tbuckley/cabot-search huggingface dataset:
Prognostic significance of VDR, DKK-1, and DKK-4 expression in colorectal cancer
Authors: J. A. Posey, S. Koya, V. R. Katkoori, D. E. Davis, U. Manne
Journal: Journal of Clinical Oncology (2009)

e15047 Introduction: Inactivation of the vitamin D receptor (VDR) and up-regulation of its down-stream molecules, Dickkopf-1 (DKK-1) and DKK-4 are implicated in the aggressive progression of colorectal adenocarcinomas (CRC). In this study, the expression of these molecules was evaluated in sporadic CRCs, and their expression levels were assessed for correlation with patient prognosis. Methods: By the qRT-PCR, 98 CRCs and matching normal tissues were analyzed for expression of VDR, DKK-1, and DKK-4 at the mRNA level. These levels were normalized to b-actin expression and calculated as ratios of copy numbers. The expression levels were assessed for correlation with clinicopathological features and for their prognostic importance. The survival probabilities were estimated by the Kaplan-Meier method. Results: VDR expression was 1.5 times lower in CRCs (53 of 98, 54%) than in their corresponding normal tissues. Expression of DKK-1 was found in 51 of 98 (52%) of the CRCs and in 29 of 98 (29%) of the normal tissues. Expression of DKK-4 was found in only 14 of 98 (14%) of the CRCs and in none of the normal tissues. VDR expression was 2.0 fold lower in tumors that exhibited metastasis, and poor differentiation and in large tumors ( &gt; 5) cm as compared to tumors without metastasis, well or moderately differentiated tumors and tumors of small size (&lt; 5 cm), respectively. In contrast, increased (3-fold) expression of DKK-1 and DKK-4 was observed in tumors with distant and/or nodal metastases as compared to tumors without such metastases. Expression of DKK-1 was higher in tumors with poor differentiation and in large tumors. There was an inverse relationship between VDR and DKK-4 expression. Survival analyses suggested that CRCs expressing DKK-1 (log rank, P = 0.046) and those with decreased or lack of expression of VDR (log rank, P = 0.043) were associated with poor patient survival. There was, however, no prognostic value for DKK-4 expression (log rank P=0.624). Conclusions: These findings suggest that, for CRCs, increased expression of DKK-1 and reduced or lack of expression of VDR, are associated with aggressiveness and with a poor prognosis for patients. These results provide evidence augmenting the VDR-DKK- pathway may represent a rational therapeutic strategy in colorectal carcinoma. No significant financial relationships to disclose.
Attending to Psychologic Symptoms and Palliative Care
Authors: Manish Agrawal, Ezekial J. Emanuel
Journal: Journal of Clinical Oncology (2002)

Article Tools EDITORIALS Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES No companion articles ARTICLE CITATION DOI: 10.1200/JCO.2002.20.3.624 Journal of Clinical Oncology - published online before print September 21, 2016 PMID: 11821440 Attending to Psychologic Symptoms and Palliative Care Manish AgrawalxManish AgrawalSearch for articles by this author , Ezekial J. EmanuelxEzekial J. EmanuelSearch for articles by this author Show More Center for Clinical Bioethics and Center for Cancer Research, Warren G. Magnuson Clinical Center, National Cancer Institute, National Institutes of Health, Bethesda, MD https://doi.org/10.1200/JCO.2002.20.3.624 First Page Full Text PDF Figures and Tables © 2002 by American Society of Clinical Oncology
Time to secondary resistance (TSR) after interruption of imatinib (IM) in advanced GIST: Updated results of the prospective French Sarcoma Group randomized phase III trial on long-term survival.
