tbuckley/cabot-search huggingface dataset:
Preclinical activity of the JAK1/2 inhibitor ruxolitinib on malignant plasma cell growth and survival.
Authors: Renate Burger, Tim Bugdahn, Matthias Staudinger, Matthias Peipp, Andreas Günther, Martin Gramatzki
Journal: Journal of Clinical Oncology (2012)

e18565 Background: In multiple myeloma, cytokines in the tumor environment, in particular interleukin-6 (IL-6), support the growth and survival of malignant plasma cells. Binding of IL-6 to its receptor leads to gp130 dimerization and activation of JAKs and STAT3. Ruxolitinib (INC424)is the first small molecule JAK inhibitor approved for the treatment of patients with myelofibrosis. The aim of our study was to evaluate the effects of ruxolitinib on malignant plasma cells. Methods: Cell growth was studied in seven myeloma cell lines including the IL-6 dependent INA-6. Ruxolitinib was tested at 0.0625 µmol/L to 8 µmol/L. Proliferation of plasma cell enriched patient samples was measured by [3]H-thymidine uptake, apoptosis by flow cytometry upon annexin V/7-AAD staining. Levels of STAT3 and ERK1/2 phosphorylation were determined by Westernblot analysis. IC50 concentrations and combination index were calculated with CalcuSyn. IL-6 levels were determined by ELISA. Results: A significant inhibition of plasma cell growth with ruxolitinib was achieved in IL-6 dependent INA-6 cells (IC50 0.22 µmol/L). Complete growth inhibition at 1 µmol/L was seen in the absence and presence of bone marrow stromal cells. Stromal cell viability and IL-6 production were not affected. The number of apoptotic INA-6 cells upon treatment with ruxolitinib at 1 µmol/L increased 3.6- and 7.2-fold (after 48 and 72 hours, respectively), consistent with the reduction of IL-6 induced STAT3 phosphorylation. A similar strong inhibitory activity of ruxolitinib (IC50 0.16 µmol/L) was observed in tumor cells of a patient with plasma cell leukemia proliferating in response to IL-6. In contrast, none of the myeloma cell lines that grow autonomously were sensitive, pointing to the kinase specificity of the drug. Using INA-6 as a model, combinations with other signaling inhibitors revealed additive to synergistic effects with PI3K, mToR and IGF-1R inhibitors. Conclusions: In multiple myeloma, ruxolitinib has a strong cytotoxic activity against malignant plasma cells that require IL-6 for growth and survival. This warrants further clinical testing but also points to the need of identifying molecular markers to predict benefit from JAK inhibitor treatment.
Genetic modification of T cells with a novel bispecific chimeric antigen receptor to enhance the control of high-grade glioma (HGG).
Authors: Meenakshi Hegde, Amanda Wakefield, Vita S Brawley, Zakaria Grada, Tiara T Byrd, Kevin K Chow, Simone S Krebs, Helen E Heslop, Stephen M Gottschalk, Eric Yvon, Nabil Ahmed
Journal: Journal of Clinical Oncology (2014)

