tbuckley/cabot-search huggingface dataset:
Effects of valproic acid as a histone deacetylase inhibitor in combination with S-1 on advanced pancreatobiliary tract cancers: Clinical study phases I and II.
Authors: Shuichi Iwahashi, Mitsuo Shimada, Toru Utsunomiya, Yuji Morine, Satoru Imura, Tetsuya Ikemoto, Yusuke Arakawa, Mami Kanamoto, Yu Saito
Journal: Journal of Clinical Oncology (2014)

306 Background: Pancreatobiliary tract cancers are the most aggressive of human cancers. Histone deacetylase (HDAC) is well known to be associated with tumori-genesis through epigenetic regulation, and its inhibitors (HDACIs) induce differentiation and apoptosis of tumor cells. We are conducting a clinical trial of combination therapy using valproic acid (VPA, a HDACI) and S-1, that is an oral fluoropyrimidine derivative consisting of 5-fluorouracil. Methods: Patients with advanced pancreatobiliary tract cancers were eligible for this clinical trial. The 12 patients, in whom a curative operation was not feasible, were enrolled in this study. Patients received S-1 orally at 80 mg/m 2 total daily dose on days 1 to 28, followed by a 14 day recovery period. They also received VPA orally at 15 mg/m 2 total daily dose, twice daily. Results: One patient had partial response (PR); ten patients were recorded as stable disease (SD); and one patient showed progressive disease (PD). Eight patients had clinically significant drug-related adverse events. The most frequent adverse events were platelet depletion and fatigue. Grade 3/4 adverse events, including anemia and platelet depletion, were observed. Significant increases in the blood concentrations of VPA were confirmed two and four weeks after VPA administration. Conclusions: This clinical study suggests that the combination therapy of VPA and S-1 for the patients with pancreatobiliary tract cancers had a manageable safety profile and preliminary antitumor activity. Clinical trial information: 000004525.
Ofatumumab in combination with high-dose methylprednisolone for the treatment of patients with relapsed or refractory chronic lymphocytic leukemia.
Authors: Januario E. Castro, Michael Y. Choi, Tomas Carvajal, Hongying Li, Danelle Frances James, Karen Messer, Thomas J. Kipps
Journal: Journal of Clinical Oncology (2013)

7124 Background: We performed a phase II, single-arm, clinical trial evaluating ofatumumab in combination with HDMP for the treatment of patients with relapsed or refractory CLL. Methods: Patients received ofatumumab at the dose of 1,000 mg weekly (half the conventional dose) for 12 weeks, without monthly maintenance doses. The HDMP dose was 1,000 mg/m 2 for 3 days of each of 3 monthly cycles. Prophylactic medications included acyclovir, bactrim, fluconazole, and allopurinol. Results: 21 patients were enrolled at a single center. The median age was 63 years (range 46–76). The median number of prior therapies was 3. 24% had unfavorable cytogenetics (Del 17p or Del 11q) and 76% had CLL cells that expressed unmutated IgVH genes or high levels of ZAP-70. 24% were fludarabine-refractory. Treatment was well tolerated. The majority of adverse events were grade 1 or 2, including insomnia, anxiety, fatigue, and infusion reactions. There were no grade 4 toxicities.19% of patients had grade 3 neutropenia, and 5% had grade 3 thrombocytopenia. Other grade 3 toxicities were hyperglycemia (71%), non-melanoma skin cancer and other skin lesions (19%), as well as acute coronary syndrome, atrial fibrillation, renal calculi, pneumonia, and hypocalcemia (1 patient each). Responses were assessed two months after completion of therapy. The overall response rate was 81% (17/21) with 5% CR (1/21), 10% nodular PR (2/21), 67% PR (14/21), 14% SD (3/21), and 5% PD. The median follow-up time was 12 months (range 5-23). The median progression-free survival (PFS) time was 9.1 months (95%CI: 7.5-NA) and the median treatment-free survival (TFS) was 11.5 months (95%CI: 10.0-NA). Patients with Del 17p or Del 11q had a significantly lower overall response rate (p-value &lt;0.001, fisher’s exact test). Conclusions: The combination of HDMP and ofatumumab is an effective, tolerable, non-myelosuppressive treatment regimen. We observed a higher ORR and longer PFS than those previously reported with single agent mAb. This regimen may be useful for patients who are unable to tolerate more aggressive, myelosuppressive therapies, or have not responded to other treatments.
