tbuckley/cabot-search huggingface dataset:
Phase I trial of high-dose bolus interleukin-2 and interferon alfa-2a in patients with metastatic malignancy.
Authors: G T Budd, S Murthy, J Finke, J Sergi, V Gibson, S Medendorp, B Barna, J Boyett, R M Bukowski
Journal: Journal of Clinical Oncology (1992)

PURPOSE Based on preclinical evidence that the antitumor effects of the combination of interleukin-2 (IL-2) and interferon alfa (IFN alpha) are greater than those of either cytokine alone, we have performed a phase I trial of recombinant IL-2 (rIL-2) and recombinant human IFN alpha 2a (rHuIFN alpha 2a) in patients with refractory malignancies. This study was an extension of an earlier trial that identified reversible myelosuppression as the dose-limiting toxicity of this combination. The present trial used modified definitions of unacceptable toxicity to allow exploration of higher doses of rIL-2. PATIENTS AND METHODS Both rHuIFN alpha 2a 10.0 x 10(6) U/m2 intramuscularly (IM) and rIL-2 were administered three times weekly for 4 consecutive weeks. IL-2 was given by intravenous (IV) bolus injection at doses that were escalated in successive cohorts of four to six patients, provided that toxicity at the preceding dose level was acceptable. Unacceptable toxicity was defined as an elevation of the serum creatinine level to greater than 5 mg/dL, an elevation of the serum bilirubin level to greater than 5 mg/dL, dyspnea at rest, hypotension refractory to pressors, altered mental status, or other toxicities of grade 3 to 4, using the National Cancer Institute (NCI) Common Toxicity Criteria. The doses of rIL-2 administered were 4.0 x 10(6), 6.0 x 10(6), 8.0 x 10(6), 10.0 x 10(6), 12.0 x 10(6), 14.0 x 10(6), 18.0 x 10(6), 22.0 x 10(6), and 26.0 x 10(6) BRMP (Hoffman-LaRoche) U/m2. At a dose of rIL-2 10.0 x 10(6) BRMP U/m2, patients were also treated with doses of rHuIFN alpha 2a of 1.0 x 10(6) and 0.1 x 10(6) U/m2. RESULTS A total of 57 patients were treated. Intolerable side effects (hypotension, pulmonary, and CNS toxicity) were produced by rIL-2 26.0 x 10(6) BRMP U/m2 and rHuIFN alpha 2a 10.0 x 10(6) U/m2. Two of 21 patients with renal cell carcinoma showed objective responses, and five of 17 patients with malignant melanoma responded. Two of these responses in melanoma were complete and continue to be longlasting. CONCLUSIONS When given with rHuIFN alpha 2a 10.0 x 10(6) U/m2 as described above, the maximum-tolerated dose of rIL-2 is 22.0 x 10(6) BRMP U/m2. This dose of rIL-2 is equivalent to 50 to 60 MIU/m2, depending on the conversion factor used. Based on this experience and other trials, we favor phase II trials in renal cell carcinoma using an alternative dose schedule of this cytokine combination, in which rIL-2 is administered by continuous infusion. We suggest that phase II trials of this combination in patients with melanoma use an rIL-2 dose of 8.0 x 10(6) BRMP U/m2 by IV bolus injection three times weekly in combination with rHuIFN alpha 2a 10.0 x 10(6) U/m2 IM three times weekly.
Peritoneal Dissemination Requires an Sp1-Dependent CXCR4/CXCL12 Signaling Axis and Extracellular Matrix–Directed Spheroid Formation
Authors: Yuta Kasagi, Yui Harada, Yosuke Morodomi, Toshiki Iwai, Satoru Saito, Kumi Yoshida, Eiji Oki, Hiroshi Saeki, Kippei Ohgaki, Masahiko Sugiyama, Mitsuho Onimaru, Yoshihiko Maehara, Yoshikazu Yonemitsu
Journal: Cancer Research (2016)

