tbuckley/cabot-search huggingface dataset:
Phase I and correlative science trial of UCN-01 plus cisplatin (CDDP) in advanced solid tumors: A California Cancer Consortium study
Authors: P. C. Mack, P. N. Lara, J. Longmate, P. H. Gumerlock, T. W. Synold, J. H. Doroshow, D. R. Gandara
Journal: Journal of Clinical Oncology (2004)

9591 Background: UCN-01 (7-hydroxystaurosporine), a novel kinase inhibitor, promotes sequence-specific abrogation of DNA damage-induced G2 arrest by inhibition of checkpoint regulators Chk1 and Chk2, potentiating the activity of CDDP, particularly in cells with a dysfunctional p53. We previously reported the preliminary results of an NCI-sponsored phase I trial designed to determine the safety, maximum tolerated dose (MTD) and pharmacokinetics (PK) of escalating doses of CDDP over 5 dose levels as a 1 hour infusion prior to fixed-dose UCN-01 (45 mg/m2/d), delivered as a 72-hour continuous infusion in cycle 1, then over 36 hours in subsequent cycles. Cycle length = 3 weeks (Gandara, ASCO 2003). Here we report the results of the correlative science and PK studies, and the final clinical results of the phase I trial. Methods: PK was assessed using high performance liquid chromatography (HPLC). Molecular analysis by Western blotting evaluated the effects of UCN-01 on key cell cycle-associated targets in serial patient tumor specimens. Results: Patient characteristics - male/female: 3/7, performance status 0–1/2: 8/2, prior chemotherapy (yes/no): 9/1. Accrual was halted at dose level 2 (cisplatin 30 mg/m2) due to dose limiting toxicities (DLT) in 2 of 3 pts. One partial response was seen. PK parameters for plasma and salivary UCN-01 were similar to those seen with single-agent UCN-01. Terminal UCN-01 half-life was > 300 hours. Western blot analysis of pre- and post-treatment tumor biopsies in 3 patients showed mobility shifts of Chk1 and Cdc25C consistent with changes in phosphorylation status. In one patient who progressed rapidly, dramatically increased levels of cyclin B and moderately increased Cdk1 phosphorylation in the post-treatment sample were indicative of a CDDP-induced G2 arrest and failure of UCN-01-induced G2 abrogation. Conclusions: These findings are consistent with predicted cell cycle regulatory effects of UCN-01 in modulating the molecular target (Chk1). Further studies of UCN-01 and platinum compounds using alternative dose schedules are warranted, and are ongoing. (CA62505, ACS-CRTG 19701-CCE) No significant financial relationships to disclose.
Thymidylate synthase activity as a significant prognostic marker in patients with renal cell carcinoma
Authors: Y. Mizutani, H. Nakanishi, T. Nakamura, T. Nomoto, K. Mikami, K. Okihara, O. Ukimura, A. Kawauchi, A. Fujito, T. Miki
Journal: Journal of Clinical Oncology (2004)

