tbuckley/cabot-search huggingface dataset:
Sensitization of prostate cancer cells to TRAIL-induced apoptosis by CDDP: Involvement of NF-κB, YY1 and RKIP in upregulation of DR5 expression
Authors: M. Neshat, S. Baritaki, S. Huerta-Yepez, A. Katsman, T. Delgado, K. Umezawa, T. Sakai, K. C. Yeung, D. Chatterjee, B. Bonavida
Journal: Journal of Clinical Oncology (2005)

3189 Background: Treatment of the androgen-independent, p53- PC-3 prostate cancer cells with CDDP or the NO donor, DETANONOate, resulted in inhibition of NF-κB activity, upregulation of DR5 expression and sensitization to TRAIL-induced apoptosis. CDDP-dependent mechanisms of regulation of DR5 were examined. Methods: Apoptosis was assessed by PI staining and by activated caspase-3; DNA-binding activity by EMSA; transcription by luciferase reporter systems; and protein expression by flow cytometry and western analysis. Results: Preliminary findings demonstrated that inhibition of NF-κB activity by CDDP and DETANANOate, as measured by NF-κB reporters, was corroborated in PC-3 cells. DHMEQ, an inhibitor of NF-κB nuclear translocation, paralleled CDDP and DETANONOate effects and resulted in upregulation of DR5 expression and sensitization to TRAIL-induced apoptosis. DR5 promoter activity was augmented by deletion of the -1224 to -605 region (Yoshida et al., FEBS Lett., 2001, 507: 381–5), or direct mutation of YY1 binding motif at -800 to -796. DR5 upregulation and sensitization to TRAIL was further demonstrated by YY1 siRNA. RKIP has been shown to regulate the level of activity of NF-κB, MAPK and GPCR-dependent pathways. Forced RKIP overexpression inhibited CDDP-dependent DR5 induction, suggesting that CDDP-induced response is the outcome of positive and negative regulatory mechanisms. Conclusions: The findings reveal for the first time that CDDP- mediated sensitization of tumor cells to TRAIL-induced apoptosis results in inhibition of NF-κB-dependent transcription of YY1. Inhibition of YY1 upregulates DR5 expression and sensitizes the tumor cells to TRAIL-induced apoptosis. The findings identify NF-κB, YY1 and RKIP as new targets for therapeutic intervention for reversal of tumor cells resistance to TRAIL. No significant financial relationships to disclose.
Immunoablative Therapy with Autologous Stem Cell Transplantation in the Treatment of Poor Risk Multiple Sclerosis.
Authors: Tomas Kozak, Eva Havrdova, Jiri Pitha, Karolina Mayerova, Gregora Evzen, Kobylka Petr, Vodvarkova Sarka, Pachl Jan, Trneny Marek, Dolezil David, Fiedler Jiri, Koza Vladimir
Journal: Blood (2005)
Stereotactic body radiation therapy (SBRT) combined with chemotherapy for locally advanced pancreatic adenocarcinoma.
