tbuckley/cabot-search huggingface dataset:
Phase II study with immunotherapy with dendritic cells (DC) and intratumoral hiltonol in patients with advanced solid tumors.
Authors: José María López-Picazo, Carlos Alfaro, Jose Luis Perez-Gracia, Maria Rodriguez-Ruiz, Alfonso Gurpide, Miguel Fernandez de Sanmamed, Salvador Martin-Algarra, Alberto Benito, David Cano, Alvaro Gonzalez, Inmaculada Rodriguez, Juan Pablo Fusco, Rafael Martinez-Monge, Ignacio Melero
Journal: Journal of Clinical Oncology (2014)

TPS3113 Background: DC vaccines have proved efficacy in the treatment of cancer and combination strategies are expected to increase anti-tumor activity. Our study explores the efficacy of intratumoral Hiltonol, a potent TLR3 agonist in combination with an autologous vaccine of DC loaded with self-tumor lysates that we developed in a previous pilot trial (Alfaro C, J Immunology 2011) in patients with solid tumors. Hiltonol is an stabilized form of polyI:C, a nucleic acid that mimics viral RNA. It induces local release of cytokines that promote inflammation, induce type I interferon and favour traffic of leukocytes to infiltrate the tissue. Preclinical data indicates that intratumoral administration of Hiltonol triggers pro-inflammatory changes that increase the efficacy of DC vaccination. Methods: In this phase II study, 25 patients with advanced solid tumors non-amenable for conventional treatment are being treated with Hiltonol and DC vaccinations. The vaccination protocol includes the following strategies: (1) pretreatment with cyclophosphamide to decrease regulatory T cells; (2) maturation and activation of DC with TNF-alpha, interferon-alpha and poly I:C, a potent inducer of type I interferon; (3) use of autologous tumor as antigenic source to expose DC to antigens that are exclusive of tumor cells; and (4) daily intradermal doses vaccinations during four consecutive days in 2 cycles every 4 weeks. Two intratumoral ultrasound-guided injections of Hiltonol 0.25 mg are administered on alternate days the week following each DC cycle. Sample size has been calculated using a two-stage Simon´s Minimax design, with alpha error α= 0.05 and beta-error=0.10 for P0=0.05 and P1=0.25. The main objective is response rate. Secondary objectives include assessment of toxicity, overall survival and immunologic response (in vitro lymphocyte responses against tumor antigens; delayed hypersensitivity reactions; and assessment of DC maturation by expression of pro-inflammatory cytokines). Clinical trial information: NCT01734564.
Prognostics factors in previously untreated urothelial cancer patients ineligible for cisplatin-based chemotherapy: An external validation of the Bajorin risk groups.
Authors: Sandra Collette, Richard Sylvester, Joaquim Bellmunt, Graham Mead, Jan M. Kerst, Michael Gordon Leahy, Pablo Maroto, Thierry Gil, Sandrine Marreaud, Gedske Daugaard, Iwona Anna Skoneczna, Ronald De Wit, Maria De Santis
Journal: Journal of Clinical Oncology (2013)

4529 Background: In patients with urothelial cancer who are unfit for Cisplatin chemotherapy, EORTC phase II/III trial 30986 investigated two carboplatin-based chemotherapy regimens: Gemcitabine/Carboplatin (GC) and Methotrexate/Carboplatin/Vinblastine (M-CAVI). The trial did not show any significant differences in efficacy (response rate, OS, PFS) between the treatments; however the incidence of severe acute toxicity was slightly higher on M-CAVI. We now investigate the prognostic factors for survival. Methods: 238 patients with impaired renal function (Glomerular Filtration Rate (GF) &lt;60 mL/min) or poor performance status (PS 2) were randomized by 29 institutions between GC and M-CAVI. The median follow-up was 4.5 years and, with 218 deaths reported (progression of malignant disease in 72%), the overall survival median was 9.3 months in the GC arm and 8.1 months in the M-CAVI arm. Univariate and multivariate Cox prognostic factor regression models for overall survival were developed on the whole population stratified by treatment arm. Results: In the multivariate analysis, the risk of death significantly increased (p&lt;0.10) with WHO-PS 2, hemoglobin ≤ 12 g/dl (women) or ≤ 13.6 g/dl (men), the presence of visceral metastases and even more with the presence of liver metastases. The risk of death was not influenced by the site of the primary tumour, white blood cell or platelet count. In addition, the prognostic factors had a stronger effect in the M-CAVI arm than in the GC arm. Conclusions: This prognostic factors analysis confirms the Bajorin classification based on visceral metastases and performance status. However, we were also able to show the importance of hemoglobin and that in the patients with visceral metastases, the subgroup of patients with liver metastases had a significantly worse prognosis than the patients with only other visceral metastasis. Clinical trial information: NCT00014274.
A 5-Year Observational Study of Patients With Treatment-Resistant Depression Treated With Vagus Nerve Stimulation or Treatment as Usual: Comparison of Response, Remission, and Suicidality
Authors: Scott T. Aaronson, Peter Sears, Francis Ruvuna, Mark Bunker, Charles R. Conway, Darin D. Dougherty, Frederick W. Reimherr, Thomas L. Schwartz, John M. Zajecka
Journal: American Journal of Psychiatry (2017)

