tbuckley/cabot-search huggingface dataset:
Concomitant blockade of EGFR and MEK overcomes acquired resistance to anti-EGFR therapy in colorectal cancer cells and patients’ avatars.
Authors: Alberto Bardelli, Sandra Misale, Sabrina Arena, Giulia Siravegna, Simona Lamba, Katia Bencardino, Alessio Amatu, Emanuele Valtorta, Calogero Lauricella, Andrea Sartore-Bianchi, Federica Di Nicolantonio, Salvatore Siena
Journal: Journal of Clinical Oncology (2014)

2626 Background: The anti-EGFR antibodies cetuximab and panitumumab are approved for the treatment of RAS wild-type colorectal cancer (CRC) patients. The clinical efficacy of EGFR targeted antibodies is limited by the development of acquired (secondary) resistance. Here we investigated the molecular bases of relapse to anti-EGFR blockade in CRC cells and patients' samples and use xenotransplants to define a clinically applicable strategy to overcome acquired resistance. Methods: Molecular profiling of circulating tumor DNA was used to identify the emergence of mutations in plasma samples of patients who relapsed after anti EGFR therapies. Xenografted tumors (avatars) from patients who relapsed after EGFR blockade were established and exploited to assess the efficacy of drugs aimed at bypassing acquired resistance. Results: Emergence of concomitant mutations in KRAS and NRAS was detected in samples from 5 CRC patients who developed resistance to anti-EGFR antibodies. Acquired resistance to cetuximab and panitumumab was modeled in 4 CRC cell models. Resistant cells were a mixture of clones bearing alterations in KRAS, NRAS and BRAF thus closely recapitulating the patients’ findings. Pathway analyses revealed that, although genetically polyclonal, resistant cells consistently displayed MEK and ERK activation but, surprisingly, were refractory to MEK inhibition. However, the resistant derivatives were sensitive to the concomitant inhibition of MEK and EGFR independently from their genetic status. Mouse xeno-transplants of lung and liver biopsies from two CRC patients who responded and subsequently relapsed upon EGFR therapy showed exquisite sensitivity to combinatorial treatment with the MEK inhibitor pimasertib and EGFR blockade with cetuximab. Conclusions: These observations provide a rational strategy to overcome the clonal heterogeneity that emerges when CRCs are treated with anti EGFR antibodies. We propose that MEK inhibitors, in combination with cetuximab or panitumumab, should be evaluated in CRC patients who become refractory to anti-EGFR therapies. A clinical trial (ARES) has been initiated to test this hypothesis.
Cabazitaxel after Docetaxel in patients with metastatic, castration-resistant, prostate cancer (mCRPC): A prospective, observational study about toxicity profile and quality of life.
Authors: Giovanni Mansueto, Michele De Tursi, Raffaele Ratta, Maria Agnese Fabbri, Silvia Quadrini, Nello Salesi, Antonio Rozzi, Isabella Sperduti, Fabrizio Ciancola, Teresa Gamucci
Journal: Journal of Clinical Oncology (2015)

e16054 Background: in the TROPIC trial, cabazitaxel+prednisone(CbzP) improved survival vs Mitox+P in patients(pts) with mCRPC who progressed on or after docetaxel(D). Few data are available in the real world about toxicity and quality of life(QoL) impact of Cbz Methods: we evaluated safety, QoL and symptoms improvement during CbzP in 52 consecutive patients with mCRPC. They received Cbz(25 mg/m2 Q3W)+P(10 mg/day) as 2nd(n = 39) or 3rd(n = 13) line after D until progression or unacceptable toxicity. ESAS was administered at each cycle-day one. Improvement of ESAS items has been identified as “early”(at 2ndcycle) and “best”(best score during treatment) Results: 52 pts are evaluable for safety and efficacy, 35 pts for QoL. Median age is 70,4 y(range 53–88). At baseline, 25/52 pts(48%) had cardiovascular/metabolic comorbidity, 8% visceral metastasis, 38% ≥ 2 metastatic sites. A median of 6.78 cycles of CbzP were administered per pt; 11 pts(21.5%) received ≥ 10 cycles. Three pts required a dose reduction due to adverse events(AEs). Overall, 53% of pts(n = 27) had at least one, all grade, AE. Grade 3–4 AEs: neutropenia 23.5%(2% febrile), anemia 7.8%, fatigue 2% with no treatment-related death reported. Median number of ESAS administered per pt was 6.0. QoL results: overall median ESAS “early” improvement was 18%(range 6-65%) in 45.7% of pts; median “best” improvement was 38%(range 3-100%) in 65.7% of pts. Pain “early” improvement was seen in 54.3% of pts, “best” in 74.3%. Asthenia “early” improvement in 28.6% of pts, “best” in 57.1%. Wilcoxon test for overall ESAS score was 0.62 for “early” and 0.0001 for “best” period. Benefit on pain was statistically significant both in the “early”(p = 0.01) and in the “best”(p = 0.0001) phase. With a median follow-up of 10 months(mos), median PFS was 5 mos(CI95% 2-8) and median OS was18 mos(CI95% 10-32) Conclusions: our study provide additional safety and QoL data for CbzP in a real-life group of pts with mCRPC. Toxicity was mild and manageable. Pain relief appears early during treatment. Conversely, overall ESAS improvement became significant only after 2nd cycle, probably due to a more slow benefit on different items
Preliminary efficacy, safety, pharmacokinetics, pharmacodynamics, and quality of life study of pegylated recombinant human arginase 1 in patients with advanced hepatocellular carcinoma.
Authors: Thomas Cheung Yau, Paul Ning-Man Cheng, Pierre Chan, Roberta Pang, Ronnie Tung Ping Poon
Journal: Journal of Clinical Oncology (2014)

