tbuckley/cabot-search huggingface dataset:
Final results of a phase I study of lapatinib (LAP) and cetuximab (CET) in patients with CET-sensitive solid tumors.
Authors: John F. Deeken, Hongkun Wang, John Marshall, Deepa Suresh Subramaniam, Jimmy J. Hwang, Aiwu Ruth He, Corinne Ramos, Rosemarie A. Hardesty, Kenneth Steadman, Louis M. Weiner, Michael J. Pishvaian
Journal: Journal of Clinical Oncology (2013)

2616 Background: Acquired resistance to anti-EGFR MoAb therapy may be via EGFR-ErbB2 heterodimerization and pathway reactivation. Dual anti-EGFR treatment was recently found to be active in colon cancer. We performed a phase I trial of CET and LAP to determine the DLTs, MTD, and clinical activity of the combination. Methods: Pts received CET at 400mg/m2 then 250 mg/m2 weekly, combined with daily LAP in a 3+3 dose escalation trial. LAP dose levels (DL) were (1) 750mg, (2) 1000mg, and (3) 1250mg. Cycles lasted 3 weeks, toxicity was assessed through C2, and pts were restaged every 2 cycles. Baseline and post-C1 tumor biopsies were analyzed for phosphoprotein activation in 36 EGFR/ErbB2 pathway proteins. Germ-line pharmacogenetic (PGx) variations were correlated with efficacy and toxicity. Results: Between 10/2010 and 10/2012, 22 pts were enrolled - colon (8), lung (8), head and neck (4), and anal cancers (2) - and 59% had prior anti-EGFR therapy. 18 pts were evaluable for toxicity, and 18 for response. Mean treatment was 3.8 cycles (range 1 - 12); 3 patients are still on trial. One DLT occurred at DL1 (gr 3 rash) and DL2 (gr 3 diarrhea). No pt on DL3 experienced a DLT. No pt experienced a gr 4 toxicity; gr 3 toxicities anytime on therapy included rash (17%), diarrhea (6%), fatigue (6%), lymphopenia (6%), and hypomagnesemia (6%). Rash was experienced by 94% of pts (gr 1=50%, gr 2=28%, and gr 3=17%). Partial responses (PR) occurred in 4 pts (22%), stable disease (SD) in 8 (44%), and disease progression in 6 (33%), for a clinical benefit rate of 67%. Seven of 13 (54%) pts on prior EGFR therapy had SD or PR. Down-regulation of phosphorylated EGFR/ErbB2 pathway components correlated with response; distinct pathway components were up-regulated in non-responders, including PI3K, Jak/Stat, MAPK, and IGF. PGx variants in FcRII correlated with response (p=0.045); no variants correlated with toxicity. Conclusions: The RP2D is CET 250 mg/m2 weekly and LAP 1250mg daily. Treatment was well tolerated with few grade 3 toxicities and a significant 67% clinical benefit rate. Non-responders showed up-regulation of EGFR pathway components – components which are druggable, warranting further study. A trial in colorectal cancer is ongoing. Clinical trial information: NCT01184482.
Update of the single-arm phase II L-MIND study of MOR208 + lenalidomide (LEN) in relapsed/refractory diffuse large B-cell lymphoma (R-R DLBCL): Response rates in patient subgroups with poor prognosis.
Authors: Kami J. Maddocks, Johannes Duell, Eva González Barca, Wojciech Jurczak, Anna Marina Liberati, Zsolt Nagy, Aleš Obr, Gianluca Gaidano, Marc André, Nagesh Kalakonda, Martin H. Dreyling, Pier Luigi Zinzani, Maren Dirnberger-Hertweck, Johannes Weirather, Sumeet Vijay Ambarkhane, Gilles A. Salles
Journal: Journal of Clinical Oncology (2019)