4630 Background: 5-fluorouracil ( 5-FU ) is an anticancer chemotherapeutic agent clinically used against various cancers including renal cell carcinoma ( RCC ). 5-FU inhibits thymidylate synthase ( TS ) and blocks DNA synthesis. TS is the key enzyme in the DNA synthetic process. Little is known about the significance of TS in RCC. We investigated the activity of TS in 68 RCC and evaluated the association between the level of TS activity and the stage/grade of RCC. The relationship between TS activity in primary cultured RCC cell lines and their sensitivity to 5-FU was also examined. Methods: The levels of TS activity in non-fixed fresh frozen RCC and normal kidney were determined biochemically by the 5-fluoro-2'-deoxyuridine 5'-monophosphate binding assay. The sensitivity of primary cultured RCC cell lines to 5-FU was assessed by the microculture tetrazolium dye assay. Results: The activity of TS was approximately 5-fold higher in RCC compared to normal kidney. TS activity in T3/4 RCC was 2.5-fold higher than that in T1/2 RCC. TS activity in M1 RCC was 2.5-fold higher than that in M0 RCC. In addition, TS activity in Stage III/IV RCC was 3-fold higher than that in Stage I/II RCC. The levels of TS activity in Grade 3 RCC were 3-fold and 2-fold higher than that in Grade 1 and Grade 2 cancer, respectively. Patients with low TS activity had a longer disease-specific survival as compared to those with high activity in the 5-year follow-up. TS activity in primary cultured RCC cell lines was positively correlated with their sensitivity to 5-FU. Conclusions: The present study is the first study to demonstrate that the level of TS activity correlated with both the progression of the stage and the increase of the grade of RCC, and was a significant prognostic indicator in patients with RCC. In addition, higher TS activity in primary cultured RCC cell lines predicted higher sensitivity to 5-FU. These results suggest that high TS activity may be associated with malignant potential of RCC, and that it may be possible to use 5-FU for RCC with high TS activity. No significant financial relationships to disclose.
Effect of aromatase inhibitor therapy on cognitive function
Authors: I. Makhoul, P. Eslinger, D. Popescu, H. Harvey, K. Parkinson, A. Lipton
Journal: Journal of Clinical Oncology (2004)

846 Background: Aromatase inhibitors (AI) have gained widespread use in the treatment of breast cancer (BC). Estrogens may have direct influence on memory, cognitive function and emotions. Chemotherapy (CT) for BC has also been incriminated in cognitive dysfunction Methods: : Postmenopausal women with ER/PgR + metastatic BC treated with AI as first line hormonal therapy and those with early stage or locally advanced ER/PgR + BC treated with chemotherapy followed by AI in the adjuvant setting were eligible to the study. Ten neuropsychological tests were administered before and 3, 6, and 12 months after starting the treatment with AI. Patients who received CT had their baseline testing 4–6 weeks after completion of CT and before starting their AI. Neuropsychological tests evaluated general cognition, visual memory, verbal memory, attention-concentration, verbal fluency, semantic fluency, and emotional status. Results beyond two standard deviations were considered abnormal Results: Fourteen patients have been enrolled in the study to date and enrollment continues. Five patients had metastatic BC; 9 patients had early stage or locally advanced (1 patient) disease and required CT after surgery. All patients had ER and/or PgR positive disease. One patient died after baseline evaluation. Two patients withdrew from the study. All of the remaining patients (11) had their baseline evaluation; 3 patients had up to 6 month evaluation and 5 patients have completed their one year follow-up. Three patients had no change after one year of follow-up, 2 patients, both have received CT, had decline in verbal memory (1) or visual memory (1) tests at three months followed by recovery at later testing. Three patients, none of them received CT, had decline in verbal memory measures that did not recover at one year (1) or six months (2). Measures of depression and anxiety showed no significant change throughout the study. Conclusions: Lasting decline in verbal memory may be associated with AI (3 patients of 8). Chemotherapy may result in transient decline of memory function that seems to improve by 6 months to one year with no additive effect to AI. Further patient accrual and data analysis would confirm these preliminary findings. No significant financial relationships to disclose.
Nano-Pulse Stimulation is a physical modality that can trigger immunogenic tumor cell death
Authors: Richard Nuccitelli, Amanda McDaniel, Snjezana Anand, John Cha, Zachary Mallon, Jon Casey Berridge, Darrin Uecker
Journal: Journal for ImmunoTherapy of Cancer (2017)

