tbuckley/cabot-search huggingface dataset:
A study of real-time CLIA-enabled whole genome tumor sequencing: Results for testicular cancer and sarcomatoid RCC.
Authors: Alan Haruo Bryce, Mitesh J. Borad, Rachel M. Condjella, Jan B. Egan, Mia D. Champion, Katherine S Hunt, Robert R. McWilliams, Ann E. McCullough, Ahmet Kurdoglu, Jessica Aldrich, Tyler Izatt, Sara Nasser, Alexis Christoforides, Lori Phillips, Winnie S. Liang, Michael T. Barrett, David W. Craig, John D. Carpten, A. Keith Stewart
Journal: Journal of Clinical Oncology (2014)

463 Background: The genomic assessment of cancer has been revolutionized by next-generation sequencing and is increasingly being applied in the clinic to guide therapeutic decision-making. Time to reporting of results, specimen quantity, and analyte quality have constrained initial clinical applications to gene panels and whole exome based strategies. Methods: Patients underwent surgical resection, excisional or core biopsies, or bone marrow biopsy. Samples were analyzed by whole genome or exome sequencing and RNA sequencing, bioinformatics analysis, and therapeutic target prioritization by a multi-disciplinary Clinical Genomics Board. All prioritized targets were CLIA validated using Sanger sequencing, RT-qPCR, FISH, or IHC as appropriate. Treatment was delivered using off-label FDA approved drugs, clinical trials, or single patient INDs. Results: We have enrolled 40 patients with advanced, treatment-refractory cancers of whom sequencing data is available on 33. The initial 6 patients were evaluated in a non-CLIA pilot phase and 27 in the CLIA enabled phase. Upon availability of the initial report, identified targets of putative therapeutic relevance were then prioritized by the CGB in 22/27 patients (81%) for subsequent CLIA validation. Eleven patients have been treated with genomically selected therapy with partial response in 3/10 assessed patients. A testicular cancer patient had aberrations in two testes specific genes, a copy number gain in TSSK6 and a novel gene fusion between thyroid hormone receptor associated protein 3 (THRAP3) and Tektin 2 (TEKT2). Additionally, a case of papillary renal cell carcinoma had an amplification of YAP1 and a previously unreported P287T mutation in CCND1, suggesting potential benefit with a CDK4/6 inhibitor. Treatment is ongoing and results will be reported. Conclusions: Integrated whole genome analysis in a CLIA setting is feasible. Integration of SNV, copy number and transcriptional data may allow for selection of putative driver genes to enhance targeted therapy decisions. Barriers for future broader implementation include the need for reduced time from biopsy to report and availability of therapies.
Efficacy of pomalidomide plus low-dose dexamethasone in multiple myeloma patients despite previous use of lenalidomide.
Authors: J. Mikhael, V. Rajkumar, V. Roy, S. R. Hayman, R. Fonseca, K. Detweiler Short, B. LaPlant, K. M. Laumann, A. Dispenzieri, M. Lacy
Journal: Journal of Clinical Oncology (2011)

8067 Background: Pomalidomide (CC4047 or Pom) is the newest oral immunomodulatory agent. It yields less neuropathy than thalidomide (thal) and less myelosuppression than lenalidomide (len). Pom/dex has demonstrated response rates (>PR) of 63% in relapsed MM (Lacy, JCO 2009) and 32% in len-refractory MM (Lacy, Leukemia 2010) using a 2mg/day dose. The MTD has been determined to be 4 mg/day but the optimal dose has not yet been defined. We report a phase II trial using the Pom 4mg with dex to study its efficacy in patients with prior len. Methods: Patients must have had 1-3 lines of prior therapy (including len). Pom 4mg daily was given orally on days 1–28 (28-day cycle) with oral dex given 40 mg daily on days 1, 8, 15 and 22. All patients received DVT prophylaxis with aspirin 325 mg daily or therapeutic anticoagulation. Results: 61 patients with relapsed MM were enrolled. Median age was 65 years (32-82), and 40 were male. Median time from diagnosis to enrollment was 37 months (1-84). Fifteen (25%) patients had high risk disease as defined by mSMART (mSMART.org). Sixty (98%) patients received prior len, 29 (47%) had bortezomib, 13 (21%) thal, 47 (77%) auto transplant and 3 (5%) allo transplant. Toxicities at least possibly attributed to drug included grade 3/4 anemia (7/0%), grade 3/4 leukopenia (27/2%), grade 3/4 thrombocytopenia (3/2%). Grade 3 non-hematologic toxicities occurred in 18% of patients and included fatigue 5%, thrombosis 5%, hyperglycemia 5% and pneumonia 5% (no grade 4). Grade 1/2 neuropathy occurred in 18/8%, (no grade 3 or 4). Twenty three (38%) patients required dose reductions in dex. Confirmed responses (>PR) were seen in 21 patients (35%), of which 7 (12%) were VGPR, 14 (23%) PR, 8 (13%) MR, 25 (42%) SD and 6 (10%) PD. Median time to response was 1.1 months (0.8-2.8). With a median follow-up 4.1 months, 67% remain progression free, and 97% remain alive. Conclusions: This large phase II demonstrates that Pom/dex is active and very well tolerated in patients who have already been treated with len. Objective response is seen in 48% despite being heavily pre-treated with IMiDs, bortezomib and transplant. This study reconfirms therapeutic benefit for Pom/dex in patients relapsing after other novel therapies.
Treatment and overall survival (OS) in metastatic renal cell carcinoma (mRCC): A Swedish population-based study (2000–2008).
Authors: Ulrika Harmenberg, Sven Lundstam, Thomas Wahlgren, Jan Kowalski, Maria Jakobsson, Rickard Sandin, Börje Ljungberg, Per Sandström
Journal: Journal of Clinical Oncology (2012)