The impact of bone health on endocrine treatment strategy in older adults with early-stage, hormone receptor–positive breast cancer.
Authors: S. K. Pal, A. Hurria, L. Wong, A. Naeim
Journal: Journal of Clinical Oncology (2010)

9058 Background: Little age-specific data guides management of bone health (BH) in patients receiving adjuvant endocrine therapy for breast cancer (BC). Furthermore, it is unclear how BH should modulate the decision between aromatase inhibitor (AI) and tamoxifen (TAM) therapy in this setting. The goal of the current study is to assess the impact of BH on the medical oncologists' (MO) or geriatricians' (G) recommendation for either TAM or AI in older adults with early stage, hormone-receptor (+) (HR+) BC, and to understand concomitant recommendations for management of BH. Methods: MOs (n=151) and Gs (n=158) responded to an on-line survey based on a hypothetical 75 yo female with T1N0, ER/PR(+), HER2(−) BC who had received lumpectomy/axillary lymph node dissection. Assuming concomitant treatment with Ca/Vit D and either normal bone density or osteopenia, practitioners were queried regarding choice of endocrine therapy (TAM, AI or no therapy), need for bisphosphonate (bis), and (assuming TAM as initial therapy) whether a change to AI would be considered. In another scenario assuming concomitant treatment with Ca/Vit D, osteoporosis, and 2 prior fractures, the same practitioners were queried regarding choice of endocrine therapy and management strategies for worsening osteoporosis while on AIs. Results: With declining BH (i.e., from normal to osteopenic to osteoporotic), MOs were less likely to recommend an AI and more likely to recommend TAM (p<0.0001 for both). In contrast, no consistent trend was observed amongst Gs, who recommended TAM more frequently in each scenario. For both normal BH and osteopenia, Gs were more likely than MOs to recommend adjunctive bis therapy (p<0.0001), and were less likely to suggest switching from TAM to an AI after 2-3 years of TAM therapy (p<0.01). In the setting of worsening osteoporosis, the majority of Gs (82%) and MOs (85%) recommended discontinuation of AI therapy and initiation of TAM. Conclusions: Variations in BH may alter the recommendation for TAM or AI therapy in the older adult with HR+, early stage BC. Differences in treatment approach were noted between MOs and Gs; further research is necessary to determine factors contributing to these differences. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Genentech Novartis, Pfizer Abraxis BioScience, Amgen, Genentech, Pfizer, sanofi-aventis
Investigation of thrombospondin 1 (THBS1) as prognostic and predictive factor of neoadjuvant chemotherapy for advanced gastric cancer.
