tbuckley/cabot-search huggingface dataset:
Neuroendocrine differentiation patterns in metastases from advanced prostate cancer.
Authors: Rafael E. Jimenez, Debashis Nandy, Rui Qin, Rachel Carlson, Winston Tan, Manish Kohli
Journal: Journal of Clinical Oncology (2014)

5085 Background: Neuroendocrine differentiation (NED) in advanced prostate cancer (APC) is considered an aggressive phenotype with poor outcome and limited treatment options. Diagnosis depends on histological confirmation, which is not routinely performed during clinical care. Thus, information on NED in metastatic APC is rather limited. We evaluated an archival set of metastatic site biopsies (MSB) to determine NED expression patterns in APC. Methods: We searched medical and pathological databases for APC patients (pts) who underwent MSB during routine clinical care. Formalin-fixed, paraffin-embedded tissue sections were analyzed by immunohistochemistry (IHC) for expression of chromogranin-A (CGA) and synaptophysin (SYN), and graded as 0, 1+, 2+, or 3+, according to staining in none, <10%, 11-50%, or >50% of tumor cells, respectively. A score of 1+ or greater was considered positive. NED was considered present if positivity for either marker was observed Results: From 1994 to 2013, 237 MSB from 187 pts were identified (39, 9, and 2 pts had two, three and four MSB, respectively). MSB included bone (102), lung (40), liver (40), lymph node (20), bladder (14), soft tissue (11), brain (4), others (4). All tumors were adenocarcinomas or poorly differentiated carcinomas. No small cell carcinomas were identified. A total of 183 MSB from 157 pts were successfully stained for both markers, of which 92 MSB (50%) from 79 pts (50%) showed positive NED (72/142 1st, 16/29 2nd, 3/6 3rd, and 1/1 4th MSB). In 7 of these patients the NED was demonstrated in a successive MSB, after a negative 1stMSB. NED expression was positive in 41% bone sites, compared to 53% of non-bone sites (p=0.112). Clinical annotation was available for 72 pts, of which 47 underwent MSB during hormone sensitive stage (HSPC) and 25 during castrate resistant (CRPC) stage (median PSA 5.6 and 7.5 ng/ml, respectively). NED expression was observed in 21 (44%) HSPC cases, and 14 (56%) of CRPC cases (p=0.36). Conclusions: NED in APC was more common in this cohort than historically reported. This may have relevant prognostic or therapeutic implications. More than one MSB may be necessary to document NED in a patient with APC, as patterns of NED may vary within the same patient.
Overall survival beyond first-line docetaxel in patients with metastatic castrate-resistant prostate cancer treated with abiraterone acetate or enzalutamide.
Authors: Mi Hwa Heo, Se Hoon Park, Hee Kyung Kim, Jinhyun Cho, Youjin Kim, Hansang Lee
Journal: Journal of Clinical Oncology (2017)

e570 Background: In post-docetaxel setting of metastatic castrate-resistant prostate cancer (mCRPC), survival benefit with abiraterone acetate or enzalutamide is well established. This retrospective study was performed with the data obtained our cancer chemotherapy registry to evaluate real-world mCRPC patient outcomes. Methods: All consecutive patients treated with either abiraterone acetate or enzalutamide in post-docetaxel setting between 2013 and 2014 were included. The decision for administering second-line agents was, in most cases, at the discretion of the treating oncologists. The primary endpoint of this study was overall survival (OS), and the secondary endpoints included safety, prostate-specific antigen (PSA) response ( ≥ 50% decline) and progression-free survival (PFS). Univariate and multivariate analyses for OS were performed on the recognized baseline parameters and therapy. Results: A total of 54 eligible mCRPC patients received either abiraterone acetate (n = 25) or enzalutamide (n = 29). At the time of commencing second-line therapy, the patients’ median age was 70 years (range, 45-86) and 30 patients (56%) had a symptomatic disease. Visceral disease was present in 12 patients, and 12 had bone-only metastasis. Both were well-tolerated without significant toxicities. PSA response was observed in 36% and 52% for abiraterone acetate and enzalutamide, respectively. The estimated median PFS and OS were 5 and 15 months, respectively. Multivariate analysis revealed that the presence of clinical symptoms was the only independent prognostic factor for OS. Conclusions: Within the limitation of small sample size, the results are consistent with existing literature suggesting that both abiraterone acetate and enzalutamide appear to be effective as second-line therapy for docetaxel-pretreated mCRPC.