<h3>Background</h3> We have been developing a non-thermal, drug-free tumor therapy called Nano-Pulse Stimulation (NPS) that delivers ultrashort electric pulses to tumor cells which eliminates the tumor and inhibits secondary tumor growth. We hypothesized that the mechanism for inhibiting secondary tumor growth involves stimulating an adaptive immune response via an immunogenic form of apoptosis, commonly known as immunogenic cell death (ICD). ICD is characterized by the emission of danger-associated molecular patterns (DAMPs) that serve to recruit immune cells to the site of the tumor. Here we present evidence that NPS stimulates both caspase&nbsp;3/7 activation indicative of apoptosis, as well as the emission of three critical DAMPs: ecto-calreticulin (CRT), ATP and HMGB1. <h3>Methods</h3> After treating three separate cancer cell lines (MCA205, McA-RH7777, Jurkat E6-1) with NPS, cells were incubated at 37&nbsp;°C. Cell-culture supernatants were collected after three-hours to measure for activated caspases 3/7 and after 24 h to measure CRT, ATP and HMGB1 levels. We measured the changes in caspase-3 activation with Caspase-Glo® by Promega, ecto-CRT with anti-CRT antibody and flow cytometry, ATP by luciferase light generation and HMGB1 by ELISA. <h3>Results</h3> The initiation of apoptosis in cultured cells is greatest at 15&nbsp;kV/cm and requires 50 A/cm<sup>2</sup>. Reducing this current inhibits cell death. Activated caspase-3 increases 8-fold in Jurkat E6-1 cells and 40% in rat hepatocellular carcinoma and mouse fibrosarcoma cells by 3&nbsp;h post treatment. This increase is non-linear and peaks at 15–20&nbsp;J/mL for all field strengths. 10 and 30&nbsp;kV/cm fields exhibited the lowest response and the 12 and 15&nbsp;kV/cm fields stimulated the largest amount of caspase activation. We measured the three DAMPs 24 h after treatment. The expression of cell surface CRT increased in an energy-dependent manner in the NPS treated samples. Expression levels reached or exceeded the expression levels in the majority of the anthracycline-treated samples at energies between 25 and 50&nbsp;J/mL. Similar to the caspase response at 3&nbsp;h, secreted ATP peaked at 15&nbsp;J/mL and then rapidly declined at 25&nbsp;J/mL. HMGB1 release increased as treatment energy increased and reached levels comparable to the anthracycline-treated groups between 10 and 25&nbsp;J/mL. <h3>Conclusion</h3> Nano-Pulse Stimulation treatment at specific energies was able to trigger the emission of three key DAMPs at levels comparable to Doxorubicin and Mitoxantrone, two known inducers of immunogenic cell death (ICD). Therefore NPS is a physical modality that can trigger immunogenic cell death in tumor cells.
Lenalidomide, Bortezomib, and Dexamethasone with Transplantation for Myeloma
Authors: Michel Attal, Valerie Lauwers-Cances, Cyrille Hulin, Xavier Leleu, Denis Caillot, Martine Escoffre, Bertrand Arnulf, Margaret Macro, Karim Belhadj, Laurent Garderet, Murielle Roussel, Catherine Payen, Claire Mathiot, Jean P. Fermand, Nathalie Meuleman, Sandrine Rollet, Michelle E. Maglio, Andrea A. Zeytoonjian, Edie A. Weller, Nikhil Munshi, Kenneth C. Anderson, Paul G. Richardson, Thierry Facon, Hervé Avet-Loiseau, Jean-Luc Harousseau, Philippe Moreau
Journal: New England Journal of Medicine (2017)

High-dose chemotherapy plus autologous stem-cell transplantation has been the standard treatment for newly diagnosed multiple myeloma in adults up to 65 years of age. However, promising data on the use of combination therapy with lenalidomide, bortezomib, and dexamethasone (RVD) in this population have raised questions about the role and timing of transplantation.
Under Scope of the Current Redefinition Process of Optimal Response in Multiple Myeloma: Assesment of Molecular Response by Fluorescent PCR of Ig Genes Has Similar Applicability and Prognosis Impact to Immunophenotypic Response. (A GEM/PETHEMA study),
Authors: Elena Fernandez Redondo, Joaquin Martinez-Lopez, Ramón García-Sanz, María-Angeles Montalbán, Pilar Martinez-Sanchez, Bruno Paiva, Maria-Victoria Mateos, Laura Rosiñol, Maria Luisa Martin, Rosa M. Ayala, Rafael Martinez, Javier Lopez, Adrian Alegre, Joan Besalduch, Joan Bargay, MT Hernandez, Maria Eugenia Sarasquete, P. sanchez-Godoy, Manuel Callis, Manuela Fernandez, Joan Blade, Jesus F. San Miguel, Juan José Lahuerta
Journal: Blood (2011)
Primary tumor histology and location as predictive factors for clinical outcome in metastatic gastric cancer (GC) patients receiving first-line chemotherapy.
Authors: Alessandro Bittoni, Mario Scartozzi, Riccardo Giampieri, Luca Faloppi, Maristella Bianconi, Alessandra Mandolesi, Michela Del Prete, Mirco Pistelli, Luca Cecchini, Italo Bearzi, Stefano Cascinu
Journal: Journal of Clinical Oncology (2013)

