tbuckley/cabot-search huggingface dataset:
Detection of cerebral spinal fluid (CSF) circulating melanoma cells (CMC) for the diagnosis of melanoma leptomeningeal metastasis (LM).
Authors: Xuling Lin, Martin Fleisher, Larisa Shagabayeva, Antonio Marcilio Padula Omuro, Elena Pentsova
Journal: Journal of Clinical Oncology (2015)

e13061 Background: Currently, LM diagnosis is based on CSF cytology and findings on MRI, but sensitivity of these techniques is low, and diagnosis is usually confirmed late in the disease course. Identification of CSF circulating tumor cells captured with EpCAM-based enrichment may improve diagnostic sensitivity in epithelial tumors, but melanoma cells do not express EpCAM. Utilizing alternative techniques, CMC have been identified in the blood of melanoma patients. We hypothesized that identification of CMC in the CSF may be used in the diagnosis of melanoma LM. Methods: With IRB approval, we identified 15 patients with metastatic melanoma and clinical suspicion of LM. CSF CMC analysis was performed using immunomagnetic enrichment of cells expressing CD146. Evaluation and enumeration of cells were followed by nuclear staining using 4, 6-diamidino-2- phenylindole (DAPI) and immunofluorescence detection of high-molecular weight melanoma-associated antigen (HMW-MAA), CD45 and CD34. Enumeration of CMC in CSF was correlated with CSF cytology obtained at the same lumbar puncture and MRI results. Positive CSF CMC was defined as any sample containing more than 1 CMCs/3 ml ( ≥ 0.33 CMC/ml) Results: Fifteen samples from 13 patients were analyzed. Ten CSF samples could be analyzed successfully; in other 5 samples, analysis failed due to technical problems (focus failure). CSF CMCs were found in a total of 6/10 samples (median of 17cells/mL, range 0.33-67). In three of them there was confirmed LM on MRI or cytology (one sample: 31 CMCs/mL; one with 36 CMCs/mL, and one with 67 CMCs/ml). The remainder three patients had no LM but all of them had brain metastasis (median 0.66 CMCs/ml, range 0.33-3.7). Among the negative CSF CMCs, no patient had LM and three had brain metastasis. Conclusions: We provide proof-of-principle that CMCs can be found in the CSF of patients with melanoma with LM. However, as defined, this technique may be overly sensitive, as patients with brain metastasis without LM also displayed CMCs, suggesting larger studies are required for establishing optimal enumeration cutoffs. In addition, high test failure rate will need to be addressed.
Eric D. Wittkower 1899–1983
Authors: Herbert Weiner, Adolf-Ernst Meyer, W. Senf, H. Kordy, M. von Rad, W. Bräutigam, Peter E. Sifneos, Cairns Aitken, Chase Patterson Kimball, Alec Ramsay, Michael von Rad, Johannes Siegrist, Adolf-Ernst Meyer, Herbert Weiner, Adolf-Ernst Meyer, Hubert Speidel, W. Bräutigam, M. von Rad, Adolf-Ernst Meyer, Antje Haag, Christian Müller, Volker Tschuschke, Walter Volk, Reinhard Költzow, Fritz A. Muthny, Adam J. Krakowski, A. Heerlein, G. de la Parra, S. Aronsohn, F. Lolas, W. Ehlers, D. Czogalik, E. Gaus, M. Klingenburg, K. Köhle, Hertha Appelt, Bernhard Strauss, K.W. Bash, Hans-Werner Künsebeck, Wolfgang Lempa, Hellmuth Freyberger, Eike G. Fischer, Nora E. Falke, Antje Haag, Adam J. Krakowski, M.A. Rea, D.H. Hellhammer
Journal: Psychotherapy and Psychosomatics (1984)
A phase II trial of mid-treatment FDG-PET adaptive, individualized radiation therapy plus concurrent chemotherapy in patients with non-small cell lung cancer (NSCLC).