New tool for monitoring molecular response in chronic myeloid leukemia.
Authors: Talha Badar, Rajyalakshmi Luthra, Hagop M. Kantarjian, Elias Jabbour, Gautam Borthakur, Naval Guastad Daver, Xuelin Huang, Rajesh Singh, Brittany Alvarez, Tom Morrison, Jorge E. Cortes
Journal: Journal of Clinical Oncology (2015)

e22136 Background: CML monitoring by PCR methodology has improved test sensitivity over cytology but suffers from inadequate standardization in most labs due to variations inherent in the existing method. Standardized nucleic acid quantification (SNAQ)test is anovel competitive template based peripheral blood b2a2/b3a2 transcript abundance method. It uses mixtures of b2a2 or b3a2 and GusB competitive templates and melting curve analysis to provide desired quality controls. A pilot study was conducted to evaluate the imprecision and linearity of real-time qPCR laboratory developed test (LDT) and SNAQ for monitoring BCR-ABL. Methods: Thirty six CML patients treated at our institution were enrolled in this pilot study. Their peripheral blood samples were analyzed for BCR-ABL by LDT and SNAQ method at MD Anderson Molecular Diagnostic Laboratory (L1 and S1) and Cancer Genetics Institute (L2 and S2). Results: Each test result (n = 36) was ranked against all the other samples tested by the same method. The Pearson correlation between SNAQ and LDT was met with correlations of 0.97, 0.96, 0.96, and 0.94 with L1 xS1, L1x S2, L2xS1 and L2 xS2 respectively. ANOVA of log %BCR-ABL interlaboratory results indicated a significant difference between LDT methods (p < 0.001), but not with the SNAQ methods (p = 0.98). Imprecision was estimated using the Bland-Altman method and indicated that sample results from L2 had outlier. However, L1 PCR results had significant correlation with S1 and S2 results (p < 0.007). The linear regression analysis indicated L2 LDT was a source of method bias and had quality assurance issue. Post hoc analysis of method agreement showed the SNAQ method did not generate any outliers and had a 95% limit of agreement of ±3-fold between laboratories, whereas L1 and L2 LDT method had significant differences despite reporting in international scale, with 95% limit of agreement of 2 to 20-fold. Conclusions: In this pilot study, SNAQ methodology performed well suggesting it might be able to overcome some of the limitations encountered by some of the LDT currently in clinical practice. Additional studies with more patients and correlation with clinical outcomes are required to confirm this observation.
The PACOVAR-trial: A multicenter phase I trial of pazopanib (GW786034) and metronomic cyclophosphamide in patients with recurrent platinum-resistant ovarian cancer.