Authors: Marie Kate Gurka, Christine M Kim, Nadim G Haddad, John Carroll, Aline C Charabaty, Patrick G Jackson, K. William Harter, Jimmy J. Hwang, Louis M. Weiner, John Marshall, Sean P. Collins, Michael J. Pishvaian, Keith Robert Unger
Journal: Journal of Clinical Oncology (2014)

361 Background: The role of conventionally fractionated radiation therapy in the management of locally advanced pancreatic cancer (LAPC) is controversial. One concern about concurrent chemoradiation relates to the timing of systemic chemotherapy. In contrast to conventional radiation therapy, SBRT delivers high doses in a shorter duration resulting in minimal disruption in chemotherapy. Here we report our results of patients treated with SBRT and chemotherapy for LAPC. Methods: Twenty-seven patients treated with SBRT for LAPC at our institution from January 1, 2008 to December 31, 2012 were included in this retrospective analysis. Treatment was delivered in 5 fractions of 5 or 6 Gy per fraction in one week. The PTV included the pancreatic mass plus adjacent vasculature in most patients. The majority of patients received concurrent chemotherapy. Median time from diagnosis to SBRT was 1.9 months. Toxicities were scored using the CTCAE v.3. Survival was calculated using the Kaplan-Meier method. Results: The median age was 63 (range 45 – 90). ECOG performance status ranged from 0 – 2 and median Charlson Comorbidity Index was 3, range 0 – 7. All patients completed radiation as prescribed except one, who is excluded from survival analysis. Twenty-five patients received concurrent chemotherapy: 18 received gemcitabine, 6 received mFOLFOX and 1 received capecitabine. Two other patients received sequential chemotherapy. At the time of this analysis, 25 patients had died and the median OS from diagnosis was 13 months. Median PFS was 8.7 months. The first site of radiographic failure was local in 2 patients, local and distant in 1, and distant in 17. Of the other 7 patients, most died after clinical deterioration with no evidence of progression at last imaging. Acute toxicity was minimal. Severe late SBRT-related toxicities included one grade 4 biliary stricture and a grade 5 gastric hemorrhage without prior radiographic tumor progression. Conclusions: SBRT combined with gemcitabine or 5-FU based chemotherapy for LAPC is convenient, feasible and generally well tolerated. The outcomes of SBRT combined with chemotherapy compare favorably to the results of treatment with chemotherapy and conventional RT.
Developing a new model of care for patients with cancer who present to the emergency department: The Mayo Clinic experience.
Authors: Debra A. Wong, Tom R. Fitch, Eric Prommer, Yu-Hui Chang, Christopher A. Lipinski
Journal: Journal of Clinical Oncology (2014)

61 Background: Patients with cancer often have complex symptoms and morbidity that prompt frequent Emergency Department visits. The length of stay in the ED for cancer patients exceeds that of patients without cancer. Patients with cancer are also more likely to be admitted, but are often discharged within 72h. Protracted ED visits, extensive investigations, and the burdens of even a short admission may be distressing and may not be aligned with patients’ care goals and preferences. Furthermore, the healthcare resources dedicated to these patients is considerable and has economic implications. We recently established a Supportive Care Infusion Center (SCIC), an on-campus outpatient unit where patients can receive treatments for symptom relief and comfort; they are assured integrated palliative care with routine oncologic care. We believe there is a subset of cancer patients who can be safely transferred from the ED to the SCIC for appropriate care. Methods: We are retrospectively evaluating cancer patients admitted through the ED to validate clinical parameters likely to lead to admission, and also identify any differences between patients admitted for &lt;72h vs &gt;72h. Patients are analyzed based on symptoms, cancer type, prior cancer therapies, performance status, comorbidities, and presence/absence of advance care planning as well as previous contact with Palliative Care. Data are also being gathered on patient outcomes, including mortality within 60d of admission. Results: Previously established indicators predictive of admission included shortness of breath and SIRS criteria, which our current review validates. We also observe that patients admitted for &gt;72h have greater symptom burden and comorbidities and have received multiple lines of therapy. They also less frequently have advance care planning in place. Data analysis is ongoing. Conclusions: There exists a difference between cancer patients admitted &gt;72h and those discharged within 72h. Awareness of these characteristics may lead to improved workflow in the ED. Identifying patients who may be suitable for transfer to an outpatient supportive care unit rather than short-term admission will also facilitate cost-effectiveness. Future direction includes evaluation of outcomes such as mortality, quality of life, and patient-caregiver satisfaction.
Impact of precancer multimorbidity clusters on survival and functional outcomes after cancer in older patients.
