bluuebunny/crossref_metadata_2025_split huggingface dataset:
Can gene expression microarray (GEM) provide a diagnosis in cases of carcinoma of unknown primary?
Authors: Bridgewater J. A. , Floore A. , Warmoes M. O. , Veer van’t L. 
Published: March 2020

20117 Patients with CUP constitute approximately 5% of all malignancies and have no primary site of malignancy despite standard investigation, a poor prognosis secondary to metastatic disease and generate despondency amongst clinicians. GEM may provide an improved diagnostic tool and improve prognosis for patients through the use of more site specific chemotherapy. CupPrint is a 1900 gene custom microarray optimized for paraffin samples which uses a compiled database of 591 cancer cases to provide a statistically proven method for the discrimination of 39 different tumor types. Few data are available on the practical application of this novel technique. We have taken paraffin samples from 21 cases of “true” CUP where standard investigation failed to determine a primary site of malignancy although there were some cases were more uncertain than others. Three 4μm sections from the paraffin blocks were analysed and reviewed in the context of the histology reports, an independent histological review and the clinical history. 2 datasets were available for 1 patient and 3 datasets for another. A case by case analysis will be given but in summary, 16/21 diagnoses confirmed the clinicians suspicion. There was a clinical/CupPrint inconsistency in 4/21 patients and a pathological/CupPrint inconsistency in 1 patient. All CupPrint diagnoses were possible clinically. There was a consistency between identical samples analysed blindly by CupPrint and a consistency between different sites of tumour metastasis in the same patient. For most patients there was a consistency within the “K-Nearest Neighbors” analysis (see http://www.agendia.com). Clinical suspicion coincides with CupPrint certainty such that in those patients for whom there was no suspected site of primary, the “K-Nearest Neighbours” analysis did not match. 11/21 patients had had palliative chemotherapy with a further 4 yet to be receive treatment thus 15/21 patients could receive palliative chemotherapy. 5 patients are still alive. CupPrint is a promising analytical tool in order to more appropriately direct systemic palliative treatment in patients with CUP. These data need to be expanded to demonstrate a survival benefit of CupPrint guided treatment in a randomized clinical study. [Table: see text]
Phase I trial of a novel epothilone, KOS-1584, using a weekly dosing schedule
Authors: Stopeck A. , Thomas E. , Jones S. , Cohen J. , Cropp G. , Zhou Y. , Feng L. , Kersey K. , Hannah A. L. , Burris H. 
Published: March 2020

2041 Background: Several epothilones are progressing through phase 1–3 clinical trials treating solid tumor malignancies. KOS-1584 is a 3rd generation epothilone with 3–12 fold increased potency compared to Epothilone D (as measured by in vitro cytotoxicity, in vivo xenografts or induction of G2/M arrest by flow cytometry) and improved pharmacologic/pharmacokinetic profile (enhanced tumor tissue penetration and reduced exposure to the CNS). This dose-escalation trial explores a weekly administration schedule of KOS-1584. Methods: Define the MTD, toxicity profile and PK of KOS-1584 when administered to patients with advanced solid malignancies via 1-hour infusion on Days 1, 8 and 15 every 4 weeks. Plasma PK and pharmacodynamics (serial sampling of PBMCs for soluble and polymerized microtubules by immunoblot) were assessed. Results: 12 pts (7 F; median age 60; median ECOG PS 1; median prior regimens 4, range 2–13) enrolled in 5 dose levels (0.8, 1.5, 2.5, 5.0 and 7.5 mg/m2). To date, no Cycle 1 DLT has been seen; one Grade 3 episode of arthritis occurred in Cycle 2. Drug-related toxicities, all Grade 1 or 2 in severity: fatigue (n=3), anorexia (n=2) and individual patients with constipation, nausea, mucositis, dehydration, headache and pruritus. Neurotoxicity has not been observed. PK/parent (n=8): t½ 18.5 ± 6.8h, Vz 504 ± 234 L and CL 19.7 ± 6.1 L/h (none of these parameters showed evidence of dose dependency). 