Authors: Michael Hans Robert Eichbaum, Marcus Schmidt, Eva-Maria Grischke, Gerhard Gebauer, Hans-Christian Fricke, Florian Lenz, Esther Bischofs, Markus Wallwiener, Frederik Marme, Andreas Schneeweiss, Christof Sohn, Joachim Rom, Christine Mayer
Journal: Journal of Clinical Oncology (2015)

5557 Background: A combined therapy consisting of the investigational anti-VEGFR tyrosine kinase inhibitor pazopanib (GW786034, paz) and metronomic oral cyclophosphamide may offer a well-tolerable treatment option to patients with recurrent platinum-resistant epithelial ovarian cancer (EOC). Methods: This study was designed as a multicenter phase I trial evaluating the optimal dose for paz as well as activity and tolerability of a combination regimen consisting of paz and metronomic cyclophosphamide 50mg daily p.o. in monthly cycles. Patients with histologically proven recurrent platinum-resistant EOC were included. Dose escalation of paz followed a phase I design in three dose levels (DL) of 400mg, 600mg and 800mg daily p.o. , respectively. Toxicity and survival data were obtained. Results: 16 patients were treated within this trial, mean age was 66 years. In DL I and II one dose limiting toxicity (DLT) was seen in one patient out of six (AST-elevation, hypertonus). Within DL III, two patients out of four showed a DLT (AST-elevation), leading to a maximum tolerated dose (MTD) of 600mg paz daily. Median number of administered cycles was 6 (2-13), with three patients being treated for at least 13 months. Median progression-free survival (PFS) and overall survival (OS) were 6.7 months and 15.2 months, respectively. A total of 254 adverse events (AE) occurred. The most often documented AE were leukopenia in 14.6% of the cases, followed by elevation of ALT (10.2%) and elevation of AST (9.5%). Moreover, 27 AE were probably or very likely related to cyclophosphamide (10.6%) and 55 AE were probably or very likely related to paz (21.7%). A total of five serious adverse events (SAE) occurred in four patients. The events were hypertension as well as sepsis, vomiting, ileus and fatigue. Besides sepsis, which had a fatal outcome, all other SAE were recovered. Conclusions: Paz 600mg daily p.o. and metronomic cyclophosphamide 50mg daily p.o. is a feasible regimen for patients with platinum-resistant recurrent, pre-treated EOC. Further evaluation of this palliative regimen in phase II setting is warranted. Clinical trials information: NCT01238770. Clinical trial information: NCT01238770.
Clinical and correlative science results in a phase II study of UCN-01in combination with irinotecan in recurrent triple-negative breast cancer (TNBC).
Authors: Cynthia X. Ma, Matthew J. Ellis, Gina R. Petroni, A. Craig Lockhart, Michael Naughton, Timothy J. Pluard, Christiana Brenin, Joel Picus, Allison N Creekmore, Tibu N. Mwandoro, Zhanfang Guo, Shirong Cai, Christine Ryan, Erin Yarde, Jeremy Hoog, Janet Dancey, Mark Watson, Helen Piwnica-Worms, Paula M. Fracasso
Journal: Journal of Clinical Oncology (2012)

3047 Background: Chk1 inhibitors enhance chemotherapy efficacy by inducing “mitotic catastrophe” in p53 deficient TNBC preclinical models. Irinotecan (I) combined with UCN-01, a nonselective Chk1 inhibitor, showed promising activity in TNBC in our phase I study. The primary objective of the phase II trial was to determine the efficacy and toxicity. Correlatives included assessing tumor molecular subtype, TP53, PTEN and pathways targeted by UCN-01. Methods: Pts with measurable, metastatic (met) TNBC, prior anthracycline (A) and taxane (T), received I (100-125 mg/m 2 IV on days (d) 1, 8, 15, 22) and UCN-01 (70 mg/m 2 IV on d2 and 35 mg/m 2 on d23 and later doses) on a 42-d cycle (C). Archival tumors and serial peripheral blood mononuclear cells (PBMC) and optional tumor biopsies were collected. Results: Twenty five pts were enrolled. All had prior A and T. The median no. of prior regimens for met disease was 3 (range 1-4). Toxicities included neutropenia, diarrhea, nausea, vomiting, and hyperglycemia. Best responses included 1 PR, 8 SD (range 2.3-8.6 mos) for a clinical benefit rate (CR+PR+SD&gt;6 mos) of 3/25 (12%), 95% CI (3, 31%). The median PFS and OS were 2.3 and 11.3 mos, respectively. pS6 was examined since UCN-01 inhibits PDK1. pS6 was reduced in PBMC 24h post UCN-01, but close to baseline by d8. Immunostain of cleaved caspase 3 (CC3), pHistone H3 (pHH3), γH2AX, and pS6 were done on serial biopsies from 4 pts with adequate biopsy materials. In all cases, pS6 was reduced 24h post UCN-01. Results for other markers were variable. One case with TP53 deletion showed an induction of CC3, with an increase in pHH3 and γH2AX, suggesting abrogation of cell cycle arrest and enhanced DNA damage. Among 15 with sufficient specimen for analysis, most were basal-like (basal 10, basal/HER2-E 1, HER2-E 2, Luminal B 2) by PAM50, low in PTEN level (11) and carried mutations in TP53 (8). Median OS was 5.5 (95% CI: 2, 11.3) mos in TP53 mutant and 20.3 (95% CI: 2.9, - ) mos in wild type populations (p=0.004). Conclusions: This regimen had limited activity in TNBC. Despite the long half-life, drug activity is not detectable by d8 based on PBMC analysis. Our data indicates that future trials in TNBC should consider p53 status.