Authors: Fengming Kong, Randall K Ten Haken, Matthew J Schipper, James Hayman, Nithya Ramnath, Khaled Aref Hassan, Martha Matuszak, Timothy Ritter, Nan Bi, Weili Wang, Mark Orringer, Kemp Bailey Cease, Theodore Steven Lawrence, Gregory Peter Kalemkerian
Journal: Journal of Clinical Oncology (2013)

7522 Background: We have found that FDG-PET response during chemoradiation for patients with NSCLC is heterogeneous and predicts outcome. We hypothesized that dose escalated treatment targeted to the FDG-avid tumor would improve local tumor control. Methods: This is a phase II trial for patients with locally advanced, inoperable/unresectable NSCLC. Conformal radiotherapy (RT) was given in 30 daily fractions. RT dose was individualized to a fixed risk of lung toxicity and adaptively escalated to the residual tumor on mid-tx FDG-PET up to a total physical dose of 86 Gy. Patients had concurrent weekly followed by consolidation carboplatin/paclitaxel. The primary endpoint was local-regional tumor control (LRTC) at 2 years. Survival was calculated from RT start. Results were compared to stage-matched patients treated during the same time period with standard RT dosing (60-66 Gy). The data are presented as median (95% CI) unless otherwise specified. Results: 42 patients were enrolled: median age 63 years (range 45-83); 28 (67%) male; 39 (93%) smokers; 39 (93%) stage III; and 45% squamous cell. The mean gross tumor volume was 154 cc (range 10-617 cc). Median physical dose reached was 84 Gy (range 63-86 Gy), equivalent to 90 Gy in 2 Gy fractions (biological effective dose 108 Gy). 8 patients (19%) had RT-induced lung toxicity and 13 (31%) grade ≥2 esophagitis. Minimum and median follow-up were 10 and 25 months, respectively. The 2-year rates of in-field LRTC, overall LRTC, and LR-PFS were 84% (63-94%), 68% (47-82%), and 43% (27-58%), respectively. 14 patients progressed: 7 (50%) first at distant sites; 5 (36%) at nodal regions; 2 (14%) at primary tumor. Median overall survival was 26 months and 2-year overall survival rate was 51% (34-65%). These results compared favorably to stage-matched patients treated with standard-dose RT [2-year overall survival 23% (8-41%)]. Conclusions: These results support our hypothesis that adapting RT by escalating dose to the FDG avid region detected mid-tx improves 2-year local-regional tumor control. Adaptive RT may also improve overall survival. RTOG 1106 is currently testing this regimen in a randomized fashion. Clinical trial information: NCT01190527.
A randomized phase II trial comparing different schedules of nab-paclitaxel (nabP) combined with gemcitabine (GEM) as first line treatment for metastatic pancreatic adenocarcinoma (PDAC).
Authors: Philippa Corrie, Wendi Qian, Bristi Basu, Duncan Ian Jodrell, Stephen Falk, Chinenyu Iwuji, Harpreet Wasan, Daniel H. Palmer, Martin Scott-Brown, Jonathan Wadsley, Seema Safia Arif, A. Burcu Babaoglan, Katy Marie Dalchau, Aarthi Gopinathan, Anita Chhabra, Andrea Machin, Albrecht Neesse, David A. Tuveson, Juan W. Valle
Journal: Journal of Clinical Oncology (2017)

342 Background: NabP+GEM chemotherapy improves survival compared with standard GEM monotherapy as treatment for advanced PDAC. A PDAC mouse model showed that delivery of nabP prior to GEM generated a higher intratumoural dFdC:dFdU ratio, which correlated with improved outcome. Therefore, scheduling may be critical to optimise clinical benefit. Methods: Patients were randomised to receive nabP+GEM, either concomitantly (CON) or sequentially (SEQ), 24 hours apart. After 6 cycles, patients benefiting from treatment could continue the same regimen until disease progression. The primary endpoint was progression-free survival (PFS) assessed by 8-weekly CT scanning; secondary endpoints included safety, response rate, overall survival (OS) and quality of life (QoL). Results: Between March 2014 and 2016, 146 patients (71 SEQ, 75 CON) from 19 UK sites were randomly assigned. Median age (range) was 66 (45-82) years; Karnofsky performance status was 70 (in 12% of patients), 80 (27%), 90 (38%) or 100 (24%); 47% of primary tumours were situated in the pancreatic head; 84% had liver metastases. Median number of cycles was 4 SEQ, 3 CON; 50 patients (34%) received ≥ 6 cycles of treatment (41% SEQ, 28% CON). A 24+2hr interval was achieved in over 90% SEQ administrations. Most patients stopped treatment prior to 6 cycles due to disease progression/death (42%) or toxicity (41%). Grade ≥ 3 adverse events experienced by ≥ 10% patients (SEQ, CON) were neutropaenia (54%, 30%), febrile neutropaenia (12%, 12%), fatigue (22%, 16%), vomiting (7%, 11%) and anaemia (10%, 5%). G-CSF was administered to 35 patients (23 SEQ, 12 CON). To date, 109 patients have died. 6-month PFS by SEQ and CON arms was 46.7% and 33.8%; median PFS was 5.8 and 4.3 months. 12-month OS by SEQ and CON arms was 29.1% and 20.1%; median OS was 10.1 and 7.9 months. The objective response rate was 44% SEQ and 30% CON. Mean baseline QoL Global health status was 60.6 SEQ and 63.4 CON. The change from baseline (mean) at 24 weeks was -2.1 SEQ and -12.1 CON. Conclusions: Sequential delivery of nabP and GEM improves progression-free and overall survival. Although more myelosuppressive, QoL was maintained. Clinical trial information: ISRCTN71070888.
