tbuckley/cabot-search huggingface dataset:
The potential diagnostic role of procalcitonin for bacteremia in a large cohort of solid cancer patients.
Authors: Iacopo Fioroni, Bruno Vincenzi, Alice Zoccoli, Silvia Angeletti, Lucia De Florio, Giordano Dicuonzo, Antonio Picardi, Marco Caricato, Daniele Santini, Giuseppe Tonini
Journal: Journal of Clinical Oncology (2014)

e20664 Background: In cancer patients (pts), commonly used systemic inflammatory response syndrome (SIRS) or sepsis diagnostic criteria lack of specificity, hence the importance to identificate an early useful diagnostic markers. Several studies showed procalcitonin (PCT) is a biomarker able to differentiate sepsis or bacterial infections from systemic non-infectious inflammatory syndrome. We studied the correlation between bacteremia and PCT levels in a large cohort of advanced solid cancer patients. Methods: In this retrospective study we consecutively enrolled pts observed at Campus Bio-Medico University of Rome between January 2009 and March 2013. For all pts demographic/clinical data and laboratory parameters were collected. In particular all pts had a solid cancer diagnosis, fever (T>38.2 °C), PCT value and hemoculture results available before antibiotics. PCT was assessed in our central laboratory by an immunoluminometric assay; the normal reference range was 0-0,5 ng/dl. A ROC analysis was performed to measure predictive accuracy of PCT and the areas under the curves (AUC) were computed. Results: A total of 431 solid tumor pts were included: a cohort of 154 pts had positive blood culture and 277 negative. Pts were then divided into two groups according to PCT values (≤/>0,5 ng/dL): we observed that 160 pts had a PCT value ≤ 0,5 ng/dL, while 271 >0,5 ng/dL. Among pts with PCT value ≤ 0,5 ng/dL, Negative blood cultures were found in 128 pts while only 32 showed a positive one. Considering pts with PCT value >0,5 ng/dL, 149 showed a negative blood culture and 122 a positive one. Distributing pts according to Gram Positive (G+) or Negative (G-) bacteremia ROC analysis showed that the optimal cut-off value in G- infected pts was >2,23 (sensitivity: 65,7%, specificity:78,2%, AUC 0,771; P<0.001). In G+ and Fungi infection the best criterion was >4,06 (sensitivity: 32,1%, specificity: 85,8%, AUC= 0,575; P=0,082). Conclusions: Serum PCT level can potentially be used as a diagnostic tool to exclude bacteremia with an higher sensitivity and specificity for G- infections and to inform critical management decisions regarding antibiotic usage, in solid tumor pts admitted with fever and suspected bloodstream infection.
The APC I1307K polymorphism as a significant risk factor for CRC in average-risk Ashkenazi Jews.
Authors: Ben Boursi, Tal Sella, Eliezer Liberman, Ravit Geva, Einat Shmueli, Eyal Sagiv, Dina Kazanov, Sarah Kraus, Nadir Arber
Journal: Journal of Clinical Oncology (2012)

1507 Background: The I1307K adenomatous polyposis coli gene variant, prevalent among Ashkenazi Jews, may increase risk for colorectal neoplasia. We studied the clinical importance of screening for this polymorphism in 3305 Israelis undergoing colonoscopic assessment. Methods: Blood samples and risk factor information were collected from individuals undergoing colonoscopic examination at our medical center. Germline genetic analysis for the APC I1307K variant was performed using real-time PCR for DNA extracted from peripheral mononuclear cells. Results: The overall prevalence of the I1307K polymorphism was 8.0% (10.1% among Ashkenazi while only 2.7% among Sephardic Jews, p&lt;0.001). The overall adjusted odds ratio (OR) for CR neoplasia among carriers was 1.51(95% CI, 1.16 –1.98). Among average risk Ashkenazi Jews, the OR was 1.76 (95% CI 1.26-2.45). On the contrary, among Sephardi subjects the OR was 0.996 (95% CI, 0.51-1.93). A multiplicative interaction was identified between Ashkenazi ethnicity and APC I1307K carrier status (P INTERACTION =0.055). The histopathological features of adenomas and cancers did not differ between carriers and non-carriers. Conclusions: The APC I1307K gene variant is an important risk factor for CRC in average risk Ashkenazi jews and should be considered for screening in this population.