7521 Background: MOR208, an Fc-enhanced, humanized, anti-CD19 monoclonal antibody has shown single agent activity in patients (pts) with R-R DLBCL and encouraging activity when combined with LEN in the phase II L-MIND study. Here we report an update with primary endpoint and subgroup analyses (cut off June 5, 2018). Methods: Key inclusion criteria were adequate organ function, ≤3 prior lines of therapy, including ≥1 anti-CD20 therapy, and ineligibility for stem cell transplantation. Treatment comprised up to 12, 28-day (d) cycles (C) of MOR208, 12 mg/kg IV, q1w C1–3 (loading dose on d4 of C1), and q2w C4–12 + LEN 25 mg PO d1–21, C1–12. Pts progression-free after 12 C received MOR208 q2w until progression. The primary endpoint was independent review committee (IRC)-assessed ORR as per Cheson 2007 criteria. Results: Recruitment is complete (N = 81): median age 72 years (range 41–87), median of 2 prior therapies, 19 (23%) of pts had early relapse (≤12 months [mo] from diagnosis), 32 (40%) were rituximab (RTX) refractory (no response to or progression during or within 6 mo of a prior RTX therapy), 34 (42%) were refractory to their last therapy, 21/40 (26%/49%) pts had non-germinal center B cell-like (GCB)- / GCB-DLBCL, and 42 (52%) had an International Prognostic Index (IPI) of 3–5. MOR208 + LEN therapy was well tolerated; 72% of pts stayed on a LEN dose of ≥20 mg/day. Treatment-related serious adverse events, mainly infections (10%) or neutropenic fever (5%), occurred in 17% of pts. Investigator (INV)-assessed complete response (CR) and partial response rates were 33% and 25%, respectively, giving an ORR of 58%, comparable to the IRC assessment (ORR 54%; CR 32%). ORR was 46% in pts with ≥2 prior therapies, 59%/56% in rituximab- / last treatment-refractory pts, 58% in early relapse pts, 57% in pts with a baseline IPI of 3–5, and 71% in pts with non-GCB- vs 53% with GCB-DLBCL. INV-assessed median PFS and OS (ITT analysis) were 16.2 mo (95% CI: 6.3–NR) and not reached (95% CI: 18.6–NR), respectively. Conclusions: MOR208 + LEN shows encouraging activity including a durable PFS in R-R DLBCL, and in pt subgroups with poor prognosis. Clinical trial information: NCT02399085.
Deleted in liver cancer 3 (DLC-3), a novel Rho GTPase-activating protein gene, inhibits cell growth and is down-regulated in cancer
Authors: Marian E. Durkin, Veronika Ullmannova, Ming Guan, Nicolae C. Popescu
Journal: Cancer Research (2006)

2569  Two members of the deleted in liver cancer gene family, DLC-1 and DLC-2, are emerging as bona fide tumor suppressor genes that can inhibit cancer cell growth and motility. DLC-1 and DLC-2 are approximately 120 kDa polypeptides that serve as GTPase activating proteins (GAPs) for members of the Rho family of small GTPases, converting them to the inactive, GDP-bound form. In this report, we characterize a gene on chromosome Xq13 that encodes DLC-3 (also known as STARD8), a novel member of the DLC family. Two DLC-3 transcripts that differ at the 5’ end have been identified. DLC-3a encodes a polypeptide of 1103 amino acids that is around 50% identical in amino acid sequence to DLC-1/DLC-2 and has a similar structural organization, consisting of an N- terminal sterile alpha motif (SAM) domain, a serine-rich domain, the RhoGAP domain, and a C-terminal lipid binding START domain. A second isoform (DLC-3b, KIAA0189) appears to arise from the use of an alternative promoter and would yield a protein lacking the SAM domain. The high degree of sequence identity between the RhoGAP domain of DLC-3 and those of DLC-1 and DLC-2, which were shown to act as GAPs for RhoA and Cdc42, suggests that DLC-3 may have similar activity. The DLC-3 gene is widely expressed, overlapping with the distribution of the DLC-1 and DLC-2 transcripts. DLC-3 mRNA levels were low or absent in a significant number of breast, ovarian, liver, and prostate cancer cell lines. Using a Cancer Profiling Array (Clontech) to compare DLC-3 expression in matched tumor and normal human tissues, a decrease or loss of DLC-3 mRNA was observed in kidney, lung, ovarian, uterine, and breast cancer samples. By RT-PCR, down-regulation of DLC-3 was detected in primary prostate carcinomas and benign prostate hyperplasia relative to normal prostate tissue. Transfection of MCF-7 breast cancer cells and 22Rv1 prostate cancer cells with a DLC-3a expression vector suppressed cell growth and colony formation. These results indicate that DLC-3 may play a role in the control of cell proliferation, and its deregulation may contribute to breast and prostate tumorigenesis.
Comment on “PP2A inhibition sensitizes cancer stem cells to ABL tyrosine kinase inhibitors in BCR-ABL human leukemia”
Authors: Danilo Perrotti, Anupriya Agarwal, Claire M. Lucas, Goutham Narla, Paolo Neviani, Maria D. Odero, Peter P. Ruvolo, Nicole M. Verrills
Journal: Science Translational Medicine (2019)

