 ). NBTC staining showed normal mitochondrial activity in skin cells after all PIB modalities.The results of this study show that PIB can effectively and safely kill bacteria like MRSA on the skin surface and might have the potential of skin decolonization in vivo.
Abstract B030: MEK5 downregulation enhances radiosensitization of human prostate cancer cells by inhibiting DNA repair
Authors: Constantinos G. Broustas
Journal: Cancer Research (2018)

Abstract Radiotherapy is commonly used to treat a variety of solid human tumors, including localized prostate cancer. However, treatment failure almost always ensues due to tumor intrinsic or acquired radioresistance. Mitogen-activated protein kinase kinase 5 (MAP2K5 or MEK5), belongs to the family of MAP kinases. It is activated by the upstream kinases MEKK2 and MEKK3 at Ser311/Thr315. MEK5, in turn, phosphorylates and activates extracellular signal-regulated kinase 5 (ERK5 or BMK1) at Thr218/Tyr220. MEK5/ERK5 pathway plays a pivotal role in tumor initiation and progression. MEK5 protein is overexpressed in prostate cancer cells compared with normal prostate epithelial cells, and MEK5 levels are correlated with prostate cancer metastasis. High expression of ERK5 in prostate cancer is also found to correlate with poor disease-specific survival and can serve as an independent prognostic factor. To determine whether the MEK5/ERK5 pathway is activated in response to ionizing radiation (IR), RNA interference was used to deplete MEK5 from PC3 and DU145 cells. Western blot analysis demonstrated that control cells with normal levels of MEK5 exposed to 3-Gy γ-rays had an increase in phospho-ERK5 levels at 5 and 15 min post-IR, diminishing at later time points. No activated ERK5 was detected in MEK5-depleted cells. Downregulation of MEK5 did not impact on cell cycle checkpoint activation in irradiated cells. In contrast, depletion of MEK5 markedly impaired phosphorylation of DNA-PKcs at Ser2056 in response to IR treatment. Furthermore, MEK5 knockdown did not influence the initial appearance of γH2AX or 53BP1 foci after irradiation, but significantly delayed the resolution of radiation-induced γH2AX and 53BP1 foci, detectable even 48 h post-irradiation, indicating a DNA repair defect. Cell based assay showed that nonhomologous end-joining is compromised in PC3 cells with ablated MEK5 protein expression. Finally, long-term clonogenic survival analyses and short-term cell growth assays indicated that MEK5 knockdown sensitized PC3 and DU145 prostate cancer cell lines to IR. Likewise, the topoisomerase II inhibitor etoposide that causes double-strand breaks also sensitized MEK5-depleted cells. These data indicate that MEK5 influences the response of prostate cancer cells to radiation and MEK5 downregulation is associated with delayed double-strand break repair kinetics. Inhibition of MEK5 in combination with radiation may provide a strategy to improve survival of prostate cancer patients. Citation Format: Constantinos G. Broustas. MEK5 downregulation enhances radiosensitization of human prostate cancer cells by inhibiting DNA repair [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr B030.
Place of death in gastrointestinal cancer patients: Retrospective study in Japanese general hospital.
Authors: Toshihiko Matsumoto, Shogo Kimura, Hitomi Himei, Takao Tsuzuki, Shinjiro Takagi, Masahiro Takatani, Hirofumi Morishita
Journal: Journal of Clinical Oncology (2018)

e22189 Background: Place of death is widely known that it is important factor for quality of life of advanced cancer patients and caregivers. Although there are few studies that examine gastrointestinal cancer patients’ place of death and association between patients characteristic and place of death. Methods: We retrospectively analyzed metastatic or unresectable gastrointestinal cancer patients who received systemic chemotherapy at Himeji red cross hospital and died between August 2016 and February 2018. All patients received medical care by mediical oncologist. Results: 63 patients who received chemotherapy at Himeji Red Cross Hospital and died were analyzed.The patients’characteristics were as follows: median age, 67(21-84) years; male/female, 46/17; performance status(PS) (0/1/2/3), 13/29/19/8; primary site (colorectal/stomach/esophagus/pancreas/biliary tract), 8/29/5/15/6; and receiving palliative care by palliative care unit: 39 patients. The median overall survival (OS) was 7.2 (0.16-40.6) months and median survival time from last chemotherapy administration was 1.3 (0.13-12) months. 38 patients(60%) died at Himeji red cross hospital, 13 patients(21%) died at palliative care hospital and 12 patients(19%) died at home. In univariate analysis, receiving palliative care by palliative care unit, OS less than 6 months and Charlson Comorbidity Index(CCI) over 9 patients were risk factor of death at hospital. In multivariate analysis, receiving palliative care by palliative care unit (OR = 4.967, 95% CI, 1.001–29.87, P = 0.0497) and less than 6 months OS(OR = 6714, 95% CI, 3.137–not evaluated, P = 0.0061) were risk factor of death at hospital . Conclusions: Only 19% metastatic or unresectable gastrointestinal cancer patients died at home in Japanese real world. This study suggested that patients who received palliative care by palliative care unit and who survived less than 6 months might become hard to die at home.