tbuckley/cabot-search huggingface dataset:
Risks and benefits of phase 1 oncology trials in the era of personalized medicine.
Authors: Camille Chakiba, Thomas Grellety, Sophie Cousin, Antoine Italiano
Journal: Journal of Clinical Oncology (2016)

e18116 Background: Although crucial to developing new anti-cancer treatments, phase I trials in oncology remain ethically controversial. Critics argue that they have no therapeutic intent and offer participants no reasonable prospect of benefit. However, the emergence of targeted therapies has modified the landscape of drug development in oncology. Methods: We reviewed all non-pediatric phase 1 oncology trials published in English in 2014 and 2015. We report the rates of response to treatment, of stable disease, of serious adverse events and of treatment-related deaths. Results: We analyzed 236 trials involving 8267 participants, all of whom were assessed for toxicity and 7218 of whom were assessed for a response to therapy. 107 trials (45%) focused on a specific population (tumor type and/or molecular profile) and 29 trials (13%) required a positive biomarker as an inclusion criterion. The MTD was reached in only 114 studies (48%). Of 3868 participants for whom data on SAE were available, 22.6% had at least one SAE. The overall rate of death due to toxic events was 0.53%. The overall response rate ORR (i.e., for both complete and partial responses) was 19.3%. and was significantly higher in clinical trials focusing on a specific population than in “all comers” one (30 vs 6.5%, p < 0.0001). Monoclonal antibodies targeting growth factor receptors were less likely to induce objective response than tyrosine kinase inhibitors, cytotoxic or immune-modulating agents. An additional 35.7 percent of participants had stable disease or a less-than-partial response. Conclusions: Rates of response vary among the various types of phase 1 oncology trials. However, overall response rates among modern phase 1 oncology trials is significantly higher than previously reported. This is related to the increasing sophistication of trial design through the use of targeted and biological therapies in selected patients.
Updated efficacy and &gt; 1-y follow up from IMvigor210: Atezolizumab (atezo) in platinum (plat) treated locally advanced/metastatic urothelial carcinoma (mUC).
Authors: Robert Dreicer, Jean H. Hoffman-Censits, Thomas W. Flaig, Enrique Grande, Ani Sarkis Balmanoukian, Gunhild von Amsberg, Christine Theodore, Simon Chowdhury, Sergio Bracarda, Jessica Mary Clement, Evan Y. Yu, Arash Rezazadeh Kalebasty, Guenter Niegisch, Stephane Culine, Michael S. Gordon, Na Cui, Sanjeev Mariathasan, Fatema A. Legrand, Oyewale O. Abidoye, Daniel Peter Petrylak
Journal: Journal of Clinical Oncology (2016)

4515 Background: A majority of mUC patients (pts) treated with chemo ultimately progress, and subsequent therapy is often accompanied by low ORRs and short OS. Atezo (MPDL3280A) has been found to be safe and effective in plat treated pts. Here we report updated efficacy in pts with > 1-y median follow up. Methods: IMvigor210 (NCT02108652) cohort 2 mUC pts who progressed during/following plat received atezo 1200 mg IV q3w until loss of clinical benefit. PD-L1 status was centrally scored on tumor-infiltrating immune cells (IC; SP142 IHC assay): IC2/3, 1, 0. Confirmed RECIST v1.1 ORR (RECIST, central review) and modified (m)RECIST ORR (investigator) were co-primary endpoints. DOR, OS and safety were secondary (data cut Nov 27, 2015). Results: 310 efficacy/safety evaluable pts had median age 66 y; 37% had prior cystectomy; 41% had ≥ 2 prior regimens for mUC; 39% had chemo within past 3 mo. Responses were consistent in IC2/3 pts (26% RECIST ORR; 29% mRECIST) as well as across all IC subgroups, and enriched in pts with higher IC status (Table). RECIST responses were seen in pts with ECOG PS1 (8% ORR; 16/193), CrCl < 60 mL/min (13%; 14/110), Hb < 10 g/dL (7%; 5/69), visceral mets (10%; 24/243) and ≥ 4 prior mUC regimens (8%; 2/24). Responses were ongoing in 37/46 pts (80%) per RECIST and 46/60 (77%) per mRECIST. mDOR was not reached in IC2/3, IC1/2/3 and all comers. With longer follow up (median 14.4 mo [range 0.2-17.1]) an evolution of responses including additional CRs was seen. mOS and 1-y OS were notable in all IC subgroups (Table). Atezo remains well tolerated. Conclusions: Atezois an efficacious monotherapy in heavily pretreated mUC pts. Durable responses occurred across predefined IC subgroups, including pts with poor prognostic factors. Clinically meaningful OS was seen. With sustained efficacy coupled with favorable safety, atezo shows promise as a new standard of care in plat treated mUC (expanded access study: NCT02589717). Clinical trial information: NCT02108652. n RECIST mRECIST OS ORR, % 95% CI CR, n ORR, % 95% CI CR, n mOS, mo 95% CI 1-y OS, % 95% CI IC2/3 100 26 18, 36 12 29 20, 39 8 11.9 9.0, NEa 50 40, 60 IC1/2/3 207 18 13, 24 14 23 17, 29 16 9.0 7.1, 10.9 40 33, 47 Allb 310 15 11, 19 17 19 15, 24 18 7.9 6.7, 9.3 37 31, 42 aNot estimable; b IC0, 1, 2/3
Abstract 3691: MDM2 but not MDM4 promotes retinoblastoma cell proliferation through p53-independent regulation of MYCN translation
Authors: Donglai Qi, David E. Cobrinik
Journal: Cancer Research (2016)