5.0 mg/m2 Cmax 122.4 ± 60.6 ng/mL; AUCtot 688.2 ± 212 ng/mL*h. Dose proportional increase in exposure and Cmax was observed over the dose range tested to date. At 5.0 mg/m2 the1-hr infusion Cmax is 3-fold higher and AUCtot 50% higher than for the same dose delivered over 3 hours. As predicted by allometric scaling from animals, Vz is ∼4-fold and t½ 2-fold higher than that of Epothilone D. Activity consisted of extended stable disease (a patient with colon cancer for 3 cycles). Dose-dependent increases in polymerized microtubules were observed: prior to infusion ∼10% of tubulin was in its polymerized form; this increased to 20%, 30%, 35% and 48% for the 1st 4 dose levels at infusion end. Conclusions: Accrual is continuing in order to define the optimal dose on this regimen. Exposure and Cmax remain linear within this dose range; slower clearance is observed for the same dose administered over 1 hour compared to 3 hours. [Table: see text]
A finalized phase II report of pemetrexed (P) plus gemcitabine (G) as front-line chemotherapy for patients with peritoneal mesothelioma (PM)
Authors: Simon G. R. , Janne P. A. , Langer C. , Clarie V. , Dowlati A. , Gadgeel S. M. , Kelly K. , Ye Z. , Obasaju C. K. , Hood K. E. , Kindler H. L. 
Published: March 2020

2050 Background: P in combination with cisplatin is approved for the treatment of malignant pleural mesothelioma. In an expanded access program, P ± cisplatin was shown to have activity in PM. P plus G are synergistic in preclinical models, but the activity of this combination in PM is unknown. The primary objective of this study was to determine time to disease progression in pts with PM receiving P plus G. Methods: Twenty pts were accrued. Treatment consisted of G 1250 mg/m2/30 minutes on D 1 and 8, and P 500mg/m2 /10 minutes on D 8, immediately before G. Treatment was repeated every 21 days for a total of 6 cycles or until progressive disease. All received folic acid, vitamin B12 and steroid prophylaxis. Results: Median age was 67.5 years (range: 46–79). Histology was epithelial:other = 14:6, M:F = 15:5, and ECOG PS 0:1:2 = 9:6:4. A total of 93 cycles (median 6) were administered. Patient-specific Grade 3/4 hematologic toxicity included neutropenia (60.0%), febrile neutopenia (10%; including one toxic death), anemia (5%), and thrombocytopenia (0%). Grade 3/4 nonhematologic events were fatigue (20.0%), constipation (10.0%), diarrhea (5.0%), peripheral neuropathy (5.0%), and dyspnea (5.0%). Median relative dose intensity was 94.5% for P and 82.9% for G respectively. Investigator-reported response rate was 15% (95% CI: 3.2–37.9%) with 1CR, 2PR, 7SD, 7PD, and 3 Unknown. Median time to progressive disease (MTTPD) and median survival (MS) were and 16.5 months (95% C: 6.6-TBD) and 19.1 months (95% CI: 6.6-TBD) respectively. Conclusions: P plus G is well tolerated in patients with PM. The clinical benefit rate (PR + SD) of 50%, MTTP and MS suggest that this non-platinum doublet can be a reasonable alternative to a platinum doublet in this disease. [Table: see text]
Pemetrexed in combination with paclitaxel: A phase I clinical and pharmacokinetic trial in patients with solid tumors
Authors: Graefe T. , Bolling C. , Lubbing C. , Latz J. , Blatter J. , Hanauske A. 