LB100 does not sensitize CML stem cells to tyrosine kinase inhibitor–induced apoptosis.
New Functions of Long Noncoding RNAs during EMT and Tumor Progression
Authors: Chunlai Li
Journal: Cancer Research (2019)

Epithelial-to-mesenchymal transition (EMT) is orchestrated by aberrant activation of EMT transcription factors and expression of downstream target genes resulting in increased tumor initiation, metastatic potential, and therapeutic resistance. In this issue of Cancer Research, Wang and colleagues show that the long noncoding RNA SATB2-AS1 is dysregulated in colorectal carcinoma and correlates with poor survival and prognosis. They present a new functional mechanism illustrating how the SATB2-AS1-SATB2-Snail axis is involved in epigenetic modification that regulates colorectal carcinoma progression.See related article by Wang et al., p. 3542.
Proof of concept of the abscopal effect in MSS GI cancers: A phase 2 study of ipilimumab and nivolumab with radiation in metastatic pancreatic and colorectal adenocarcinoma
Authors: A. Parikh, J. Clark, J. Wo, B. Yeap, J. Allen, L. Blaszkowsky, D. Ryan, B. Giantonio, C. Weekes, A. Zhu, E. Van Seventer, L. Ly, L. Matlack, B. Foreman, L. Drapek, D. Ting, R. Corcoran, T. Hong
Journal: Annals of Oncology (2019)
Editor's Note: MicroRNA-519c Suppresses Hypoxia-Inducible Factor-1α Expression and Tumor Angiogenesis
Authors: Shih-Ting Cha, Pai-Sheng Chen, Gunnar Johansson, Chia-Yu Chu, Ming-Yang Wang, Yung-Ming Jeng, Sung-Liang Yu, Jin-Shing Chen, King-Jen Chang, Shiou-Hwa Jee, Ching-Ting Tan, Ming-Tsan Lin, Min-Liang Kuo
Journal: Cancer Research (2019)

The editors were made aware of concerns by a reader regarding potential manipulation of data in [this article][1] ([1][2]). An internal review by the editors determined that the same RT-PCR bands appear to be duplicated in the A549/HIF-1α and MDA-MB-231/GAPDH panels in Fig. 1B. In addition, it
Update on Severe Isotype-Matched Immunosuppression By Hevylite® Confirms Its Predictive Value in MGUS Patients: A Real-Life Study
Authors: Juana Jimenez, Nuno Barbosa, Tiago Moreira Pais, Maria Luisa Campos, Mª Antonia Peñálver, Carmen Hernando de Larramendi
Journal: Blood (2018)
A phase I study of milademetan in combination with quizartinib in patients (pts) with newly diagnosed (ND) or relapsed/refractory (R/R) <i>FLT3</i>-ITD acute myeloid leukemia (AML).
Authors: Naval Guastad Daver, Weiguo Zhang, Richard Graydon, Vikas Dawra, Jingdong Xie, Prasanna Kumar, Michael Andreeff
Journal: Journal of Clinical Oncology (2019)