Abstract Retinoblastomas can arise from cone photoreceptor precursors in response to the loss of pRB function. Some aspects of cone precursor-specific circuitry cooperate with pRB loss to initiate this process and subsequently continue to contribute to the malignancy. Intrinsic high level MDM2 expression is a key component of this circuitry and is thought to inactivate p53-mediated tumor surveillance that could otherwise be induced by aberrant cell cycle entry. However, the MDM2-related MDM4 has also been proposed to abrogate p53-mediated tumor surveillance in the absence of detectable MDM2. Here we report that high-level MDM2 but not MDM4 has a consistent, critical role in retinoblastoma cell proliferation. Reduction of MDM2 and MDM4 only weakly induced p53, yet reduction of MDM2 but not MDM4 severely impaired proliferation and survival through a p53-independent mechanism. Specifically, MDM2 up-regulated the translation of another component of the cone circuitry, MYCN, in retinoblastoma cells. These findings indicate that high-level MDM2 expression is needed in order to perform a critical p53-independent function and may obviate the need for genomic alterations to the p53 pathway in retinoblastoma cells. Citation Format: Donglai Qi, David E. Cobrinik. MDM2 but not MDM4 promotes retinoblastoma cell proliferation through p53-independent regulation of MYCN translation. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3691.
Sickle Cell Trait, Rhabdomyolysis, and Mortality among U.S. Army Soldiers
Authors: D. Alan Nelson, Patricia A. Deuster, Robert Carter, Owen T. Hill, Vickee L. Wolcott, Lianne M. Kurina
Journal: New England Journal of Medicine (2016)

Studies have suggested that sickle cell trait elevates the risks of exertional rhabdomyolysis and death. We conducted a study of sickle cell trait in relation to these outcomes, controlling for known risk factors for exertional rhabdomyolysis, in a large population of active persons who had undergone laboratory tests for hemoglobin AS (HbAS) and who were subject to exertional-injury precautions.We used Cox proportional-hazards models to test whether the risks of exertional rhabdomyolysis and death varied according to sickle cell trait status among 47,944 black soldiers who had undergone testing for HbAS and who were on active duty in the U.S. Army between January 2011 and December 2014. We used the Stanford Military Data Repository, which contains comprehensive medical and administrative data on all active-duty soldiers.There was no significant difference in the risk of death among soldiers with sickle cell trait, as compared with those without the trait (hazard ratio, 0.99; 95% confidence interval [CI], 0.46 to 2.13; P=0.97), but the trait was associated with a significantly higher adjusted risk of exertional rhabdomyolysis (hazard ratio, 1.54; 95% CI, 1.12 to 2.12; P=0.008). This effect was similar in magnitude to that associated with tobacco use, as compared with no use (hazard ratio, 1.54; 95% CI, 1.23 to 1.94; P<0.001), and to that associated with having a body-mass index (BMI; the weight in kilograms divided by the square of the height in meters) of 30.0 or more, as compared with a BMI of less than 25.0 (hazard ratio, 1.39; 95% CI, 1.04 to 1.86; P=0.03). The effect was less than that associated with recent use of a statin, as compared with no use (hazard ratio, 2.89; 95% CI, 1.51 to 5.55; P=0.001), or an antipsychotic agent (hazard ratio, 3.02; 95% CI, 1.34 to 6.82; P=0.008).Sickle cell trait was not associated with a higher risk of death than absence of the trait, but it was associated with a significantly higher risk of exertional rhabdomyolysis. (Funded by the National Heart, Lung, and Blood Institute and the Uniformed Services University of the Health Sciences.).
Abstract 3057: Synthetic novel Psammaplin A derivatives enhance radiation lethality in human cancer cells
Authors: Jin Ho Kim, Chan Woo Wee, Hak Jae Kim, Soo Youn Suh, Eun Sook Ma, Boom Soo Shin, Il Han Kim
Journal: Cancer Research (2016)

