tbuckley/cabot-search huggingface dataset:
A prospective trial for defining a subset of patients with limited metastatic gastric cancer who may be candidates for bimodal treatment strategies: FLOT3.
Authors: Salah-Eddin Al-Batran, Ralf Hofheinz, Nils Homann, Gerald Illerhaus, Uwe Marc Martens, Jan Stoehlmacher-Williams, Harald Schmalenberg, Kim Barbara Luley, Nicole Prasnikar, Matthias Egger, Stephan Probst, Joerg Thomas Hartmann, Markus Hermann Moehler, Dirk Arnold, Wolfgang Fischbach, Claudia Pauligk, Wael Hozaeel, Stefan Paul Moenig, Arnulf H Hölscher, Elke Jäger
Journal: Journal of Clinical Oncology (2012)

4090 Background: The utility of surgery for metastatic gastric cancer is debated. A prospective trial was performed to evaluate a prognostic model for selecting patients (pts) treated with systemic chemotherapy (ct) who may also be candidates for surgical intervention. Methods: Using a predefined algorithm pts with untreated gastric cancer were prospectively stratified into 3 groups: operable (OD), limited metastatic (LD), or extensive metastatic (ED) disease and treated with 5-FU, oxaliplatin, leucovorin and docetaxel (FLOT). LD was defined as: distant intra-abdominal lymph node metastases only or/and a maximum of 1 organ involved, normal serum alkaline phosphatase, &lt; 5 liver lesions, no visible carcinomatosis (peritoneum or pleura), and ECOG ≤ 1. All other metastatic pts were ED. Pts with OD received 4 preoperative ct cycles followed by surgery and 4 postoperative cycles. Pts with LD received 8 cycles with surgery allowed for complete macroscopic resection. Pts with ED received 8 cycles with surgery allowed for palliation only. The study had 80% power to detect a HR of 0.55 for overall survival in favor of the LD group (vs. ED group; 2-sided log-rank p=0.05). Results: 238 of 252 pts included were eligible (OD/LD/ED: 51/60/127). LD pts had distant lymph nodes only (41%), liver (22%), lung (17%), localized peritoneal involvement (7%), or others (13%). A median of 8 ct cycles was applied to all groups. Median OS was 22.9 vs. 10.7 months in pts with LD vs. ED, respectively (HR 0.37; 95% CI, 0.25 – 0.56; p &lt;0.001). LD was the strongest predictor of OS in the multivariate analysis including all single determinants of LD status (p=.002). Surgical resection was conducted in 96%, 62%, and 12% in the OD, LD, and ED groups, of which R0 resection (primary) was achieved in 82%, 81% and 33%, respectively. Within the LD arm, operated pts had better outcome than non-operated pts (median OS 31.3 vs. 15.9 months; p=.004) and pts with lymph node only involvement had best outcome. Conclusions: This clinical model identifies a subset of pts with (limited) metastatic gastric cancer who have a favorable outcome and who may be candidates for bi-modal treatment strategies.
Erythrocyte Sialoglycoproteins Engage Siglec-9 to Maintain Neutrophil Quiescence in the Bloodstream
Authors: Anel Lizcano, Ismael Secundino, Simon Dohrmann, Ross Corriden, Lingquan Deng, Sandra Diaz, Victor Nizet, Ajit P. Varki
Journal: Blood (2016)
Brain metastases (BM) of nonseminomatous germ cell tumors (NSGCT): What population of patients should be screened?