10027 Background: Highly targeted immunotherapy with adoptively transferred chimeric antigen receptor (CAR) T cells has shown considerable efficacy against some refractory childhood malignancies. Downregulation/mutation of targeted antigen can however create antigen loss escape variants. Multispecific T-cell approach could therefore further improve their therapeutic efficacy. Methods: We created a novel bispecific CAR that incorporates two extracellular antigen-recognition domains; one for HER2 (from HER2 monoclonal antibody FRP5) and the other for IL-13Rα2 (a mutated IL-13 molecule), in tandem (TanCAR). TanCAR was rationally designed by in silico modeling. Intracellular domain consists of a CD28/zeta-signaling chain. TanCAR encoding DNA was then synthesized and force expressed on T cells using retroviral system. Surface expression of extracellular domain of the TanCAR in its entirety was confirmed using HER2/IL-13Rα2 specific methods on flowcytometry. Functionality of TanCAR T cells was evaluated using standard immunoassays. Orthotopic murine model of HGG was used for in vivoexperiments. Results: 50-80% of T cells expressed the TanCAR on cell surface. In cytotoxicity assays, bispecific TanCAR T cells showed improved killing of IL-13Rα2 and HER2 positive HGG cell lines and autologous HGG cells over the control T cells from the same donor. Though TanCAR T cells were effectively activated and secreted immunostimulatory cytokines on recognizing HER2 and IL-13Rα2 proteins individually, cytokine secretion was significantly higher on simultnaeous exposure to both target antigens. Adoptively transferred TanCAR T cells induced regression of established HGG xenografts. Conclusions: TanCAR T cells can distinctly target HER2 or IL-13Rα2 individually as well as both antigens simultaneously.TanCAR T cells exhibit enhanced effector functionality in vitro and anti-tumor activity in vivo, demonstrating their potential for therapeutic application. Targeting the heterogeneity in HGG with such a multi-specific T-cell approach could potentially achieve near complete targeting of tumor subpopulations and reduce the risk of recurrence.
Clinical pharmacologic considerations for the phase II/III dose/regimen of the investigational Aurora A kinase (AAK) inhibitor MLN8237 (alisertib): Pharmacokinetics (PK), pharmacodynamics (PD), and exposure-safety relationships.
Authors: Karthik Venkatakrishnan, Xiaofei Zhou, Jeffrey Ecsedy, Hadi Danaee, Hugh Xiao, Hongliang Shi, Diane R. Mould, Howard Fingert, Ely Benaim, Robert Kleinfield, Ashley Milton
Journal: Journal of Clinical Oncology (2012)

2597 Background: MLN8237, an oral selective AAK inhibitor, is primarily metabolized by multiple glucuronidation enzymes including the polymorphic UGT1A1. Phase 1 studies included comprehensive PK and PD sampling. We report integrated PK, PD, and PK-safety analyses in support of dose/regimen selection for phase 2/3 studies. Methods: Phase 1 studies in adults with advanced cancers evaluated dosing on d 1-7 in 21-d cycles or d 1-21 in 35-d cycles. Data from 294 patients in 4 phase 1 and 2 phase 2 studies contributed to population PK modeling. PD endpoints included mitotic index (MI) in skin and chromosome alignment and spindle bipolarity (CA/SB) in mitotic tumor cells. Logistic regression analyses evaluated relationships between MLN8237 PK parameters and DLTs (N=86) or CNS adverse events (AEs; n=134) in 2 phase 1 studies. Results: MLN8237 displayed dose-linear PK (5-200 mg/d), described by a 2-compartment model with first order absorption. Covariate analyses did not reveal significant effects of age, body size, sex, UGT1A1 genotype, or creatinine clearance (≥30 mL/min). Exposure-related increases in skin MI and decreases in CA/SB in tumor mitotic cells confirmed AAK inhibition by MLN8237. At the MTD of 50 mg BID (d 1-7 dosing) geometric mean steady-state exposures (48,200 nM.hr) were comparable to those associated with ≥50% CA/SB reductions in mitotic tumor cells (57,300 nM.hr). Exposures at the 21-d MTD (QD dosing) were lower, favoring 50 mg BID (d 1-7 dosing) for further development. At 50 mg BID (d 1-7 dosing) logistic regression relating MLN8237 AUC to DLT rate estimated a DLT probability of 8% (95% CI 3-20%). Similar analyses identified C max rather than AUC as the predictor of CNS AEs, supporting BID dosing in adults to reduce peak concentrations while preserving total systemic exposure. Conclusions: MLN8237 exhibits dose-linear PK independent of age, body size, mild or moderate renal impairment, or UGT1A1*28 polymorphism. Exposures achieved at or near 50 mg BID are expected to result in tumor AAK inhibition, supporting a pharmacologically active dose range for future clinical development.
CD30 positive anaplastic large cell lymphoma mimicking Langerhans cell histiocytosis
Authors: Navid Ezra, Gregory Van Dyke, Scott Binder
Journal: Clinical Cancer Research (2008)