Clinical, Hematological, and Biologic Characteristics in Chronic Myelomonocytic Leukemia Patients with a JAK2 V617F Mutation
Authors: Klaus Geissler, Agnes Barna, Eva Jäger, Temeida Alendar, Elmir Ljubuncic, Ruth Jilch, Thomas Nösslinger, Michael Pfeilstöcker, Heinz Tüchler, Regina Reisner, Thamer Sliwa, Felix Keil, Sonja Burgstaller, Josef Thaler, Sigrid Machherndl-Spandl, Otto Zach, Ansgar Weltermann, Peter Bettelheim, Reinhard Stauder, Ilse Schwarzinger, Gregor Hörmann, Ulrich Jäger, Wolfgang R. Sperr, Paul Knöbl, Bruno Schneeweiss, Jörg Berger, Rajko Kusec, Leopold Öhler, Armin Zebisch, Heinz Sill, Ulrich Germing, Peter Valent
Journal: Blood (2016)
BARIS: A phase I trial to evaluate the safety and tolerability of combined BIBF 1120 and RAD001 in solid tumors and to determine the maximum tolerated dose (MTD) of the combination.
Authors: Matthias Scheffler, Lucia Nogova, Masyar Gardizi, Marc Christiaan Allardt Bos, Irini Papachristou, Martin Sos, Thomas Zander, Christian Mattonet, Juergen Wolf
Journal: Journal of Clinical Oncology (2012)

TPS3115 Background: Simultaneious inhibition of several signallingpathways involved in angiogenesis as well as in tumor cell growth regulation by kinase inhibitor combination therapy may increase therapeutic efficacy. Here we evaluate the combination of the mTOR-inhibitor RAD001 (everolimus) and the triple kinase (FGFR, VEGFR, PDGFR) inhibitor BIBF 1120in a phase I trial in advanced solid tumors.In addition we use DCE-MRI for early identification of patients with benefit from BIBF 1120. Methods: This is an open-label, monocentric phase I trial with three dosage arms in a classical "3+3" design: Patients in arm A receive 5 mg of RAD001 and 2 x 150 mg BIBF 1120, in arm B 10 mg RAD001 and 2 x 150 mg BIBF 1120 will be administered, whereas in arm C, 10 mg of RAD001 and 2 x 200 mg BIBF 1120 will be given. There is no interindividual dose escalation, and the enrollment of the patients will be performed sequentially. Eligible are all patients with relapsed or refractory advanced/metastatic solid tumors (UICC stage IV) and an ECOG performance state of 0-1 for whom no further standard therapies are available and who have predefined adequate organ functions. All patients will start with a 2-week run-in phase of 2 x 200 mg BIBF 1120. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) scans will be performed at baseline staging, on day 3 and day 14. On day 14, there will also be 12 hours-pharmacokinetic (PK) assessment. Combination therapy within the forementioned dosage arms starts on day 15. After two weeks of combination therapy, on day 29, a DCE-MRI scan and 12-hours PK will be performed. Restaging for the evaluation of the efficacy will be performed on day 57. The safety of this combination will be assessed throughout the complete therapy phase using CTC-AE V4.0, with predefined dose-limiting toxicities (DLTs) being assessed until day 42. Patients who experience clinical benefit (i.e., response or stable disease) on day 57 with adequate tolerability of the combination will further receive the medication, as long as the benefit lasts. The trial is registered under NCT01349296 (clinicaltrials.gov). Recruitment in arm A has started in February 2012.