e15137 Background: This study was designed to evaluate the efficacy, safety profile, pharmacokinetics/pharmacodynamics (PK/PD) and quality of life (QoL) of pegylated recombinant human arginase 1(Peg-rhAgr1) in patients with advanced hepatocellular carcinoma (HCC). Methods: Advanced HCC patients were given weekly doses of Peg-rhAgr1 (1600 U/kg). Tumour response was assessed every 8 weeks using RECIST 1.1 and modified RECIST criteria. Results: A total of 20 patients were recruited, of whom 15 were deemed evaluable for treatment efficacy. Eighteen patients (90%) were hepatitis-B carriers. Median age was 61.5 (range 30-75). Overall DCR was 13%, with 2 of the 15 patients achieving stable disease for >8 weeks. Median progression-free survival (PFS) was 1.7 (95% CI: 1.67-1.73) months, with a median overall survival (OS) of all 20 enrolled patients being 5.2 (95% CI: 3.3-12.0) months. PFS was significantly prolonged in patients with adequate arginine depletion (ADD) over >2 months versus those who had ≤2 months of ADD (6.4 versus 1.7 months; p=0.01). The majority of adverse events (AEs) were grade 1 and 2 non-hematological toxicities. Transient liver dysfunctions (25%) were the most commonly reported serious AEs and likely due to disease progression. Pharmacokinetic and pharmacodynamic data show that Peg-rhAgr1 induced rapid and sustained arginine depletion. The overall quality of life of the enrolled patients was well preserved. Conclusions: Peg-rhAgr1 is well tolerated with a good toxicity profile in patients with advanced HCC. A weekly dose of 1600U/kg is sufficient to induce ADD. Significantly longer PFS times were recorded for patients who had ADD for >2 months. Clinical trial information: NCT01092091.
A comparison of survival by site of metastatic resection (MR) in metastatic colorectal cancer (mCRC).
Authors: Brandon David Bernard, Gillian Gresham, Leo Chen, Caroline Speers, Winson Y. Cheung, Hagen F. Kennecke, Howard John Lim, Daniel John Renouf
Journal: Journal of Clinical Oncology (2014)

