tbuckley/cabot-search huggingface dataset:
A Phase II study of cabozantinib for metastatic triple-negative breast cancer (TNBC).
Authors: Sara M. Tolaney, David R. Ziehr, Hao Guo, William Thomas Barry, Michaela Jane Higgins, Steven J. Isakoff, Jane E. Brock, Elena Ivanova, Cloud Paweletz, Michelle Demeo, Nikhil H. Ramaiya, Beth Overmoyer, Rakesh K. Jain, Dan G. Duda, Eric P. Winer
Journal: Journal of Clinical Oncology (2015)

1080 Background: Data suggests that MET expression and activation are important for initiation and progression of TNBC. We evaluated the efficacy of cabozantinib (XL184), a novel inhibitor of multiple receptor tyrosine kinases, including MET and VEGFR2, in patients with metastatic TNBC. Methods: In this single-arm, two-stage Phase 2 study, patients with metastatic TNBC with measurable disease by RECIST v1.1 and up to 3 lines of prior chemotherapy in the metastatic setting received cabozantinib 60 mg daily on a 21-day cycle. Patients were restaged 6 weeks following treatment initiation and every 9 weeks thereafter. The primary endpoint was objective response rate (ORR). If ≥ 1/13 pts responded at stage 1, 22 more will be enrolled. If ≥ 4/35 responded, the null rate (5%) would be rejected in favor of a 20% rate of activity. Predefined secondary endpoints included progression free survival (PFS) and toxicity. Results: Thirty-five patients (median age 50 years, range 31-78) initiated protocol therapy and were included in this analysis. Patients had 0 (n = 6, 17%), 1 (n = 18, 51%), 2 (n = 4, 11%), or 3 (n = 7, 20%) prior lines of chemotherapy for metastatic disease. Two patients achieved confirmed PR (ORR 9% [95% CI 1-25%]) and 3 achieved unconfirmed PR; 18 patients (51%, 95% CI: 34-69%) had SD as their best response. The clinical benefit rate at 15 weeks was 31% (95% CI 17-49%) and the median PFS was 1.9 months (95% CI 1.3-3.3). The most common toxicities (all grades) were fatigue (77%), diarrhea (40%), mucositis (37%), and palmar-plantar erthrodysesthesia (PPE) (37%). There were no grade 4 toxicities. Twelve (34%) patients required dose reduction, 4 due to PPE and 8 due to other toxicities. Ongoing studies are exploring MET expression and amplification in archival tumor samples, MET amplification in circulating tumor cells, and plasma biomarkers of response to cabozantinib. Conclusions: In patients with metastatic TNBC, cabozantinib monotherapy showed evidence of antitumor activity. Adverse events requiring dose reduction occurred in about one-third of patients. Biomarker changes and their association with outcome will be presented at the meeting. Clinical trial information: NCT02260531.
Complications After Metastasectomy for Renal Cell Carcinoma—A Population-based Assessment
Authors: Christian P. Meyer, Maxine Sun, Jose A. Karam, Jeffrey J. Leow, Guillermo de Velasco, Sumanta K. Pal, Steven L. Chang, Quoc-Dien Trinh, Toni K. Choueiri
Journal: European Urology (2017)
ChemoID assay for glioblastoma.