Peritonitis carcinomatosa is an advanced and intractable state of gastrointestinal and ovarian cancer, where mechanistic elucidation might enable the development of more effective therapies. Peritoneal dissemination of this type of malignancy has been generally thought to initiate from "milky spots" of primitive lymphoid tissues in the peritoneal cavity. In this study, we offer evidence challenging this idea, based on the finding that tumor implantation and directional dissemination was not required for the presence of milky spots, but rather SCF/CXCL12-expressing niche-like cells located at the border regions of perivascular adipose tissue. Interestingly, we found that peritoneal cavity lavage fluid, which specifically contains peritoneal collagen type IV and plasma fibronectin, dramatically facilitated spheroid formation of murine and human colon cancer cells. Spheroid formation strongly induced the expression of CXCR4 in an Sp1-dependent manner to promote niche-directed metastasis. Notably, disrupting sphere formation or inhibiting Sp1 activity was sufficient to suppress tumor dissemination and potentiated chemosensitivity to 5-fluorouracil. Our findings illuminate mechanisms of peritoneal cancer dissemination and highlight the Sp1/CXCR4/CXCL12 signaling axis as a rational target for the development of therapeutics to manage this intractable form of malignancy.
Dosimetry study of a phase II multiple-dose intracavitary administration of <sup>131</sup>I-TM601 in adult patients with recurrent high-grade glioma
Authors: S. Shen, L. B. Nabors, J. J. Raizer, J. B. Fiveash, S. Spies, R. Costello, A. M. O’Neill
Journal: Journal of Clinical Oncology (2009)

e13006 Background: Postoperative radiotherapy for glioma has been shown to improve survival with increased radiation doses. Dose escalation of external beam radiotherapy or brachytherapy is limited by normal brain radionecrosis. Radiolabeled targeting molecules can deliver localized radiation to tumor and reduce normal brain radionecrosis. TM601, or synthetic Chlorotoxin, is a peptide derived from scorpion venom that specifically binds to tumor cells. Here we report dosimetry results of an imaging sub-study of a phase II trial, in which weekly doses of 131 I-TM601 were infused into surgically created tumor resection cavities for 3 or 6 weeks. Methods: Five out of 76 patients treated in a phase II trial were imaged after receiving 1, 3, or 6 doses of 40 mCi/0.8 mg 131 I-TM601 intracavitarily. For each imaging study, 5 sequential SPECT images (1–168 hour) were registered with MRI to determine the 131 I-TM601 radiation dose to the 2-cm tumor cavity margin. Five sequential body scans were also acquired to determine 131 I-TM601 radiation dose to extra-cranial organs. Results: 131 I-TM601 is a rapidly penetrating and clearing radiolabeled peptide. The median residual activity in the cavity at 7 days post injection was 8.4%. Median radiation dose to the cavity margin was 121 cGy/mCi and ranged 52- 338 cGy/mCi in 5 subjects. The median coefficient of variation (intra-patient inter-fraction) for the 2-cm margin dose was 14.7% and ranged 7.1–18.9%. Median tumor cavity volume was 11.4 mL, and ranged 5.2 - 35.5 mL. There was no observed correlation between the 2-cm margin dose and the cavity volume. Median radiation dose to thyroid, kidneys, red marrow, and body was 8.3, 1.3, 0.4, and 0.6 cGy/mCi, respectively. Conclusions: Radiation dose ratio for 2-cm cavity margin-to-normal tissues was quite high. While intra-patient reproducibility was relatively good, cumulative effect of the residual activity was only meaningful within a week. These results support the multi-dose fractionation scheme for 131 I-TM601 to minimize normal tissue toxicity, including radiation necrosis, and extend continuous irradiation to clinical or sub-clinical residual tumor cells after surgery. [Table: see text]
Clinical, Endoscopic, and Histologic Characteristics of Ipilimumab-Associated Colitis
Authors: Eduard Cornelis Verschuren, Alfonsus Johannes van den Eertwegh, Janneke Wonders, Rob Michel Slangen, Foke van Delft, Adriaan van Bodegraven, Andra Neefjes-Borst, Nanne Klaas de Boer
Journal: Clinical Gastroenterology and Hepatology (2015)
Novel dual PPARα/γ ligands, TZD18 and compound 48, as growth inhibitors of CML cell lines
Authors: Chuanbing Zang, Janina Bertz, Hongyu Liu, Marlies Wachter, Kurt Possinger, H. Koeffler, Elena Elstner
Journal: Cancer Research (2007)

AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA

5612 

Despite of progress in therapy of CML with imatinib, resistances during treatment frequently occur and remain a therapeutic challenge. In this study, we investigated the activity of two novel dual ligands specific for peroxisome proliferator-activated receptor α and γ (PPARα/γ), TZD18 and compound 48 (C48), against CML cell lines. Culture of CML cell lines, both imatinib-sensitive (K562, KU812 and KCL22) and -resistant (K562sr, KU812sr and KCL22sr), with TZD18 or C48 resulted in growth inhibition in a dose- and time-dependent manner without obvious toxicities on normal CD34 positive hematopoietic stem cells as assessed by clonogenic assay. The observed inhibition was much stronger than that either of conventional PPARγ ligand, pioglitazone (PGZ) or PPARα ligand, WY14,643. However, these effects seemed not to be mediated by activation of either PPARα or γ receptors, since antagonists for PPARγ and/or PPARα could not reverse these inhibitions. G0/G1 cell cycle arrests have been observed after exposure to TZD18 or C48 indicating that inhibition of cell cycle progression may account for the observed growth inhibition. Western blot analysis of cell cycle regulators confirmed these results, namely, expression of cyclin dependent kinase (CDK) inhibitor p27kip1 was enhanced, whereas levels of cyclin E, cyclin D2 and CDK 2 were decreased when these cells were treated with either TZD18 or C48.

Recent published data indicates that autocrine secretion of GM-CSF is crucial for growth and imatinib resistance of CML cells. We found now, for the first time, that both TZD18 and C48 reduced the secretion of GM-CSF significantly in both imatinib-sensitive and -resistant CML cells suggesting that interference of autocrine growth regulation by GM-CSF may be one of the mechanisms responsible for PPARα/γ ligands induced growth inhibition in CML cells.

Finally, of more clinical importance, these ligands enhanced either additively or synergistically the anticancer-effects of imatinib in both imatinib-sensitive and -resistant cells.

Overall, our findings clearly suggest that these PPARα/γ ligands, alone or in combination with imatinib, may have potential clinical application in treatment of CML in an adjuvant setting either before or after development of imatinib resistance.
Xanthine oxidoreductase and chemosensitivity in non-small cell lung cancer
Authors: R. Myint, M. Batus, P. Bonomi, P. Gattuso, W. H. Warren, M. Liptay, P. Faber, S. Basu, X. Xu, A. W. Kim
Journal: Journal of Clinical Oncology (2009)

11077 Background: Xanthine oxidoreductase (XOR) is an enzyme involved in the degradation of purines into uric acid and reactive oxygen species and activation of the MAP kinase pathway involved in apoptosis. Decreased XOR expression was shown in recent studies to be associated with more aggressive disease in breast (Linder et al. Clin Cancer Res. 2005;11:4372–4381) and gastric cancers (Linder et al. J Clin Pathol. 2006;59:965–971). The goal of our study was to show that decreased XOR expression was associated with decreased survival in non-small cell lung cancer (NSCLC). Methods: Tissue specimens from 82 patients (pts) were stained using a XOR specific antibody (36 male and 46 female, age range from 40 to 92 years). These included 41 adenocarcinoma, 31 squamous cell, 8 poorly/moderately differentiated, and 2 bronchioloalveolar. XOR staining intensity was measured on a scale of 0 through 4 (0 being no staining). XOR intensity was correlated with clinical characteristics and outcomes using log rank and COX PH regression analysis. Results: Of the 82 pts, 34 received adjuvant chemo, and of these, 15 specimens had low XOR intensity (0–1). These 15 pts received adjuvant chemo and had a median survival of 543 days. In comparison, 19 of the 34 pts receiving adjuvant chemo had specimens with high XOR intensity (2–4). Their median survival was significantly longer at 2,023 days (p=0.007, hazard ratio=0.33). Conclusions: Although we had a small sample size, in our retrospective study, we found that pts who received adjuvant chemo had a longer survival if their tumors expressed high levels of XOR. XOR could be a potential predictor for responsiveness to adjuvant chemo in patients with NSCLC. Pts with decreased XOR may be less responsive to chemo and thus be able to avoid a toxic treatment if it is not significantly beneficial. [Table: see text] No significant financial relationships to disclose.
Abstract 11965: Heart Rate Reduction with Ivabradine Improves Regional Contractile Function and LV Dyssynchrony in a Mouse Model of Reperfused Myocardial Infarction
Authors: Daniel M O'Connor, Robert S Smith, Bryan A Piras, Dan Lin, John A Hossack, Brent A French
Journal: Circulation (2012)