3529 Background: MR of liver limited disease is an effective therapy for patients (pts) with mCRC. Despite limited data, this approach has been expanded to include MR in other sites. We compared survival for mCRC pts undergoing MR of liver metastasis vs MR in other sites. Methods: Pts with mCRC who underwent MR in British Columbia over 5 time cohorts between 1995 and 2010 were reviewed. Pts without data on the site of MR or survival were excluded. Overall survival (OS) was defined as the time from diagnosis of metastasis to death. Kaplan Meier methodology and log-rank tests were used to compare the impact of site of MR on OS. Multivariate Cox regression was performed to assess for the impact of MR on OS, adjusting for known prognostic factors. Results: 2,082 pts with mCRC were identified; 1,197 men (57.5%) and 885 women (42.5%); 236 (1995-96), 206 (2000), 351 (2003-4), 546 (2006), 743 (2009-10). Median age at diagnosis of mCRC was 69 (14-94). 544 pts (30.0%) received a MR: 207 liver (38.1%), 57 lung (10.5%), 11 liver and lung (2.0%), 98 peritoneal (18.0%), 50 ovarian (9.2%), 34 brain (6.3%) and 87 other (16.0%). Pts that did not undergo MR had an OS of 13.4 months (ms) vs 41.8 ms for those that had MR of liver, lung or ovary (HR 0.31 (0.27-0.36); p<0.0001). By MR subgroup, OS was 46.2 ms for liver, 43.0 for lung, 41.2 for liver and lung, 13.4 for peritoneum, 21.8 for ovary, and 15.8 for brain. When compared to MR of liver, no significant difference in OS was observed for MR in lung (p=0.61) or liver and lung (p=0.26). Multivariate OS data are shown in the Table. Conclusions: MR of lung and liver and lung appears to confer a comparable survival advantage to MR of liver limited disease. Additional investigation is needed to further select pts most likely to benefit from MR. Multivariate analysis for OS HR p-value MR (liver, lung, or ovar)y 0.36 (0.31-0.42) <0.0001 Age (< 65 vs ≥ 65) 0.89 (0.63-1.27) 0.54 Sex (M vs F) 1.03 (0.94-1.13) 0.51 Primary (colon vs rectum) 1.11 (1.00-1.20) 0.03 M1 at presentation (N vs Y) 0.85 (0.77-0.95) 0.0016 ChemoTx (Y vs N) 0.48 (0.24-0.82) 0.009 Primary resection (Y vs N) 0.57 (0.49-0.65) <0.0001 2000 vs 1995-96 1.40 (1.10-1.60) 0.0012 2003-4 vs 1995-96 1.30 (1.10-1.60) 0.005 2006 vs 1995-96 1.30 (1.10-1.60) 0.0006 2009-10 vs 1995-96 1.40 (1.20-1.60) 0.0001
Review: Palliative care improves quality of life and symptom burden but does not affect mortality at 1 to 3 months
Authors: Patricia F. Harris
Journal: Annals of Internal Medicine (2017)

Source Citation Kavalieratos D, Corbelli J, Zhang D, et al. Association between palliative care and patient and caregiver outcomes: a systematic review and meta-analysis. JAMA. 2016;316:2104-14. 27893131
Histological and molecular phenotype changes of castration-resistant prostate cancer and acquired resistance to hormonal therapy.
Authors: HaiTao Wang, Jiao Zhang, Shiqin Wei
Journal: Journal of Clinical Oncology (2015)

e16006 Background: Castration-resistant prostate cancer (CRPC) remains a major clinical challenge. To date, the mechanisms responsible for histological evolution and subsequent acquired drug resistant clinical behavior in prostate cancer remain poorly elucidated. Methods: Biopsies of paired castration-sensitive and castration-resistant tumors were obtained from 30 prostate cancer patients. DNA was extracted from all tumor and corresponding normal tissue samples and underwent whole exome sequencing using the Illumina HiSeq2500. Histology was confirmed by H&E staining, and immunohistochemical staining for AR, Ki-67, CD56, Syn, P53, AURKA, N-myc, RB, E-cadherin, vimentin were performed on both the castration sensitive and castration resistant samples to be suggestive of subtyping progressive diseases. Results: The histological and molecular phenotype changes of CRPC shows high between-tumor heterogeneity. CRPC specimens harbored recurrent gene alterations including AR amplification, P53 mutation, PTEN loss, MYCN amplification, RB loss, PIK3CA mutation, PLK1 mutation, etc. According to histological and molecular phenotype change, we propose the following CRPC subtyping: 1) AR-dependent adenocarcinoma (60%,18/30); 2) AR-negative adenocarcinoma (13.3%, 4/30); 3) transformed neuroendocrine carcinoma (6.7%, 2/30); 4) Others, including adenocarcinoma with EMT transformation (10%, 3/30) and with neuroendocrine differentiation(10%, 3/30). The “one size fits all” model should no longer be used in CRPC and therapy should be tailored to individual patients according to patient and tumor characteristics, as well as molecular subtypes and targets. Conclusions: The histological and molecular phenotype changes of CRPC shows high between-tumor heterogeneity. There is evidence of an increase in Ki67, p53 mutation, PTEN loss, MYCN amplification, PLK1 mutation in some individuals that may explain resistance in individuals and merit treatment targeted to those pathways. Biopsy at progressive disease will be necessary to identify the relevant target for individuals.
Cognitive dysfunction, brain-derived neurotrophic factor and IL-6 levels in cancer patients with depression
Authors: C. F. Jehn, B. Becker, S. Pfeiffer, M. Krebs, K. Possinger, B. Flath, A. Dieing
Journal: Journal of Clinical Oncology (2006)