TPS7067 Background: Fms -like tyrosine kinase 3 internal tandem duplication ( FLT3-ITD) mutations occur in ≈ 25% of pts with AML and are associated with poor prognosis. Quizartinib is a highly potent, selective, next-generation type II FLT3 inhibitor. In the phase 3 QuANTUM-R trial, quizartinib prolonged overall survival vs salvage chemotherapy in pts with R/R FLT3-ITD AML. MDM2 downregulates the p53 tumor suppressor and is upregulated in pts with AML. Targeting MDM2 may restore p53 activity in pts with wild-type p53 AML. Milademetan, a novel and specific MDM2 inhibitor, showed activity in an ongoing phase 1 trial in pts with AML or myelodysplastic syndromes (MDS). Preclinical studies have shown that quizartinib plus milademetan may act synergistically to target FLT3-ITD and restore p53 activity in FLT3-ITD/ TP53 wild-type AML [Andreeff et al. ASH 2018, abstract 2720]. Methods: This open-label phase 1 study (NCT03552029) has 2 parts: dose escalation (part 1) followed by dose expansion (part 2), with 2 planned cohorts. Key inclusion criteria include FLT3-ITD AML (primary or secondary to MDS) and adequate renal, hepatic, and clotting functions. Key exclusion criteria include acute promyelocytic leukemia, prior treatment with a MDM2 inhibitor, QTcF interval &gt; 450 ms, significant cardiovascular disease, and unresolved toxicities from prior therapies. Dose escalation and expansion cohort 1 includes R/R pts. Expansion cohort 2 includes ND pts unfit for intensive chemotherapy. During dose escalation, quizartinib will be administered once daily in 28-day cycles, with 3 proposed levels (30, 40, and 60 mg). Milademetan will be administered on days 1-14 of each 28-day cycle, with 3 proposed levels (90, 120, and 160 mg). The quizartinib dose will be escalated first, followed by the milademetan dose with no simultaneous escalation, guided by modified continual reassessment with overdose control. Primary objectives are safety and tolerability, optimum dosing schedule, maximum tolerated dose, recommended dosing for the expansion cohort, and phase 2 dosing. Secondary objectives are pharmacokinetics and preliminary efficacy. This study is recruiting. Clinical trial information: NCT03552029.
Transgenerational transfer of gene-modified T cells
Authors: Cormac Cosgrove, Emilia R. Dellacecca, Joost H. van den Berg, John B. Haanen, Michael I. Nishimura, I. Caroline Le Poole, Hans E. N. Bergmans
Journal: Journal for ImmunoTherapy of Cancer (2019)

Tumor immunotherapy using gene-modified T cells has already met with considerable success in the treatment of metastatic melanoma and B cell lymphoma. With improving patient prognoses, new questions arise. In particular, the long-term consequences of treatment among individuals of childbearing age could now be considered. Former patients can carry a cohort of transgenic memory T cells long after treatment has ceased and the effector T cell population has contracted. When patients become parents well after treatment is completed, expectant mothers may still pass transgenic T cells to their unborn children. Consequences should be more measurable if the mother also breastfeeds the baby. Maternal T cells may shape immune responses in the child, can tolerize the child to maternal antigens, and might cause either beneficial or adverse effects in the offspring. The hypothesis put forth is that transgenic T cells transferred from mother to child during and after pregnancy might have consequences that have not been adequately considered to date. Depending on the targeted antigen and the MHC eventually required to present it, such transfer may be beneficial, uneventful or even damaging. Such potential consequences are addressed in this paper. The transgenic T cells might form a pocket of memory T cells in secondary lymphoid organs of the child, expand upon antigen stimulation, and react. However, simple measures might be devised to avoid any reason for concern. These considerations provide ample incentive to probe transgenerational transfer of transgenic T cells.
Computer algorithms show potential for improving dermatologists' accuracy to diagnose cutaneous melanoma: Results of the International Skin Imaging Collaboration 2017
Authors: Michael A. Marchetti, Konstantinos Liopyris, Stephen W. Dusza, Noel C.F. Codella, David A. Gutman, Brian Helba, Aadi Kalloo, Allan C. Halpern, H. Peter Soyer, Clara Curiel-Lewandrowski, Liam Caffery, Josep Malvehy
Journal: Journal of the American Academy of Dermatology (2019)
Hyperprogressive disease on immune checkpoint therapy in advanced solid malignancies: A systematic review.
Authors: Xiao X. Wei, Nieves M. Chanza, Eric Chi-Ching Ko, Carol Mita, Katherine M. Krajewski, Toni K. Choueiri, Osama E. Rahma, Lauren Christine Harshman
Journal: Journal of Clinical Oncology (2019)