389 Background: This retrospective register study assessed OS in all mRCC patients in Sweden diagnosed before (2000–2005) and after (2006–2008) the introduction of targeted therapies, plus factors and treatment options influencing OS. Methods: Three Swedish national health registers were used: the Swedish Cancer register (diagnosis and death), the National Patient Register (in-/out-patient data), and the Swedish Prescribed Drug Register. From 2000-2008, 3,243 patients were identified with mRCC; 602 were recorded as receiving 1st-line treatment. Cox proportional hazards regression analysis, including estimation of adjusted OS, was used in three models with the covariates: diagnosis period, age, gender, institution size, nephrectomy status, geographic region (all models); mRCC treatments, defined as any tyrosine kinase inhibitor (TKI; Model 1; n=417); sunitinib (SU), sorafenib (SO), and interferon-alfa (IFN-α) in the 1st-line setting (Model 2; n=602 [SU=244, SO=110, IFN-α=248]); and variations of these drugs as 1st- and 2nd-line treatment sequences (Model 3; n=602). Results: Amongst mRCC patients diagnosed from 2006–2008 compared with 2000–2005, median adjusted OS was 16.1 vs. 10.9 months, respectively (HR=0.76, 95% CI: 0.69, 0.83; P&lt;0.001). In all three models, factors independently associated with significantly improved OS included female gender, large institution, and prior nephrectomy. Prescription of any TKI (Model 1: HR=0.82, 95% CI: 0.73, 0.93; P=0.002) and 1st-line SU treatment (Model 2: HR=0.79, 95% CI: 0.67, 0.94; P=0.007) were associated with significantly improved OS compared with other or no treatments. A similar significant improvement in OS was also confirmed for patients treated with SU only in Model 3; however, due to a low number of observations, the model had insufficient statistical power to be appropriate for all sequences. Conclusions: An improved OS for mRCC patients was demonstrated for the period 2006-2008 compared with 2000-2005. Although the observed survival advantage is multifactorial in origin, contribution of targeted therapies is highly probable. Of the drugs studied, given design limitations, only SU was associated with improved OS.
Sorafenib and bevacizumab combination targeted therapy in advanced neuroendocrine tumor: A phase II study of the Spanish Neuroendocrine Tumor Group (GETNE0801).
Authors: D. E. Castellano, J. Capdevila, R. Salazar, J. Sastre, V. Alonso, M. Llanos, R. Garcia-Carbonero, A. Abad, I. Sevilla, I. Duran
Journal: Journal of Clinical Oncology (2011)