e15081 Background: Recently, a new classification for GC has been proposed, based on Lauren’s histology and on anatomic tumour location, identifying three subtypes of disease: type 1 (proximal non diffuse GC), type 2 (diffuse GC) and type 3 (distal non diffuse GC). Aim of our analysis was to compare clinical outcome, in terms of response rate (RR), progression-free survival (PFS), and overall survival (OS), according to different GC subtypes (1, 2, 3) in metastatic GC patients (pts) receiving first-line chemotherapy. Methods: Advanced GC pts treated with a first-line combination chemotherapy were included in our analysis. Pts were divided in three subgroups (type 1, type 2, and type 3) as previously defined. Results: A total of 248 advanced GC pts were included: most of pts belonged to type 2 (45.15%) and type 3 (43.55%); type 1 included 28 pts (11.30%). The majority of pts (65.4%) received a fluoropyrimidine-based chemotherapy doublet while the remaining 88 pts received a three drugs regimen including a platinum derivate and a fluoropyrimidine with the addition of an anthracycline, a taxane or mytomicin C. Most of pts (55.5%) received a second-line treatment, with FOLFIRI o taxanes. The three subgroups resulted comparable for relevant clinical factors such as ECOG PS, tumour stage, number of metastatic sites, previous surgical resection, first-line combination and use of second-line treatments; as expected peritoneal carcinosis was more common in type 2 pts. RR was found to be higher in type 1 pts (RR= 46.1%) and type 3 (34,3%) compared to type 2 (20,4%), (p= 0.015). Type 2 pts presented a shorter PFS, median PFS 4.2 months, compared to type 1, mPFS= 7.5 months, and type 3, mPFS= 5.9 months (p= 0.007) and also a shorter OS with a median OS of 9,8 months vs 11.5 months for type 1 and 11.0 for type 3 (p= 0.024). Conclusions: Our analysis suggests that GC subtypes may be important predictors of benefit from chemotherapy in advanced GC patients. Future clinical trials should take in account these differences for a better stratification of patients. Biomarkers analysis on tumour samples are ongoing.
Residual Disease Monitoring By High Throughput Sequencing Provides Risk Stratification in Childhood B-ALL and Identifies a Novel Subset of Patients Having Poor Outcome
Authors: Brent L. Wood, David Wu, Ilan M. Kirsch, Beryl Crossley, David Williamson, Charles Gawad, Michael J. Borowitz, Meenakshi Devidas, Kelly W. Maloney, Eric Larsen, Naomi Winick, Elizabeth Raetz, William L. Carroll, Stephen P. Hunger, Mignon L. Loh, Harlan Robins
Journal: Blood (2016)
High risk of brain metastases in surgically staged IIIA NSCLC patients treated with surgery, chemotherapy and radiation
Authors: H. J. Mamon, B. Yeap, J. Reblando, S. Shrager, M. T. Jaklitsch, J. M. Lukanich, D. J. Sugarbaker, E. Baldini, P. Janne, R. Bueno
Journal: Journal of Clinical Oncology (2004)