Introduction: Ivabradine selectively inhibits the If channel of the sinoatrial node, slowing heart rate. Few studies have examined the effects of ivabradine on the mechanical properties of the hear...
Suppression of growth of human malignant B cells by naked monoclonal antibodies that target ectoepitopes of the Igα/Igβ (CD79) component of the human B cell antigen receptor complex
Authors: Fumihiko Matsuno, Victor Filadora, Deborah VanKouwenberg, Masanori Tsujie, Tomoko Tsujie, Hilda Tsai, Ben Seon
Journal: Cancer Research (2007)

4107   The disulfide linked heterodimer of Igα (mb1, CD79a) and Igβ (B29, CD79b) is noncovalently associated with the cell membrane Ig on B cells and play the pivotal role in the antigen-dependent signal transduction. Previously we reported a novel heterodimeric cell membrane antigen that was strongly expressed on some malignant B cells including prolymphocytic leukemia and non-Hodgkin’s lymphoma cells (1989, 1993). This antigen was found by use of three newly generated monoclonal antibodies (mAbs) termed SN8, SN8a and SN8b. Subsequently we determined that this antigen was the human homologue of murine Igα/Igβ (1993, 1994). These mAbs were the first proven mAbs defining ectoepitopes of Igα/Igβ. SN8 and SN8a defined ectoepitopes of Igβ (1993), whereas SN8b defined an ectoepitope of Igα (A.G. Polson  et al.  2006). In the present study, we tested our hypothesis that naked (unconjugated) mAbs targeting the ectoepitopes of Igβ and/or Igα may be valuable for treating patients with B cell malignancies. SN8 showed dose-dependent growth suppression of malignant B cells while an isotype-matched control IgG and an isotype-matched control mAb SN2 showed no significant suppression. Cross-linking of the mAb and antigen using anti-mouse IgG antibodies or human CD32-transfected murine L cells enhanced the growth suppression by SN8. SN8b also suppressed growth of malignant B cells. The suppressive activities of these mAbs were further evaluated in SCID mice bearing BALL-1a B-cell tumors. A preliminary experiment suggested that SN8 and SN8b defining Igβ and Igα, respectively, synergize in suppression of the tumor growth. This conclusion was supported by the subsequent experiment. Systemic administration of SN8 improved survival of the tumor-bearing mice when the mice were followed for 180 days. SN8b was less effective than SN8. Combined use of SN8 and SN8b showed supraadditive antitumor efficacy and suggested therapeutic synergy. The results appear to support our hypothesis that naked SN8 may be useful for treating B cell malignancies and this potential will be enhanced by combined use of SN8 with SN8b.
Abstract 16336: Calcium Channel Blockers Improve Exercise Capacity and Lower NT-proBNP Levels Compared to Beta Blockers in Patients with Permanent Atrial Fibrillation
Authors: Sara R Ulimoen, Steve Enger, Are H Pripp, Michael Abdelnoor, Harald Arnesen, Knut Gjesdal, Arnljot Tveit
Journal: Circulation (2012)

Introduction Rate control of atrial fibrillation (AF) is a main treatment modality, but there is still a lack of data regarding the effects of the different rate reducing drugs. Hypothesis We hypot...
Lifestyle Interventions to Improve Exercise Tolerance in Obese Older Patients With Heart Failure and Preserved Ejection Fraction
Authors: Nanette K. Wenger
Journal: JAMA (2016)

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A phase I study of panobinostat (LBH589) with capecitabine with or without lapatinib.
Authors: N. W. Peacock, S. F. Jones, D. A. Yardley, J. C. Bendell, J. R. Infante, P. B. Murphy, H. A. Burris
Journal: Journal of Clinical Oncology (2010)