4113 Background: Sorafenib (S) and bevacizumab (B) as single agents have shown efficacy in NETs phase II trials. S+B combination has shown manageable toxicity in phase I trials in solid tumors. The aim of this study was to evaluate the efficacy and toxicity of the STI's combination in NETs. Methods: Phase II, controled clinical trial, carried out in 10 centers in Spain. Eligibility criteria: measurable, non-resectable, histologically confirmed moderately or well-differentiated NETs; 1 prior chemotherapy treatment allowed; ECOG PS 0–2. Duration of treatment: 6 months. Pts received S 200 mg bid (days 1 to 5 of each week) and B 5mg/Kg once every 2 weeks (day 1 of week 1). Efficacy results were calculated with intention to treat sample (n=41). Results: 44 pts were enrolled, 59.1% men. Median age was 60 years (range 32–76) and ECOG PS was 1 for 54.5% of pts. Carcinoid tumors: 31 pts and islet cell carcinoma (ICC): 13 pts were evaluated. Histology grade was well-differentiated in 95.5% of pts. Target lesions of pts at baseline were mainly in the liver (86.4%) and lymphatic nodes (31.8%). ORR (RECIST 1.1) was 9.8% and DCR 95.1%. PR was documented in 3 pts with carcinoid tumors and 1 PR with ICC. Estimated PFS was a median of 12.4 months (95%CI: 9.4-16.2) and a PFS rate at 6 months of 90.9% (30/33). A total of 8 pts finished the study prematurely: 6 due to adverse events and 2 due to consent withdraw. Most common grade 3-4 toxicities were hand-foot syndrome (20.5%) and asthenia (15.9%). No major response was observed with Chromogranin/5-HIAA analysis. Conclusions: This is the first study of targeted STI's combination in advanced NETs. The final results of the combination of low-dose sorafenib + bevacizumab showed a potential clinical benefit, albeit with moderate toxicities. Further studies should be confirm the real value of the targeted combination therapies in this setting, according to International Consensus Report (Kulke M, et al; JCO published online on January 24, 2011).
Serum 25-hydroxyvitamin D testing at Memorial Sloan-Kettering Cancer Center.
Authors: K. M. Wesa, K. S. Yeung, G. Jacobs, M. Coleton, B. R. Cassileth
Journal: Journal of Clinical Oncology (2011)

9121 Background: Vitamin D (D) is a fat soluble vitamin/hormone involved in calcium homeostasis. In vitro, animal model and clinical studies show that D affects immunomodulation, apoptosis and cellular differentiation in addition to skeletal effects. D is obtained primarily through UV exposure (sunlight) or through fortified foods (milk). A recent IOM report stated most people have sufficient vitamin D levels and that supplementation is not necessary. D testing and results of serum D levels at MSKCC were evaluated to characterize the D status of MSKCC patients. Methods: A search was performed for MSKCC patients with for whom serum vitamin D 25-hydroxy levels evaluated were taken from January 1, 2003 to June 31, 2010. Demographic information including age, race, BMI and survival status also were obtained. Results: There were 23,909 serum 25-hydroxy vitamin D tests ordered from January 1, 2003 through June 30, 2010 for 12,817 unique individuals. The largest volume of tests (57%) was performed in breast cancer patients. The next largest volume was for colorectal cancer patients (9%), followed by leukemia (7%) and lymphoma (7%). Only 311 (1.3%) of the patients with endometrial cancer had D levels obtained. 75.8% of patients were deficient in vitamin D as defined by serum levels <30 ng/ml. The median vitamin D level was 24.6 ng/ml. In 2003 there were 396 D tests ordered; 846 D tests in 2006; 1711 D tests in 2007; 3928 D tests in 2008 and 8133 D tests in 2009. The majority of patients (53%) did not have serial D testing. Conclusions: The vast majority of patients who had their serum vitamin D level monitored were deficient. An exponential increase in the volume of vitamin D tests ordered over the past 3 years was seen. Most patients are D deficient (defined by serum 25-hydroxy D < 30 ng/ml). A recent IOM consensus statement described most people as sufficient in D, however our study does not support this conclusion. Whether treating D deficiency would improve patient outcome remains to be determined. D status should be considered for all patients deficiency corrected. Clinical trials evaluating D repletion and survival are warranted.
Validation of a transplant-related mortality (TRM) risk score for pediatric patients undergoing allogeneic haematopoietic stem cells transplantation.
Authors: P. Angelini, A. Gassas, I. Zaidman, J. Doyle, T. Schechter
Journal: Journal of Clinical Oncology (2011)