7173 Background: Lung cancer is the leading cause of cancer mortality in the US. Many patients with stage IIIA disease are treated with a combination of surgery, chemotherapy and radiation, though the optimal combination remains under investigation. We sought to review our experience with surgically-staged IIIA (N2) NSCLC, focusing on the patterns of failure in a large cohort of patients consecutively treated from 1988–2000. Methods: The records of 177 surgically staged patients, all of whom underwent resection by Thoracic Surgeons at the Brigham and Women's Hospital, were reviewed. Collected data including stage, histology, use of chemotherapy and radiation, initial and subsequent sites of failure, and survival. 124 patients have died; follow-up is 35 months among the remaining patients. Results: The median survival from the time of surgery was 21.0 months, with a 3-year overall survival (OS) of 34%. Post-operative mortality was 3%. Nodal down-staging to N0 disease correlated with OS and progression-free survival (PFS) (p<0.001). The use of combination chemotherapy with platinum and a taxane correlated with improved OS over other platinum-based chemotherapy (p=0.007). The most common site of recurrence was the brain. Twenty-seven percent of patients recurred in the brain as their first site of failure, and 32% of patients developed brain metastases at some point in their course. In patients with non-squamous histology and residual nodal involvement after neoadjuvant therapy, the risk of brain metastases was 53% at 3 years. Conclusions:Patients treated with neo-adjuvant therapy for N2-positive stage IIIA NSCLC enjoy an advantage in both OS and PFS if their lymph node status is down staged to N0. The addition of taxanes to platinum may be an important improvement in the therapy of NSCLC. As brain metastases constitute the most common site of failure in these patients, future studies focusing on the incorporation of PCI or chemotherapy that crosses the blood-brain barrier may improve the outcome in patients with IIIA NSCLC. No significant financial relationships to disclose.
Retrospective analysis of topotecan administered weekly in heavily pretreated recurrent epithelial ovarian carcinoma patients
Authors: D. O'Malley, A. Makkenchery, J. Tangir, M. Kelly, M. Azodi, S. Chambers, P. Schwartz, T. Rutherford
Journal: Journal of Clinical Oncology (2004)

5079 Background: The established regimen of topotecan (1.5 mg/m2 on days 1 - 5 of a 21-day cycle) in recurrent ovarian cancer may be limited by noncumulative myelosuppression. Limited clinical data are available for the efficacy of weekly topotecan administration. This retrospective analysis evaluated the clinical utility of topotecan administered weekly in heavily pretreated ovarian cancer patients (pts). Methods: Records from stage III/IV ovarian cancer pts treated with weekly topotecan after failure of ≥ 1 prior regimen (1 of which must have contained platinum) were reviewed. Pts received topotecan (starting dose ∼2.5 mg/m2) on days 1, 8, and 15 of a 28-day cycle, or a small variation of this schedule. Pts were treated to progression, with antitumor responses assessed after 3 cycles by CA 125 levels. Results: Thirty-five heavily pretreated (median prior treatments, 2; range, 1 - 7) pts received a mean of 5 cycles of topotecan (range, 1 - 13 cycles). Thirty-two pts had definable platinum sensitivity (16 sensitive, 8 resistant, 8 refractory). Median age was 56 years. A total of 174 cycles (525 weeks) of topotecan were administered and the majority of pts were started at ≥ 2.5 mg/m2 (11 at ≥ 3 mg/m2; 21 at 2.5 mg/m2; 3 at ≤ 2 mg/m2). Hematologic toxicity was generally mild, and there were no grade 4 toxicities. Grade 3 hematologic toxicity, including leukopenia, neutropenia, thrombocytopenia, and anemia, was observed in 2, 2, 1, and 0 pts, respectively. No pts experienced grade 3 or 4 nonhematologic toxicity and only 7 pts had nonhematologic toxicity ≤ grade 2. Based on serial CA 125 measurements, there were 2 (6%) complete responses, 4 (11%) partial responses, and 12 (34%) pts with stable disease. Conclusions: Weekly topotecan is active and very well tolerated compared with historical data with the standard 5-day schedule. Higher dose levels may be warranted due to the high tolerability shown for weekly topotecan. Weekly topotecan may be an appropriate treatment option for recurrent ovarian cancer pts, especially heavily pretreated pts who might require dosing schedules with improved tolerability. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration GlaxoSmithKline GlaxoSmithKline
Disparities and unmet need for e-mail use in cancer patients
Authors: A. M. Flores, D. M. Dilts, B. A. Murphy
Journal: Journal of Clinical Oncology (2004)