Radioimmunotherapy in non-Hodgkin's lymphoma (NHL) using a fractionated schedule of DOTA-conjugated, <sup>90</sup>Y-radiolabeled, humanized anti-CD22 monoclonal antibody, epratuzumab
Authors: J.-F. Chatal, J.-L. Harousseau, F. Griesinger, J. Meller, C. Renner, C. M. Kirsch, R. Naumann, J. Kropp, W. A. Wegener, D. M. Goldenberg
Journal: Journal of Clinical Oncology (2004)

2545 Background: A phase I/II, multi-center, dose-escalation trial was conducted to establish the safety, optimal dosing, and preliminary efficacy of 90Y-epratuzumab administered weekly for 2 or 3 consecutive wks to pts with B-cell NHL who failed ≥1 regimen of standard chemotherapy. Methods: Eligibility criteria included <25% BM involvement, plts >100,000 cells/mm3, and measurable disease by CT with no single mass >10 cm. Pts received 1.5 mg/kg/wk epratuzumab with 111In-epratuzumab co-administered the 1st wk. Twenty-six pts with a median of 3 prior treatments have been treated, including 15 pts without prior bone marrow transplant (BMT) at 5–10 mCi/m2/wk (total 90Y dose, 15–22.5 mCi/m2) and11 pts with prior BMT escalated separately at 2.5–5 mCi/m2/wk (total 90Y dose, 5–10 mCi/m2). Results: Dose escalation is continuing, with no serious AEs considered treatment-related. One pt in each escalation arm had protocol-defined DLT (>12 wk platelet recovery); otherwise, therapy was well tolerated with no significant toxicity besides transient hematologic depression, including 4 pts retreated without additional toxicity. 111In imaging demonstrated antibody tumor targeting, and hot/cold PK demonstrated stability of DOTA chelation ≥1 wk. In 22 pts with treatment evaluations, 13 pts (59%) had an objective response (OR) by IWG criteria, including pts with and without BMT [5/9 (56%) and 8/13 (62%), respectively], with indolent and aggressive disease [8/10 (80%) and 5/12 (42%), respectively], across histologies [follicular NHL, 9/12 (75%); DLCL, 2/4 (50%); mantle cell, 2/6 (33%)], and in pts failing rituximab (9/15, 60%). Most OR's were complete responses (CR/CRu, 9/13, 69%), and 3/5 pts assessed after CR onset now have responses >6 mo, including 2 pts continuing >1 yr. Conclusion: This study shows the feasibility and safety of a dose-fractionation schedule of a 90Y-labeled anti-CD22 Mab, obtaining therapeutic responses across all pt groups, including durable complete responses, and achieving higher cumulative doses than other RAIT agents given as single doses. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Immunomedics Immunomedics Immunomedics Immunomedics
Gender disparity: Overlooking hereditary prostate cancer.