154 Background: Immune checkpoint therapy has changed the treatment landscape for many malignancies. As these agents are rapidly being incorporated into clinical practice, a subset of patients appear to have an accelerated tumor growth rate (TGR) after treatment initiation, a phenomenon termed hyperprogressive disease (HPD). Methods: A systematic search of original articles published between January 2000 and June 2018 was performed using PubMed, Embase, and Web of Science. Studies were eligible for inclusion if they reported on HPD in adult patients with advanced solid malignancies treated with checkpoint inhibitors and provided a specific HPD definition. Abstracts from ASCO, ESMO, and IASLC meetings were also included. Prespecified outcomes of interest included criteria used to define HPD, incidence of HPD, and association between HPD with baseline clinical or molecular characteristics and survival outcomes. Results: Of 700 studies screened, 12 retrospective studies were eligible, 3 of which evaluated patients treated in the context of clinical trials. Lung cancer and melanoma were the most common of the diverse histologies represented. The most common treatment was anti-PD1/PD-L1 monotherapy. A variety of criteria were utilized to define HPD, including TGR, RECIST progression, and time to treatment failure. HPD incidence ranged from 2% to 29%, and the only clinical factor significantly associated with HPD in more than one study was increased age. MDM2/4 and EGFR alterations appear to be associated with a higher incidence of HPD. HPD was significantly associated with poor overall survival in 3 studies. Conclusions: It remains unclear whether HPD reflects worsening disease caused by immunotherapy or is simply a manifestation of unfavorable, treatment unresponsive disease biology. There is a need to establish a consensus definition for HPD, and to examine HPD in prospective cohorts with appropriate comparison arms.
Incremental Utility of Adjuvant Chemotherapy in Muscle-invasive Bladder Cancer: Quantifying the Relapse Risk Associated with Therapeutic Effect
Authors: Filippo Pederzoli, Marco Bandini, Alberto Briganti, Elizabeth R. Plimack, Günter Niegisch, Evan Y. Yu, Aristotelis Bamias, Neeraj Agarwal, Srikala S. Sridhar, Cora N. Sternberg, Ulka N. Vaishampayan, Christine Théodore, Jonathan E. Rosenberg, Lauren C. Harshman, Joaquim Bellmunt, Matthew D. Galsky, Andrea Gallina, Andrea Salonia, Francesco Montorsi, Andrea Necchi
Journal: European Urology (2019)
Increase in circulating ACE-positive endothelial microparticles during acute lung injury
Authors: Yusuke Takei, Mitsuhiro Yamada, Koji Saito, Yoshinobu Kameyama, Hisatoshi Sugiura, Tomonori Makiguchi, Naoya Fujino, Akira Koarai, Hiroaki Toyama, Kazutomo Saito, Yutaka Ejima, Yu Kawazoe, Daisuke Kudo, Shigeki Kushimoto, Masanori Yamauchi, Masakazu Ichinose
Journal: European Respiratory Journal (2019)