Authors: Noriko Matsumoto
Journal: Journal of Clinical Oncology (2013)

49 Background: Curative R0 operation is the best treatment for patients with Stage II/III gastric cancer, but still there are recurrent cases. Although chemotherapy is an important treatment, there is no evidence of neoadjuvant chemotherapy (NAC) for both R0 operated advanced gastric cancer and inoperable cases. Thrombospondin 1 (THBS1) plays a role in angiogenesis in many cancers, and we reported that THBS1 could be prognostic factor of Stage IV gastric cancer and predictive factor of S-1+ paclitaxel chemotherapy. The aim of this study is to investigate THBS1 plays as prognostic and predictive factor of neoadjuvant chemotherapy for advanced gastric cancer. Methods: Study 1. Investigation of THBS1 as prognostic factor in R0 cases: 129 patients with R0 operated for stage II/III gastric cancer (II: 56, III: 73) were enrolled in this study. THBS1 expression was investigated by immunostaining with resected specimen. Relationship between THBS1 expression and disease free survival (DFS), and recurrence rate were evaluated. Study 2. Investigation of THBS1 as predictive factor in unresectable cases: Among 111 patients who had unresectable gastric cancer, 55 patients had NAC (NAC (+) group; S-1+PTX i.p.: 23, Docetaxel+CDDP+S-1 (DCS): 17, S-1+CDDP 6, Docetaxel{S-1 (DS): 5, S-1 alone: 4) were compared with NAC (-) group (n=56) by evaluation of relationship between immunohistological expression of THBS1 and overall survival. Results: Study 1: There were 39 (30%) gastric cancers with positive staining for THBS1, 19 patients (49%) recurred cancer and 5-year DFS was 20% in THBS (+) group. Among 90 patients of THBS (-) group, 19 patients (20%) recurred, and DFS was 73%. Study 2: there were 32 (29%) unresectable gastric cancers with THBS1 (+). NAC (+) group showed 30.4% of 2-year OS, whereas 13.1% of NAC (-) group. Among NAC (+) group, 24 (43.6%) patients showed response of NAC, and among responder group, 13 (54%) patients showed THBS1 (+), whereas 10 (28.6%) patients showed THBS (+) in non-responder group. Conclusions: THBS1 expression showed reverse correlation with prognosis and positive correlation with prediction of neoadjuvant chemotherapy for Stage II/III gastric cancer.
Association of levels of circulating dendritic cells and CD4 T cells with quality of life and morbidity based on Karnofsky performance score after HSCT
Authors: V. Reddy, J. Schold, J. Levine, E. Nunez, E. Padron
Journal: Journal of Clinical Oncology (2008)

9644 Background: Dendritic and CD4 T cells are sentinel participants in the immunologic response. High levels of Dendritic cells have been associated with decreased mortality and AGVHD after HSCT (Reddy V et al Blood 2004). We hypothesized that a robust reconstitution of dendritic cells and CD4 T cells will be associated with enhanced performance status as measured by Karnofsky score. The reliability and validity of the Karnofsky score as a measure for morbidity has been extensively studied and was thus used in our analysis. Methods: We measured immune reconstitution in 122 patients with high risk hematopoetic malignancies undergoing allogeneic transplantation. Flow cytometry was used to analyze DC and CD4 T-cells at engraftment defined by HLA-DR%plus;, CD11c%plus;, and CD123%plus; and CD3%plus;/CD4%plus; respectively. The primary study endpoint was 30-day Karnofsky score. The study utilized a multivariate linear model to evaluate factors independently associated with the Karnofsky score. Results: Karnofsky scores ranged from 50% to 100% in the population with a median level of 80%. Patients with high DC count at engraftment (> 5/mm3) (p=0.02), high CD4 count at engraftment (p=0.046) and related transplants (p=0.02) had significantly higher Karnofsky scores at 30 days post-transplantation. There were no differences in Karnofsky score by gender, graft source or conditioning type. Conclusions: High DC and CD4 count are likely to have better morbidity scores via Karnofsky performance scores, a long recognized marker of well being. Whether improved immune reconstitution leads to improved quality of life or vice versa requires additional studies. No significant financial relationships to disclose.
Colorectal cancer cases with de novo germ-line mutations in <i>MLH1</i>, <i>MSH2</i>, and <i>MSH6</i> from the Colon Cancer Family Registry.