Published: March 2020

2051 Background: Pemetrexed (Alimta [AL]) and paclitaxel (P) are clinically active in a variety of tumors. The primary objective of this trial was to determine the maximum tolerated dose (MTD) of the ALP combination; secondary objectives were: determination of dose-limiting toxicities (DLTs), definition of a recommended phase II dose, pharmacokinetic (PK) characterization and the anecdotal collection of antitumor activity. Methods: Escalating doses of P (3h infusion, d1 and d8) and AL (10 min infusion, d8 prior to P) were given in a 21d cycle. Results: 59 patients (pts) were enrolled. DLTs occurred at the following ALP (mg/m2) doses: 400/30 [G3 bilirubin (b), G3 and G4 thrombocytopenia (plts)]; 500/30 (G4 plts); 500/40 (G3 b); 500/75 (G4 ANC); 500/100 (G4 leukopenia, G4 ANC). With G4 leukopenia and G4 ANC in 4/6 pts and febrile neutropenia in 1 pt, the MTD was reached at the ALP (mg/m2) dose of 500/120. To confirm safety at the recommended dose-level, another 6 patients were treated at the ALP (mg/m2) dose of 500/100. 18 pts [mesothelioma (3), esophagus (2), lung (1), liver (1), renal (1), stomach (1), thyroid (9)] showed stable disease as best response. 4/14 (29%) pts with thyroid carcinoma showed long lasting partial responses [duration (months) 29+, 22, 18, 15]. One additional PR (2) was observed in a pt with penile carcinoma. AL PK when administered with P were consistent with those for AL administered as a single-agent. Conclusions: The ALP combination is safe and shows broad clinical activity. 500/100 mg/m2 is the recommended dose for further studies. Promising antitumor activity was observed in thyroid cancer. A phase II trial in thyroid carcinoma will be conducted. [Table: see text]
Dose escalation phase of a phase I/II study of GTI-2501, an antisense to the R1 subunit of ribonucleotide reductase (RNR) and docetaxel in patients with metastatic hormone-refractory prostate cancer
Authors: Ko Y. , North S. , Berry S. R. , Ernst D. S. , Klotz L. , Murray P. , Venner P. 
Published: March 2020

2078 Background: GTI-2501 (GTI) is a 20-mer oligonucleotide that is complementary to the R1 subunit of the RNR mRNA. The R1 protein is overexpressed in multiple tumour cell lines. GTI displays anti-tumour activity against prostate cancer xenografts in mice as a single agent and in combination with mitoxantrone. GTI also adds to the anti-tumour efficacy of taxanes in breast cancer xenografts in mice. A Phase 1 study of a 14 day continuous infusion of GTI in patients with solid tumours showed no dose limiting toxicities at doses up to 210.9 mg/m2/day. The objective of this dose escalation phase of a phase I/II study was to define a safe phase II dose of GTI in combination with docetaxel (D) in men with metastatic hormone refractory prostate cancer (HRPC). Methods: Men with metastatic HRPC were enrolled at 3 centres in Canada. GTI was given as a 14d continuous IV infusion every 21d with D IV infusion started 2 hrs prior to the end of the GTI infusion. Planned dose escalation cohorts are summarized in table . Results: 13 men were enrolled to the 3 cohorts. All patients are evaluable for toxicity. There was one possible DLT - an episode of grade 4 neutropenia reported at cycle 2 day 1 in the highest dose cohort - but the duration of neutropenia could not be confirmed. 3 additional patients were accrued to that cohort with no DLTs. The most common gr 3/4 toxicity was attributable to D (10 pts with Gr 3/4 neutropenia). The observed incidence of Gr 3/4 neutropenia was expected since patients had weekly CBCs. Only 1 patient had febrile neutropenia. 11 pts had fatigue (4 Gr 3) related to D and /or GTI. Other GTI attributable adverse events were Gr 1/2 including transient rises in transaminases and PTT. The pharmacokinetic data which is summarized in the table will be presented in full at the meeting. Conclusions: GTI can be given safely at its highest planned dose with standard doses of D. A Phase II evaluation of the GTI + D combination is planned for men with HRPC. [Table: see text] [Table: see text]
In vitro characterization and pre-clinical pharmacokinetics of CP-870,893, a human anti-CD40 agonist antibody
Authors: Bedian V. , Donovan C. , Gardner J. , Natoli E. , Paradis T. , Alpert R. , Wang H. , Shepard R. , Wentland J. , Gladue R. 