B42  Cutaneous T-cell lymphomas (CTCL) are uncommon and complex malignancies that constitute a rare subset of non-Hodgkin’s lymphomas of T-cell origin. CTCLs are a diverse group of disorders that display a wide range of clinical and histopathological presentations primarily involving the skin. A less common cutaneous T-cell lymphoma variant is CD30+ anaplastic large cell lymphoma (ALCL). We report on a 56-year-old female with a clinical and histopathological presentation consistent with a histiocytosis and immunohistochemistry suggestive of anaplastic large cell lymphoma. The constellation of histologic and immunologic features favored a CD30 lymphoproliferative disorder of T-cell lineage even though there were accompanying numerous dendritic histiocytes and Langerhans cells. Although there was a large number of CD1a positive Langerhans cells and dendritic cells present, the sheets of CD30 positive atypical lymphoid cells which express T-cell markers was consistent with CD30 positive lymphoproliferative disease and favors CD30 positive Anaplastic Large Cell Lymphoma (ALCL) over Langerhans histiocytosis. The absence of ALK staining favored a primary cutaneous origin. This case signifies a CD30+ anaplastic large cell lymphoma of the skin which clinically and histopathologically mimics a Langerhans Cell Histiocytosis (LCH).
Defining a nine-biomarker panel for predicting bladder cancer outcome in combination with smoking intensity: A report from the Los Angeles Cancer Surveillance Program.
Authors: Anirban Pradip Mitra, Jose E Castelao, Debra Hawes, Denice D Tsao-Wei, Xuejuan Jiang, Shan Rong Shi, Lillian L Young, Ram H Datar, Eila C Skinner, John Peter Stein, Susan G. Groshen, Mimi C Yu, Ronald K Ross, Donald G Skinner, Victoria K Cortessis, Richard J Cote
Journal: Journal of Clinical Oncology (2012)

4575 Background: Urothelial carcinoma of the bladder (UCB) is a disease of alterations in several cellular pathways. Routine molecular profiling studies do not account for smoking, a well established risk factor for UCB, and its influence on outcome. This study assessed the prognostic potential of a multi-pathway protein panel across all UCB stages in a population-based cohort after accounting for clinicopathologic factors and smoking history. Methods: 212 UCB patients from the LA CSP, part of the NCI/SEER cancer registry, were included. "Smoking intensity" analyzed biologic and molecular impact of smoking by combining smoking status, duration of smoking and number of cigarettes smoked daily into a composite covariate. Tumors were profiled for Bax, caspase-3, Apaf-1, Bcl-2, p53, p21, COX2, VEGF and E-cadherin alterations by IHC. Univariate analyses and multivariable modeling examined associations with outcome. Results: Median follow up was 13.2 years. Age, pathologic stage, adjuvant therapy (all p&lt; 0.001) and surgical modality (p = 0.05) were associated with survival. Increasing smoking intensity was associated with worse outcome (P &lt; 0.001). Apaf-1 (p = 0.005), E-cadherin (p = 0.014) and p53 (p = 0.032) were univariately prognostic; E-cadherin remained prognostic after multivariate analysis (p = 0.04). Combined alterations in all 9 biomarkers were prognostic by univariate (p &lt; 0.001) and multivariate (p = 0.006) analysis. A multivariate model that included all 9 biomarkers and smoking intensity was more accurate in predicting prognosis than models comprising of standard clinicopathologic covariates without (p &lt; 0.001) or with (p = 0.018) smoking intensity. Conclusions: The study confirms detrimental effects of smoking on UCB prognosis. Apaf-1, E-cadherin and p53 individually predicted UCB survival. Increasing number of biomarker alterations was significantly associated with worsening survival, although markers contained in the panel were not necessarily prognostic individually. Predictive value of the nine-biomarker panel with smoking intensity was significantly higher than that of routine clinicopathologic parameters alone.
Multicentric Reticulohistiocytosis Mimicking Malignancy on 18F-FDG PET/CT
Authors: Masatoshi Hotta, Ryogo Minamimoto, Daisuke Suzuki, Atsuko Takahashi
Journal: Clinical Nuclear Medicine (2017)