Authors: A. Le Cesne, I. L. Ray-Coquard, B. Bui Nguyen, A. Adenis, M. Rios, F. Bertucci, F. Duffaud, D. Cupissol, C. Chevreau, E. Bompas, A. Cioffi, S. Chabaud, D. Perol, J. Blay
Journal: Journal of Clinical Oncology (2011)

10015 Background: We previously demonstrated that interruption of IM treatment after 1, 3, and 5 yrs in responding patients (pts) with advanced GIST are associated with rapid relapse. The impact of IM interruption on secondary resistance and overall survival (OS) with longer-term follow-up was unclear. Methods: This prospective multicenter BFR14 study was initiated in June 2002 and closed for accrual in July 2009. Pts with GIST free of progression after 1, 3 or 5 yrs of IM 400 mg/day were randomly assigned to continue (C arm) or interrupt (I arm) IM. Reintroduction of IM (same dose) upon progression was allowed for pts in the I group. Primary endpoint was Progression Free Survival (PFS). Secondary endpoints included OS and time to secondary resistance (TSR) defined as time to progression under IM treatment (i.e. first progression in the C arm and progression after reintroduction of IM in the I arm). Results: As of January 2011, 434 pts were included in this trial. Fifty-eight, 50 and 27 non progressive pts at 1, 3 and 5 yrs were randomized and median follow-up from randomization were 74, 47 and 18 months, respectively. Results are summarized in the table. PFS was significantly lower in the I arms than in C arms. IM reintroduction allowed tumor control in 94% (49/52) of pts. The rates of pts with relapse at 2 yrs post-randomisation decreases with the duration of treatment: 38%, 20% and 0% of pts randomised after 1, 3 and 5 yrs of IM treatment in the C arm. No difference for TSR or OS is observed between the 2 arms. Conclusions: Reintroduction of IM allowed tumor control in almost all pts. IM interruption had no impact on TSR The rate of secondary resistance decreases with longer duration of IM treatment. Parameter 1 year 3 years 5 years Randomized patients All (I arm/C arm) 58 (32/28) 50 (25/25) 27 (14/13) Median PFS (months) I arm/C arm 7/29 9/Not reached 13/Not reached Tumor control after IM reintroduction (pts) (tumor control/IM reintroduction) 23/25 20/20 6/7 2 years PFS (%) I arm/C arm 60/62 87/80 NE Abbreviation: NE, not yet evaluable.
Randomized phase II trial of docetaxel, with or without doxercalciferol, in advanced, androgen-independent prostate cancer
Authors: S. Attia, J. Eickhoff, G. Wilding, J. Blank, H. Rezazadeh, D. Shevrin, M. Glode, A. Jumonville, M. Eastman, G. Liu
Journal: Journal of Clinical Oncology (2007)

5119 Background: Docetaxel is the standard of care for advanced androgen-independent prostate cancer (AIPC). Doxercalciferol, a vitamin D analog (1a-hydroxyvitamin D 2 ), has single-agent activity in AIPC (Clin Cancer Res 9(11), 2003). Preclinical evidence supports combining vitamin D with chemotherapy to treat AIPC. Here we report results of a multi-institutional trial combining docetaxel and doxercalciferol. Methods: Patients with chemo-naive AIPC were randomized 1:1 to receive, on a four week cycle, docetaxel (35 mg/m 2 IV; days 1, 8 and 15) with either doxercalciferol (10 mcg PO daily, days 1–28) or placebo in a double-blind fashion. The primary endpoint was to compare progression-free survival (PFS). Secondary endpoints were to assess overall survival (OS), objective response (RECIST), PSA response (consensus criteria), and toxicity. PFS and OS were analyzed on an intent-to-treat basis. Eligibility criteria included no prior cytotoxic therapy; radiographic evidence of metastasis; performance status ≤ 2 and no recent history of nephrolithiasis. Results: Seventy patients were randomized. Median follow-up time was 16.2 months (range, 0–40.5 months). Median PFS in the doxercalciferol arm was 14.9 months (95% CI: 8.7–16.6 months) versus 11.9 months (95% CI: 8.9–16.4 months) in the placebo arm (p=0.73). Median OS in the doxercalciferol arm was 18.1 months (95% CI: 14.9–26.2 months) and 17.9 months (95% CI: 12.1–24.6 months) in the placebo arm (p=0.63). Twenty-nine patients in the doxercalciferol arm and 33 in the placebo arm were evaluable for objective response. No complete responses were seen. Partial response rate was 14% (doxercalciferol) vs. 15% (placebo) (p=0.88). PSA response rate was 44% (95% CI: 29%-60%) in the doxercalciferol arm and 42% (95% CI: 27%-59%) in the placebo arm (p=0.87). Grade 3/4 toxicity rates were 38% in the doxercalciferol arm and 39% in the placebo arm (p=0.99). Conclusions: Despite encouraging data with other vitamin D analogs combined with docetaxel in AIPC, the addition of daily doxercalciferol to weekly docetaxel did not enhance median PFS, OS or tumor response. Toxicity was similar between treatment groups. Further evaluation of vitamin D analogs in combination with chemotherapy in AIPC remains of interest. No significant financial relationships to disclose.