Published: March 2020

2539 Background: CD40 is expressed on B-cells, monocytes, dendritic cells, other normal tissues and tumors. Previous studies showed that CD40 stimulation enhances antigen presentation, breaks tolerance, bypasses T-cell help, and induces apoptosis in CD40pos tumor cells. We report the in vitro activity and primate pharmacokinetics of a human anti-CD40 agonist antibody, CP-870,893, currently in clinical trials for the treatment of cancer. Methods: CP-870,893 was identified as a CD40 agonist antibody by screening lead molecules generated through the Abgenix Xenomouse® platform. Agonist activity was determined using upregulation of B-cell and monocytes derived dendritic cell surface markers, as well as dendritic cell IL-12 induction. BIAcore and equilibrium binding were utilized to determine affinity, and competition studies with CD40L were conducted on BIAcore. CP-870,893 was administered to cynomolgus monkeys i.v. at various doses, serum antibody levels were evaluated over time in an ELISA assay, and B-cell markers were monitored by FACS. Results: CP-870,893 (IgG2, kappa) binds CD40 with sub-nanomolar affinity, and does not block binding of CD40L. When human whole blood is incubated with CP-870,893, upregulation of key surface molecules involved in antigen presentation (MHC Class II, CD80, CD86, CD23 and ICAM-1) is observed with an EC50 of 5–50 ng/ml. Human monocytes derived dendritic cells, when stimulated with CP-870,893, upregulate activation markers (MHC Class II, CD80 and CD83) with an EC50 of 100–300 ng/ml, and secrete high levels of IL-12p40. In the presence of a second stimulus, such as LPS, human dendritic cells also secreted bioactive IL12-p70 when stimulated with CP-870,893 (EC50 ∼ 150 ng/ml). In addition, a CD40 positive human B-cell tumor line, when stimulated with CP-870,893, becomes susceptible to killing by human CTLs. In cynomolgus monkey studies, the clearance of CP-870,893 decreased with increasing dose. Circulating B-cell numbers decreased, and surface molecules were upregulated on B-cells. Conclusions: These data support the potential utility of CP-870,893 as an immune enhancing agent in cancer immunotherapy, by activating antigen presenting cells, and by enhancing the immunogenicity of CD40 positive tumor cells. [Table: see text]
Anti-tumor activity of partially HLA-matched irradiated blood mononuclear cells in patients with advanced malignancies
Authors: Strair R. , Gharibo M. , Taber BS K. , Kuriyan M. , Dipaola R. , Stein M. , Todd M. , Rubin A. , Lattime E. , Medina D. 
Published: March 2020

2552 Background: We previously demonstrated the safety and efficacy of HLA-haploidentical blood mononuclear cells (MNCs) administered in the absence of preparative therapy to patients with metastatic renal cell carcinoma (RCC) (J Clin Oncol 21:3785–91.2003). The efficacy of this therapy is evaluated further in patients with advanced malignancies. Methods: Patients with advanced malignancies who had HLA- haploidentical donors were enrolled. Donors underwent 12–15 L leukapheresis. MNCs were processed by irradiation (25 Gy) and immediately infused. Disease evaluation was undertaken every 8 weeks. Repeat infusions were given every 8 weeks until disease progression. Results: 30 patients with diverse diagnoses, including 9 patients with a hematological malignancy were treated. Three of 13 patients with RCC had disease response, and 1 of 2 patients with melanoma had a mixed response. A patient with imatinib mesylate-refractory chronic myelogenous leukemia (CML) had a transient response. A patient with refractory acute myelogenous leukemia (AML) had disease response in conjunction with therapy. Treatment was associated with minimal toxicity and radiographic responses in patients with RCC did not occur until after 2–3 treatments. Host CD8+ cells reactive with the Pr-1 peptide of proteinase 3 were induced in association with disease response in a patient with AML. Additional studies identifying disease targets and mechanisms by which infusion of irradiated HLA-haploidentical cells are associated with disease response are ongoing. Conclusions: Disease response is seen with irradiated allogeneic MNCs administered outside the context of hematopoietic stem-cell transplantation. Evidence for anti-tumor activity is seen in isolated patients with RCC, melanoma, CML and AML. The temporal nature of the response in RCC in combination with the very limited survival of the infused cells raises the possibility of induction of a host-mediated anti-tumor effect. This hypothesis is supported by induction of host CD8+ T cells reactive with a tumor-associated peptide in a patient with AML. Given the lack of toxicity, broad availability of related haploidentical donors and the relative low financial cost, this form of cellular therapy should be developed further. No significant financial relationships to disclose.