Characterization of tumor mutation burden (TMB) in gastrointestinal (GI) cancers.
Authors: Mohamed E. Salem, Joanne Xiu, Benjamin Adam Weinberg, Wafik S. El-Deiry, Louis M. Weiner, Zoran Gatalica, Zhuqing Liu, Hesham El Ghazaly, Nianqing Xiao, Jimmy J. Hwang, Philip Agop Philip, Anthony Frank Shields, Heinz-Josef Lenz, John Marshall
Journal: Journal of Clinical Oncology (2017)

530 Background: GI cancers are generally insensitive to immune checkpoint inhibitors (ICIs). Response to ICIs has been shown to correlate with TMB. Herein, we attempt to quantify TMB in GI cancers and its correlation with PD-1/PDL-1 expression. Methods: Tumor from various GI sites: right-sided and left-sided colon cancers (RT and LT), rectal cancer (RC), small bowel adenocarcinoma (SBA), gastric adenocarcinoma (GA), anal cancer (SCCA), hepatocellular carcinoma (HCC), esophageal adenocarcinoma and squamous cell carcinoma (EA and E-SCC), biliary cancer (BC), pancreatic adenocarcinoma (PA), and pancreatic neuroendocrine tumors (PNET), were analyzed by NextGen sequencing. TMB was calculated using only somatic nonsynonymous missense mutations sequenced with a 592-gene panel. MSI was assessed by fragment analysis. Correlation of PD-1/PD-L1 expression with TMB was calculated by student’s t test. Results: In total, 1375 tumors were examined. Among the different GI cancer types, RT and LT had the highest TMB (mean: 11.6 and 9.9 mutations [mut]/megabase [MB]), whereas BC and PA had the lowest levels (mean: 5.7 and 4.9 mut/MB) (Table). Overall primary tumors had higher TMB than metastases (mean: 8.3 vs. 6.5 mut/MB, p = 0.037). Using a cut-off of 17 mut/MB to define high vs. low TMB, high TMB was seen in all 24 MSI-H and 2 MSS colon tumors with POLE mutations, but not in other MSS colon tumors (n = 325, p &lt; 0.0001). Similarly, among 6 GA tumors tested for MSI, high TMB was seen in 2 MSI-H while low TMB was seen in the 4 MSS tumors. Overall high TMB was seen most frequently in RT (12%), GA (11%), and SCCA (8%), and least frequently in PA (1.3%) and E-SCC (0%). PD-1 correlated with TMB in some tumor types (RT and RC), as did PD-L1 (RT and HCC). Conclusions: TMB varies among GI cancers. Forthcoming prognostic analysis to assess the correlation between TMB and response to ICIs in GI cancers is underway. [Table: see text]
Trends in Thyroid Cancer Incidence and Mortality in the United States, 1974-2013
Authors: Hyeyeun Lim, Susan S. Devesa, Julie A. Sosa, David Check, Cari M. Kitahara
Journal: JAMA (2017)

Thyroid cancer incidence has increased substantially in the United States over the last 4 decades, driven largely by increases in papillary thyroid cancer. It is unclear whether the increasing incidence of papillary thyroid cancer has been related to thyroid cancer mortality trends.To compare trends in thyroid cancer incidence and mortality by tumor characteristics at diagnosis.Trends in thyroid cancer incidence and incidence-based mortality rates were evaluated using data from the Surveillance, Epidemiology, and End Results-9 (SEER-9) cancer registry program, and annual percent change in rates was calculated using log-linear regression.Tumor characteristics.Annual percent changes in age-adjusted thyroid cancer incidence and incidence-based mortality rates by histologic type and SEER stage for cases diagnosed during 1974-2013.Among 77 276 patients (mean [SD] age at diagnosis, 48 [16] years; 58 213 [75%] women) diagnosed with thyroid cancer from 1974-2013, papillary thyroid cancer was the most common histologic type (64 625 cases), and 2371 deaths from thyroid cancer occurred during 1994-2013. Thyroid cancer incidence increased, on average, 3.6% per year (95% CI, 3.2%-3.9%) during 1974-2013 (from 