Neuroprotective effects of goshajinkigan (TJ-107) in colorectal cancer patients receiving oxaliplatin-based chemotherapy: A double-blind, placebo-controlled, randomized phase II trial from the GONE Study Group.
Authors: T. Matsui, T. Kono, T. Hata, Y. Munemoto, M. Fukunaga, N. Nagata, M. Nishioka, J. Hasegawa, K. Kunieda, S. Morita, J. Sakamoto, H. Mishima
Journal: Journal of Clinical Oncology (2011)

e14007 Background: Oxaliplatin-induced peripheral neuropathy (OPN) often results in the early discontinuation of oxaliplatin-based therapy in the palliative and adjuvant setting. In a retrospective study, the Japanese traditional medicine TJ-107 was associated with reduced OPN in Japan (Kono 2009). We performed a randomized, double-blind, placebo-controlled trial (GONE Study) in colorectal cancer patients to assess the ability of TJ-107 to prevent OPN. Methods: Ninety-three patients receiving oxaliplatin-based chemotherapy (FOLFOX4 or mFOLFOX6) were centrally randomized to receive either TJ-107 (2.5 g three times daily) or a placebo. Both treatments were continued after oxaliplatin therapy was suspended. OPN was assessed at baseline, every two weeks until Cycle 8, and every four weeks thereafter until the 26th week according to CTCAE. The primary endpoint was the incidence of Grade 2 or higher peripheral OPN after eight cycles of chemotherapy. The secondary endpoints were the incidence of each grade of OPN after each cycle and response rate (RR). Results: Eighty-nine patients were included in the statistical analysis, including 44 in the TJ-107 group and 45 in the placebo group. Data of the incidence of Grade 2 or higher OPN, and Grade 3 at the 8th cycle and the 26th week was summarized in Table. A risk reduction of 12% and 42% in the probability of Grade 2 or higher OPN at the 8th cycle and the 26th week in favor of TJ-107 was reported, respectively. Severe toxicities (% Grade 3), reported with 74% and 51% risk reduction were (TJ-107 vs. placebo) at the 8th cycle and the 26th week, respectively. The RR was 55.5% in the TJ-107 group and 39.1% in the placebo group. Conclusions: TJ-107 was shown to be efficient in reducing the risk of Grade 2 or higher OPN without having a negative influence on the RR and was encouraging for performing a much larger conventional phase III trial. OPN at the 8th cycle OPN at the 26th week TJ-107 Placebo Relative risk [95%CI] TJ-107 Placebo Relative risk [95%CI] Grade2+ 27.0 % 30.7 % 0.88 [0.43-1.78] 25.7 % 44.1 % 0.58 [0.30-1.15] Grade 3 2.7 % 10.2 % 0.26 [0.03-2.25] 5.7 % 11.7 % 0.49 [0.10-2.48]
Pattern of restoration of the immune alterations by the treatment with high doses of Interferon alpha in high risk melanoma patients
Authors: E. Reyes, M. Arroyo, T. Portugal, A. B. Mallo, F. Navarro, R. Molina, J. L. Lopez, A. De La Hera, J. Cassinello, M. Alvarez-Mon
Journal: Journal of Clinical Oncology (2004)

7534 Background: IFNa is currently use in the adjuvant treatment of patients with high risk of melanoma. The mechanism of action of IFNa is complex. Since it, IFNa is able to modulate different regulatory and effectors cells of the immune system. Therefore, the optimization of the clinical use of IFNa requires the analysis of the biological effects of the biotherapy. Herein, we have investigated the effects of high doses of IFNa in the expression of chemokine receptors by peripheral blood (PB) lymphocytes and the spontaneous cytotoxic (NK) activity of PB mononuclear cells (PBMC) in patients with high risk melanoma. Methods: 15 patients with melanoma stage III were treated with intravenous IFNa 20MU/m2 5 days per week for 4 weeks follow by intramuscular IFNa 10 MU/m2 3 days per weeks for 48 weeks. PBMC were obtained by venous puncture before the first dose of IFNa, every last day of the first 4 weeks of treatment, and at 3, 6, 9 and 12 months of the maintenance treatment. The expression of differentiation antigens and chemokine receptors were measured by direct surface immunofluorescence and flowcytometry. NK activity was measured by 51Cr release assay using as targets K562 cells. 