Activation of human peripheral blood immune cells in vitro by sodium stibogluconate (SSG) and SSG/IL-2 combination
Authors: Yi T. , Fan K. , Finke J. , Bukowski R. , Borden E. C. 
Published: March 2020

2557 Background: SSG, an inhibitor of SHP-1 and SHP2 which are negative regulatory signaling tyrosine phosphatases, suppressed the growth of murine renal carcinoma (Renca) in combination with IL-2 via an interferon (IFN)-γ+ T cell-dependent mechanism (J Immunol 175:7003–8, 2005). Activation of primary human immune cells by SSG or SSG/IL-2 would provide additional supporting evidence for SSG clinical evaluation in combination with IL-2. Methods: Peripheral blood of healthy and melanoma donors were treated in vitro with SSG or SSG/IL-2 and then subjected to ELISPOT assays and FACS analysis for quantification of TH1 (IFN-γ+) and TH2 (IL-5+) cells. Results: Characterization by ELISPOT assays of peripheral blood identified IFN-γ+ cells with marked increase (9.1x) following SSG/IL-2 treatment in contrast to the modest increases induced by SSG alone (2.1x) at its clinically achievable dose (20 μg/ml) or by IL-2 (3.1x) at its Cmax of low-dose schedule (30 IU/ml). SSG at an even higher dose (100 μg/ml) was less effective alone (1.5x) or in combination with IL-2 (7.8x). IL-5+ cells were not induced by the agents individually or in combination. Induction of peripheral IFN-γ+ cells by SSG/IL-2 was detectable after 4 and 16 h. Increased effectiveness of the SSG/IL-2 combination vs. the individual agents in inducing IFN-γ+ cells in vitro was detected by ELISPOT assays in the peripheral blood from 7 healthy donors and 6 melanoma patients. FACS analysis showed that the combination induced IFN-γ+ cells in the CD4+ and CD8+ lymphocytes and also increased lymphocytes expressing the activation marker CD69 in both CD4+ (2–5x) and CD4− populations (∼ 3x). Conclusion: SSG, a compound used clinically for treatment of leishmaniasis, can interact with IL-2 in vitro to activate immune cells in peripheral blood of healthy and melanoma donors. Results provide further rationale, in addition to the mouse tumor data, for proof of concept clinical trials for effecting augmentation of IL-2 through inhibition of negative regulatory signaling phosphatases. No significant financial relationships to disclose.
Cancer therapy with tumor cell lysate pulsed monocyte-derived dendritic cells in patients with metastastic colon cancer: Improvement by danger signals
Authors: Neβelhut T. , Lorenzen D. , Marx D. , Chang R. , Neβelhut J. , Matthes C. , Cillien N. , Stücker W. , Peters J. 