Authors: Kelly Kenzik, Joshua Richman, Erin E. Kent, Maria Pisu, Smita Bhatia
Journal: Journal of Clinical Oncology (2016)

291 Background: While multimorbidity clustering is a significant problem in older adults, the impact of clusters present prior to cancer on post-diagnosis survival and function is unknown. We used SEER-Medicare Health Outcomes Survey data for 4583 cancer patients to address this research gap. Methods: Patients with prostate (1741), breast (BC: 1345), colorectal (CRC: 904) and lung (593) cancer with pre- and post-diagnosis survey data were included. Surveys assessed comorbidity and activities of daily living (ADLs). Previously defined multimorbidity clusters were cardiovascular disease (CVD), skeletal, metabolic, pulmonary + major depressive disorder (MDD), and gastrointestinal (GI) + MDD. Cox regression models estimated hazard ratios (HR) for death after cancer diagnosis. Among those without pre-cancer ADL impairment, modified Poisson regression models estimated relative risk (RR) for developing post-cancer functional impairment (ADL ≤ 4). Models controlled for age, race, education, poverty level, stage, and treatment (radiation, surgery). Results: Median age at cancer diagnosis was 74y (65-103). Post-diagnosis mortality: After 6y median follow-up, mortality was 30%; 5y survival was 74%.Prostate, BC and CRC patients with pre-diagnosis CVD clusters were at increased risk of death compared to those without CVD cluster (HR 1.9, 2.0, 1.7, respectively, p &lt; 0.05). Compared to those without the cluster, prostate and BC patients with metabolic cluster were at increased risk (HR 1.7, 1.9, respectively, p &lt; 0.05) and prostate cancer patients with pulmonary conditions + MDD or GI + MDD (HR 1.9, 2.1, respectively, p &lt; 0.05) were at increased risk. Post-diagnosis functional impairment: Prevalence of moderate functional impairment at a median of 1y after cancer diagnosis was 31%. Prostate, lung, and CRC survivors with GI + MDD had a significant RR of developing impairment (RR 1.8, 1.8, and 1.7, p &lt; 0.001). For BC patients, those with skeletal cluster had a 2.1 RR (p &lt; 0.001). Conclusions: Specific multimorbidity clusters prior to cancer are associated with post-cancer mortality and ADL impairment and identify at-risk groups where interventions can be instituted to decrease morbidity and mortality.
Pre-Transplantation Level of Minimal Residual Disease Detected by Quantitative Real-Time IgH-PCR Is a Prognostic Parameter in Patients with Multiple Myeloma.
Authors: Roland Fenk, Mark Korthals, Guido Kobbe, Ulrich Steidl, Thorsten Graef, Ulrich-Peter Rohr, Leilani Ruf, Barbara Hoyer, Frank Neumann, Rainer Haas, Ralf Kronenwett
Journal: Blood (2004)
The association of ERCC1 and clinical outcomes of women with advanced ovarian cancer
Authors: D. Teoh, R. Halloway, J. Cohen, M. Gu, W. Ricketts, J. M. Hu, J. Y. Shin, C. B. Powell, L. Chen, J. K. Chan
Journal: Journal of Clinical Oncology (2008)

5575 Background: To determine the significance of excision repair cross complementation group 1 (ERCC1) in optimally debulked stage IIIC serous ovarian cancer after platinum and taxol chemotherapy. Methods: All patients were identified from two academic health centers. Pretreatment tumor biopsy specimens were analyzed for ERCC1 expression by immunohistochemistry. Patients were divided into two groups: those who recurred or had persistent disease within 12 months, and those who recurred after 12 months. Pathologic evaluation was performed without identifying clinical information. Time to progression and survival analyses were estimated using Kaplan Meier method. Results: Of 96 patients, the median age was 59 years. 68% were White, 18% Asian and 13% Other. All patients underwent primary surgical staging and were diagnosed with FIGO stage IIIC disease. All tumors were of papillary serous histology. The grading of immunostaining revealed that 16% of tumors had grade 1, 60% grade 2, and 24% had grade 3 staining intensity. In the subset of patients with 3+ staining intensity, the median time to progression was 12 months compared to 19 months in those who had grade 1 or 2 immunostaining (p=0.099). There were no statistical differences in the overall survival between these two groups of patients. Multivariate analysis was performed to identify independent prognostic factors for disease-free and overall survival. Conclusions: Our data suggest that ERCC1 expression may predict for early recurrence in this pilot study. Further studies are warranted to confirm these findings. No significant financial relationships to disclose.