Authors: Alexey Tryakin, Mikhail Fedyanin, Vladimir Aleshin, Zoja Mikhina, Tatiana Zakharova, Urii Sergeev, Avgust Garin, Sergei Tjulandin
Journal: Journal of Clinical Oncology (2013)

e15583 Background: BM from NSGCT present in 5-15% of pts with metastatic disease. There is no uniform consensus what population of pts with NSGCT should be screened for BM. Methods: Among 1700 pts with metastatic GCT who were treated in our center from 1990 to 2009 we identified 20 (1.1%) pts with BM: 11 pts had BM at initial presentation. No pts with BM of seminoma were identified. The minimal f.-up time after the end of treatment was 24 months. None of 9 pts with BM at relapse had brain imaging initially and 6 (67%) had BM as the only site of relapse. Since 2005 we have started routine brain MRI for all new pts with hCG level above 50000 IU/l. BM were found in 4 (14%) of 28 those pts, incl. 3 pts with asymptomatic BM. Before 2005 there were 38 pts with hCG level above 50000 IU/l and BM were seen in only 3 (7,9%) pts, who had specific symptoms. For further analysis we combined pts with initially presented BM (n=11) and pts who had BM as the only site of relapse (n=6), because in later group BM were obviously missed before 1-st line of chemotherapy. Results: Factors associated with BM were multiple (n&gt;3) pulmonary mets &gt;2cm - all 17 pts, IGCCCG poor prognosis -13 (76%) pts, initial hCG &gt; 50000 IU/l - 9(53%) pts. Among 43 pts with multiple pulmonary mets and hCG &gt; 50000 IU/l 9 (21%) pts had BM: sensitivity 53%, specificity 93%, PPV 21%, NPV 98%. Screening of BM in this population would miss 47% of them. Among 142 pts with multiple pulmonary mets and intermediate or poor IGCCCG prognosis 17 (12%) pts had BM: sensitivity 100%, specificity 76%, PPV 12%, NPV 100%. Conclusions: Pts with elevated hCG level above 50000 IU/l and multiple (n&gt;3) pulmonary mets &gt;2cm have high incidence (21%) of BM. Brain imaging of pts with multiple (n&gt;3) pulmonary mets &gt;2cm and intermediate or poor IGCCCG prognosis is recommended.
Updated results of a phase I first-in-human study of the BCL-2 inhibitor ABT-199 (GDC-0199) in patients with relapsed/refractory non-Hodgkin lymphoma (NHL).
Authors: Matthew Steven Davids, John Francis Seymour, John F. Gerecitano, Brad S. Kahl, John M. Pagel, William G. Wierda, Mary Ann Anderson, David E. Darden, Cathy E. Nolan, Lori A. Gressick, Jianning Yang, Brenda J. Chyla, Todd A. Busman, Alison M. Graham, Elisa Cerri, Sari H. Enschede, Rod A. Humerickhouse, Andrew W Roberts
Journal: Journal of Clinical Oncology (2013)

8520 Background: BCL-2 is highly expressed in NHL, including mantle cell lymphoma (MCL), and is a promising therapeutic target as it is involved in NHL pathogenesis and mediates resistance to many cytotoxics. ABT-199 is a second generation inhibitor with 500-fold higher affinity for BCL-2 (K i &lt;0.10 nM) than BCL-X L (K i =48 nM). Methods: Objectives of this Ph 1 dose-escalation study include evaluations of safety, pharmacokinetics and preliminary efficacy in patients (pts) with relapsed or refractory (R/R) NHL. A single oral dose (50-400 mg) was administered followed by 6 days off drug prior to the initiation of continuous once daily dosing. Due to concerns of potential tumor lysis syndrome (TLS), a 2 to 3 wk lead-in period with step-wise escalation to the target cohort dose was implemented. Dose cohorts up to 900 mg have been evaluated to date. Results: As of January 2013, 31 pts have been enrolled (median age 68 y (range 35-85); 20 males; median prior therapies 3 (range 1-7). 13 (42%) and 4 (13%) had bulky adenopathy (&gt;5 and &gt;10 cm, respectively). The most common AEs (≥15% of patients) were nausea (36%), diarrhea (26%), dyspepsia, vomiting, fatigue, pyrexia and cough (16% each). Gr 3/4 AEs occurring in &gt;1 patient were anemia, neutropenia (4 pts each), and febrile neutropenia (2 pts). Two of 14 pts in cohort 5 experienced DLTs at the target dose of 600 mg: Gr 3 febrile neutropenia and Gr 4 neutropenia. Although Gr 3/4 thrombocytopenia was observed in 3 pts, it was not dose dependent. Gr 3 TLS was seen after the initial dose in 1 pt with very bulky MCL (&gt;10 cm). With a median follow-up of 5 months (range 0.5-15), 17 have discontinued: 13 due to PD, 2 due to AEs and 2 who received a BMT. Of the 29 pts evaluable for efficacy, the overall best response rate was 55% with 1 DLBCL pt achieving a CR and 15 (52%) a PR (8/8 MCL, 3/3 Waldenstrom macroglobulinemia, 2/7 follicular lymphoma and 2/7 DLBCL pts). Conclusions: ABT-199 is highly active in R/R NHL, particularly in MCL. Additional dosing and scheduling modifications are currently being explored to optimize the efficacy/safety profile of this active new agent. ABT-199 warrants further single-agent and combination trials in NHL. Clinical trial information: NCT01328626.