8632 Background: Increased proinflammatory cytokines (IL-6) and decreased brain-derived neurotrophic factor (BDNF) levels have been implicated in the pathophysiology of depression. Depression has been shown to be associated with cognitive dysfunction. The objective of this study was to assess the correlations between cognitive dysfunction, IL-6 and BDNF in cancer patients (pts) with depression. Methods: Depression was assessed in 55 patients with metastatic cancer by the Hospital Anxiety and Depression Scale (HADS) and diagnosis was established according to DSM-IV criteria. Cognitive function was assessed by the Auditory Verbal Learning Test (AVLT). Plasma concentrations of Interleukin-6 and BDNF were measured at 8 AM the same day. In the statistical analysis the Mann-Whitney test and the Pearson correlation were applied. Results: Pts characteristics (n=55): median age 60 y (25–85); 76.9% Females, 23.1% males. 52% of pts had depression. There were no significant differences in mean age or Karnofsky-index between pts with and without depression. Depression was associated with a significant higher median IL-6 level (14.8 vs. 3.7 pg/ml; p&lt;0,001). For Cognitive function only the longterm memory was significantly reduced in depression (p=0.01). However, there was no difference in BDNF levels between both groups (p=0.164). There were correlations between HADS-D score and IL6 (r=4.11; p=0.002), IL-6 and BDNF (r= −0.42; p=0.001), BDNF and longterm memory (r=0.48; p=0.02). No correlations were found for level of depression (HADS-D score) and BDNF levels (r= −0.20; P=0.14). Conclusions: Depression and increased plasma IL-6 concentrations are strongly associated in pts with cancer. There seems to be no association between BDNF and depression in cancer pts. However there is a positive correlation between the cognitive function, at least for longterm memory, with BDNF. No significant financial relationships to disclose.
Lapatinib with trastuzumab for heavily treated HER2-positive metastatic breast cancer (mBC).
Authors: Miguel J. Sotelo, Luis Manso, José Ángel Garcia Saenz, Eva M. Ciruelos, Fernando Moreno, Cesar Mendiola, Hector Callata, Ismael Ghanem, Santiago Cabezas, Jose-Luis Gonzalez-Larriba, Eduardo Diaz Rubio
Journal: Journal of Clinical Oncology (2013)

e11561 Background: Trastuzumab and lapatinib show complementary and non-cross resistant mechanisms of anti-HER2 action. Dual HER2 blockade has been preclinically and clinically assessed with encouraging results. Trastuzumab and lapatinib combination is effective in terms of survival in patients with heavily pretreated HER2-positive mBC. We aim to report our experience with lapatinib plus trastuzumab in this setting. Methods: Descriptive retrospective study of trastuzumab plus lapatinib activity in patients with HER2-overexpressing metastatic breast cancer treated in two institutions from 01/2007 to 12/2012. The objective of this analysis is to report the response rate (RR), progression-free survival (PFS) and toxicity. Results: 23 HER2-positive mBC patients previously treated with trastuzumab received trastuzumab plus lapatinib based therapy. 15 patients (65%) received 2 or more previous lines. 17 patients (74%) had visceral disease. Chemotherapy (CT) was added to the dual HER2 blockade treatment in 13 patients (56%) whereas hormonotherapy (HT) was added in 8 patients (35%) and 2 patients (9%) received lapatinib plus trastuzumab without any other agent. Chemotherapeutic drugs most used were: capecitabine (54%) and vinorelbine (15%). RR: partial response 22% (5/23), stable disease 39% (9/23). Median of follow-up was 11 months. PFS in the overall population was 4 months. PFS in patients with CT was 5 months, while PFS in patients with HT was only 2. PFS in hormone receptor positive and negative was 3 and 5 months respectively. The most common toxicities were: diarrhea (48%), anemia (39%), asthenia (39%) and hand-and-foot syndrome (17%). Grade ≥ 3 toxicity was diarrhea (26%) and hand-and-foot syndrome (9%). The incidence of cardiotoxicity was 9% (grade 2). Conclusions: These findings suggest that dual HER2 blockade in combination with CT is feasible and active in heavily pretreated HER2-positive mBC patients. However, further investigation is warranted to demonstrate superiority over sequential blockade with trastuzumab and lapatinib in this setting.
Antibody-Mediated Inhibition of Tspan12 Ameliorates Vasoproliferative Retinopathy Through Suppression of β-Catenin Signaling
Authors: Felicitas Bucher, Ding Zhang, Edith Aguilar, Susumu Sakimoto, Sophia Diaz-Aguilar, Mauricio Rosenfeld, Zhao Zha, Hongkai Zhang, Martin Friedlander, Kyungmoo Yea
Journal: Circulation (2017)