Blood-based CHRNA3 single nucleotide polymorphisms (SNPs) and outcome in advanced non-small cell lung cancer (NSCLC) patients (p)
Authors: R. Rosell, J. L. Ramirez, M. Sanchez-Ronco, D. Isla, T. Moran, M. Cobo, B. Massuti, M. Taron, D. Carbone, I. De Aguirre
Journal: Journal of Clinical Oncology (2009)

8033 Background: Nicotonic acetylcholine receptors (nAChRs) are associated with resistance to gemcitabine (gem), cisplatin (cis) and paclitaxel in NSCLC cell lines. Three SNPs of CHRNA3, CHRNA5 and LOC123688 increase lung cancer risk. These SNPs may have influenced outcome in p treated in our phase III trial (Cobo et al. J Clin Oncol 2007;25:2747–54). Methods: Stage IV NSCLC p were treated with customized chemotherapy based on ERCC1 mRNA expression. p in the control arm received docetaxel (doc)/cis; p in the genotypic arm with low ERCC1 levels (low genotypic group [LG]) received doc/cis; p in the genotypic arm with high ERCC1 levels (high genotypic group [HG]) received doc/gem. DNA was extracted from lymphocytes, and CHRNA3 (rs1051730), CHRNA5 (rs16969968) and LOC123688 (rs8034191) SNPs were genotyped with the Taqman allele discrimination assay. Results: A significant interaction was found for CHRNA3 and PS (P = 0.02). In p with PS 0, CT p had a better response than both CC (P = 0.01) and TT (P = 0.02) p, and LG p also had a better response (P = 0.01). When the CHRNA3 genotype was added in the multivariate analysis for progression-free survival (PFS), an improvement was observed in the LG in PS 0 p (P = 0.02). PS 0 p in the LG with the CT genotype attained an 84% response, 12.1-month PFS, and 19-month median survival (MS) ( Table ). Conclusions: CHRNA3 genotyping can improve customized chemotherapy based on tumor ERCC1 mRNA in stage IV NSCLC p with PS 0. [Table: see text] No significant financial relationships to disclose.
Lymphoma Remissions Caused by Anti-CD19 Chimeric Antigen Receptor T Cells Are Associated With High Serum Interleukin-15 Levels
Authors: James N. Kochenderfer, Robert P.T. Somerville, Tangying Lu, Victoria Shi, Adrian Bot, John Rossi, Allen Xue, Stephanie L. Goff, James C. Yang, Richard M. Sherry, Christopher A. Klebanoff, Udai S. Kammula, Marika Sherman, Arianne Perez, Constance M. Yuan, Tatyana Feldman, Jonathan W. Friedberg, Mark J. Roschewski, Steven A. Feldman, Lori McIntyre, Mary Ann Toomey, Steven A. Rosenberg
Journal: Journal of Clinical Oncology (2017)

Purpose T cells genetically modified to express chimeric antigen receptors (CARs) targeting CD19 (CAR-19) have potent activity against acute lymphoblastic leukemia, but fewer results supporting treatment of lymphoma with CAR-19 T cells have been published. Patients with lymphoma that is chemotherapy refractory or relapsed after autologous stem-cell transplantation have a grim prognosis, and new treatments for these patients are clearly needed. Chemotherapy administered before adoptive T-cell transfer has been shown to enhance the antimalignancy activity of adoptively transferred T cells. Patients and Methods We treated 22 patients with advanced-stage lymphoma in a clinical trial of CAR-19 T cells preceded by low-dose chemotherapy. Nineteen patients had diffuse large B-cell lymphoma, two patients had follicular lymphoma, and one patient had mantle cell lymphoma. Patients received a single dose of CAR-19 T cells 2 days after a low-dose chemotherapy conditioning regimen of cyclophosphamide plus fludarabine. Results The overall remission rate was 73% with 55% complete remissions and 18% partial remissions. Eleven of 12 complete remissions are ongoing. Fifty-five percent of patients had grade 3 or 4 neurologic toxicities that completely resolved. The low-dose chemotherapy conditioning regimen depleted blood lymphocytes and increased serum interleukin-15 (IL-15). Patients who achieved a remission had a median peak blood CAR+ cell level of 98/μL and those who did not achieve a remission had a median peak blood CAR+ cell level of 15/μL ( P = .027). High serum IL-15 levels were associated with high peak blood CAR+ cell levels ( P = .001) and remissions of lymphoma ( P < .001). Conclusion CAR-19 T cells preceded by low-dose chemotherapy induced remission of advanced-stage lymphoma, and high serum IL-15 levels were associated with the effectiveness of this treatment regimen. CAR-19 T cells will likely become an important treatment for patients with relapsed lymphoma.