Phase II study of irinotecan and paclitaxel for patients with recurrent small cell lung cancer (SCLC)
Authors: T. K. Owonikoko, S. Ramalingam, J. Forster, Y. Shuai, T. Evans, W. E. Gooding, M. Sulecki, C. P. Belani
Journal: Journal of Clinical Oncology (2007)

18011 Background: Recurrent SCLC has a poor prognosis and is devoid of treatment options that improve overall survival. Irinotecan and paclitaxel are both active agents against SCLC, and have synergistic preclinical interactions. We conducted a phase II study to evaluate the efficacy and safety of the combination of irinotecan and paclitaxel for patients with recurrent SCLC. Methods: Patients with SCLC who relapsed following one prior chemotherapy regimen were eligible. Other pertinent inclusion criteria were: ECOG performance status 0–2, adequate bone marrow, hepatic and renal function and willingness to provide informed consent. Patients with untreated brain metastasis were excluded. Paclitaxel (75 mg/m 2 ) and irinotecan (50 mg/m 2 ) were administered on days 1 &amp; 8 of every 3-week cycle. Treatment was continued until progression up to a maximum of 6 cycles or unacceptable toxicity. The primary endpoint was response rate. Toxicity was graded by CTC version 2.0. The simon two-stage design was utilized and the estimated sample size was 55 patients (stage I - 23 patients; stage 2 - 32 patients). The study has a 90% power to detect a response rate of 30%, with an alpha error rate of 10%. Results: 55 patients have been enrolled and complete data are available for 32 patients at the time of this report. Patient baseline characteristics are: male 53%, PS 0–44%; PS 1–47% and PS 2–6%. The median age is 61 years. Fifteen patients received ≥ 4 cycles. Salient grades 3–5 toxicities seen: neutropenia (13%), fatigue (13%); diarrhea (3%), hypersensitivity (3%) and hyponatremia (3%).The objective response rate is 37% (95% CI 19%-55%) with 9 PRs and 1 CR. Additional 8 patients (24%) had stable disease. The median survival is 19.6 weeks (95% CI 15.1–29.4) and the 1-year survival rate is 15%. Conclusions: The combination of irinotecan and paclitaxel is well tolerated and has promising anti-cancer activity in recurrent SCLC. Updated data on all 55 patients will be available at the time of the presentation. No significant financial relationships to disclose.