Objective: The Treatment-Resistant Depression Registry investigated whether adjunctive vagus nerve stimulation (VNS) with treatment as usual in depression has superior long-term outcomes compared with treatment as usual only. Method: This 5-year, prospective, open-label, nonrandomized, observational registry study was conducted at 61 U.S. sites and included 795 patients who were experiencing a major depressive episode (unipolar or bipolar depression) of at least 2 years’ duration or had three or more depressive episodes (including the current episode), and who had failed four or more depression treatments (including ECT). Patients with a history of psychosis or rapid-cycling bipolar disorder were excluded. The primary efficacy measure was response rate, defined as a decrease of ≥50% in baseline Montgomery-Åsberg Depression Rating Scale (MADRS) score at any postbaseline visit during the 5-year study. Secondary efficacy measures included remission. Results: Patients had chronic moderate to severe depression at baseline (the mean MADRS score was 29.3 [SD=6.9] for the treatment-as-usual group and 33.1 [SD=7.0] for the adjunctive VNS group). The registry results indicate that the adjunctive VNS group had better clinical outcomes than the treatment-as-usual group, including a significantly higher 5-year cumulative response rate (67.6% compared with 40.9%) and a significantly higher remission rate (cumulative first-time remitters, 43.3% compared with 25.7%). A subanalysis demonstrated that among patients with a history of response to ECT, those in the adjunctive VNS group had a significantly higher 5-year cumulative response rate than those in the treatment-as-usual group (71.3% compared with 56.9%). A similar significant response differential was observed among ECT nonresponders (59.6% compared with 34.1%). Conclusions: This registry represents the longest and largest naturalistic study of efficacy outcomes in treatment-resistant depression, and it provides additional evidence that adjunctive VNS has enhanced antidepressant effects compared with treatment as usual in this severely ill patient population.
Novel SIRT1 Agonists, SRT501 and SRT2183, Induce Expression of DNA Repair Genes and Apoptosis of Ph− Acute Lymphoblastic Leukemia Cells Alone and in Combination with the HDAC Inhibitor LBH589..
Authors: Anna Scuto, Mark Kirschbaum, Jennifer M Cermak, Peter Atadja, Richard Jove
Journal: Blood (2009)
Phase 1 study of infusional or bolus deflexifol (a novel formulation of 5FU, folinic acid, and cyclodextrin) after failure of standard treatment.
Authors: Philip R. Clingan, Stephen P. Ackland, Marie Ranson, Paul De Souza, Ali Tafreshi, Morteza Aghmesheh, Daniel Brungs, Madhu Bala Garg, Suzanne Parker, Rebecca Jokela
Journal: Journal of Clinical Oncology (2017)