Prospective evaluation of low-dose ketoconazole plus hydrocortisone (HC) in chemotherapy-pretreated castration-resistant prostate cancer (CRPC) patients.
Authors: Ernest N. Lo, Laurel A. Beckett, Chong-xian Pan, Daniel Robles, Jennifer Marie Suga, Jacob Sands, Primo Lara
Journal: Journal of Clinical Oncology (2014)

227 Background: Ketoconazole (keto), a known CYP17 inhibitor, is a traditional systemic treatment for CRPC. However, most of the published data has been in the pre-chemo setting; its efficacy in the post-chemo setting has not been as widely reported. Chemo-naive patients treated with attenuated doses of keto (200-300 mg TID) had prostate specific antigen (PSA) response rate (&gt; 50% decline) ranges from 21%-62% and treatment was well tolerated. We hypothesized that low dose keto would likewise possess efficacy and tolerability in the CRPC post-chemo state. Methods: CRPC patients with ECOG PS 0-3, adequate end organ function, who had received at least one chemo were treated with low-dose keto (200 mg PO TID) and HC (20 mg PO q AM and 10 mg PO q PM) until progression, as defined by either RECIST or PSA rise &gt; 50% from nadir or baseline. Primary endpoint was PSA response rate (&gt; 50% reduction from baseline). A Simon minimax design was used. PSA response of &gt; 25% was to be considered promising for further study (versus null rate of &lt; 5%); 25 patients were required. Secondary endpoints included PSA response &gt; 30%, progression-free survival (PFS), duration of stable disease, and evaluation of adverse events (AE). Results: 29 patients were accrued: median age was 71 (range 55-86) and median pretreatment PSA was 76 ng/mL (range 7-11,420 ng/ml); all had prior docetaxel-based chemotherapy. 28 patients were evaluable for response; all were evaluable for toxicity. PSA response of &gt;50% was seen in 48% of patients and 59% of patients had a PSA response of &gt; 30%. Median PFS was 138 days; median duration of stable disease was 123 days. 12 patients had grade 3 or 4 toxicity on treatment. Of the 17 grade 3 AEs, only 3 were considered ‘probably’ or ‘possibly’ related to treatment, while none of the 2 grade 4 AEs were considered related to treatment. Conclusions: In docetaxel pre-treated CRPC patients, low-dose keto + HC is a well-tolerated, relatively inexpensive and clinically active treatment option. PSA response with low-dose keto appears comparable to that of abiraterone in this patient context. A prospective randomized study of available post-chemo options is needed to assess comparative efficacy. Clinical trial information: NCT00895310.
The effect of gender and age on gene expression in sporadic renal cell carcinoma.
Authors: S. M. Haake, A. R. Brannon, K. Hacker, K. Rathmell
Journal: Journal of Clinical Oncology (2011)

e15120 Background: Certain aspects of the epidemiology of sporadic renal cell carcinoma (sRCC) are established but not characterized at the level of gene expression. For example, the male:female ratio in sRCC is 2:1. Furthermore, it is not known whether different genes are expressed in different age groups. In the current experiment we tested the hypothesis that both gender and age would affect gene expression in sRCC. Methods: A literature search was performed to identify large sRCC publically available gene array data sets. Five such data sets met inclusion criteria. Initially the larger data sets were examined individually with Significance Analysis of Microarray (SAM) to preliminarily identify genes of interest. Next, the data sets were merged utilizing algorithms to eliminate microarray batch effect to generate a meta-array which included 252 tumors with gender annotation (154 male, 98 female) and 251 tumors with age annotation (ages 32 – 85, ave 61). The combined data sets, which comprise data on 11,144 genes, were then reanalyzed by SAM. Results: Several genes were preferentially expressed in one gender relative to the other. Some examples include the histone demethylase gene KDM5D (M > F) and the histone demethylase KDM6A (M < F) (all p < 0.05), both of which would be predicted to affect global histone methylation patterns emerging as a major source of epigenetic regulation in sRCC. With regard to age, older patients preferentially expressed several genes including EPHA2 (angiogenesis and tumor neovascularization) and PHC1 (histone H2A modification). Conclusions: Certain genes are expressed differently in men versus women, which may lend insights into the mechanisms of tumor development and the gender discrimination that has long been observed. Furthermore, differential gene expression across ages suggests that inherent subgroups may exist among the young and old.