Crystal deposition triggers tubule dilation that accelerates cystogenesis in polycystic kidney disease
Authors: Jacob A. Torres, Mina Rezaei, Caroline Broderick, Louis Lin, Xiaofang Wang, Bernd Hoppe, Benjamin D. Cowley, Vincenzo Savica, Vicente E. Torres, Saeed Khan, Ross P. Holmes, Michal Mrug, Thomas Weimbs
Journal: Journal of Clinical Investigation (2019)

The rate of disease progression in autosomal-dominant (AD) polycystic kidney disease (PKD) exhibits high intra-familial variability suggesting that environmental factors may play a role. We hypothesized that a prevalent form of renal insult may accelerate cystic progression and investigated tubular crystal deposition. We report that calcium oxalate (CaOx) crystal deposition led to rapid tubule dilation, activation of PKD-associated signaling pathways, and hypertrophy in tubule segments along the affected nephrons. Blocking mTOR signaling blunted this response and inhibited efficient excretion of lodged crystals. This mechanism of "flushing out" crystals by purposefully dilating renal tubules has not previously been recognized. Challenging PKD rat models with CaOx crystal deposition, or inducing calcium phosphate deposition by increasing dietary phosphorous intake, led to increased cystogenesis and disease progression. In a cohort of ADPKD patients, lower levels of urinary excretion of citrate, an endogenous inhibitor of calcium crystal formation, correlated with increased disease severity. These results suggest that PKD progression may be accelerated by commonly occurring renal crystal deposition which could be therapeutically controlled by relatively simple measures.
Decreased survival in cervical cancer patients with thromboembolic events
Authors: G. M. Jacobson, M. Goodheart, B. Smith, J. Lammli
Journal: Journal of Clinical Oncology (2007)

16034 Background: We have previously reported on the incidence of thromboembolic events (TE) in cervical cancer patients treated with definitive chemoradiation.Patients with TE seemed to have decreased survival compared to those without TE. We reviewed a larger cohort to compare the survival of cervical cancer patients with and without TE. Materials and Methods: We performed a retrospective chart review of cervical cancer patients diagnosed and treated at the University for Iowa from January 1997 until December 2003. Data sources included the University of Iowa Tumor Registry, the Gynecologic Oncology Tumor Data Base, and the relevant ICD-9 codes to identify cervical carcinoma and types of TE in both inpatients and outpatients. Statistical analysis included the Pearson chi-squared test for categorical variable, and the two-sample t-test for continuous factors. Log-rank tests were used for survival analysis along with the generation of Kaplan-Meier survival curves. Multivariate analysis was performed with Cox proportional hazards regression. All tests are two sided and carried out at the 5% level of significance. Results: Three hundred and fifty nine (359) patients were treated with surgery or chemoradiation; thirty-six patients (10%) developed TE. There were significant associations between thromboembolic status and pelvic irradiation (p=0.0493), chemotherapy (p=0.0118), and stage (p=0.0197). Survival could not be estimated for patients not experiencing a thromboembolism; survival did not drop below 50% by the end of follow-up. Median survival time for patients with thromboembolism was 4.5 years. According to log-rank test, this difference was significant (p-value&lt;0.0001). Conclusion: The incidence of thromboembolic events in this cohort of cervical cancer patients was 10%. TE was associated with a significant decrease in survival. No significant financial relationships to disclose.
Potent Ex Vivo Anti-Tumor Activity in Relapsed Refractory Multiple Myeloma Using Novel DR5-Specific Antibodies with Enhanced Capacity to Form Hexamers upon Target Binding
Authors: Hilma J van der Horst, Marije B Overdijk, Esther Cw Breij, Martine Chamuleau, Henk M Lokhorst, Tuna Mutis
Journal: Blood (2017)
“Druggable” alterations detected by ion torrent in metastasis colorectal cancer patients.