4.56 per 100 000 person-years in 1974-1977 to 14.42 per 100 000 person-years in 2010-2013), primarily related to increases in papillary thyroid cancer (annual percent change, 4.4% [95% CI, 4.0%-4.7%]). Papillary thyroid cancer incidence increased for all SEER stages at diagnosis (4.6% per year for localized, 4.3% per year for regional, 2.4% per year for distant, 1.8% per year for unknown). During 1994-2013, incidence-based mortality increased 1.1% per year (95% CI, 0.6%-1.6%) (from 0.40 per 100 000 person-years in 1994-1997 to 0.46 per 100 000 person-years in 2010-2013) overall and 2.9% per year (95% CI, 1.1%-4.7%) for SEER distant stage papillary thyroid cancer.Among patients in the United States diagnosed with thyroid cancer from 1974-2013, the overall incidence of thyroid cancer increased 3% annually, with increases in the incidence rate and thyroid cancer mortality rate for advanced-stage papillary thyroid cancer. These findings are consistent with a true increase in the occurrence of thyroid cancer in the United States.
Phase I study of gemcitabine (G), dasatinib (D), and erlotinib (E) in advanced pancreatic carcinoma (PC).
Authors: Dana Backlund Cardin, Laura Williams Goff, Emily Chan, Jennifer Whisenant, Lori R. Arlinghaus, Thomas Yankeelov, Tatsuki Koyama, Jordan Berlin, Nipun B. Merchant
Journal: Journal of Clinical Oncology (2017)

315 Background: The combination of E with G remains the only approved targeted therapy for PC based on significant, yet modest, improved overall survival when compared to G alone in a phase III clinical trial. We have shown previously that adding the Src inhibitor D with E and G resulted in synergistic attenuation of tumor growth in vivo. The purpose of this study was to assess the safety of D given with E and G. Methods: This investigator-initiated study used 3+3 dose-escalation to determine the maximum tolerated dose in advanced PC patients (pts). Dose escalation started at 70 mg daily of D, 100 mg daily of E, and G on days 1, 8, and 15 (800 mg/m 2 ) of a 28-day cycle. Diffusion-weighted MRI (DW-MRI) measurements (ADC) were collected prior to and at four weeks in a subset of pts (n=3). Results: Nineteen pts were enrolled. One pt experienced a DLT at the starting dose (L 0 ); however, given the side effects observed in the first two pts, D was reduced to 50 mg (L -1 ). At L -1 , one DLT was observed in 1/6 pts and the dose was re-escalated to L 0 . Zero DLTs were observed in the next four pts at L 0 thus D was escalated to 100 mg (L 1 ). Seven pts were treated at L 1 as one pt was not evaluable for safety. In this cohort, 1/6 pts experienced a DLT. Although L 1 was tolerable, dose escalation was stopped as it was felt L 1 was within the therapeutic window and escalation would enhance toxicity with minimal benefit. Most frequent toxicities (%) were anemia (89), elevated aspartate aminotransferase (79), fatigue (79), nausea (79), elevated alanine aminotransferase (74), lymphopenia (74), leukopenia (74), neutropenia (63), and thrombocytopenia (63), most Gr1/2. Zero responses were observed, but disease stabilization (SD) occurred in 9/13 (69%). Median duration of SD was 4 months, and median OS was 7.7 mos. At the time of data cutoff, two pts are still alive and in follow-up. Increase in ADC on MRI reflected a decrease in tumor cellularity suggesting therapeutic benefit; disease assessment at 8 weeks was SD. Conclusions: The most tolerable dose was determined to be 70 mg of D, 100 mg of E, and 800 mg/m 2 of G. Clinical activity of this combination was observed as SD occurred in 69% of pts. DW-MRI could be a promising technique to assess clinical benefit early during the course of therapy. Clinical trial information: NCT01660971.