TPS812 Background: 5FU is a commonly used anti-cancer agent first synthesized in 1957, and is now most commonly used in combination with FA, which enhances its clinical activity. Physical incompatibilities between 5FU and LV necessitate the infusion of each component separately, often through a central line due to high pH; resulting in adverse events, which leads to poor outcomes due to treatment interruption and discontinuation. A novel all in one reformulation of 5FU/LV at physiological pH has been developed as an alternative to serial administration of 5FU and LV in a high Ph solution [Locke JM, Anticancer Drugs 2009]. Preclinical testing demonstrated that the reformulation is stable bioequivalent to 5FU with reduced side effects [Stutchbury TK, Anticancer drugs 2011]. Methods: An open label phase 1 dose escalation study is underway in 2 schedules (bolus and infusion) to assess the safety and tolerability in patients with advanced malignancy after failure of standard treatment (including fluoropyrimidine regimens). To determine the maximum tolerated dose defined as: 2 out of 6 patients experience DLTs dose escalation is halted and declared DLT Dose. The previous dose level will be considered for expansion to x6 patients to confirm Maximum Tolerated Dose (MTD). Also to determine pharmacokinetic profile. Patients enrolled in Cohorts 1 to 4, have been completed without DLT. Dose-limiting toxicity (DLT) is defined as: Any Grade 3 or 4 non-haematologic toxicity (CTACE criteria). Patients developing Grade 3 or 4 diarrhoea, failing maximal anti-diarrheal medications. Febrile neutropenia, Grade 4 neutropenia &gt; 7 days, Grade 4 thrombocytopenia &gt; 7 days Any grade of thrombocytopenia associated with bleeding. Currently proceeding with (bolus 575mg/m2 weekly x 6, infusion 3600mg/m2/46h q2W). Limited sampling PK of 5-FU and dihydoFU is being conducted (3 at each of the 5 dose levels, doses 1 and 6). In both schedules to assess PK variability, adequacy of dosing in comparison to previous reports. The incidence of AEs and SAEs (CTACE 4.03) will be summarized by severity and relationship to study treatment. Clinical trial information: 044867.
Brain radiosurgery and ipilimumab (Ipi) in melanoma brain metastases (MBM) patients: Does an enhanced immune response induce radionecrosis (RN)?
Authors: Leila Khoja, Goldie Kurtz, Mark Bernstein, Anthony M. Joshua, David Hogg, Gelareh Zadeh, Normand Laperriere, Cynthia Menard, Barbara-Ann Miller, Paul N. Kongkham, Eshetu G. Atenafu, Marcus O. Butler, Caroline Chung
Journal: Journal of Clinical Oncology (2015)

e20019 Background: The anti-CTLA4 antibody, ipi, improves survival in metastatic melanoma. Combined radiotherapy (RT) and ipi may increase immune response to improve outcomes but also increase toxicity. This study reports the outcomes, including incidence of radionecrosis (RN), in patients (pt) with MBM treated with ipi and brain radiosurgery (SRS) and whole brain treatment (WBRT). Methods: Pt with MBM treated with WBRT or SRS and ipi at the Princess Margaret from 2008-2014 were reviewed to evaluate clinical characteristics, time between RT and ipi treatment, toxicity, response and survival. Results: We identified 54 pts treated with ipi and RT (SRS and/or WBRT), 34 who were evaluable (20 were excluded due to lack of follow up imaging), (see table). Median follow up was 7.4 months (m); OS 6.4m, PFS 2.7m. No RN was seen with WBRT alone, but RN occurred in 11/27 (41%) pt who received SRS: 7 received RT within 4m of ipi (SRS = 4, SRS+WBRT = 3) and 4 received RT outside of this window (SRS = 2, SRS+WBRT= 2). Larger tumor volume and V12Gy was associated with a higher rate of RN. Symptomatic RN was treated with steroids in 6 pt. Only 1 of 6 pt needed surgical excision, which showed necrosis, inflammatory T cells, macrophages, and treated melanoma. Intracranial MBM progression during ipi occurred in 7 pt: 6 discontinued ipi after 1-3 cycles and 1 continued to complete all 4 cycles ipi. Eventual MBM response was seen in the pt who completed ipi and 1 pt who received 3 cycles. Conclusions: When brain RT is combined with ipi, RN occurred in 41% of pts treated with SRS (± WBRT) and ipi but 0% after WBRT and ipi. Symptomatic RN generally responded to steroids. In 1 case requiring surgery, pathology demonstrated an increased immunological effect. MBM progression during ipi did not prohibit later cranial response. Characteristic Number Age Median (range) 53 (24-82) Sex Male 22 Female 12 Ipilimumab infusions Median (range) 4 (1-4) Radiotherapy treatment SRS 12 SRS + WBRT 15 WBRT 7 Median SRS dose (range) 21(15-24) Median no. fractions 2(1-4) LDH Median (range) 242 (155-1148)
Antimicrobial peptide levels are linked to airway inflammation, bacterial colonisation and exacerbations in chronic obstructive pulmonary disease
Authors: Louise J.P Persson, Marianne Aanerud, Jon A. Hardie, Roy Miodini Nilsen, Per S. Bakke, Tomas M. Eagan, Pieter S. Hiemstra
Journal: European Respiratory Journal (2017)