Authors: Weijia Fang, Milan Radovich, Anwu Zhou, Yulong Zheng, Peng Zhao, Wenying Huang, Chenyu Mao, Yi Zheng, Yankai Jia, Shusen Zheng
Journal: Journal of Clinical Oncology (2013)

e22192 Background: The frequency and poor prognosis of metastasis colorectal cancer (mCRC) emphasizes the need of better markers for both treatment and prognosis. Here we describe an approach of identifying somatic variants in exonic regions of key cancer genes. Methods: Formalin-fixed paraffin embedded (FFPE) tissues biopsied from mCRC patients were collected. DNA was extracted and sequenced on the Ion Torrrent Personal Genome Machine.For targeted amplification, we used the Ion AmpliSeq Cancer Panel which is designed to detect 739 mutations in 604 loci from 46 oncogenes and tumor suppressor genes with as little as 10ng of input DNA.Sequencing results were then analyzed using the Ampliseq Variant Caller plug-in within Ion Torrent Suite Software. Ingenuity Pathway Software was used to do pathway analysis. Cox regression was tested regarding the potential relationship between the alteration numbers and the clinical factors including response rate, disease free survival and overall survival, etc. Results: Among 10 specimens, we identified 66 genetic alterations in 24 genes after excluding the germline mutations according the dbSNP database. 41% of those alterations were also present in the COSMIC database (Catalogue of Somatic Mutations in Cancer). No clinical factor was found to be significantly associated with the alteration numbers by univariate analysis. Notably, there are 11 genes including the expected APC, BRAF, KRAS, PIK3CA and TP53 that were mutated in at least 2 samples. Pathway analysis identified “Colorectal Cancer Metastasis Signaling” as the top mutated canonical pathway. This analysis further revealed mutated genes in the classic signal pathways of Wnt, PI3K/AKT, and TGF-beta/SMAD as significantly present. Interestingly, 90% of specimens harbored at least one “druggable” alteration (range from 1 ~ 6)that has been linked to a target treatment or is currently being investigated in clinical trials. Those pairs of drug and targeted genes are vemurafenib to BRAF; cetuximab to EGFR; palifermin to FGFR2; pazopanib to FGFR3; AEE 788 to KDR and BEZ235 to PIK3CA. Conclusions: DNA deep sequencing of key cancer related genes enables identification of “druggable” mutations for individual colorectal cancer patients.
JAK2 Variants Associated with Secondary-AML from MPN
Authors: Christopher B Benton, Prajwal C Boddu, Courtney D. DiNardo, Prithviraj Bose, Feng Wang, Naveen Pemmaraju, Devendra Kc, Sherry Pierce, Keyur P. Patel, Marina Konopleva, Farhad Ravandi, Guillermo Garcia-Manero, Tapan Kadia, Jorge E. Cortes, Hagop M. Kantarjian, Michael Andreeff, Srdan Verstovsek
Journal: Blood (2017)
Overall survival (OS) and risk of distant failure among malignant salivary gland tumors (MSGTs) in a large single-institution registry cohort.
Authors: Cristina P. Rodriguez, Teresa Mason, Solange Mongoue-Tchokote, Will Stott, Peter Andersen, John M Holland, Neil D. Gross
Journal: Journal of Clinical Oncology (2012)

e16045 Background: MSGTs are rare, biologically diverse cancers. Registry data and large series suggest 5-year OS exceeding 50%, superior to historical data and attributed to postoperative radiation (pXRT). Hypothesizing OS has remained poor despite modern therapy, we reviewed our cancer registry (OHSUCR), which began collecting data on MSGTs in 1995. Methods: We interrogated the OHSUCR for pts with MSGTs (WHO classification) and obtained data on age, sex, race, AJCC stage, histology, primary site, surgery, pXRT. OS was estimated using the Kaplan Meier (KM) method. The log rank test was used to compare OS among pts treated with and without pXRT, and those diagnosed between 1995-2000, 2001-2005, and 2005-present. Results: 110 pts with MSGTs were entered into the OHSUCR from 5/1996 to 5/2011. The median age was 60 (range 10-90), 65 (59%) were male, and 106 (96%) were white. The primary site was: 101 (92%) parotid, 3 (3%) unspecified major salivary gland, 4 (3%) submandibular gland, and 2 (2%) minor salivary gland. MSGT histologies were: 41 (37%) mucoepidermoid carcinoma, 24 (22%) adenoid cystic carcinoma, 21 (19%) adenocarcinoma, 12 (11%) acinar cell carcinoma, 5 (4%) carcinoma ex pleomorphic adenoma, 3 (3%) epithelial-myoepithelial carcinoma, 1 (1%) undifferentiated carcinoma, 1 (1%) small cell carcinoma, 1(1%) salivary duct carcinoma, 1 (1%) carcinosarcoma. AJCC Stage was: I in 29, (26%) II in 20 (18%), III in 16 (15%), IV in 45 (41%). 102 (96%) underwent surgical resection, 73 (66%) pXRT. 89 (81%) pts were rendered disease free, although 23 (21%) eventually recurred, 20 in distant sites. At the time of analysis 57 (52%) pts were alive and disease free. With a median follow up of 30 months (range 1 to 165), the 5 year KM OS for the entire cohort is 46%. Median survival was not influenced by pXRT (p=0.93) or period of diagnosis (1995-2000, 2001-2005, or 2005-present; p=0.83). Conclusions: In this large single institution series, pts with MSGT remain at high risk for mortality despite routine administration of pXRT. Distant metastasis is the most common pattern of failure indicating a clear unmet need for improved systemic therapy for MSGTs.