Phase I study of panobinostat (LBH589) and letrozole in post-menopausal women with metastatic breast cancer.
Authors: Winston Tan, Jacob B Allred, Alvaro Moreno-Aspitia, Donald W. Northfelt, James N. Ingle, Edith A. Perez
Journal: Journal of Clinical Oncology (2012)

e13501 Background: Loss of estrogen receptor alpha gene expression has been associated with insensitivity to endocrine therapy in human breast cancer patients. Histone deacetylase (HDAC) inhibitors have recently been found to restore sensitivity to the estrogen receptor by modulation of the estrogen and progesterone receptors. This had been shown with both aromatase and tamoxifen refractory and in triple negative cell lines . We performed a Phase I study of the combination of LBH589 (panobinostat) and letrozole to evaluate safety and tolerability in patients with metastatic breast cancer prior to the performance of a phase II trial. Methods: We enrolled postmenopausal women with metastatic breast cancer, ECOG PS 0 or 1, ANC&gt;1500/mm 3 , platelets&gt;100,000/mm 3 , normal total bilirubin, and ALT/AST adequate laboratory tests were eligible. Letrozole dose was 2.5 mg/day orally. Dose of LBH589: Level 1, 20 mg orally three times weekly; Level 2, 30 mg orally three times a week. Results: 12 patients (dose level 1:6 patients, dose level 2: 6 patients) have been enrolled. 43 cycles of treatment have been given to these12 patients. Initial cohort of 3 patients at the 20 mg dose level had no dose limiting toxicity (DLT). At the 30 mg dose level 3/6 patients had DLT (thrombocytopenia grade 1: 2 pts; grade 3:1 pt; grade 4: 1 pt; and diarrhea grade 3: 1 pt. One pt at the 30 mg dose level has a confirmed partial response and remains on study after 6 cycles of treatment. Subsequent cohort of 3 patients had 1 dose DLT with doubling of the creatinine. The main DLT was thrombocytopenia in 3/6 pts at the 30 mg dose level. Conclusions: The recommended dose for phase II testing of LBH589 is 20 mg orally 3 times per week in combination with standard dose letrozole.
A phase II study of MEK162 (binimetinib [BINI]) in combination with imatinib in patients with untreated advanced gastrointestinal stromal tumor (GIST).