Authors: Pier Paolo Claudio, Sarah E Mathis, Rounak Nande, Logan Lawrence, Anthony Alberico, Terrence D Julien, Rida S Mazagri, Robert Marsh, Paul Muizelaar, Krista L Denning, Jagan Valluri
Journal: Journal of Clinical Oncology (2015)

e13028 Background: Glioblastoma multiforme (GBMs) are brain tumors with low survival rates due to the presence of chemoresistant Glioma Cancer Stem-Like Cells (GCSLCs). Development of a test that identifies the most effective chemotherapy management for GCSLCs offers great promise for personalized anticancer treatments. Methods: We have developed a drug response assay (ChemoID) designed to predict the response of GCSLCs and bulk of tumor cells of a given patient by measuring cell death following chemotherapy treatments at clinically relevant doses. In a blinded study of 11 patients affected by Glioblastoma Grade IV we assessed the accuracy of the ChemoID assay by comparing the test results to clinical response. Tumors were classified as responsive (60-100% cell kill), intermediate (30-60% cell kill), and non-responsive (0-30% cell kill) to chemotherapy. Treatment was blinded to assay results. MRI and CT scan determined response to therapy. The effectiveness of the ChemoID predicted drugs and clinical response was also compared to the response of patients' derived xenografts (PDX) treated with the most effective and least effective ChemoID predicted drugs. Results: Thesensitivity or resistance of GCSLCs to Temozolomide (TMZ) predicted the patients' treatment outcome at 6 months in 11 out of 11 cases in GBM patients receiving TMZ regimen. Results from the 11 GBM patients analyzed suggest that the prediction of chemosensitivity on primary cells was 100% sensitive, but only 50% specific with a positive predictive value of 54.55% and a negative predictive value of 100%. The prediction of chemosensitivity on the GCSLC population was 100% sensitive and 100% specific, with a positive and a negative predictive value of 100%. Results from animal studies conducted in 5 PDXs were also found in agreement with the clinical outcomes. Conclusions: In our preliminary studies, comparing the response (% cell death) of primary GBM cells and enriched GCSLCs to TMZ to the patients' clinical treatment response to TMZ at 6 months follow-up in 11 patients revealed that the chemosensitivity of the GCSLCs accurately predicted the clinical outcome of the patients. Ultimately, of these 11 patients, the only clinical remission was observed in the patient with TMZ sensitive GCSLCs as predicted by ChemoID assay.
Antibacterial Surfaces: Colloidal Gold Nanoclusters Spiked Silica Fillers in Mixed Matrix Coatings: Simultaneous Detection and Inhibition of Healthcare‐Associated Infections (Adv. Healthcare Mater. 6/2017)
Authors: Shahad K. Alsaiari, Mohammed A. Hammami, Jonas G. Croissant, Haneen W. Omar, Pradeep Neelakanda, Tahir Yapici, Klaus‐Viktor Peinemann, Niveen M. Khashab
Journal: Advanced Healthcare Materials (2017)

A smart antibacterial mixed-membrane coating consisting of lysozyme@gold nanoclusters-coated mesoporous silica nanoparticles encapsulating antibacterial agents in an amphiphilic polymer matrix is described by Niveen M. Khashab and co-workers in article number 1601135. The membrane successfully senses and inhibites bacterial contaminations on X-ray dental plates via a bacteria-responsive controlled release mechanism. The monitoring of the contamination is simply visualized under UV-light and demonstrated the applicability of the coating on biomedical devices.
Factors affecting PS deterioration at the time of relapse after the first-line EGFR-TKI therapy in EGFR-mutant advanced NSCLC.