Molecular profiling (MP)-selected therapy for the treatment of patients with advanced pancreaticobiliary cancer (PBC).
Authors: Ron Epelbaum, Einat Shacham-Shmueli, Ravit Geva, Ayala Hubert
Journal: Journal of Clinical Oncology (2013)

195 Background: For patients (pts) with advanced PBC who are able to pursue additional therapy, treatment selection is often empiric and clinical benefits are usually modest. Our goal was to study clinical outcomes of MP-guided treatment in advanced PBC. Methods: This retrospective analysis included pts with advanced PBC whose tissue samples underwent MP (IHC, microarray [MA], and sequencing analyses) using Target Now (Caris Life Sciences, Irving, TX). These pts received ≥1 lines of therapy for advanced PBC before their treatment was guided by MP. The MP-guided therapy was considered to have clinical benefit if the TTP ratio between the longest TTP on MP-guided therapy and the TTP on the last therapy pre-MP was ≥1.3. Results: Out of 20 pts included in the analysis, 16 had advanced cancer of the pancreas. Median age was 59 yrs (range: 30-81), 85% were male, and 60% had PS of 1. Pts had 1-4 treatment regimens (median: 1) prior to MP. MP identified 1-7 (median: 4) actionable targets per pt. The most commonly identified targets by IHC were: negative or low TS (80%), high TOPO1 (70%), negative or low ERCC1 (52%), and high SPARC (40%). In all 14 pts that had MA results, multiple actionable targets were identified. Of 14 pts with KRAS sequencing analysis, 10 pts (71%) had mutations. Post-MP, pts had 1-4 (median: 1) treatment regimens, most commonly FOLFIRI/XELIRI, FOLFOX/XELOX, capecitabine, and nab-paclitaxel. The total number of regimens post-MP was 33, of which 29 were evaluable for decision impact analysis. In 24 (83%) of cases, treatment decision was modified due to the MP results. Out of the 20 pts, 4 received ≤1 cycle of MP-guided therapy during rapidly progressing disease and were excluded from the clinical outcome analysis. Of the 16 evaluable pts, 6 (37.5%) had a TTP ratio of ≥1.3 (one-sided exact binomial test vs a null hypothesis of ≤15% with TTP ratio ≥1.3, P=0.0056; therefore the null hypothesis is rejected). Conclusions: In our retrospective analysis of a small, yet well-defined, cohort of pts with advanced PBC, MP often influenced treatment decisions and over a third of pts experienced a longer TTP (compared to the last regimen pre-MP), highlighting the promise in MP for treatment selection.
Targeting the Rho-ROCK pathway to treat pancreatic cancer: The use of unique preclinical models to ascertain the effects on cancer growth and metastasis.