Authors: A. K. Win, M. A. Jenkins, D. D. Buchanan, J. P. Young, S. N. Thibodeau, J. L. Hopper, N. M. Lindor
Journal: Journal of Clinical Oncology (2011)

3538 Background: Lynch syndrome is caused by a germ-line mutation in a DNA mismatch repair (MMR) gene. Carriers are at high risks of colorectal (CRC), endometrial and some other cancers. To date, there have been only a few reports on single cases with de novo mutations in MLH1 or MSH2. We now report a case series of de novo mutations in MMR genes from the Colon Cancer Family Registry. Methods: Screening for germ-line MLH1, MSH2, MSH6 and PMS2 mutations was performed for: all incident CRC cases recruited from cancer registries (population-based probands) displaying microsatellite instability (MSI) or positive immunohistochemistry (IHC); and the earliest-onset CRC cases in multiple-case families recruited from clinics (clinic-based probands) regardless of MSI or IHC status. Mutation testing was performed by denaturing high pressure liquid chromatography, followed by confirmatory DNA sequencing. All relatives of probands with a deleterious mutation who donated a blood sample underwent testing for the mutation identified in the proband. For this study, a de novo mutation was defined as a mutation in a proband that was not detected in the parents, siblings, spouse, and children. Results: Of 261 probands with MMR gene mutations for whom it was possible to classify the de novo status, six (2.3%; 95%CI 0.9–5.0%) were de novo and 255 (92.7%; 95%CI 95.0–99.1%) were not de novo. Of the de novo mutation carriers, three were in the 202 clinic-based probands (1.5%; 95%CI 0.3–4.5%) and three were in the 59 population-based probands (5.1%; 95%CI 1.2–14.5%). Two were in MLH1, three in MSH2, and one in MSH6 (details in table). Conclusions: De novo mutations are rare causes of Lynch syndrome with prevalence in MMR gene mutation carriers of between 1 in 100 and 1 in 20. Summary of de novo MMR mutation carriers. Case Gene Exon Mutation description Age at CRC (year) TNM stage Source Family history of CRC (age) 1 MLH1 1-19 deletion 27 T3N1M0 Population Father (48) 2 MLH1 13 c.1459C>T p.Arg487X 36 T3N0M0 Clinic No 3 MSH2 8 deletion 32 T3N0M0 Population Uncle (41) 4 MSH2 5 c.942+3A>T p. Val265_Gln314del 49 T3N1M9 Clinic Son (43) 5 MSH2 6 c.1034G>A p.Trp345X 31 T3N0M9 Clinic Uncle (unknown) 6 MSH6 4 c.1422_1423delGCinsAT p.Gln475X 31 T3N0M9 Population No
Relapse incidence and leukemia-free survival (LFS) in patients (pts) older than age 60 with AM undergoing stem cell transplantation: A report of the East German Study Group Hematology and Oncology (OSHO).
Authors: D. Niederwieser, G. Maschmeyer, T. Fischer, L. Uharek, R. Kortmann, U. Hegenbart, P. Dreger, M. Herold, H. G. Sayer, H. Wolf, U. Kreibich, D. Hähling, C. Junghanss, N. Grobe, R. Krahl, T. Lange, H. K. Al-Ali, W. Pönisch, C. Nehring, G. Doelken
Journal: Journal of Clinical Oncology (2011)

6523 Background: Complete remission rates similar to those of younger pts are obtained in elderly AML pts (OSHO AML 1997). However, OS and LFS remain dismal because of extremely high relapse rates. In the AML 2004 study, reduced intensity conditioning SCT was introduced to reduce relapse in patients with a compatible related/unrelated donor. In this analysis we compared outcome of patients with a donor to patients without a donor. Methods: Of the 663 pts, 597 were entered into the study specific arm and 66 in the common arm of the German Intergroup Study. Of those 447 and 52 pts were evaluable, respectively. The majority of pts were male (56.9%), the median age 68 years and the median Karnofsky score 80%. Karyotype was normal in 46.9% and unfavorable in 21.2%, while 55.9% had de novo AML. Induction therapy consisted of AraC 100 mg/m2 c. i. over 7 days / Daunorubicin 60 mg/m2 i.v. on days 3 - 5 in the standard arm and of AraC 2g/m2 on days 1, 3, 5 and 7 / mitoxantrone 10 mg/m2 i.v. day 1 - 3 in the study arm. SCT were performed following reduced intensity conditioning. Results: CR was observed in 62% of pts after induction in the study arm and in 62% in the standard arm. A total of 76 pts had a stem cell donor and 129 no donor. There was no significant difference between the populations except for median age 68 in the chemotherapy vs. 65 a in the SCT arm (p<0.001). OS at 3 a was 35 ± 6% in the chemotherapy compared to 49 ± 6% in the SCT arm. Accordingly, LFS at 3 a was 27 ± 5% for chemotherapy as compared to 39 ± 7% in the SCT arm (p=0.04) and due to reduced relapse incidence (73±5% vs. 45±7%, respectively; p 0.001). Only SCT and favorable risk cytogenetics were independent factors for increased LFS. Both variables were independent risk factors for lower relapse rate, as was de novo AML. In contrast, high WBC at diagnosis and SCT were significantly associated in a multivariate analysis with increased treatment related mortality. Conclusions: SCT in comparison to chemotherapy is associated with increased LFS and lower relapse independently of cytogenetic risk. The biggest differences in LFS and relapse between SCT and chemotherapy were noted among pts with high risk cytogenetic disease.
Identification of pre- and post-treatment markers of efficacy in patients with renal cancer treated with MVA-5T4 in a phase III study.
Authors: R. Harrop, W. H. Shingler, M. McDonald, P. Treasure, R. J. Amato, R. E. Hawkins, H. Kaufman, J. de Belin, M. Goonewardena, S. Naylor
Journal: Journal of Clinical Oncology (2011)

2542 Background: Few immunotherapy compounds have demonstrated a direct link between the predicted mode of action of the product and benefit to the patient. Since cancer vaccines are thought to have a delayed therapeutic effect, identification of the active moiety may enable the development of an early marker of efficacy. Methods: Patients with renal cancer and requiring first-line treatment for metastatic disease were randomized 1:1 to receive MVA-5T4 or placebo alongside Sunitinib, IL-2 or IFN-a in a multi-centre phase III trial. Antibody responses were quantified following the 3rd and 4th vaccinations. A surrogate for 5T4 antibody response (the immune response surrogate; IRS) was constructed and then used in a survival analysis to evaluate treatment benefit. Results: 733 patients were randomized (365 MVA-5T4, 368 placebo) and immune responses were assessed in 590 patients at baseline and at least one post-treatment time-point. The magnitude of the induced 5T4 antibody response showed a significant association with enhanced patient survival within the MVA-5T4 treated group. We have constructed an immune response surrogate using a linear combination of pre-treatment 5T4 antibody levels, hemoglobin and hematocrit. The IRS showed a strong correlation with the observed 5T4 immune response and was shown to be a significant predictor of treatment benefit. Importantly, the IRS was also associated with immune response and survival in an independent dataset comprising renal, colorectal and prostate cancer patients treated with MVA-5T4 in phase I-II studies. Conclusions: A surrogate for 5T4 antibody response has been generated. This IRS was a predictor of treatment benefit in renal cancer patients receiving MVA-5T4 in a phase III study. The derivation of the IRS formed part of an exploratory, retrospective analysis; however, if confirmed in future studies, the results have important implications for the development and use of the MVA-5T4 vaccine.
Expression of prostate-specific membrane antigen (PSMA) on circulating tumor cells (CTCs) in castration-resistant prostate cancer.