Abstract DNA methyltransferase (DNMT) inhibitors show not only anticancer effects but radiosensitization activity. Psammaplin A (PsA), a known DNMT inhibitor, enhances radiation lethality of human cancer cells, but the chemical instability hampers in vivo application of PsA. The purpose of the present study was to synthesize novel radiosensitizers using PsA as the backbone structure. Eight novel PsA-based derivatives (MA2, MA3, MA5, MA6, MA7, MA8, MA9 and MA5M) were synthesized. They were tested for in vitro cytotoxicity and radiosensitizing effects in A549 (lung cancer) and U373MG (glioblastoma) cells using a clonogenic assay. A paired ratio t-test was used to test a statistical significance of sensitizer enhancement ratios of the compounds. All 8 PsA derivatives inhibited in vitro cell survival with 50% inhibitory concentrations ranging 16-150 μM (A549) and 15-50 μM (U373MG). MA7, MA9 and MA5M significantly enhanced radiation lethality in A549 cells, while compounds MA2, MA3 and MA7 showed a significant radiosensitization in U373MG cells (p&amp;lt;0.05). MA3 and MA6 marginally radiosensitized A549 and U373MG cells, respectively (p&amp;lt;0.10). For further investigation, we selected MA3 and MA7, because only these two compounds showed radiosensitization in both A549 and U373MG cell lines. A DNMT activity assay showed that MA3 inhibited DNMT1 activity, but that MA7 showed no inhibitory effect on DNMT1. Pharmacokinetic parameters were determined in mice by a validated LC-MS/MS assay method using a non-compartmental analysis. The average degradation half-life of MA3 and MA7 was under 10 minutes in mouse serum. In the present study, we synthesized two novel PsA-derived compounds that enhanced radiation lethality in two human cancer cell lines. However, they lacked chemical stability to allow for in vivo experiments. Based on the present study, a further study is necessary to improve bioavailability of PsA-derived radiosensitizers. [Supported by 2013M2A2A7043683] Citation Format: Jin Ho Kim, Chan Woo Wee, Hak Jae Kim, Soo Youn Suh, Eun Sook Ma, Boom Soo Shin, Il Han Kim. Synthetic novel Psammaplin A derivatives enhance radiation lethality in human cancer cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3057.
Abstract 1057: Bioluminescent assays for investigating cellular energy metabolism
Authors: Donna M. Leippe, Mary Sobol, Mike Valley, Natasha Karassina, Sarah Duellman, Jolanta Vidugiriene, Jim Cali
Journal: Cancer Research (2016)

Abstract Cellular energy metabolism is recognized to have a central role in many cell processes and is an increasingly important area of study in many research fields such as cancer, immunology, obesity, diabetes and neurology. To facilitate these studies, we have taken advantage of key features of bioluminescence, such as increased sensitivity and wide assay windows, to develop assays for measuring energy metabolites. These assays are easy-to-use plate-based assays with streamlined protocols that require minimal cell sample processing. The assays can be used to measure consumption of major fuel sources such as glucose and glutamine from the cell medium, as well as lactate and glutamate secretion. The sensitivity (1-5pmol/sample), broad linear range (0.1-100 uM) and wide dynamic range (maximum signal-to-background &amp;gt; 100 fold) allow all four metabolites to be measured from the same sample of medium and over time, with earlier detection from fewer cells compared to other methods. The assays are also sensitive enough to detect intracellular levels of glutamine, glutamate and lactate and changes in those levels. Additional assays have been developed to measure glucose uptake and NAD/NADH levels in cells. Analysis of these metabolites provides information regarding the energetic state of the cell. In this poster we provide examples demonstrating the utility of these assays to detect a glycolytic shift in cancer cells, monitor cell growth and differentiation with associated changes in glucose uptake and glycolysis, and evaluate insulin sensitivity in primary adipocytes. Citation Format: Donna M. Leippe, Mary Sobol, Mike Valley, Natasha Karassina, Sarah Duellman, Jolanta Vidugiriene, Jim Cali. Bioluminescent assays for investigating cellular energy metabolism. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1057.
Abstract 487: Usefulness of exosome quantification by cholesteryl ester transfer protein activity as a biomarker for human esophageal squamous cell carcinoma (ESCC)
Authors: Yasunori Matsumoto, Masayuki Kano, Yasunori Akutsu, Naoyuki Hanari, Isamu Hoshino, Kentaro Murakami, Akihiro Usui, Hiroshi Suito, Masahiko Takahashi, Ryota Otsuka, Hisahiro Matsubara
Journal: Cancer Research (2016)