Authors: Ping Chi, Li-Xuan Qin, Ciara Marie Kelly, Sandra P. D'Angelo, Mark Andrew Dickson, Mrinal M. Gounder, Mary Louise Keohan, Sujana Movva, Benjamin Nacev, Aimee Marie Crago, Sam S. Yoon, Gary A. Ulaner, Moriah Martindale, Mercedes M. Condy, Haley Phelan, Matthew Biniakewitz, Samuel Singer, Sinchun Hwang, Cristina R. Antonescu, William D. Tap
Journal: Journal of Clinical Oncology (2020)

11508 Background: ETV1 and KIT are lineage-specific master transcriptional and signaling survival factors in GIST. In preclinical models, dual lineage targeting of ETV1 by MEK inhibition with BINI and KIT by imatinib are synergistic in suppressing GIST tumorigenesis and progression. This single-arm phase II study is designed to test the efficacy of the BINI+imatinib as a first-line treatment in patients (pts) with advanced GIST. Methods: Adult pts with untreated advanced GIST received imatinib (400mg daily) plus BINI (30mg twice daily), 28-day cycles. The primary endpoint (EP) was RECIST1.1 objective response rate (ORR) (complete response [CR]+partial response [PR]). The study was designed to detect a 20% improvement in the ORR of imatinib alone (unacceptable rate of 45%; acceptable rate of 65%). A sample size of 44 patients was required, using an exact binomial test, one-sided type I error of 0.08 and type II error of 0.1. Confirmed PR in &gt; 24 pts would be considered positive. Secondary EPs included RR by Choi and EORTC criteria, resectability conversion rate (RCR), progression free survival (PFS), overall survival (OS) and long-term AEs. Correlatives included characterization of tumor genomics by MSK-IMPACT, cfDNA by MSK-ACCESS, ETV1 protein levels and transcriptomes and signaling inhibition. Results: At data cutoff of Jan 31, 2020, 38/39 pts with advanced GIST of all genotypes, including 3 KIT/PDGFRA-wild type GIST pts, were evaluable for primary EP. Median age 60 (range 29-78), 29% female. 26/38 pts with confirmed PR; Best ORR was 68.4% (two-sided 95% CI, 51-83%; one-sided 90% CI, 57-100%). 8/9 pts became resectable after treatment; RCR was 88.9% (95% CI, 52-100%). 13 pts remain on trial (2-159 weeks [wks]). 9 pts discontinued trial due to disease progression (11-159 wks); one pt progressed within 3 months, indicating primary resistance. Grade 3/4 toxicity included CPK elevation (asymptomatic, 61%), neutrophil decrease (11%), maculopapular rash (8%), anemia (8%). No unexpected toxicities observed. Correlation of outcome with MSK-IMPACT, MSK-Access and paired tumor biopsies will be presented. Conclusions: This study met its primary endpoint. BINI plus imatinib is highly effective in treatment-naive advanced GIST, with expected and manageable long-term treatment-associated toxicities. The combination strategy warrants further evaluation in direct comparison with imatinib in the frontline treatment of GIST. Clinical trial information: NCT01991379 .
In Reply
Authors: Matthew P. Goetz, James M. Rae, Stephanie L. Safgren, Matthew M. Ames, Daniel W. Visscher, Carol Reynolds, Fergus Couch, Wilma L. Lingle, David A. Flockhart, Zeruesenay Desta, Edith A. Perez, James N. Ingle
Journal: Journal of Clinical Oncology (2006)
Circulating tumor (ct)-DNA alterations in metastatic castration-resistant prostate cancer (mCRPC): Association with outcomes and evolution with therapy.
Authors: Guru Sonpavde, Rebecca J Nagy, A. Oliver Sartor, Gregory Russell Pond, Theodore Stewart Gourdin, Lakshminarayanan Nandagopal, Elisa M. Ledet, Neeraj Agarwal, Emma Carroll, Gurudatta Naik, Jue Wang, Mehmet Asim Bilen, Petros Grivas, Richard B. Lanman, AmirAli Talasaz, Michael B. Lilly
Journal: Journal of Clinical Oncology (2017)

149 Background: Cell-free ctDNA may be prognostic and evolve following therapy. We report ctDNA profiling of patients (pts) with mCRPC and their association with clinical outcomes and evolution with therapy. Methods: Pts with mCRPC that underwent baseline ctDNA analysis for potentially actionable alterations using Guardant360 before new systemic therapy were identified. Data were requested for clinical factors, current and prior therapy, TTF (time to failure) and survival. A 70-gene cfDNA next generation sequencing panel from a CLIA-licensed, CAP-accredited laboratory (Guardant Health, Inc.) offers complete exon sequencing for 29 genes, critical exons in 39 genes and amplifications (16 genes), fusions (6 genes) and indels (3 genes) harvested from 10 mL of peripheral blood. Alterations were reported and association of alterations with outcomes and prior therapy was examined. Results: Of 514 with confirmed mCRPC, 482 (94%) had ≥ 1 ctDNA alteration. The median age was 70 years (range 39-91). The most common recurrent somatic mutations were in TP53 (36% of patients), AR (22%), APC (10%), NF1 (9%), EGFR, CTNNB1 and ARID1A (6% each) and BRCA1, BRCA2 and PIK3CA (5% each) The most common genes with increased copy numbers were AR (30%), MYC (20%) and BRAF (18%). Clinical outcomes were available for 163 pts, of whom 46 (28.8%) were untreated for mCRPC. A higher number of ctDNA alterations was associated with shorter TTF (HR: 1.05, p = 0.026). AR alterations had a trend for shorter TTF (HR: 1.42, p = 0.053) and survival (HR: 2.51, p = 0.09). Pts who received prior therapy had new alterations in AR (56% vs. 37%, p = 0.028) compared to untreated pts. Serial ctDNA profiling of 64 pts revealed the evolution of alterations in AR, BRCA1 and BRCA2 following therapy. Conclusions: ctDNA was frequently detected in patients with mCRPC, and alterations appear similar to tumor tissue alterations. A higher number of overall gene alterations and AR alterations appeared associated with poor clinical outcomes and new AR and BRCA alterations appeared following therapy. These data suggest that developing salvage agents targeting AR alterations and PARP inhibitors hold promise.