Published: March 2020

2563 Background: The prognosis of colon cancers with hematogenous spread remains poor at 12–20 months. We report the use of a dendritic cell based immunotherapy to improve patient survival, especially with cell culture conditions mimicking infection. Methods: After isolating monocytes from the blood of 39 patients with metastasized colon cancer, dendritic cells were generated ex vivo in the presence of recombinant cytokines (IL-4; GM-CSF) and autologous serum. The DC loaded with tumor cell lysate were administered to the patients intradermally. Culture conditions were tested for upregulation of costimulatory molecules, downregulation of IL-10 and upregulation of IL-12 secretion by ELISPOT and fluorescence cytometry. Results: DC vaccination induced a clinical response in 9 (23%) patients with a median overall survival after onset of DC-therapy of 12 months (11–44 months for responders and 1–20 months for non-responders) and 23 months after diagnosis of metastases (16–63 months for responders and 1–23 months for non-responders). These data show that a dendritic cell based immunotherapy may prolong the patients overall survival. However, complete remissions are rare. This can be due to weak stimulation of CTL response due to insufficient antigen presentation, lack of costimulatory molecules as well as secretion of IL-10 rather than IL-12 by the DC’s. Here we could show that Toll-like receptors (TLR) ligands like Poly-I:C or lipopeptides as so called danger signals in combination with interferons can induce an upregulation of costimulatory molecules accompanied by inhibition of IL-10 and induction of IL-12 secretion in vitro. By using these culture conditions we induced a clinical complete remission of liver metastases after failure of standard therapy in one patient (overall survival after onset of DC-therapy 13 months, after diagnosis 24 months). Conclusions: According to Matzinger’s hypothesis an effective immune response occurs only by responding to a danger signal associated with infection or stress. Thus, cell culture condition should be used with TLR ligands mimicking a bacterial or viral infection. In general, a dendritic cell based immunotherapy can be successful in advanced stages of colon cancer patients. [Table: see text]
Identification of RGS5 as a tumor-associated antigen expressed in a broad range of human malignancies and recognized by antigen specific cytotoxic T cells
Authors: Brossart P. , Boss C. , Brauer K. , Weinschenk T. , Kanz L. , Stevanovic S. , Rammensee H. , Grünebach F. 
Published: March 2020

2569 Background: Identification of tumor-associated antigens (TAA) have resulted in the development of therapeutic vaccines for the treatment of cancer. We applied an integrated functional genomics approach to identify TAA in malignant tissues of patients with renal cell carcinoma (RCC). Methods: A comparative DNA chip analysis of tumor and the corresponding non-malignant tissue from patients with RCC followed by sequencing of peptides bound to the HLA-class I molecules by mass spectrometry was applied to identify novel TAA in RCC. To confirm the immunogenicity of identified epitopes cytotoxic T lymphocytes (CTL) were generated using dendritic cells (DC). Results: RGS5 was found to be overexpressed in 16 of 29 analyzed RCC (5.7–29.9 fold) as compared to non-malignant renal tissue. Two peptides derived from RGS5 binding to either HLA-A*02 or 03 were identified. RGS5 was previously shown to be expressed in pericytes and promote tumor angiogenesis. Using RT-PCR analysis we found that RGS5 is expressed on a broad variety of tumor cells including RCC, colorectal, breast and ovarian cancer, malignant melanoma and multiple myeloma as well as in acute and chronic leukemias making this protein an interesting candidate for the development of vaccination strategies to target the tumor cells and the tumor vessels. CTL that were induced using the RGS5 peptides lysed autologous DC pulsed with the cognate peptide or transfected with in vitro transcribed RGS5 RNA as well as HLA-matched tumor cell lines. The specificity and HLA restriction was confirmed using blocking monoclonal antibodies and in cold-target inhibition assays. We next utilized DC transfected with RGS5 RNA to generate specific CTL. Using this approach we confirmed the processing and presentation of the identified peptides by malignant cells. These CTL lysed tumor cells in antigen specific manner while sparing non-malignant cells. In an ongoing vaccine trial RGS5 peptides could safely be given to RCC patients resulting in the induction of peptide specific CTL responses. Conclusions: Our results demonstrate that RGS5 is a novel tumor rejection antigen expressed in a wide range of malignancies that can be applied to target malignant cells and tumor angiogenesis. [Table: see text]