6607 Background: Early risk stratification of patients undergoing haematopoietic stem cells transplantation (HSCT) is essential to allow timely intervention, and compare results among different Institutions. Reliable risk scores are missing in the paediatric setting. Bacigalupo et al identified bilirubin and blood urea nitrogen levels at day 7 post transplantation as early predictors of outcome. Recently, a TRM risk score has been developed and validated in a paediatric European series of patients (Matthes-Martin score). We validated the Matthes-Martin score in our Institution’s allogeneic HSCT series. Methods: A retrospective data collection of all pediatric patients age 0-18 years of age that underwent allogeneic HSCT between April 2002- March 2007 was done. Survival analysis was performed considering death from primary disease as competing factor. Total TRM and 1-year TRM were correlated with individual risk factors and Matthes-Martin and Bacigalupo scores Results: During the study period 221 HSCT were performed in 198 patients. One patient was lost to follow-up, leaving 220 HSCTs evaluable (119 males, median age at HSCT 6.9 years, range 3 months -17.7 years). 127 HSCTs were performed for malignant disease, and 93 for benign diseases. A total of 47 TRMs occurred (21.4%), 43 of which during the first year post transplant. Type of donor (matched sibling v alternative, Log Rank test P=0.009), GvHD prophylaxis (Cyclosponine-Methotrexate v Cyclosporine-methylprednisone or other, Log Rank test P=0.003), prior BMT (Log Rank test P<0.01) and development of grade III-IV acute (Log Rank test P<0.001) or extensive chronic GvHD (Log Rank test P<0.001) correlated with 1-year TRM. Both Bacigalupo score and Matthes-Martin correlated with 1-year TRM (Log Rank test P=0.006 and P=0.045 respectively) and total TRM (Log rank test P=0.002 and P=0.037 respectively). Positive and negative predictive values for Bacigalupo and Matthes-Martin scores were comparable. Conclusions: Matthes-Martin and Bacigalupo scores were comparable in predicting total and 1-year TRM in our series.
Comparative benefits of nab-paclitaxel over gemcitabine or polysorbate-based docetaxel in experimental pancreatic cancer.
Authors: Niranjan Awasthi, Katherine T Ostapoff, Changhua Zhang, Margaret A. Schwarz, Roderich Schwarz
Journal: Journal of Clinical Oncology (2013)

192 Background: Gemcitabine (Gem), a standard cytotoxic therapy for pancreatic cancer, has shown limited clinical benefits. Nanoparticle albumin-bound (nab) paclitaxel (NPT), an approved treatment for breast cancer, has shown efficacy as mono- and combination therapy in multiple tumor types including pancreatic, lung and ovarian cancer. We evaluated the NPT treatment benefits compared with Gem or solvent-based taxane docetaxel (DT) in experimental pancreatic cancer. Methods: In vitro cell proliferation and protein expression were measured by WST-1 assay and immunoblotting. Tumor growth and animal survival studies were performed in murine xenografts. Intratumoral proliferative activity was measured using Ki67 nuclear antigen staining. Results: For AsPC-1, BxPC-3, MIA PaCa-2 and Panc-1 cells in vitro, Gem IC 50 levels were 23.9 mM, 506 nM, 332 nM and 14.5 nM; DT IC 50 levels were 30 nM, 4.6 nM, 37.5 nM and 27 nM; and NPT IC 50 levels were 7.6 mM, 208 nM, 519 nM and 526 nM. NPT addition decreased Gem IC 50 to 1.7 mM, 189 nM, 123 nM and 913 nM; DT addition decreased Gem IC 50 to 436 nM, 470 nM, 124 nM and 0.2 nM in AsPC-1, BxPC-3, MIA PaCa-2 and Panc-1 cells, respectively. NPT and DT treatment increased stathmin phosphorylation and decreased tubulin expression in vitro. In a heterotopic in vivo model, net tumor growth inhibition after Gem, DT and NPT was 67, 31 and 72 percent, while intratumoral proliferative index inhibition was 41, 53 and 68 percent, respectively. In an intraperitoneal model, median animal survival was significantly longer in the NPT treatment group (41 days, p&lt;0.002 vs. control and Gem) compared to Gem (32 days, p=0.005 vs. control), DT (32 days, p=0.005 vs. control) and controls (20 days). Animal survival in NPT-Gem and DT-Gem sequential treatment groups was 43 and 40 days, and thus not superior to NPT alone. Conclusions: Nab-paclitaxel has significantly superior antitumor activity as a single agent in experimental pancreatic cancer compared with gemcitabine or docetaxel. These findings provide a strong rationale for considering nab-paclitaxel as first-line monotherapy in patients with pancreatic cancer.
A phase II and pharmacokinetic trial of oral S-1 combined with gemcitabine (GEM) in patients with metastatic pancreatic cancer (MPC)
Authors: K. Nakamura, T. Yamaguchi, T. Ishihara, K. Sudo, A. Kobayashi, H. Tadenuma, H. Ishiguro, H. Saisho
Journal: Journal of Clinical Oncology (2005)