Authors: Tomoki Tamura, Katsuyuki Hotta, Hiroko Gotoda, Yuka Kato, Eiki Ichihara, Toshio Kubo, Mitsune Tanimoto, Katsuyuki Kiura
Journal: Journal of Clinical Oncology (2014)

e19102 Background: EGFR-TKI is now one of the standard therapies in advanced NSCLC in the first-line setting. It yields an excellent PFS, but most of pts recur. Although they should receive subsequently the standard cytotoxic chemotherapy, about 15-30% of pts could not possibly because of poor PS at the time of recurrence in our cohort [Kato Y, ASCO 2012]. We here investigated the pattern of relapse and potential factors affecting disease progression with PS deterioration during the first-line EGFR-TKI therapy. Methods: Consecutive 48 pts with advanced EGFR-mutant NSCLC who had had PS of 0-2 and then recurred after the initiation of EGFR-TKI therapy in the first-line setting between 2003 and 2012 were retrospectively assessed. Results: Eighteen (38%) had CNS mets at the time of diagnosis, 13 of whom received local therapy before initiating EGFR-TKI, whereas 11 and 5 pts had bone mets with or without the prior local therapy. Median time to progression was 14.7 months (95%CI; 8.1-16.5). The relapse sites included CNS (n=15), intrapulmonary (n=14), primary (n=11), and bone (n=9). At the time of relapse, PS deteriorated to 3 or worse in 8 (17%) most commonly due to symptomatic CNS relapse. Preexisting CNS involvement was a significant predictor for the development of PS 3 or worse, irrespective of the local therapy for the involvement prior the EGFR-TKI therapy; the adjusted odds ratios for PS deterioration were 12.1 (1.0-143.5; p=0.05) and 47.3 (1.5-1502.7, p=0,03) in pts with or without the previous CNS therapy, respectively. Pts with PS deterioration at the time of relapse received the subsequent standard cytotoxic chemotherapy less frequently (1/7; 14% vs. 31/37; 84%, p<0.01) and had a worse post-progression survival than those without (median: 3.2 vs. 28.8 months, p<0.01). Conclusions: Pts with prior CNS mets had a high risk of PS deterioration possibly through CNS failure when they recurred in the first-line EGFR-TKI therapy, whichever they received CNS therapy before initiating EGFR-TKI therapy. They had less chance to receive the subsequent cytotoxic therapy, so further research is needed to clarify the benefit of concurrent EGFR-TKI and cytotoxic chemotherapy especially in such population.
EGFR-activating mutations and treatment with tyrosine-kinase inhibitors (TKI) to revert poor-prognosis (PP) associated with liver metastases (LM) in stage IV non-small cell lung cancer (NSCLC) patients (pts).
Authors: Eduardo Castanon, Maria D. Lozano, Juan Pablo Fusco, Estefania Arevalo, Omar Esteban Carranza, José María López-Picazo, Jose Luis Perez-Gracia, Alfonso Gurpide, Ignacio Gil-Bazo
Journal: Journal of Clinical Oncology (2013)

e19106 Background: LM appear in 20-30% of pts diagnosed with NSCLC and they confer PP. However, whether the clinical outcome of NSCLC pts with LM harboring molecular alterations in EGFR, KRAS and EML4-ALK genes is substantially different depending on their distinct status is still unknown. Methods: A total of 268 consecutive stage IV NSCLC pts were included. The tumor molecular analysis for EGFR, KRAS and EML4-ALK was available in 205 pts (76.5%), 136 pts (50.7%) and 31 pts (11.6%), respectively. An EGFR mutation was observed in 32 pts (15.6%), KRAS was mutated in 28 pts (20.6%) and EML4-ALK gene rearrangement was observed in 3 pts (9.6%). We aimed to determine whether the molecular status of EGFR, KRAS and EML4-ALK has an impact on the clinical outcome of stage IV NSCLC pts. Results: Most of the pts were men (71.3%). The most common histology was adenocarcinoma (59.3%). Overall, 34% of the pts showed LM at any time of the disease course. Among the whole cohort, median OS for LM pts was 16 months vs 42 months for pts with metastases other than LM (p&lt;0.001). Among pts with LM and EGFR mutations, the one-year survival rate was 85.7% vs 54.3% for pts with LM and EGFR wild-type (p=0.03). We analyzed whether pts received EGFR TKI or standard chemotherapy (SC). For the subgroup of pts carrying EGFR mutations and receiving TKI, the 18-month survival rate was 75% for those showing LM vs 80% (p=0.44) for those without LM. In contrast, for the subgroup of EGFR wild-type pts receiving SC, the 18-month survival rate was 32.4% for those showing LM vs 74.9% for those without LM (p&lt;0.001). No impact of KRAS or EML4-ALK molecular alterations on OS of pts with LM was observed. Conclusions: The presence of LM at any time of the disease curse negatively impacts on the clinical outcome of NSCLC pts. However, the presence of EGFR activating mutations significantly improves the OS of those with liver spread, reaching a similar OS to subjects with no LM. Pts with EGFR mutations and LM may revert the PP associated to LM when an EGFR TKI is prescribed.