1115 Background: In vivo experiments have demonstrated synergy when the histone deacetylase (HDAC) inhibitors are combined with chemotherapy. This phase I trial was designed with three objectives: Part 1 to establish the maximum tolerated dose (MTD) and dose limiting toxicities (DLT) of panobinostat in combination with capecitabine; Part 2 to assess the safety and tolerability when panobinostat is combined with lapatinib; and part 3 to evaluate the tolerability and effectiveness of the triplet combination of panobinostat, capecitabine, and lapatinib in women with metastatic breast cancer. This abstract describes the results from Part 1 of the trial. Methods: Eligible patients aged ≥18 years with histologically documented metastatic or locally advanced, incurable malignancy for whom capecitabine would be an appropriate treatment option were enrolled. Capecitabine doses of 825 and 1,000 mg/m2 BID 14 of 21 days were administered with oral panobinostat 30 mg twice weekly. Cycles were repeated every 21 days until disease progression or toxicity warranted drug discontinuation. Patients were reevaluated for response every 2 cycles. Results: Between 6/08 and 12/08, 15 patients (Cohort 1 > 4; Cohort 2 > 11; median age 54 years[range 45-69]; 47% male) received 56 cycles of treatment (median 2 cycles; range 1-15). One patient experienced a DLT of grade 4 thrombocytopenia at the highest dose level with two additional patients experiencing grade 3 thrombocytopenia warranting dose reductions. Other grade 3 toxicities reported in 1 patient each (7%) included anemia, dehydration, fatigue, peripheral edema, and hand-foot syndrome. One patient with metastatic breast cancer experienced an objective response and 27% have had stable disease as their best response. Conclusions: Accrual to Part 1 of the study is complete. The combination of panobinostat and capecitabine is well-tolerated at the recommended doses of 30 mg twice weekly continuously and 1,000mg/m2 BID × 14 days every 21 days. Patient accrual will continue in women with metastatic breast cancer based on the recommended dose established in part 1, but the dosing schedule for panobinostat will change to 20 mg three times weekly for parts 2 and 3. No significant financial relationships to disclose.
Serum lactate dehydrogenase (LDH) as a biomarker for survival with mTOR inhibition in patients with metastatic renal cell carcinoma (RCC).
Authors: A. J. Armstrong, D. J. George, S. Halabi
Journal: Journal of Clinical Oncology (2010)

4631 Background: No predictive biomarkers currently exist in GU cancers. LDH is an enzyme detectable in serum that is often elevated in multiple cancers including RCC, has prognostic importance and is regulated by the PI3 kinase/Akt/mTOR pathway and tumor hypoxia/necrosis. We sought to evaluate pretreatment LDH as a predictive biomarker in patients with metastatic RCC. Methods: We evaluated pretreatment and post-treatment serum LDH in 404 poor-risk RCC subjects treated with the mTOR inhibitor temsirolimus or interferon alpha (IFN) in an international phase III randomized trial. Kaplan-Meier estimator and the proportional hazards model were used to examine the association of LDH with overall survival. Results: Mean baseline serum normalized LDH was 1.23 times the upper limit of normal (range 0.05 to 28.5x ULN). Among 140 subjects with elevated LDH, survival was significantly improved with temsirolimus (6.9 vs. 4.2 months, log- rank p<0.002). Among 264 subjects with normal LDH, survival was not improved with temsirolimus as compared to interferon therapy (11.7 vs. 10.4 months, log-rank p=0.514). There was a statistically significant interaction effect noted between normalized LDH and treatment group (p=0.031). The hazard ratio (HR) for death was 1.98 (95% confidence interval (CI) 1.6-2.5, p<0.0001) for patients with LDH>1x ULN compared to patients whose LDH ≤ 1x ULN. Adjusting for known prognostic factors, the HR for death was 2.01 for patients with LDH>1 ULN vs. ≤1 ULN (95% CI=1.6-2.6, p<0.0001). Post- treatment LDH at 2 months increased 1.7% vs. 27% in the IFN and temsirolimus arms, respectively. A decline in LDH with therapy was prognostic of OS (p<0.0001) but this association was weak (HR=1.00). Conclusions: Serum LDH is a potential pretreatment predictive biomarker for the survival benefit conferred by mTOR inhibition in patients with poor risk RCC. Further investigation of the predictive role of LDH as a measure of benefit with mTOR inhibition in other RCC risk groups and other tumor types is warranted. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Pfizer-Wyeth, Wyeth Pfizer Pfizer, Wyeth