Uptake and disparities of neoadjuvant therapy for stage III non-small cell lung cancer.
Authors: Daniel Jacob Becker, Benjamin Philip Levy, Michael L. Grossbard
Journal: Journal of Clinical Oncology (2013)

6571 Background: The optimal use and sequence of radiation therapy (RT), chemotherapy, and surgery for patients with stage III non-small cell lung cancer (NSCLC) is unknown. We conducted a cross-sectional study using the Surveillance Epidemiology and End Results (SEER) population-based cancer registry to examine the relationship between year of diagnosis and receipt of neoadjuvant RT for patients with stage III NSCLC diagnosed in the United States from 2000 to 2008, with additional focus on the role of race and treatment location. Methods: Thirteen SEER registries were used for data analysis. Patients diagnosed with stage III NSCLC treated with both surgery and RT between the years 2000 and 2008 were included. We used multiple logistic regression to describe the relationship between type of therapy for lung cancer and year of diagnosis. Covariates identified for analysis included age, grade, sex, race, ethnicity, and SEER registry. Results: The total sample size was 393,711 of which 5,949 patients met our inclusion criteria. The cohort had a mean age of 64, was predominantly white (85.8%) and had predominantly high grade tumors (50.9%). Use of neoadjuvant RT for stage III NSCLC was lowest in 2000 and higher in every year from 2002 to 2008 (OR 1.325 in 2002, p= 0.035; 1.921 in 2007, p&lt;0.0001). Substantial heterogeneity among registries existed, with more neoadjuvant RT use in Seattle and San Francisco-Oakland (OR 1.83, 1.698 p&lt;0.0001 and 0.0002 respectively) and less use in Metropolitan Detroit, New Jersey and Louisiana (OR 0.754, 0.570, 0.493, p=0.25, &lt;0.0001, and &lt;0.0001 respectively). Black race was significantly associated with lack of neoadjuvant therapy without controlling for registry, but the association weakened after controlling for registry (OR 0.81, p=0.072). Conclusions: The use of neoadjuvant RT for stage III NSCLC substantially increased from 2000 to 2008. Location of treatment was strongly associated with receipt of neoadjuvant therapy and outweighed the association of race and therapy. The effort to equitably distribute care should focus additional study on the important role of regional and local medical culture in determination of medical care.
Abstract 15239: ER Stress May Underlie Differences in Foam Cell Lipid Droplet Autophagy in AKR and DBA/2 Mouse Macrophages
Authors: Peggy Robinet, Stela Z Berisha, Brian Ritchey, Jonathan D Smith
Journal: Circulation (2013)

Atherosclerosis in various mouse models is sensitive to the genetic background, and we have previously shown that apoE-deficient DBA/2 mice have 10-fold larger lesion areas than apoE-deficient AKR ...