Antimicrobial peptides (AMPs) are effectors of host defence against infection, inflammation and wound repair. We aimed to study AMP levels in stable chronic obstructive pulmonary disease (COPD) and during acute exacerbations of COPD (AECOPD), and to examine their relation to clinical parameters and inflammatory markers. The 3-year Bergen COPD Cohort Study included 433 COPD patients and 325 controls. Induced sputum was obtained and analysed for levels of the AMPs human cathelicidin (hCAP18/LL-37) and secretory leukocyte protease inhibitor (SLPI), and for the inflammatory markers interleukin (IL)-8, IL-6 and tumour necrosis factor-α (TNF-α) using immunoassays. Systemic hCAP18/LL-37 and vitamin D levels were also studied. Treating AMPs as response variables, non-parametric tests were applied for univariate comparison, and linear regression to obtain adjusted estimates. The risk of AECOPD was assessed by Cox proportional-hazard regression. Sputum AMP levels were higher in patients with stable COPD (n=215) compared to controls (n=45), and further changed during AECOPD (n=56), with increased hCAP18/LL-37 and decreased SLPI levels. Plasma hCAP18/LL-37 levels showed a similar pattern. In stable COPD, high sputum hCAP18/LL-37 levels were associated with increased risk of AECOPD, non-typeable Haemophilus influenzae colonisation, higher age, ex-smoking and higher levels of inflammatory markers. Altered levels of selected AMPs are linked to airway inflammation, infection and AECOPD, suggesting a role for these peptides in airway defence mechanisms in COPD.
Feasibility and safety of front-line bevacizumab (BEV)-containing therapy after neoadjuvant (NA) chemotherapy (CT) for ovarian cancer (OC): The ROSiA experience.
Authors: Jacob Korach, Nicoletta Colombo, Irina Davidenko, Cesar Mendiola, Frédéric Selle, Antonio Gonzalez-Martin, Andrea De Censi, Patricia Pautier, Mihai Meirovitz, Edgar Petru, Prafull Ghatage, Roberto Hegg, Aristotelis Bamias, Peter Gocze, Ewa Chmielowska, Zanete Zvirbule, David T. Bollag, Ulrich Freudensprung, Amit M. Oza
Journal: Journal of Clinical Oncology (2013)

5541 Background: BEV significantly improved the efficacy of front-line CT for OC in the GOG-0218 and ICON7 phase III trials. The ongoing single-arm ROSiA study, which has completed recruitment of 1039 patients (pts), is assessing BEV + CT in routine oncology practice. Unlike GOG-0218 and ICON7, prior NACT is permitted. We assessed the surgical safety of BEV + CT in the subgroup of pts with prior NACT. Methods: Inclusion criteria include: FIGO stage IIb–IV or grade 3 stage I–IIa epithelial ovarian, fallopian tube, or primary peritoneal carcinoma; no prior post-surgical therapy for OC; and ECOG PS 0–2. Pts with uncontrolled hypertension or clinical signs/symptoms of GI obstruction or history of abdominal fistula, GI perforation, or intra-abdominal abscess in the preceding 6 mo are excluded. Pts in the NA subgroup were enrolled into the study after up to 4 cycles of NACT without BEV. After interval debulking, pts received BEV 15 mg/kg q3w (or 7.5 mg/kg at the investigator’s discretion) in combination with CT (paclitaxel [175 mg/m 2 d1 q3w or 80 mg/m 2 qw] + q3w carboplatin [AUC 5 or 6]), to a maximum total of 8 cycles including the pre-study NA cycles. Single-agent BEV was continued until progression, unacceptable toxicity, or for up to 36 cycles in total. The primary objective is evaluation of safety (CTCAE v4.03). Additional endpoints include efficacy (including PFS, response rate, OS) and exploratory translational research. Results: Of the 1039 pts enrolled in ROSiA, 150 (14%) had received NACT. Of these, most had stage IIIc (60%) or IV (29%) disease; 65% had residual disease ≤1 cm; and 19% underwent bowel resection. At the data cut-off 22 mo after enrollment began, median follow-up from post-surgery study entry was 12.6 mo; 69 patients (46%) remained on BEV therapy. At cut-off, pts had received a median of 13 cycles of BEV (range 1–31), including 4 cycles (range 1–6) of BEV in combination with CT after surgery. To date, no pts have had grade ≥3 wound-healing complications during study therapy; 1 pt experienced grade 4 GI perforation 10 weeks after surgery (3 weeks after the first BEV dose), which resolved within 4 weeks. Conclusions: NACT followed by BEV + CT was feasible and tolerable. Clinical trial information: NCT01239732.
Treatment timing of life-extending therapies and adherence of corticosteroids among metastatic castration-resistant prostate cancer patients with conditions sensitive to corticosteroid use.
Authors: Cat N Bui, James Spalding, Li Wang, Onur Baser
Journal: Journal of Clinical Oncology (2013)