Authors: Lauren Bowling, Carin Espenschied, Michelle Jackson, Bryan Mak, Holly LaDuca
Journal: Journal of Clinical Oncology (2017)

85 Background: Prostate cancer (PC) has been associated with germline mutations in several genes, most often BRCA2. Recently, 11.8% of men with metastatic PC were found to have germline mutations in BRCA and other DNA-repair genes. These mutations are equally inherited by men and women, both have elevated cancer risks, and National Comprehensive Cancer Network (NCCN) testing and management guidelines exist for male and female carriers. Despite this, over 95% of patients who have hereditary cancer multi-gene panel testing (MGPT) are women. We sought to describe detection rate and mutation spectrum of MGPT in men with PC compared to women with breast cancer (BC). Methods: Test results were reviewed for PC patients and female BC patients who had MGPT (Jun 2013 – May 2016) for up to 49 genes. Clinical history was obtained from test request forms. Results: Of 654 PC probands, 100 germline mutations were identified in 93 men (14.2%), significantly more than women with BC (8.6%; 6,215/71,728; p = 2.5e-5). Most mutations in PC patients were in BRCA (40.9%), followed by ATM (20.4%), CHEK2 (15.0%) and Lynch syndrome-associated genes (9.7%). Of the 100 total mutations, 94% were in genes that would impact management recommendations for them and/or their relatives. The median time from PC diagnosis to MGPT was 6 years, compared to 1 year for female BC. Nearly 57% (53/93) of mutation-positive men had multiple primary cancers, 79.2% of which had PC first. Of BRCA positives with multiple primaries (n = 21), over 90% developed PC followed by subsequent cancers, yet testing was not initiated until another cancer developed. Conclusions: In this cohort of men with PC, MGPT identified germline mutations at significantly higher rates than females with BC. Furthermore, 59.1% (55/93) of mutation positive PC probands had BRCA and/or ATM, making them possibly eligible for a PARP-inhibitor clinical trial. Unfortunately, time from PC diagnosis to MGPT was several years longer than women, allowing many to develop subsequent cancers that may have been prevented or detected earlier with knowledge of the germline mutation. Increased awareness among clinicians is needed to identify more male mutation carriers to enable appropriate cancer risk management for themselves and their relatives.
SWOG 0709: A randomized phase II “pick-the-winner” trial of erlotinib (ERL) vs. ERL plus carboplatin/paclitaxel (C/T) in patients (pts) with advanced non-small cell lung cancer (NSCLC) and impaired performance status (PS 2) as selected by serum proteomics.
Authors: Primo Lara, James Moon, Paul Joseph Hesketh, Mary Weber Redman, Stephen K. Williamson, Fred R. Hirsch, Philip C. Mack, David R. Gandara
Journal: Journal of Clinical Oncology (2015)

8040 Background: Advanced NSCLC pts with Zubrod PS2 are often excluded from clinical trials and platinum-based therapy. In SWOG 0341, ERL in PS 2 pts yielded progression-free (PFS) and overall survival (OS) of 2.1 and 5 months respectively. In a trial of ERL versus C/T in PS2 pts (Lilenbaum, JCO 2008), PFS for ERL and C/T were 1.9 and 3.5 months. Early reports suggested a potential role for serum proteomics in predicting ERL benefit beyond that of EGFR mutational status. We conducted a trial in PS2 pts enriched by serum proteomics (Veristrat-good). Methods: NSCLC pts with PS2 and Veristrat-good status were randomized to either Arm A (ERL 150 mg po QD) or Arm B (ERL 150 mg po QD d2-16 + carbo AUC 5 IV day 1, paclitaxel 200 mg/m2 IV d1 x 4 cycles, then ERL 150 mg QD). Cycles were q3 weeks. Arm B agents were pharmacodynamically separated to mitigate potential antagonism. The arm with superior observed median PFS would be selected for further evaluation, but only if ≥ 3 months. A sample size of 98 pts was based on a variety of assumed PFS probabilities for each arm. The trial prematurely closed after the FDA determined an IDE application was required for VeriStrat; however SWOG had limited resources available for such filing. Results: Of 156 pts screened, 83 (59%) were Veristrat-good, of which 59 (60%) met trial eligibility & were randomized. Treatment-related grade 4 adverse events were seen in 2 pts in Arm A (DVT, hypoMg+); 5 pts in Arm B (neutropenia 5, febrile neutropenia 1, leukopenia 1). Conclusions: In PS2 pts with advanced NSCLC and Veristrat-good status, ERL + C/T (vs. ERL alone) had better observed median PFS/OS and surpassed the protocol-specified benchmark of PFS >= 3 months required for further study. Clinical trial information: NCT00661193. Arm A: ERL (N=33) Arm B: ERL + C/T (N=26) p-value Characteristics (n,%) Median age (years) 75 71 Male sex 14 (42%) 10 (38%) Adenocarcinoma 27 (82%) 23(88%) Never smoker 6 (18%) 6 (23%) Efficacy Response rate* (n, %) 2/32 (6%) 6/26 (23%) 0.06 DCR* (n, %) 13/32 (41%) 20/26 (77%) 0.0046 PFS (median, months) 1.6 4.6 0.06 OS (median, months) 6 11 0.27 *Subset w/ measurable disease at baseline.