15 age and sex matched healthy donors were use as controls. Results: Before the biotherapy, melanoma patients showed significantly reduced expression of CXCR4 and CCR2 on the surface of CD19+ B cells (P<0.05), as well as reduced CXCR4+CD3+ T cells and CD16+CD3- NK cells (P<0.05). The expression of CXCR4 by B, T and NK cells was normalized, as compared to controls, after 4 weeks of treatment. The normalization of the expression of CCR2 in the latter lymphocyte subsets was achieved only after 3 months of treatment. NK cytotoxic activity in PBMC remained significant decreased during the first 9 months but normalization occurred after 12 months of treatment. Conclusions: This study demonstrates that high doses of IFNa promote clear immunomodulatory effects in high risk melanoma patients. Notably, the normalization of immunological parameters is sequential and beneficial accumulative effects are evident after 9 months which provides a rational to recommend maintenance therapy. No significant financial relationships to disclose.
Diagnostic accuracy and standardization of fine needle biopsy in the characterization of liver nodules in cirrhosis.
Authors: A. Sangiovanni, M. Iavarone, S. Vavassori, C. Della Corte, M. A. Manini, M. Fraquelli, G. Ronchi, A. Aghemo, M. Colombo
Journal: Journal of Clinical Oncology (2010)

e14576 Background: The diagnostic sensitivity of fine needle biopsy (FNB) for liver nodules in cirrhotic patients is both operator and disease characteristic dependant. The performance FNB needs to be not standardized. Aim: To compare the diagnostic accuracy of one vs. two FNB intra-nodule plus one extra-nodule passage. Methods: A FNB was performed with a 21-gauge trenchant needle for microhistology (Biomol, HS Hospital Service, Italy) with two passages within and one outside the nodule, and processed separately. The diagnosis was made by histology and confirmed by enhanced follow-up for non malignant lesions. FNB was repeated in all patients with unsolved histological diagnosis, i.e., similar histologic features within and outside the liver nodule. Patients with non malignant nodules underwent a repeat US every 3 months, an abdominal CT/MRI every 6 months and repeated FNB if nodules changed in size/vascular pattern. The histological diagnosis was according the International Working Party criteria. Results: 48 prospectively enrolled cirrhotics, 44 (92%) Child-Pugh A, had 67 liver nodules (mean diameter 1.9 cm); 2 (3%) < 1 cm, 39 (58%) 1-2 cm, 15 (22%) 2-3 cm, 11 (17%) > 3 cm. The final diagnosis was 41 (61%) hepatocellular carcinoma (HCC), 1 (2%) cholangiocarcinoma (CCC), 15 (22%) MRN, 4 (6%) low grade dysplastic nodule (LGDN), 4 (6%) high grade dysplastic nodule (HGDN), 2 (3%) lymphoma. 36 HCC (82%) were diagnosed with first passage whereas 5 additional HCC (8%) were diagnosed with the second passage. FNB needed to be repeated in 2 (3%) cases with similar histological features within and outside the liver nodule. In the 39 nodules of 1-2 cm, the corresponding final diagnosis was: 17 (43%) HCC, 1 (3%) CCC, 3 (8%) MRN, 11 (28%) LGDN, 5 (13%) HGDN, 2 (5%) lymphoma. Fifteen HCC (37%) were identified by one passage and 2 (5%) by two passages. FNB needed to be repeated in 2 patients. A parenchymal sub-glissonian hematoma (1%) was the only complication. Conclusions: Two passages FNB allows to increase by 12% the final diagnosis of HCC in small liver nodules detected during surveillance of patients with cirrhosis. No significant financial relationships to disclose.