e16080 Background: Corticosteroids (CS) have been integral in metastatic castration-resistant prostate cancer (mCRPC) treatment and can be used alongside life-extending therapies (LETs), despite potential toxicity effects. LET and CS timing and adherence were examined in CRPC patients in the Veterans Health Administration (VHA) dataset with conditions sensitive to CS use. Methods: Diagnosed prostate cancer patients with evidence of medical/surgical castration, at least two following prostate-specific antigen (PSA) increases (third PSA value date was the index), and ≥1 claim for cabazitaxel, docetaxel, or abiraterone acetate 06/2007-05/2012 were examined. Adherence was the total overlapping days of CS and LET prescriptions divided by total LET prescription days (≥0.8). Comorbid conditions were measured for 6 months pre-index date. Descriptive analysis, Cox proportional hazards, and logistic regression models summarized therapeutic/clinical features of CRPC or the CS-adherent patient subset. Results: Common CS-sensitive conditions among 15,585 mCRPC patients included hypertension (58.94%) and hyperlipidemia (42.56%). Fewer glaucoma (hazard ratio [HR]: 0.67), ischemic heart disease (HR: 0.78), and peripheral vascular disease (HR: 0.78) patients were prescribed LETs (all p&lt;0.01). mCRPC treated patients with comorbidities (N=858) were significantly older (71.27 vs. 68.94 years, p&lt;0.01) and more often exhibited bone metastases than those without (42.42% vs. 29.73%, p&lt;0.01). After treatment initiation, mCRPC patients with comorbidities had a shorter LET duration (125.02 vs. 133.08 days, p=0.04) within the 6-month follow-up period. Factors associated with reduced CS adherence (≥0.8) included cerebrovascular disease (odds ratio=0.0107, 95% CI: 0.012-0.966) and peripheral vascular disease (odds ratio=0.523, 95% CI: 0.276-0.991). Conclusions: Conditions sensitive to CS influence the LET receipt and duration and are associated with lower adherence when compared to non-CS-sensitive conditions. Attention should be focused on treatments using alternatives to CS for sensitive mCRPC patients.
Durability of complete remission by moxetumomab pasudotox (HA22 or CAT-8015) assessed by clone-specific real-time quantitative PCR (RQ-PCR).
Authors: Robert J. Kreitman, Evgeny Arons, Jeffrey Sapolsky, Laura Roth, Hong Zhou, Maryalice Stetler-Stevenson, Wyndham Hopkins Wilson, Mark Raffeld, David JP FitzGerald, Fei Ji, Ramy A. Ibrahim, Ira Pastan
Journal: Journal of Clinical Oncology (2012)

2503^ Background: The anti-CD22 recombinant immunotoxin moxetumomab pasudotox, also known as HA22 or CAT-8015, was recently reported in phase I testing to achieve complete remissions (CRs) in 13 (46%) of 28 patients with relapsed/refractory hairy cell leukemia (HCL); 3 of 13 patients have relapsed. Methods: To complete this trial, 20 additional patients received the highest dose level (50 µg/Kg every other day x 3 doses); none of the 48 HCL patients had dose-limiting toxicity (DLT). Results: Of the first 42 patients with &gt;6 mo of follow up off-treatment, 23 (55%) had CRs, with an overall response rate of 88%. Of the 23 CRs, 21 were evaluable for minimal residual disease (MRD) using flow cytometry of blood and immunohistochemistry of the bone marrow biopsy, and 17 (81%) were negative. Of these 17 patients, 11 (65%) were negative by bone marrow aspirate (BMA) flow cytometry. PCR using consensus primers for the heavy chain immunoglobulin (IgH) rearrangement was less specific than flow cytometry of blood, since IgH rearrangements of normal B cells, which recovered rapidly after immunotoxin treatment, were also amplified. For better MRD detection in blood, patient IgH sequences were cloned and sequence specific primers and probes designed for real-time quantitative PCR (RQ-PCR). RQ-PCR of blood was negative in 6 (100%) of 6 patients achieving flow-negativity in both blood and BMA and positive in 3 (100%) of 3 patients flow-negative in blood but not BMA (p=0.01). No relapses from CR have been observed in 10 patients who became RQ-PCR-negative in blood or flow-negative in BMA, with 5-38 (median 11) mo of follow-up. Conclusions: We conclude that clone-specific RQ-PCR is the most sensitive blood test for MRD in our HCL patients after moxetumomab pasudotox, and could be used to assess the possibility of long-term molecular remissions. We believe these results, including durable CRs without DLT, support a pivotal trial in which moxetumomab pasudotox is compared with alternative therapy. Note: this summary contains investigator reported data. This study was funded by MedImmune, LLC, and supported by NCI’s Intramural Research Program and the Hairy Cell Leukemia Research Foundation.