We report the case of a 75-year-old woman who underwent F-FDG PET/CT to evaluate the recurrence of urothelial carcinoma. PET/CT showed F-FDG-avid muscles and lymph nodes, mimicking recurrence. However, F-FDG uptake was also seen in multiple joints and subcutaneous tissue, representing an uncommon finding for recurrence. Further history taking revealed she had been pathologically diagnosed with multicentric reticulohistiocytosis (MRH) from skin biopsy, and the F-FDG PET/CT findings were consistent with MRH, a rare systemic inflammatory granulomatous disease of unknown etiology. Knowledge of the characteristic F-FDG PET/CT features of MRH is important to differentiate MRH from malignancy.
Randomized, double-blind, and multicenter phase II trial of rh-endostatin plus dacarbazine versus dacarbazine alone as first-line therapy for the patients with advanced melanoma.
Authors: Jun Guo, Chuan Liang Cui, Kangsheng GU, Min Tao, Song Xin, Tongyu Lin, Xiu Bao Ren, Shukui Qin
Journal: Journal of Clinical Oncology (2012)

8554 Background: rh-endostatin (Endostar , water-soluble, rES) is an inhibitor of angiogenesis, which is effective as single agent or in combination with chemotherapy for non-small cell lung cancer in phase I/II clinical trials. This study (NCT00813449) was a randomized, double-blind and placebo-controlled phase II trial, aimed to observe the efficacy and safety of rES with dacarbazine (DTIC) as the 1st line therapy for patients (pts) with advanced melanoma. Methods: Untreated pts with ECOG 0/1 and unresectable stage IIIC or IV melanoma (confirmed by histopathology) were enrolled, and randomized (1:1) into Arm A (DTIC 250 mg/m 2 d 1-5 + placebo d 1-14 ) or Arm B (DTIC 250 mg/m 2 d 1-5 + rES 7.5 mg/m 2 d 1-14 ). Treatment was continued in 21-day cycle until progression or intolerable toxicity occurs. Primary endpoints were progression free survival (PFS) and overall survival (OS). Secondary endpoints included objective response rate (ORR) and safety, evaluated every 2 cycles. Results: From Dec. 2008, 120 pts were enrolled and 110 pts evaluable. 30.9% of them were in M1a, 39.1% in M1b, and 29.1% in M1c. Mean treatment cycles were 3.2 (range: 1-10) in Arm A and 4.0 (range: 1-12) in Arm B. Until the last follow-up in Nov. 2011, 27 pts were still alive. The median PFS was 1.5 months (95% CI: 1.35-1.65) in Arm A and 5.0 months in Arm B (95% CI: 2.45-7.55, P=0.004, log-rank test). The median OS was 7.0 months in Arm A (95% CI: 4.41-9.59) versus 16.0 months in Arm B (95% CI: 10.46-21.54, P=0.003, Breslow test). 1-year survival rate was 22.2% versus 51.0%, and 2-year survival rate 8.9% vs.10.2%. No statistical significance was found for both ORR and toxicities. The most common toxicities were increased transaminase (28.9% in Arm A versus 56.1% in Arm B) and leucopenia (14.4% versus 13.4%). The incidence of grade 3-4 toxicity (increased transaminase and thrombocytopenia) was only 1.7% in Arm B. Conclusions: rES plus DTIC may obviously improve mPFS and mOS versus DTIC alone as the 1st line therapy for advanced melanoma. That combining therapy was well tolerated and could be recommended as a new, safe and effective regimen for untreated pts with advanced melanoma.
NHS transformation: radicalism needs realism
Authors: Nigel Edwards
Journal: BMJ (2017)