Human papillomavirus (HPV)-associated early stage non-small cell lung cancer (NSCLC).
Authors: Rathi Narayana Pillai, Camille Ragin, Gabriel Sica, Madhusmita Behera, Zhengjia Chen, Sungjin Kim, William Mayfield, Robert C. Hermann, Nabil F. Saba, Anthony A Gal, Fadlo Raja Khuri, Suresh S. Ramalingam, Taofeek Kunle Owonikoko
Journal: Journal of Clinical Oncology (2013)

7560 Background: HPV is an established risk factor for cervical and oropharyngeal cancer. It has been suggested as a potential risk factor for lung cancer based on studies conducted mostly in Asian patients with advanced NSCLC. We characterize potential role of HPV in a North American patient population with early stage NSCLC. Methods: We analyzed surgically resected samples of NSCLC patients diagnosed between 2002-2007. HPV status was determined by polymerase chain reaction (PCR) using the INNO-LiPA genotyping Extra Amplification and Genotyping Extra kits, followed by reverse hybridization line probe assay to identify specific HPV serotypes. Differences between HPV+ and HPV- patients were assessed by Chi-square, Fisher’s exact, and Wilcoxon rank-sum tests. Survival was estimated by the Kaplan-Meier method and differences between HPV+ and HPV- patients were assessed by Log-rank test. Multivariable logistic regression modeling was employed to select predictors of HPV+ NSCLC. The significance levels were set at 0.05 for all tests. Results: Paraffin-embedded tumor samples from 208 patients were analyzed; M/F (49%/51%); stage I: 80%; II: 11%; III: 9%; IV: &lt;1%; Caucasians 95.6% and African-Americans (AA) 4.4%. There were 32 (14.9%) HPV+ cases including 10 cases with HPV 16/18. Ethnicity was significantly associated with HPV status (p-value=0.033). AA patients are more likely to be HPV+ (OR: 7.373; p=0.01) and more likely to harbor high risk serotypes 16/18 (OR: 10.8; p=0.05). Regression modeling identified AA ethnicity, adenocarcinoma (ADC) histology and current smoking (parameter estimates of 2.04, -2.34 and -2.82 respectively) as predictors of HPV+ NSCLC. Smoking status and histology showed significant interaction in predicting HPV+ tumors: OR: 0.06; p=0.0023 for smokers with squamous cancer; 2.52; p=0.24 for smokers with ADC and 10.339; p=0.0293 for smokers with adenosquamous cancer. Median disease free survival (NR; p=0.42) and median overall survival (71 months; vs. 55 months) were not significantly different between HPV+ and HPV- patients. Conclusions: HPV positivity is observed in 15% of early stage NSCLC with strong association with AA ethnicity, adenosquamous histology and non-smoking status.
SWOG 1211: A randomized phase I/II study of optimal induction therapy for newly diagnosed high-risk multiple myeloma (HRMM).