Authors: Venessa T. Chin, James Conway, Adnan Nagrial, Lorraine A. Chantrill, Angela Chou, Angela Steinmann, Anthony Gill, Mark Pinese, Jiamin Wu, Amber Johns, Alison Dury, Andrew Biankin, Paul Timpson, Marina Pajic
Journal: Journal of Clinical Oncology (2015)

312 Background: Pancreatic cancer (PC) is a highly lethal and genetically heterogenous disease. Genomic sequence data from the Australian Pancreatic Cancer Genome Initiative (APGI) has identified a subset of patients with ROCK-1 amplification. ROCK-1 is a downstream target of Rho, a small GTPase that plays an important role in regulating proliferation, invasion and metastasis of cancer cells. Our aim was to analyse the effects of inhibiting ROCK-1 using specific small molecule inhibitors (Fasudil and Y-27632) in well annotated and robust pre-clinical model systems generated as part of our APGI efforts. Methods: Patient derived cell lines (PDCL) and xenografts (PDX) were used to test the effectiveness of ROCK-1 inhibitors (RI). Colony formation and 3-D organotypic assays tested cellular proliferation and invasion. In vivo, pre-clinical trials assessed the effect gemcitabine (G) +/- RI on a range of PDXs with varying tumour ROCK expression, including one G resistant model. A PDCL shown to form metastases when injected orthotopically into mice has been labeled with firefly luciferase. The effect of RI on metastasis formation will be assessed in vivo using real time imaging. Results: ROCK inhibition has a differential effect on colony formation on PDCLs in vitro, and inhibits cellular invasion. A statistically significant increase in median survival in the G + RI group compared with G alone, was seen in 3 PDXs, including the G resistant tumour. 1 PDX showed a decrease in tumour size at 200 days in the G + RI group. Conclusions: ROCK inhibition has a differential effect in vitro, but an anti-tumour effect in vivo, including overcoming resistance to G. This suggests that effects on the tumour micro-environment are an important mechanism of action. RI have the potential to be an effective therapy in PC.
Treatment of newly diagnosed children with lower-risk leukemia: A collaborative Children’s Cancer Group (CCG)/NCI pilot trial incorporating 6-thioguanine
Authors: S. S. Jacobs, L. Stork, B. C. Bostrom, R. Hutchinson, J. Holcenberg, G. H. Reaman, G. R. Erdman, J. L. Franklin, S. M. Steinberg, P. C. Adamson
Journal: Journal of Clinical Oncology (2005)

8539 Background: Although mercaptopurine (MP) is the thiopurine antimetabolite conventionally used in the treatment of childhood acute lymphoblastic leukemia (ALL), thioguanine (TG) is more potent than MP in vitro; and in patients, oral or intravenous TG achieves cytotoxic concentrations in CSF. We therefore performed a pilot study of TG administered orally and by 24 h continuous IV infusion (CIVI), as part of multi-agent chemotherapy, in children with standard risk ALL. Methods: Children with newly diagnosed standard risk ALL (age 1 - 10 yrs, WBC < 50k) were eligible. Treatment was based on the best regimen of the CCG 105 trial, with the addition of CIVI TG (480mg/m2) once during consolidation, twice during each interim maintenance and every 8 weeks during the first year of maintenance, and the substitution of oral TG (60mg/m2/d) for oral MP during maintenance. Red blood cell thioguanine nucleotides (TGNs) concentrations were determined periodically. Results: 58 (31 female) pts, median age 4.3 (range 1.4 - 9.9) yrs, were enrolled. The 8 year event-free survival was 84% (plateau reached at 4 yrs), with an 8 year overall survival of 88% (median potential follow-up 8.9 yrs). There were no CNS relapses and no toxic deaths. Toxicities following CIVI-TG included reversible neutropenia and elevated hepatic transaminases. Six pts experienced reversible veno-occlusive disease (VOD) while receiving oral TG. As the contribution of CIVI-TG to the later development of VOD was not known, the study was amended following the 5th case of VOD to discontinue CIVI TG and change all pts to oral MP. TGN concentrations during oral TG administration averaged 95 ng/8x108 RBC (range 12 -447), greater than observed with oral MP administration. Conclusions: Substituting TG for MP is associated with reversible VOD. However, the lack of CNS relapses in this pilot study suggests that TG may lower the risk of developing CNS leukemia. A subsequent randomized study of oral TG vs. MP was performed by the CCG based, in part, on the results of this trial. No significant financial relationships to disclose.