Impaired B cell function during viral infections due to PTEN-mediated inhibition of the PI3K pathway
Authors: Andrew Getahun, Scott M. Wemlinger, Pratyaydipta Rudra, Mario L. Santiago, Linda F. van Dyk, John C. Cambier
Journal: The Journal of Experimental Medicine (2017)

Transient suppression of B cell function often accompanies acute viral infection. However, the molecular signaling circuitry that enforces this hyporesponsiveness is undefined. In this study, experiments identify up-regulation of the inositol phosphatase PTEN (phosphatase and tensin homolog) as primarily responsible for defects in B lymphocyte migration and antibody responses that accompany acute viral infection. B cells from mice acutely infected with gammaherpesvirus 68 are defective in BCR- and CXCR4-mediated activation of the PI3K pathway, and this, we show, is associated with increased PTEN expression. This viral infection-induced PTEN overexpression appears responsible for the suppression of antibody responses observed in infected mice because PTEN deficiency or expression of a constitutively active PI3K rescued function of B cells in infected mice. Conversely, induced overexpression of PTEN in B cells in uninfected mice led to suppression of antibody responses. Finally, we demonstrate that PTEN up-regulation is a common mechanism by which infection induces suppression of antibody responses. Collectively, these findings identify a novel role for PTEN during infection and identify regulation of the PI3K pathway, a mechanism previously shown to silence autoreactive B cells, as a key physiological target to control antibody responses.
Lack of association of genetic variations of deoxycytidine kinase with toxicity or survival of non-small cell lung cancer patients treated with gemcitabine plus cisplatin.
Authors: Jeong Seon Ryu, Eun Soon Shin, Hyun-Jung Kim, Hae-Seong Nam, Jong-Eun Lee, Joo Han Lim
Journal: Journal of Clinical Oncology (2012)

e13065 Background: To determine whether tagging polymorphisms (tSNPs) of deoxycytidine kinase (DCK) have an effect on toxicity or prognosis in patients with non–small-cell lung cancer (NSCLC) treated with gemcitabine plus cisplatin. Methods: Three tSNPs (−201 C&gt;T, rs2306744; IVS2+9846 G&gt;A, rs12648166; IVS6+1392 T&gt;C, rs4694362) were chosen using two databases, the international HapMap Project and Japanese Single-Nucleotide Polymorphisms. Genotyping was performed using the Genome Lab SNPstream Genotyping System and SNaPShot assay kit. We evaluated the associations of the tSNPs with hematologic toxicity or overall survival of 139 NSCLC patients at stages IIIA/IIIB (59) and IV (80). Results: The median survival time of the patients was 11.9 months. Hematologic toxicity such as neutropenia, thrombocytopenia and anemia were not different by the three tSNPs or haplotypes (CGT, CAT and CAC) of DCK. The genetic variations did not affect on survival of the patients (log-rank P: 0.248 for −201 C&gt;T, 0.571 for IVS2+9846 G&gt;A, 0.686 for IVS6+1392 T&gt;C, 0,556 for CGT, 0.453 for CAT and 0.845 for CAC). In Cox model, these tSNPs and haplotypes did not reveal prognostic relevance (aHR and 95%CI: 0.954 and 0.611 to 1.489 for −201 C&gt;T; 1.193 and 0.719 to 1.979 for IVS2+9846 G&gt;A; 1.072 and 0.674 to 1.706 for IVS6+1392 T&gt;C, 0,668 and 0.205 to 2.175 for CGT, 1.043 and 0.713 to 1.525 for CAT and1.043 and 0.701 to 1.550 for CAC). Conclusions: This is the first study to focus on the association of tSNPs and their haplotypes of DCK with toxicity and survival in NSCLC patients. This suggests that genetic variations of DCK have no effect on the outcomes in the patients treated with gemcitabine-based chemotherapy.