Wishful thinking may undermine NHS initiatives to do more with less



The NHS across the UK faces an intractable set of problems that is all too obvious to those on the health service front line. After years of rising demand for services but flat healthcare funding, we seem to be nearing a point where it is no longer possible to meet the public’s expectations with the money, staff, and beds available. The main response has been to look to ways to change how services work, shifting the balance away from costly and intensive care provided in hospitals. The hope is that providing care earlier, in or near people’s homes, offers a way to do more with less.

The goals are highly ambitious. In England, the local sustainability and transformation plans (STPs) aim to reduce forecast activity by up to 30% …
A phase II study of pazopanib in recurrent or persistent ovarian (EOC), peritoneal (PPC), or Fallopian tube cancer (FTC): A Spanish Ovarian Cancer Group (GEICO) study.
Authors: Ana Oaknin, Antonio Gonzalez-Martin, Yolanda García, Silvia Catot, Cristina Caballero, Jesus Garcia-Donas, Isabel Bover, Ana Santaballa, Eva Guerra, Beatriz Pardo, Laura Vidal, Raul Marquez, Victor Rodriguez-Freixinos, Ignacio Romero, Andres Poveda
Journal: Journal of Clinical Oncology (2012)

5068 Background: Pazopanib (P) is a potent and selective multi-targeted receptor tyrosine kinase inhibitor of VEGFR-1, VEGFR-2, VEGFR-3, PDGFR-a/β, and c-kit that inhibits angiogenesis. Signaling blockade of these pathways is associated with anti-tumor and anti- angiogenesis activity. Methods: Eligible patients (pts) had persistent or recurrent EOC/PPC /FTC up to 2 prior cytotoxic regimens. They had to have received at least a platinum–based line and fulfill platinum resistant criteria. Treatment consisted of P 800 mg orally QD until disease progression or prohibitive toxicity. The primary endpoint was Clinical Benefit Rate (CBR) defined as Complete Response (CR) plus Partial Response (PR) plus Stable Disease (SD) ≥ 8 weeks by RECIST v1.1.An optimal two-stage Simon design was utilized with H1and H0set at 60%and 40% respectively; Power =90% significance level of 5% (Stage 1: = 25pts; total=66). Correlative studies to identify angiogenic biomarkers to predict response to P were performed. Results: From 12/10 to 7/11, 25 pts were enrolled, 21 pts had EOC, 2PPT, and 2FTC. Median age: 64 years (range 43-81), ECOG 0/1/2:12/11/2 pts. Prior chemotherapy regimens 1/2:10/15 pts. Median weeks on treatment: 8 (range 4-25). Most frequent adverse events (AEs) were asthenia (56%), hypertension (36%) and diarrhea, nausea and anorexia (20% each).Grade 3 toxicities: Hypertension (6pts), ALT/AST elevations (3 pts), asthenia (2 pts), DVT (1pt), Fistula (1 pt), Anemia (1 pt). Six pts required dose reduction to 600 mg due to toxicity.Reasons for stopping study treatment: PD (18pts), AEs (3pts) and investigator decision (2pts). First stage analysis showed: PR:1/25, SD: 9/25, CBR:10/25; 40% (95% CI 21.1%-61.3%).No correlation between GCIG CA-125 response and RECIST criteria was established, 8 versus 1 response respectively. Median PFS was 1.83 months (95% CI 1.67-2). Conclusions: The CBR observed at the first stage did not reach the planned statistical hypothesis (CBR:12 pts). Therefore, the lack of activity of P in platinum resistant EOC/PPT/FT led to discontinuation of the study. Translational study results will be presented in an additional abstract.
Factors affecting the administration of adjuvant therapy in patients with pancreatic adenocarcinoma.
Authors: Pablo Emilio Serrano Aybar, Peter Tae Wan Kim, Kenneth Leung, Sean P. Cleary, Steven Gallinger, Paul David Greig, Carol-anne Moulton, Alice Chia-chi Wei
Journal: Journal of Clinical Oncology (2013)