Differences in response of breast cancer molecular profiles of patients likely to respond to either tyrosine kinase inhibitors or to erbB targeted therapies
Authors: S. S. Bacus, B. Smith, Y. Yarden, N. Spector
Journal: Journal of Clinical Oncology (2004)

3097 Background: Over-expression of erbB receptors is associated with aggressive cancers. Therapeutic strategies targeting these oncoproteins are in clinical trials. One approach is the use of monoclonal antibodies to erbB1 and erbB2 such as Herceptin. Studies have attributed the therapeutic potential of Herceptin to enhance intracellular degradation resulting in inhibition erbB2. Another approach is the use of tyrosine kinase inhibitors (TKIs) that block the nucleotide-binding site of the erbB kinases, specifically erbB1 and erbB2 (such as GW572016, ZD1839). Blocking of the kinase activity, downstream signaling pathways are inhibited leading to growth arrest and apoptosis. Methods: We used cancer tissue biopsies from patients before and after treatments to understand the mechanism associated with response to targeted erbB treatments. The cancer biopsies were immunostained for erbB1 and erbB2, their phosphorylated forms, phosphorylated ERK and AKT, IGFR, pS6, p27, TGF and Heregulin. Levels and localization were analyzed using immunohistochemistry, quantitated by image analysis and confocal microscopy (antibodies were purchased from Cell Signaling and Ventana). Treatment included GW572016 and Herceptin. Results: Patients with high levels of EGFR, HER-2, which downregulate pAKT and pERK responded to TKI. Their response included translocation of pAKT and pERK for the nuclear component to the cytoplasmic component. Their response was confirmed using biological biomarkers and objective clinical response. Disease progression was associated with persistent high levels of pAKT and pERK and nuclear localization . Cancers with high AKT and pERK responded to TKI but not to Herceptin. Both treatments were not effective when IGFR was highly expressed. Moreover, translocation of activated AKT and ERK played a major role in response and resistance to TKI. Conclusions: Using biomarkers to predict and monitor response to erbB targeted therapy can help stratify best patient populations for various treatment approaches. No significant financial relationships to disclose.
A phase I study of E7080 in patients (pts) with advanced malignancies
Authors: H. Glen, D. R. Boss, R. Morrison, M. Roelvink, J. Wanders, A. Mazur, A. Gupta, A. Das, T. R. Evans, J. H. Schellens
Journal: Journal of Clinical Oncology (2008)

3526 Background: E7080 is a potent inhibitor of the split-kinase family of transmembrane growth factor receptors including VEGFRs 1 and 2, and also potently inhibits FGFR-1 and PDGFR-β tyrosine kinase activities. E7080 inhibited VEGF-driven umbilical vein endothelial cell proliferation and tube formation in vitro, and inhibited tumor growth in H460 and Colo205 mouse xenografts models in vivo at doses of 1–100mg/kg. Methods: The primary objective of this study was to determine the maximum tolerated dose (MTD) and dose limiting toxicity (DLT) of E7080 in pts with advanced solid tumors refractory to standard therapies. Eligible pts were those with ECOG PS < 2 and adequate haematologic, renal and hepatic function. E7080 was administered orally on a once daily continuous schedule in 4-week cycles. Dose escalation was by an accelerated design (100% dose increases until the 1st pt experienced toxicity ≥ grade 2). Samples for pharmacokinetic (PK) analyses were collected on days 1, 8, 15, 22 and 29. A food effect PK sub-study is ongoing at the MTD. Results: 59 pts (35 m, 24 f), median age = 55 yrs (range 25–84) were treated at dose levels (mg/day) of 0.2, 0.4, 0.8, 1.6, 3.2, 6.4, 12.5, 16, 20, 25 and 32 mg. Median number cycles = 5 (0–22). 