4114 Background: We have conducted the phase II trial of GEM with S-1, oral fluorouracil (5-FU) prodrug tegafur combined with two modulators, 5-chloro-2, 4-dihydropridine and potassium oxonate to evaluate the activity, toxicity, and pharmacokinetics of such combination in MPC patients. Methods: Eligibility criteria were pathologically-proven pancreatic cancer with metastatic lesions, appropriate performance status 0 to 2, age 20 to 74 years, adequate hematological, renal and liver functions, no prior chemotherapy, and written informed consent. S-1 was given orally (30mg/m2) bid for 14 consecutive days and GEM (1000mg/m2) was given on day 8 and 15. Cycle was repeated every 21 days. Results: 28 MPC patients were enrolled from September 2003 to September 2004. Median number of cycles was 8 (range 1 to 13). Out of total 28 evaluable patients, objective responses were observed in 14 patients (50%); 8 patients achieved stable disease and 6 patients showed disease progression. Median survival was 8.8 months (95% c.i.: 7.9 - 9.6 months). The grade 3–4 toxicities observed were leucopenia (32%), neutropenia (46%), anemia (11%), thrombocytopenia (11%), anorexia (4%), fever (7%), and interstitial pneumonia (7%). Pharmacokinetic parameters (5-FU: Cmax 94.3±27.9 ng/mL, AUC0–8 440.1±108.7 ng · hr/mL, Tmax 3±1 hrs, T1/2 2.4±0.7 hrs, GEM: Cmax 20349±3042 ng/mL, AUC0-∞ 11705±1919 ng · hr/mL, Tmax 3±1 hrs, T1/2α 2.7±1.8 min, T1/2β 20.0±3.5 min) with the administrations of oral S-1 combined GEM on day 8 in 6 patients with MPC were similar to those with administrations of S-1 on day 7 or GEM alone [J Clin Oncol.,1991;9(3):491–498]. Conclusions: The combination chemotherapy with GEM and S-1 was well tolerated and significantly high response rate has been observed. This result is very promising but survival benefit against GEM monotherapy should be demonstrated in future phase 3 studies. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Eli Lilly Japan
Correlation of elevated ALCAM shedding with patient outcome in colorectal cancer.
Authors: Amanda Georgia Hansen, Tanner Freeman, Mary Kay Washington, Kang-Hsien Fan, Yu Shyr, R. Daniel Beauchamp, Andries Zijlstra
Journal: Journal of Clinical Oncology (2012)

46 Background: ALCAM (Activated Leukocyte Cell Adhesion Molecule) is a cell-cell adhesion protein that has been highlighted as a putative biomarker for the progression of many cancers, including colorectal cancer (CRC). Current prognosis for CRC patients predominantly rely on pathologic staging classification. Although TNM staging successfully stratifies high-risk patients, there is significant variability in the rate of disease progression within each stage. Previous studies evaluating ALCAM as a biomarker for predicting colorectal cancer patient survival have published conflicting and inconclusive results. The aim of this present study was to investigate the prognostic value of ALCAM shedding, quantified using a dual stain that detects both the extracellular and the intracellular domains in formalin-fixed tissue, in colorectal patients. Methods: A novel dual-immunohistological detection of ALCAM shedding was performed on tissue microarrays constructed from 75 colorectal primary tumors and 9 healthy control specimens. Tissue was assessed by CellProfiler image analysis to obtain quantitative estimates of ALCAM shedding, defined as the detection of the intracellular domain the absence of the extracellular domain of ALCAM. Two tailed p values ≤ 0.05 were considered to be statistically significant. Results: ALCAM shedding was elevated in 33/79 (41.8%) of tissue from CRC patients compared to healthy controls (p=0.0239). Univariate analysis of CRC patients, stages I-IV, revealed a statistical significance correlating high ALCAM shedding with worse overall survival (p=0.0401). Moreover, ALCAM shedding is a predictor of overall survival (p=0.432) and more notably, disease-specific survival in stage II patients (p=0.0098). Conclusions: Detection of ALCAM shedding allows for stratification of patients according to their risk for poor long-term outcome. Considering that ALCAM is altered in a number of malignancies, the clinical correlation of ALCAM shedding to patient outcome is likely to extend beyond CRC to other cancers.
Identification of Serum Lactate Dehydrogenase (LDH) As an Independent Prognostic Biomarker in Polycythemia Vera
Authors: Ayalew Tefferi, Daniela Barraco, Sonia Cerquozzi, Terra L. Lasho, Curtis A. Hanson, Rhett P. Ketterling, Animesh Pardanani, Naseema Gangat
Journal: Blood (2016)