Circulating endothelial microparticles (EMPs) are considered to be markers of endothelial injury, and lung microvascular endothelial cells express higher levels of angiotensin-converting enzyme (ACE). The aim of this study is to examine whether the number of ACE + microvascular EMPs could be a prognostic marker for the development of acute respiratory distress syndrome (ARDS) in septic patients. The numbers of EMPs and ACE + EMPs in the culture supernatant from human microvascular endothelial cells, as well as in the blood of mouse lung injury models and septic patients (n=82), were examined using flow cytometry. ACE + EMPs in the culture supernatant from pulmonary microvascular endothelial cells increased after exposure to an inflammatory stimulus. In the mouse lung injury models, the circulating ACE + EMPs and ACE + EMP/EMP ratio were higher than in the controls (p&lt;0.001). The ACE + EMP/EMP ratio was correlated with the wet/dry lung ratio (r s =0.775, p&lt;0.001). The circulating ACE + EMPs and ACE + EMP/EMP ratio on admission were significantly increased in septic patients who developed ARDS compared with septic patients who did not (p&lt;0.001). Therefore, circulating ACE + EMPs may be a prognostic marker for the development of ARDS in the septic patients.
Use of genotype subset selections of multi-UGT1As polymorphisms to predict severe neutropenia and tumor responses of metastatic CRC patients received FOLFIRI regimen
Authors: S. Hazama, Y. Okuyama, T. Kato, N. Okayama, Y. Hinoda, J. Sakamoto, H. Mishima, Y. Fujita, Y. Hamamoto, M. Oka
Journal: Journal of Clinical Oncology (2009)

e15038 Introduction: The pharmacogenetics of irinotecan indicate that a common polymorphism in the uridine diphosphate glucuronosyltransferase 1As (UGT1As) gene predict severe toxicity. However the tumor response to irinotecan is variable and unpredictable. Methods: Two multi-center phase II studies of FOLFIRI (FLIGHT-1 and FLIGHT-2 study) were conducted for patients with metastatic colorectal cancer (CRC) in Japan. FLIGHT-1 study was first-line chemotherapy, and FLIGHT-2 study was FOLFOX-refractory second-line chemotherapy. 103 patients have been enrolled in these studies (53 patients in FLIGHT-1 and 50 patients in FLIGHT-2) from 20 institutions by April 2007 from November 2005. Seventy one patients were analyzed UGT1As polymorphisms, UGT1A1*28 (TA6&gt;TA7), UGT1A1*6 (G&gt;A), UGT1A1*60 (T&gt;C), UGT1A7 (N129K; T&gt;G), UGT1A7 (-57 T&gt;G), UGT1A9*22 (T10&gt;T9). Results: Out of 71 patients, 34 had G3/4 neutropenia or leukopenia, and 23 had tumor responses (CR +PR). G3/4 neutropenia was more frequent in patients with *6, N129K(G), -57(G), *22 allele than patients without these allele (p&lt;0.05). Other polymorphism was not the predictive factor for toxicity and tumor response, independently. On the other hand, genotype subset selection of multi-UGT1As polymorphisms was useful to predict severe toxicities and tumor responses. Only 7 patients of 22 patients with TA6/TA6 and T10/T10, or TA6/TA7 and -57(T/T), or *6(G/G) and *60(T/T) had grade3/4 toxicity. Similarly, high risk group of toxicity or high and low tumor responses groups was also predicted by genotype subset selections. Conclusions: Genotype subset selections of multi-UGT1As polymorphisms were the excellent predictor for severe toxicities and tumor responses of metastatic CRC patients received FOLFIRI regimen. No significant financial relationships to disclose.
CD74 Is Expressed in Relapsed and Refractory Multiple Myeloma and Can be Targeted with a Novel Anti-CD74 Antibody Drug Conjugate, SΤRO-001
Authors: Millicent Embry, Xiaofan Li, Abigail Yu, Cristina Abrahams, Nancy Y. Greenland, Kwun Wah Wen, Chris Jones, Venita DeAlmeida, Stellanie Krimm, Sarah Krueger, Shannon Matheny, Toni Kline, Alice Yam, Ryan Stafford, Arun P. Wiita, Trevor Hallam, Mark Lupher, Arturo Molina
Journal: Blood (2017)
Increased Frequencies of PD-1+ CD8+ Marrow-Infiltrating Lymphocytes Associated with Highly Clonal T-Lymphocyte Expansions in Relapsed and Refractory AML Patients but Not Healthy Adults
Authors: Meghali Goswami, Karolyn Oetjen, Matthew P. Mulé, Sheenu Sheela, Hong Yuen Wong, Qingguo Liu, Katherine R. Calvo, Catherine E. Lai, Christopher S. Hourigan
Journal: Blood (2016)