Authors: Saad Zafar Usmani, Antje Hoering, Rachel Sexton, Sikander Ailawadhi, Jatin J. Shah, Sandi Fredette, Brian G. Durie, Jeffrey A. Zonder, Madhav V. Dhodapkar, S. Vincent Rajkumar, Anuj Kumar Mahindra, Todd M. Zimmerman, Paul G. Richardson, Robert Z. Orlowski
Journal: Journal of Clinical Oncology (2014)

TPS8624 Background: The introduction of immunomodulatory agents and proteasome inhibitors, and advances in high dose therapy administration have made an impact on progression free survival (PFS) and overall survival (OS) for multiple myeloma (MM) patients in general, but patients with HRMM still have a poor long-term prognosis. Therefore, it is imperative to develop novel therapeutic regimens that will extend PFS and OS in this group. The SWOG 1211 is the first national and inter-group study targeting the HRMM population. Methods: Eligibility and Trial Design: A randomized phase I/II trial was designed to evaluate the efficacy of incorporating novel agents into first line therapy for HRMM patients comparing lenalidomide, bortezomib and dexamethasone (RVD) with or without addition of elotuzumab (Elo). Eligible patients must have a documented history of HRMM defined by one or more of the following: Poor risk genomics defined by 70-gene model. Translocation (14;16), translocation (14;20) and/or deletion (17p) by florescent in-situ hybridization (FISH). Primary plasma cell leukemia. Serum LDH > 2 times normal levels. Objectives: Phase I: To determine the maximum tolerated dose (MTD) of RVD-Elo. Phase II: To assess whether incorporation of the novel agent Elo into treatment algorithm of HRMM will improve PFS. Statistical Considerations: The phase I study enrolled 6 DLT evaluable patients; no DLTs were observed. The phase II study is now open and will accrue 100 eligible patients (50 per arm). An additional 10 patients (5 per arm) will be accrued to account for ineligibility/patients withdrawing consent. The median expected PFS in the control arm (RVD) is 2.2 years, based on the experience in Total Therapy 3a and 3b studies (high risk genomics defined by 70-gene model). Assuming uniform accrual of 25 patients per year, four years of accrual and an additional 2 years of follow-up yields a study with 82% power and a one-sided significance level alpha of 0.1 to detect a hazard ratio of 1.75 between two treatment arms, or an increase in median PFS from 2 years to 3.5 years in the RVD-Elo arm versus the RVD arm. Clinical trial information: NCT01668719.
HNRNPLL, a newly identified colorectal cancer metastasis suppressor, modulates alternative splicing of <i>CD44</i> during epithelial-mesenchymal transition
Authors: Keiichiro Sakuma, Eiichi Sasaki, Kenya Kimura, Koji Komori, Yasuhiro Shimizu, Yasushi Yatabe, Masahiro Aoki
Journal: Gut (2017)

Despite the recent advances in treatment of colon cancer, the prognosis is unfavourable for patients with distant metastases. The aim of this study was to identify targets for prevention and/or therapy of colon cancer metastasis.CMT93 cells, a murine rectal cancer cell line with poor metastasising activity, were transduced with lentiviral shRNA library and transplanted into the rectum of syngeneic C57BL/6 mice. Genomic DNA was collected from metastatic lesions, and the integrated shRNA were retrieved by PCR for sequencing, followed by identification of the candidate genes targeted by the shRNA.The genome-wide shRNA library screen identified Hnrnpll (heterogeneous nuclear ribonucleoprotein L-like) encoding a pre-mRNA splicing factor as a candidate metastasis suppressor gene. Knockdown of Hnrnpll enhanced matrigel invasion activity of colon cancer cells in vitro, as well as their metastatic ability in vivo. An RNA-immunoprecipitation analysis showed Hnrnpll-binding to Cd44 pre-mRNAs, and the level of Cd44 variable exon 6 (Cd44v6), a poor prognosis marker of colorectal cancer, was increased by knocking down Hnrnpll. A neutralising Cd44v6 antibody suppressed the matrigel invasion ability induced by Hnrnpll knockdown. HNRNPLL expression was downregulated when colon cancer cells were induced to undergo epithelial-mesenchymal transition (EMT). Immunohistochemistry of clinical samples indicated that colorectal cancer cells with low E-cadherin expression at the invasion front exhibited decreased HNRNPLL expression.HNRNPLL is a novel metastasis suppressor of colorectal cancer, and modulates alternative splicing of CD44 during EMT.
Aberrant NFAT2 signaling in chronic lymphocytic leukemia.