Clinicopathologic characterization and outcomes for patients with renal medullary carcinoma: Results from the National Cancer Database.
Authors: Harras B. Zaid, Robert Houston Thompson, Bradley C. Leibovich, William P. Parker, Brian Addis Costello, Lance C. Pagliaro, Stephen A. Boorjian
Journal: Journal of Clinical Oncology (2017)

456 Background: Renal medullary carcinoma (RMC) is a rare, aggressive malignancy for which relatively limited characterization exists to date. We evaluated clinicopathologic features, treatment patterns, and variables associated with outcomes for patients with RMC. Methods: We reviewed the National Cancer Database to identify patients diagnosed with RMC between 1998-2012. Overall survival (OS) was estimated using the Kaplan-Meier method. Clinicopathologic features associated with all-cause mortality (ACM) were assessed using Cox regression analysis. Results: We identified 153 patients with RMC, comprising approximately 0.04% of renal malignancies during this time period. Median age at diagnosis for RMC was 24 years (IQR 20, 31). The majority of RMC patients were black (135; 88%), male (108; 71%), and presented with unilateral, right-sided tumors (101; 66%). Notably, nearly half (72; 48.9%) presented with metastatic disease. A total of 92 (64.3%) patients underwent radical nephrectomy (RN), and 2 (1.3%) were treated with partial nephrectomy. Pathologic stage at nephrectomy was ≤pT2 in 30 patients (32.6%), pT3 in 43 (46.7%), pT4 in 7 (7.6%), and N+ in 50 (55.6%). Of the patients who underwent RN, 60 (65.2%) received multimodal therapy (MMT), including radiation (3; 3.3%), systemic therapy (49; 53.3%), and radiation + systemic therapy (8; 8.7%). Of the 59 patients who did not undergo surgical resection, the majority (46; 77.8%) presented with M1 disease. Median OS was 7.8 months for the entire RMC cohort, with 1- and 3-year OS of 34% and 11%, respectively. Notably, median OS for patients presenting with M1 and M0 disease was 5.2 months versus 11.2 months, respectively (p&lt; 0.01). On multivariable analysis, treatment with RN (HR 0.40; p=0.003) or RN+MMT (HR 0.44; p&lt;0.001) were associated with decreased ACM, whereas the presence of metastatic disease at diagnosis remained associated with an increased risk of ACM (HR 1.74; p=0.02). Conclusions: The prognosis for patients with RMC is dismal, with a median OS under 8 months. Further studies, including the development of novel therapies, are needed to establish the optimal multimodal management approach for these patients.
A phase II trial of bevacizumab and erlotinib as second line therapy for advanced hepatocellular carcinoma.