Randomized, placebo-controlled study of vinorelbine plus cisplatin with celecoxib and serum VEGF before treatment as a biomarker for patients with advanced non-small cell lung cancer.
Authors: Jun Pei, Tianqing Chu, Yuqing Lou, Chunlei Shi, Liwen Xiong, Aiqin Gu, Baohui Han
Journal: Journal of Clinical Oncology (2014)

e19066 Background: Cyclooxygenase-2 (COX-2) protein expression in patients with non-small-cell lung cancer (NSCLC) has been proved a prognostic marker for COX-2 inhibition. But we need a feasible predictive factor to instruct the COX-2 inhibition treatment. We hypothesized that high serum VEGF at the start of treatment was associated with shorter survival and that celecoxib, a potent COX-2 inhibitor, improved tumor response and survival. Methods: A study was performed in patients with stage IIIb/IV NSCLC who had pathologic confirmation, no prior chemotherapy, Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2, and adequate organ function. Treatment consisted of vinorelbine and cisplatin every 4 weeks for four cycles. Patients were randomly assigned to receive celecoxib 400 mg or placebo twice daily. Primary end point was overall survival (OS). Serum VEGF levels of all patients were detected at onset and endpoint of treatment. Results: From April 2010 to October 2012, 81 patients were randomly assigned. Toxicity was mild, and no increase in cardiovascular events was observed. The median value of VEGF was 340.98pg/ml before treatment. The mean value of VEGF decreased after 4 cycles chemotherapy. Overall survival (OS) of celecoxib group was 17.5m, longer than that of control group 15.9m(p=0.837)›Progression free survival (PFS) of celecoxib group was 8.9m, longer than that of control group 6.4m (p=0.207). OS of patients with high serum VEGF level (>=340.98pg/ml) before treatment was shorter than low VEGF level (<340.98pg/ml) group (13.2m vs 26m, p=0.000); PFS was also poor in high VEGF group (3.5m vs 8.5m, p=0.000). Conclusions: In advanced NSCLC, celecoxib does not improve survival significantly. Low pretreatment serum levels of VEGF appear to be predictive of a positive effect of celecoxib on survival.
Geographic and socioeconomic determinants of participation by elderly patients in surgical oncology trials.
Authors: John H. Stewart, Greg B. Russell, Marissa Michelle Howard-McNatt, Robin M. Petro, Edward Allen Levine, Ronny A. Bell
Journal: Journal of Clinical Oncology (2012)

6127 Background: A recent report by our group demonstrated that &lt;0.5% of elderly patients with breast, prostate and lung cancer participate in surgical oncology trials. However, little work to date has evaluated the roles of regional healthcare infrastructure and socioeconomic factors on clinical trial participation in this cohort. Methods: The NCI Cooperative Group Surgical Oncology Trial (CGSOT) database was queried for patients treated for breast, prostate and lung cancer cancer between 2000 and 2008 (n=13,541). Geographical Information Systems data were used to evaluate proximity to healthcare facilities while regional socioeconomic characteristics were obtained from the 2000 US Census and Area Resource file. Counts were used to create a proportion of respondents with the corresponding 95% confidence interval calculated using the central limit theorem. Independent t-tests were used to assess differences in outcome measures between the two age groups. Results: We found that 4136 participants in the NCI CGSOT database were 65 years of age or older. Interestingly, 92.7% of this cohort was white and 85.7% was female. Socioeconomic determinants of participation are shown in the table. Conclusions: The work presented herein suggests that elderly minority patients are less likely to participate in surgical oncology trials than their white counterparts. Furthermore, elderly participants tend to reside in less affluent areas. Future work will utilize interventions that improve the recruitment of elderly patients to these trials. [Table: see text]