Abstract Exosomes are small membrane vesicles (30-100 nm) and are thought to play an important role in tumor progression, chemoresistance, dormancy etc. However, the exosome dynamics and transportation between cancer cells and the other cells are still unclear. In addition, although it is common method to quantify exosomes using standard protein quantification methods, it is actually incorrect. In this study, we assessed the exosome dynamics with mouse model and quantify plasma exosome by cholesteryl ester transfer protein activity, which is known to be enriched within exosomes. We analyzed the relationship between exosome quantification and clinical characters in ESCC patients. In order to image and analyze the movement of cancer cell-derived exosomes, green fluorescent protein (GFP)-tagged CD63, which is a general marker of exosomes, was expressed in human esophageal squamous cancer cell line TE2. Mouse model of human ESCC were then established by s.c. injection of TE2-CD63-GFP or TE2 cell lines. Eight weeks after injection, the tumor, blood and other organs were harvested and imaged with fluorescence. Our data indicates tumor derived exosome can emitted from the tumor and circulate in the blood flow. Quantification of plasma exosome in ESCC patients (n = 64) and no malignant patient (n = 10) were performed by measurement of cholesteryl ester protein activity, and then analyzed the relationship between the exosome number and the patients’ clinical characteristics, such as age, sex, TNM classification, prognosis, tumor marker. Our data indicates the exosome number was higher in ESCC patients than no malignant patients (P = 0.0014). Althogh there were no difference in tumor depth, lymph node status, distant metastasis, the exosome number can be a prognostic marker for ESCC (P = 0.04). Citation Format: Yasunori Matsumoto, Masayuki Kano, Yasunori Akutsu, Naoyuki Hanari, Isamu Hoshino, Kentaro Murakami, Akihiro Usui, Hiroshi Suito, Masahiko Takahashi, Ryota Otsuka, Hisahiro Matsubara. Usefulness of exosome quantification by cholesteryl ester transfer protein activity as a biomarker for human esophageal squamous cell carcinoma (ESCC). [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 487.
Definition of Organ Involvement and Treatment Response in Primary Systemic Amyloidosis (AL): A Consensus Opinion from the 10th International Symposium on Amyloid and Amyloidosis.
Authors: MA Gertz, R Comenzo, RH Falk, JP Fermand, BP Hazenberg, PN Hawkins, G Merlini, P Moreau, P Ronco, [No Value] Sanchorawala, O Sezer, A Solomon, G Grateau
Journal: Blood (2004)
Clinical characteristics and treatment outcome of disease-related peripheral neuropathy in Waldenstrom's macroglobulinemia (WM).
Authors: S. P. Treon, C. A. Hanzis, L. I. Ioakimidis, C. J. Patterson, Z. R. Hunter, P. S. Brodsky, P. S. Sheehy, R. J. Manning
Journal: Journal of Clinical Oncology (2010)