e15087 Background: Adjuvant therapy for pancreatic adenocarcinoma is now considered standard of care. The proportion of patients receiving adjuvant therapy (ADT) following pancreatic resection is a good quality indicator of cancer care. The aim of this study was to evaluate factors associated with receiving ADT in patients with pancreatic cancer. Methods: Between years 2000-2010, all patients undergoing pancreaticoduodenectomy for pancreatic adenocarcinoma at a single high-volume hepatotopancreatobiliary center were evaluated. The impact of demographic, peri-operative and pathological risk factors affecting the administration of ADT were analyzed using univariate and multivariate logistic regression analysis. Results: There were 258 patients identified. Median age was 65 (37-84) years, 54% were females. There was a 15% margin positivity rate, 14% pancreatic leak rate, 14.7% major complication rate, and 1.2% 90 day/in-hospital mortality rate. Overall, 160/258 (70%) of patients received adjuvant therapy. On multivariate analysis; age, presence of major complications, node-negative disease and earlier era (2000-2004) were significantly associated with a lower probability of receiving ADT. Reasons for not receiving ADT were; patient preference: 20/67 (32%), not recommended: 14/67 (23%), disease recurrence: 12/67 (9.5%) and being medically unfit for ADT: 18/67 (11.5%). None of these reasons were different between time-periods except for fewer patients being offered ADT from 2000-2005 (15.4% vs. 2.5%, p &lt;0.001). Conclusions: Thirty percent of patients do not receive ADT following pancreatectomy. Those with advanced age; node-negative disease and those who had major complications after pancreaticoduodenectomy were less likely to receive ADT. The impact of these factors should be taken into account when considering the administration of ADT.
Cost-effectiveness analysis of proton versus photon therapy with respect to risk of growth hormone deficiency.
Authors: Raymond Mailhot, Jane Kim, Abby Hollander, Jeff M. Michalski, Nancy Tarbell, Torunn I. Yock, Shannon M. MacDonald
Journal: Journal of Clinical Oncology (2013)

e17553 Background: Proton therapy has been endorsed as a radiotherapy (RT) modality with the potential to avert many RT associated comorbidities. Currently, few proton centers exist, and no evidence-based data as yet adequately informs allotment of care. Childhood cancer survivors of central nervous system (CNS) malignancies have high prevalences of growth hormone deficiency (GHD) after hypothalamic exposure, notable for its cost of treatment greater than $10,000/year. We propose methodology to help guide proton referral of pediatric patients with CNS tumors through cost-effective analysis comparisons for proton and photon hypothalamic received dose. Methods: A Markov cohort model was designed to assess the expected costs and effectiveness for specific RT doses to the hypothalamus. Patients entered the model receiving proton or photon RT for CNS tumors at four and twelve years of age and were followed for 60 more years of life. Patients could experience two health states: GHD or healthy. Risk of GHD was based on data by Merchant et al. Costs were measured in USD and captured cost of GHD and cost of RT. Cost of proton course relative to photon was estimated at $160K. Effectiveness was measured in quality-adjusted life years (QALYs). The main outcome measure used for comparison was the incremental cost-effectiveness ratio (ICER). We assumed a societal willingness to pay threshold of $50,000/QALY. Results: Data were used to generate tables incorporating the differential cost of proton RT to project ICERs for different combinations of hypothalamic RT dose as displayed in the Table below. Conclusions: Despite the high cost of proton therapy, the cost of GHD alone can yield proton RT a cost-effective (even cost-minimizing) strategy when compared to photon RT. This work provides a guide for identifying a set of patients for which proton therapy is particularly cost-effective. [Table: see text]