Authors: Florence Lee, Angela Yu, Amanda Anderson, Dena Marrinucci, Wells W. Magargal, Vincent A. DiPippo, William C. Olson
Journal: Journal of Clinical Oncology (2014)

266 Background: Prostate-specific membrane antigen (PSMA) is expressed ubiquitously in prostate adenocarcinoma, and the intensity of expression increases with disease aggressiveness. Exploiting PSMA for therapy could potentially be aided by a minimally invasive means for measuring PSMA on tumor cells. Here we describe the development and characteristics of a novel assay for quantitating PSMA on canonical and non-canonical circulating tumor cells (CTCs). Methods: The PSMA CTC test was developed using LNCaP (high PSMA), 22Rv1 (low PSMA) and PC3 (no PSMA) cells spiked into normal blood. Nucleated blood cells were plated onto glass slides and subjected to immunofluorescent staining followed by CTC identification using the Pyxis Scanning Platform at Epic Sciences. The four-color assay evaluated PSMA expression on individual CTCs, identified as cells which are cytokeratin+, CD45-, and with an intact DAPI nucleus. Multiple antibody clones and assay conditions were evaluated, and the final PSMA CTC test has high specificity and sensitivity. Acceptance criteria included signal intensities in LNCaP versus PC3, subcellular localization of PSMA, and potential interference by a PSMA-targeted therapy. Clinical feasibility of the optimized assay was assessed on samples from CRPC patients. Results: The average PSMA signal intensity for LNCaP was 20-fold higher than that for PC3 and 10-fold higher than the minimum cutoff. PSMA displayed a predominantly membrane-localized pattern of staining that was distinct from cytokeratin. Assay performance was unaffected by the presence of PSMA ADC, a PSMA-targeted antibody-drug conjugate that is in phase II clinical testing. In feasibility tests on patient samples, the assay demonstrated utility in detecting and quantitating PSMA on individual and clustered CTCs as well as on apoptotic, cytokeratin-negative, and small cytokeratin-positive CTC candidates. Conclusions: PSMA expression was successfully detected and quantitated on diverse types of circulating cells present in the blood of patients with CRPC. Assay performance was unaffected by the presence of a PSMA-targeted therapeutic agent. PSMA CTC data are being collected in the ongoing phase II study of PSMA ADC for comparison with treatment outcomes.
Axitinib or bevacizumab (bev) plus FOLFOX or FOLFIRI as second-line therapy in patients (pts) with metastatic colorectal cancer (mCRC).
Authors: J. C. Bendell, C. Tournigand, M. Bednarczyk, A. Swieboda-Sadlej, I. Chung, C. Barone, J. C. Tarazi, B. Rosbrook, A. D. Ricart, A. F. Sobrero
Journal: Journal of Clinical Oncology (2011)

478 Background: Axitinib (AG-013736,AG), an oral selective inhibitor of vascular endothelial growth factor (VEGF) receptors 1, 2, and 3, shows activity in multiple tumor types including those refractory to front-line chemotherapy. Methods: This multicenter, open-label, randomized phase II trial compared AG and bev in combination with FOLFOX or FOLFIRI in second-line mCRC. Pts previously treated with irinotecan were randomized to mFOLFOX6 plus AG 5 mg BID or bev 5 mg/kg q2wk; pts who received oxaliplatin were randomized to FOLFIRI with AG or bev at the same doses, with stratification by performance status and prior bev therapy. Primary endpoint was progression-free survival (PFS). Results: 171 pts were randomized from March 2008 to July 2009. There were no significant differences in PFS or median overall survival (mOS) between the AG and bev arms with FOLFOX or FOLFIRI. However, there was a trend towards reduced mOS in the FOLFIRI arms with AG compared to bev, and a trend towards improved mOS with AG+FOLFOX vs bev+FOLFOX. There were more treatment discontinuations (DCs) and a higher incidence of grade ≥3 adverse events (AEs) in the AG arms (diarrhea, asthenia, fatigue; Table). Conclusions: This study did not meet the primary endpoint, showing similar PFS with AG compared to bev when added to second-line chemotherapy. A potential factor in these results was earlier DCs in the AG versus bev arms, likely secondary to increased AEs. While VEGF inhibitors may have a role in second-line treatment of mCRC, at current dosing regimens AG-based chemotherapy shows no improvement in outcome compared to bev. [Table: see text] [Table: see text]