8114 Background: Peripheral neuropathy (PN) is a debilitating morbidity in WM, whose natural history and treatment outcome is largely unknown. Methods: We examined the incidence, characteristics, and treatment outcome of disease related PN in 900 WM patients. Results: 199 (22.1%) patients had disease related PN with a higher incidence in sporadic vs. familial WM (23.5% vs. 15.6%; p=0.02). PN patients had lower serum IgM (p=0.02), B2M (p=0.02), and BM disease burden (p=0.001). Among 122 PN patients evaluated for neuropathic antibodies, 24.5%, 1.64%, and 0.81% were positive for MAG, GM1, and sulfatide antibodies, respectively. Patients with neuropathic antibodies had lower serum IgM (p=0.0002) and BM disease burden (p=0.001) vs. non-PN patients. 13/61 (21.3%) patients examined for amyloid were positive, and only 1 had a neuropathic antibody. The median time to treatment for all PN patients was 9 months. Among non-amyloid related PN patients who received PP or IVIG as their first intervention, 29/42 (69%) and 1/8 (12.5%) reported symptomatic improvement, respectively. 151 PN patients received frontline CTX which consisted of an oral alkylator, nucleoside analogue or rituximab; or rituximab combination with a nucleoside analogue, cyclophosphamide, thalidomide or bortezomib. Of these, 71 (47%) and 8 (5.3%) had improvement or complete resolution of PN following CTX, respectively. Symptomatic improvement was more likely with non-amyloid related PN (48.5% vs. 15.4%; p=0.045); in patients who achieved a major response, i.e. ≥50% reduction in serum IgM (79% vs. 35.5%; p<0.0001); those who received earlier therapy, i.e. ≤24 months (57.3% vs. 42.5%; p=0.06); and those who received rituximab combination vs. any monotherapy (59.3% vs. 37.0%; p=0.007; p=0.06 vs. rituximab alone). Conclusions: PN is a common morbidity, particularly among sporadic WM patients. PP for non-amyloid related PN is an effective interim intervention. Improvements in symptomatic neuropathy occur in half of PN patients following CTX, and are more likely to occur in WM patients with non- amyloid related PN, those who receive earlier therapy, combination therapy with rituximab, and who achieve a major response. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Biogen Idec, Celgene, Genentech, Millennium Biogen Idec, Celgene, Genentech, Millennium Celgene, Millennium
Abstract 1231: Novel chromene analogs as small-molecule microtubule destabilizers for the treatment of chemo-resistant ovarian cancer
Authors: Arpita Kulshrestha, Safaa A. Ibrahim, Gajendra K. Katara, Renukadevi Patil, Shivaputra Patil, Kenneth D. Beaman
Journal: Cancer Research (2016)

Abstract Ovarian cancer is the most lethal gynecological malignancy with a 5-year survival rate of less than 40%, primarily because of treatment failure due to emergence of chemo-resistance to standard agents. This indicates a dire need for new treatments to improve survival rates. The tubulin dynamics is a promising target for new chemotherapeutic agents. In continuation of our efforts, using medicinal chemistry approach, we recently identified small molecular inhibitors of tubulin polymerization called chromenes, as new ovarian anti-cancer agents. A set of chromene compounds were screened for anti-cancer effect on cisplatin sensitive (A2780, SKOV-3, TOV112D) and cisplatin resistant (OVCAR-3, A2780-cisR, TOV112D-cisR) ovarian cancer cells. In vitro cell viability was assessed by fluorescence based Alamar Blue assay. Our preliminary studies identified SP-6-27 (IC50 range: 0.102± 0.006 - 2.24±0.056 μM) and SP-6-37 (IC50 range: 0.258± 0.159 - 3.61±0.049 μM) as most potent chromene analogs. Both compounds exhibited a potent anticancer activity towards both cisplatin sensitive (SP-6-27 IC50: 0.14± 0.03 μM; SP-6-37 IC50: 1.35± 0.88 μM) and cisplatin resistant (SP-6-27 IC50: 0.81± 1.2 μM; SP-6-37 IC50: 2.09± 1.7 μM) cell lines. The compounds exhibited least cytotoxicity towards normal ovarian epithelial cells (SP-6-27- IC50: 83.35 ± 9.47 μM; SP-6-37- IC50: 75.77 ± 5.37 μM). Additionally, the analysis of apoptotic changes as determined by Annexin-V assay revealed an enhanced apoptosis in both cisplatin sensitive and resistant cells upon treatment with compounds SP-6-27 or SP-6-37. Together, the data demonstrates that ovarian cancer cell lines respond sensitively to SP-6-27 and SP-6-37, demonstrating that the chromene scaffold is effective in suppressing ovarian cancer cell growth. The findings indicate that the novel chromene analogs are a new class of chemotherapeutic agents that will offer advantages for the treatment of ovarian cancer. Citation Format: Arpita Kulshrestha, Safaa A. Ibrahim, Gajendra K. Katara, Renukadevi Patil, Shivaputra Patil, Kenneth D. Beaman. Novel chromene analogs as small-molecule microtubule destabilizers for the treatment of chemo-resistant ovarian cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1231.