8254 Background: Using a medically underserved sample, we assess barriers and unmet need for e-mail use between cancer patients and healthcare providers by comparing e-mail users to non-users. Methods: Participants were recruited for this cross-sectional study from a public hospital serving a minority/underserved cancer patient population. Eligibility criteria included: cancer diagnosis, outpatient status, non-institutionalized, ability to read/understand spoken English, and > 21 years old. Participants anonymously completed a validated questionnaire that queried 1) sociodemographics, 2) access (for users) or barriers (for non-users), 3) potential uses and utility of e-mail for medical communication. Results: Thirty-two respondents returned surveys; 75% do not use e-mail. Non-users are older (mean=51 v. 44 for users), have lower incomes (<$15000 v. <$20000) and have less education (some high school v. some college). The primary usage barriers are: lack of access (79%), no peer pressure (40%) and no training (39%). Factor analysis shows that communication items load on two factors: medical communication (e.g., “use for pain management”, “use for prescription refills”; 93% variance explained), and utility (e.g.,“help meet medical needs quickly”, “improve the efficiency of my care; 63% explained). Cluster analysis revealed 4 distinct groups: 1) e-mail users willing to use e-mail for medical purposes (EmMP); 2) users not willing to use EmMP; 3) non-users willing to use EmMP; 4) non-users not willing to use EmMP.Conclusions: Cancer patients express unique desires to use (or not use) e-mail to communicate with health care providers in this population. E-mail may be a technologically appropriate form of communication to individualize patient treatment and management. Further research is warranted to investigate this aspect of the digital divide. No significant financial relationships to disclose.
Abstract #3116: Heterodimeric AP-1 (JunD/c-Fos) is involved in hematopoiesis in synergy with BMP-4 during vertebrate developmen
Authors: Sung-Young Lee, Jaebong Kim, Ann Bode, Zigang Dong
Journal: Cancer Research (2009)

AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO

Activator protein-1 (AP-1) was one of the first mammalian transcription factors to be identified. AP-1 comprises Jun family members (c-Jun, JunB, and JunD) and Fos family members (c-Fos, FosB, Fra-1, and Fra-2). These proteins form homodimers of Jun or heterodimers of Jun and Fos members. AP-1 is known to regulates a wide range of cellular processes, but the function of AP-1 in Xenopus development is not very well elucidated. We investigated the role of AP-1 in Xenopus development. Interestingly, we found that overexpression of JunD and c-Fos could induce hematopoietic cells from ectoderm cells. Overexpression of JunD and c-Fos induced not only ventral mesoderm markers but also globin and blood cell-specific transcription factors (SCL, LMO-2, Neptune) in animal cap explants. However, JunD or c-Fos alone could not induce these markers involved in blood formation. In addition, we found that heterodimeric JunD/c-Fos and BMP-4 had a synergistic effect in blood formation. Moreover, in the absence of endogenous BMP-4, JunD and c-Fos could not induce hematopoietic genes. These results suggest that JunD and c-Fos play an important role in regulating hematopoiesis and are associated with BMP-4 signaling in Xenopus hematopoiesis.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 3116.
Oncostatin M drives intestinal inflammation and predicts response to tumor necrosis factor–neutralizing therapy in patients with inflammatory bowel disease
Authors: Nathaniel R West, Ahmed N Hegazy, Benjamin M J Owens, Samuel J Bullers, Bryan Linggi, Sofia Buonocore, Margherita Coccia, Dieter Görtz, Sébastien This, Krista Stockenhuber, Johanna Pott, Matthias Friedrich, Grigory Ryzhakov, Frédéric Baribaud, Carrie Brodmerkel, Constanze Cieluch, Nahid Rahman, Gerhard Müller-Newen, Raymond J Owens, Anja A Kühl, Kevin J Maloy, Scott E Plevy, Satish Keshav, Simon P L Travis, Fiona Powrie
Journal: Nature Medicine (2017)