Authors: Jonas S. Heitmann, Melanie Maerklin, Alexandra Poljak, Bettina Hackl, Juliane Stickel, Lothar Kanz, Hans-Georg Kopp, Stefan Wirths, Martin Rudolf Mueller
Journal: Journal of Clinical Oncology (2013)

7019 Background: CLL is a malignancy of mature B cells and constiututes the most common leukemia in adults. It is characterized by a progressive accumulation of clonal B cells, which coexpress CD19, CD23 and CD5. NFAT is a family of highly phosphorylated transcription factors residing in the cytoplasm of resting cells. Upon dephosphorylation by calcineurin, NFAT proteins translocate to the nucleus where they orchestrate developmental and activation programs in diverse cell types. In this study, we investigated the significance of NFAT signaling in B-CLL. Methods: NFAT2 expression and aberrant nuclear translocation in CLL cells (n=30) was assessed by Western Blotting and immunofluorescence. In addition, NFAT2 mRNA levels were measured by qRT-PCR and its DNA binding capacity was assessed using an electrophoretic mobility shift assay. Transcriptional activity of NFAT2 proteins in CLL cells was further analyzed by determining the expression of several well characterized NFAT target genes. Results: We detected a profound overexpression of NFAT2 mRNA and protein in all CLL samples. Using qRT-PCR we found that CD19+CD5+ CLL cells exhibited a significant overexpression of NFAT2 as compared to CD19+ B cells isolated from healthy donors (8-200fold). This overexpression of NFAT2 in CLL cells could also be confirmed on the protein level. We could further demonstrate that even under resting conditions significant amounts of NFAT2 protein had translocated to the nucleus in CLL cells, whereas virtually all NFAT2 was in the cytoplasm in non-malignant B cells. Nuclear NFAT2 in CLL cells was able to bind DNA but its transcriptional activity with respect to several apoptosis-regulating genes (i.e. Spp1, Pdcd1) was severely compromised. Conclusions: These results provide strong evidence that the Ca 2+ /NFAT signalling axis is constitutively activated in CD5+CD19+ CLL cells. Reduced expression of several apoptosis regulators which are known target genes of NFAT2 links deregulation of this signaling cascade to CLL progression. Further investigation is warranted to investigate the therapeutic potential of modulating Ca 2+ /Calcineurin/ NFAT signaling in CLL.
The differential clinicopathologic features and survival outcome between hepatitis C–related HCC patients in the United States versus Egypt.
Authors: Reham Abdel-Wahab, Manal Hassan, Samir-Shehata M. Eid, Hoda H. Essa, Ahmed Omar Kaseb
Journal: Journal of Clinical Oncology (2014)

e15128 Background: Hepatocellular carcinoma (HCC) represents the fifth most common neoplasm and the third cause of cancer related mortality worldwide. HCC is multifactorial in origin where approximately 40% of the American HCC patients are explained by chronic hepatitis C virus (HCV) alone. Similarly the main etiology for HCC in Egypt is HCV where 90% of Egyptian patients are attributable to chronic HCV infection. There is variation in the HCV genome between USA (genotypes 1a/1b, 2b), and Egypt (genotype-4). Despite the reports of interplay between genotype and hepatitis C severity, no data regarding the effect of HCV genotypes on HCC disease activity and overall survival are available. Methods: Baseline demographic, epidemiological, and clinical characteristics of HCV-related HCC patients were described in 143 patients from The University of Texas MD Anderson Cancer Center (USA Site) as compared to 96 HCC patients from Assiut University (Egypt Site). Univariate analysis was done using the c2or Fisher’s exact test for categorical variables and the Kruskal-Wallis test for continuous variables. Kaplan-Meier method will be used to estimate the median overall survival (OS) and the log rank test will be performed to compare subgroups of patients. Results: The median OS, 95% Confidence Interval (CI) was 12.2 months (9.5-14.9) and 18.4 months (15.1-21.6) for Egyptian and US patients respectively, P < .0001. This can be explained by more aggressive nature of the disease in the Egyptians which appears in the form of higher vascular invasion (P .004), Portal vein thrombosis (PVT) (P .0008), lymph node metastasis (P .0004), Distance metastasis (P .0001), Bilirubin (P .0001), INR (P.0001) as well as a significant lower platelet count (P .04). Conclusions: HCV-related HCC was associated with significantly worse survival and advanced clinicopathologic features in Egypt as compared to HCV-HCC in US. Future prospective studies are warranted to study differences in molecular carcinogenesis, HCV genotypes, and treatment outcomes.