53 pts are evaluable for toxicity so far. DLTs included 2 pts at 32mg (both proteinuria), 1 pt each at 16mg (hypertension), 12.5mg (proteinuria) and 6.4mg (febrile neutropenia). The MTD is 25mg daily. Dose reductions (n=12pts) were most commonly for ≥ grade 2 proteinuria (5 pts) and hypertension (5 pts). Other grade 3/4 toxicities include haemorrhage and thrombosis (n=1) and tachycardia (n=1). 37 pts are now evaluable for response: 5 pts have confirmed PR (1 sarcoma, 2 melanoma, 2 renal carcinoma), 25 pts have had stable disease for a median of 16 weeks (range 8–88). The PK was described by a 2- compartment model. Clearance was linear with dose and unchanged with multiple dosing. A saturable decrease in the distribution volume was observed with dose from 0.2 up to 1.6 mg. The covariate and food effect analyses will be reported in the full presentation. Conclusions: E7080 displays linear PK and is safe and well tolerated at doses up to 25mg daily with signs of anti-cancer activity. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Eisai Medical Research Eisai Medical Research Eisai Medical Research
Correlation of hypoxic prostate/muscle p<sub>O2</sub> (P/M P<sub>O2</sub>) ratio and biochemical failure in patients with localized prostate cancer: Long-term results
Authors: A. Turaka, M. K. Buyyounouski, A. L. Hanlon, E. M. Horwitz, R. E. Greenberg, B. Movsas
Journal: Journal of Clinical Oncology (2009)

5136 Background: Tumor hypoxia may confer radioresistance in prostate cancer. The purpose of this study was to correlate tumor oxygenation status with long term biochemical outcome following prostate bracytherapy. Methods: Custom made Eppendorf P O2 microelectrodes were used to obtain P O2 measurements from the prostate (P), focused on + biopsy locations, and normal muscle tissue (M), as a control, in the operating room using a sterile technique. A total of 11,516 measurements were obtained in 57 patients with localized prostate cancer immediately prior to prostate brachytherapy. The Eppendorf histograms provided the median P O2 , mean P O2 , and % &lt; 5 mm Hg or &lt; 10 mm Hg. All patients received brachytherapy implants (48 low dose rate and 9 high dose rate) and five patients had received prior hormonal therapy. Biochemical failure (BF) was defined using both the newer Phoenix (PSA nadir + 2 ng/mL) the prior ASTRO (three consecutive rises) definitions (dfn). A Cox proportional hazards regression model evaluated the influence of hypoxia on BF with P/M ratio as a continuous variable and dichotomized at 0.05, 0.10, and 0.20. Results: The median follow-up was 8 years (range: 0.8- 9.4 years). Twelve patients developed BF via ASTRO dfn and 8 via Phoenix dfn. On stepwise multivariate analysis, P/M ratio &lt; 0.10 was a significant predictor of BF (ASTRO, p = 0.03; Phoenix p = 0.02) in a model including initial PSA, Gleason score, T-stage, perineural invasion, age, hemoglobin and use of hormonal therapy. Kaplan-Meier freedom from BF for P/M ratio &lt; 0.10 vs. ≥ 0.10 at 8 years was 46% vs 78% (p = 0.03) for the ASTRO dfn and 66% vs 83% (p = 0.02) for the Phoenix dfn. Only one patient (in the P/M ratio &lt; 0.10) manifested distant failure. Conclusions: Hypoxia in prostate cancer (low P/M P O2 ratio) significantly predicts for poor long term biochemical outcome on multivariate analysis, suggesting that novel hypoxic strategies should be investigated. No significant financial relationships to disclose.