Authors: Ahmed Omar Kaseb, Humaid Obaid Al-Shamsi, Jeffrey Morris, Michiko Iwasaki, Lianchun Xiao, Reham Abdel-Wahab, Kanwal Pratap Singh Raghav, Manal Hassan, Hesham M. Hassabo, Robert A. Wolff
Journal: Journal of Clinical Oncology (2015)

4088 Background: The objective of the study was to evaluate the efficacy and tolerability of bevacizumab (B) and erlotinib (E) combination as second line therapy for advanced hepatocellular carcinoma (HCC). Methods: Patients who had advanced HCC that was not amenable to surgical or regional therapies, had shown progression with sorafenib therapy; Childs-Pugh score A or B liver function; Eastern Cooperative Oncology Group performance status 0, 1, or 2 received bevacizumab 10 mg/kg every 14 days and erlotinib 150 mg orally daily, continuously, for 28-day cycles. The tumor response was evaluated every 2 cycles by using Response Evaluation Criteria in Solid Tumors Group criteria. The primary objective will be to assess progression-free survival (PFS) measured at 16 weeks following initiation of therapy .The secondary objective will be to assess time to progression (TTP) and overall survival (OS). Results: A total of 44 patients were included. PFS at 16 weeks was 43% (95% CI 28% -59%), the Median TTP was 3.9 months (95% CI 2.0-8.3) and median overall survival (OS) was 9.9 months (95% CI, 8.3-15.5). Grade 3-4 adverse events included fatigue (13.3%), acne (11.1%), diarrhea (8.8%), anemia (6.6%), upper gastrointestinal hemorrhage (6.6 %). Conclusions: Bevacizumab and Erlotinib combination showed promising activity in this first US study in the second line setting. Validation studies are warranted. Clinical trial information: NCT01180959.
First-in-human phase I study of a selective VEGFR/FGFR dual inhibitor sulfatinib in patients with advanced solid tumors.
Authors: Jian-Ming Xu, Yan Wang, Lin Shen, Jifang Gong, Cheng Huang, Chen Yang Ye, Li Yang, Yang Sai, Hua MU
Journal: Journal of Clinical Oncology (2012)

3040 Background: Sulfatinib is a highly selective oral small molecule tyrosine dual inhibitor of vascular endothelial growth factor receptors (VEGFR) and fibroblast growth factor receptors (FGFR). It demonstrated potent in vivo inhibitory effects on a variety of human tumor xenografts. Methods: This phase I dose-escalation study were to determine the maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), pharmacokinetics (PK) profile, and preliminary antitumor activity, and to assess potential pharmacodynamics (PD) markers of sulfantinib when given orally in continuous cycles of 28 days, until disease progression or unacceptable toxicity. Results: Forty one patients (pts) have been enrolled and treated with doses of 50-300mg once or twice daily. Pts had a median age of 50 (36-70) yrs, with 63% male and 93% gastrointestinal tumors. Common adverse events (AEs) included fatigue, hypertension, vomiting, nausea, diarrhea, electrolyte disorder and elevated AST/ALT, mostly grade (G) 1/2. Three DLTs including a G3 coagulation disorders, upper gastrointestinal bleeding and impaired liver function were observed in the 50 and 265mg qd and 150mg bid cohorts, respectively. MTD has not been reached and the dose escalation is ongoing. Among 28 evaluable pts, 10 (36%) had stable disease (SD) for 8 weeks or longer, including liver and neuroendocrine cancer, GIST and solid-pseudopapillary tumor of pancreas. A patient with GIST had SD of 9 months at 265mg qd. There was a significant decrease in soluble VEGFR2 level and increase in FGF23 level after 4-week treatment comparing to the baseline at 265 mg or higher daily doses, indicating inhibition of both VEGFR2 and FGFR. PK analyses showed that sulfatinib was rapidly absorbed with Tmax 1.3~2.8h and half-life of 15.3~19.1h. Both Cmax and AUC displayed dose-proportional increases and no obvious accumulation occurred at day 28. Conclusions: Sulfatinib was well tolerated at doses up to 300 mg per day and demonstrated preliminary anti-tumor activity, especially in liver cancer and GIST. PD marker analysis indicates dual inhibition of VEGFR and FGFR. PK data suggests good dose proportionality in exposure without marked drug accumulation.