Anti-angiogenic biologicals represent an important concept for the treatment of vasoproliferative diseases. However, the need for continued treatment, the presence of nonresponders, and the risk of long-term side effects limit the success of existing therapeutic agents. Although Tspan12 has been shown to regulate retinal vascular development, nothing is known about its involvement in neovascular disease and its potential as a novel therapeutic target for the treatment of vasoproliferative diseases.Rodent models of retinal neovascular disease, including the mouse model of oxygen-induced retinopathy and the very low density lipoprotein receptor knockout mouse model were analyzed for Tspan/β-catenin regulation. Screening of a phage display of a human combinatorial antibody (Ab) library was used for the development of a high-affinity Ab against Tspan12. Therapeutic effects of the newly developed Ab on vascular endothelial cells were tested in vitro and in vivo in the oxygen-induced retinopathy and very low density lipoprotein receptor knockout mouse model.The newly developed anti-Tspan12 Ab exhibited potent inhibitory effects on endothelial cell migration and tube formation. Mechanistic studies confirmed that the Ab inhibited the interaction between Tspan12 and Frizzled-4 and effectively modulates β-catenin levels and target genes in vascular endothelial cells. Tspan12/β-catenin signaling was activated in response to acute and chronic stress in the oxygen-induced retinopathy and very low density lipoprotein receptor mouse model of proliferative retinopathy. Intravitreal application of the Ab showed significant therapeutic effects in both models without inducing negative side effects on retina function. Moreover, combined intravitreal injection of the Ab with a known vascular endothelial growth factor inhibitor, Aflibercept, resulted in significant enhancement of the therapeutic efficacy of each monotherapy. Combination therapy with the Tspan12 blocking antibody can be used to reduce anti-vascular endothelial growth factor doses, thus decreasing the risk of long-term off-target effects.Tspan12/β-catenin signaling is critical for the progression of vasoproliferative disease. The newly developed anti-Tspan12 antibody has therapeutic effects in vasoproliferative retinopathy and can enhance the potency of existing anti- vascular endothelial growth factor agents.
Role and strategies of radiofrequency ablation in treating advanced hepatocellular carcinoma.
Authors: Min Hua Chen, Wei Yang, Jie Wu, Wei Wu, Kun Yan
Journal: Journal of Clinical Oncology (2012)

e14701 Background: To investigate the application value and strategies of ultrasound-guided percutaneous radiofrequency ablation (RFA) in treating advanced hepatocellular carcinoma (HCC) which is common in china. Methods: A total of 655 patients with unresectablely advanced HCC underwent percuatenous RFA therapy and 92 patients with 136 tumors among them were enrolled into the study. According to the 6th UICC/AJCC-TNM system, 82 and 10 patients were in stage III and IV, respectively. The tumor size ranged from 1.5 to 8.0 cm (mean±SD, 4.5±1.6 cm). 59 patients had solitary tumor and the remaining 33 patients had multiple tumors. The Child-Pugh classification of A, B and C were 58,32 and 2 patients, respectively. Established strategies included: (1) select RFA indications based on the contrast-enhanced ultrasound (CEUS) results; (2) design radical protocols based on invasive range showed by CEUS; (3) multiple overlapping ablations based on mathematical protocol; (4) two or three bipolar RFA electrodes with three dimensional localization; (5) color US guided percutaneous ablation of tumor feeding artery (including TACE) + RFA for HCC with rich supply. The patients underwent follow-up using enhanced CT at one month, and then every three months after RFA. The ablation was considered a success if no abnormal enhancement or wash-out was detected in the treated area on the CT scan at one month. All patients after RFA received liver protection treatments. Overall survival was estimated by Kaplan-Meier analysis. Results: Early complete tumor necrosis rate after initial RFA was 90.4% (123/136 tumors). Serious complications were developed in two patients (2.2%) and no treatment-related death occurred. 3~129 months were followed up. Local recurrence rate was 15.4 %(21/136 tumors). The 1-, 3-, 5-year overall survival rates were 83.3 %, 48.3 %, 21.9%, respectively, and the median survival time was 35 months. Conclusions: RFA treatment of advanced HCC proved to be feasible. Paying attention to apply treatment strategies and liver protection therapies in RFA can effectively improve the survival.