bluuebunny/crossref_metadata_2025_split huggingface dataset:
Safety and efficacy of a triple antiemetic combination with the NK-1 antagonist aprepitant (APR) in high (HEC), moderate (MEC) and high dose chemotherapy (HDC) in multiple day chemotherapy (MDC)
Authors: Jordan K. , Kinitz I. , Behlendorf T. , Sippel C. , Voigt W. , Wolf H. H. , Schmoll H. J. 
Published: March 2020

19545 Background: 5-HT3 receptor antagonists (RA) plus dexamethasone (DEX) has been shown to induce 55–57% complete responses from emesis during the 4–5 days of cisplatin chemotherapy. The role of aprepitant in MDC remains to be defined. The antiemetic triple combination of a NK-1-RA, 5-HT3-RA and dexamethasone has not been formally investigated in more than one day chemotherapy. Methods: In this retrospective study, pts. with MDC received APR 125 mg d1, 80 mg consecutive days, granisetron (GRAN) 2 mg daily and DEX 8 mg daily for prevention of acute CINV and APR 80 mg and DEX 8 mg for 2 days for delayed CINV. Endpoints were complete response (CR, no vomiting & no use of rescue therapy) in the acute, delayed and overall phase. Results: Of 103 pts. (f/m 21/82 pts.; median age 40.6y) with various types of cancers 41 pts. (39.8%) received HEC, 44 (42.8%) MEC, and 18 pts. (17.4%) HDC. Median duration of CTX was 3.42 days (HEC 3.9 d). The most frequent regimens were ICE (35%), PEB (14.6%), I3VA (10.7%), MAID (4.9%) and IEV (5.9%). Toxicity: Singultus was reported in 6.8% and loss of appetite in 25.5%. Elevation (CTC grade 1–2) of transaminase/AP/bilirubin and creatinine were seen in comparison to pretreatment values in 15.6%/6.8%/21.1% and 7.8% of all pts.. Efficacy: Acute/delayed/overall CR in HEC was 68.3%/70.7%/63.4%, in MEC 77.3%/84.1%/77.3% and in HDC 77.8%/61.6%/55.6%. Risk factor analysis revealed that pretreatment anxiety increased the risk of vomiting significantly (p= 0.008). Conclusions: Toxicity seems not to be increased by the multiple day treatment of APR (5–7 days) in comparison to the usually used 3-day APR regimen. The CR in the acute and delayed phase in patients receiving HEC was superior to the results reported in the literature with the combination of a 5-HT3 RA and DEX. The CR in the delayed phase in MEC was better than reported by Warr et al. where pts. receiving only one day of MEC and APR mono in the delayed phase. This might be due to the combination of APR/DEX in the delayed phase in our study. These promising results have to be confirmed in a prospective randomized trial. No significant financial relationships to disclose.
Limited value of routine iron studies prior to initiation of erythropoietin therapy in patients with ovarian cancer
Authors: Riebandt G. , South S. A. , Odunsi K. , Lele S. , Rodabaugh K. 
Published: March 2020

19677 Background: Anemia is a common consequence of cancer which significantly impacts patient quality of life. The mainstay of treatment for cancer- and chemotherapy-related anemia is erythropoietin therapy. However, approximately 30% to 50% of patients will not respond to these growth factors. The literature attributes this lack of response to functional iron deficiency, when iron stores are normal but the body cannot meet the increased rate of erythropoiesis. We evaluated the iron status of patients with ovarian malignancies receiving chemotherapy and erythropoietin therapy to establish a baseline for implementation of an intervention service. Methods: After obtaining Institutional Review Board approval, we identified 55 ovarian cancer patients receiving erythropoietin therapy from January to December 2005. We then performed a retrospective chart review for patients who had iron studies available. Results: Thirty-four patients had complete iron studies performed, while an additional 10 had only a ferritin level obtained. The mean hemoglobin for all patients was 9.9g/dl (6.9–13.1) with a mean MCV (mean corpuscular volume) of 92.7fl. Four (12%) patients were iron deficient based on ferritin <100ng/ml and iron saturation <20%. However, these patients had normal MCVs, indicating iron deficiency was not the etiology of their anemia. A few patients were assessed for B12 and folate deficiency, but none were identified. Interestingly, we had 22 patients with elevated ferritin levels (greater than 322ng/ml), with the highest being 2178ng/ml. Conclusions: Our results identified a few patients who were iron deficient, but none were diagnosed with iron deficiency anemia. Therefore, the role of routine iron screening in patients with a normal MCV prior to initiation of erythropoietin therapy is in question. We believe that functional iron deficiency may contribute to anemia in our population. Therefore, we suggest that all patients receive iron supplementation at erythropoietin therapy initiation. We plan to prospectively assess the optimal route of iron administration in ovarian cancer patients in order to improve the response rate to erythropoietic growth factors. No significant financial relationships to disclose.
A common sense approach to radiation treatment planning of temporal lobe GBM
Authors: Bokstein F. , Kovner F. , Ram Z. , Templehoff H. , Kanner A. A. , Blumenthal D. T. , Corn B. 
Published: March 2020

2044 Background: Irradiation remains the cornerstone of management for glioblastoma multiforme (GBM). Guidelines adopted by the RTOG and EORTC advocate encompassing the primary tumor (sometimes with edema), and a 2 cm margin in the high dose volume. These recommendations have emerged from imaging studies and post-mortem analyses. A shortcoming of this approach is the exposure of critical structures (e.g. optic apparatus) to doses of radiation that may exceed organ tolerance. We sought to determine whether the temporal bone (rather than the aforementioned 2 cm radius) serves as a barrier to tumor spread when regarded as the anterior margin for temporal lobe lesions. We hypothesized that toxicity could be reduced without compromising tumor control. Methods: During the period 2003–2006, 250 patients with GBM were treated with surgery and primary irradiation at our institution. Chemotherapy (e.g., Stupp regimen) was given to approximately one-third of patients. 31 patients had lesions confined to the temporal lobe. All patients had MRI at baseline and at monthly intervals following a course of 60 Gy delivered by conformal techniques. The Clinical Target Volume included the primary lesion, the edema when present and a 2 cm margin except in the direction of the temporal bone. At follow-up (median = 10 months), patients were judged to have stable disease, local progression (i.e. failure within the temporal lobe), distant progression (i.e., brain failure beyond the temporal lobe) or combinations of the latter 2. Results: 11 patients have remained with stable disease. 17 have failed locally. 3 have manifested distant failure. Of the latter, only one patient failed in the infratemporal fossa. Conclusions: An acceptable level of recurrence (e.g., <5% beyond the temporal bone) is seen when the temporal bone, rather than a 2 cm margin is employed as the anterior border of the CTV. As GBM patients live longer in the era of combined modality therapy, a greater opportunity will exist to express radiation damage. The strategy proposed herein provides tumor control while respecting optic tolerance without resorting to complex, expensive approaches such as IMRT. No significant financial relationships to disclose.
Intracerebral microdialysis for determination of the neuropharmacokinetics and neuropharmacodynamics of temozolomide in patients with primary or metastatic brain tumors
Authors: Portnow J. , Badie B. , Xi B. , Liu A. , Hovda D. , Hirt D. , Synold T. W. 
Published: March 2020

2074 Background: Microdialysis (MD) is a technique for continuously analyzing concentrations of endogenous chemicals and drugs in the extracellular fluid (ECF) of a body tissue. The purpose of this study is to apply MD to the determination of the neuropharmacokinetics (nPK) and neuropharmacodynamics (nPD) of temozolomide (TMZ) following systemic administration. Methods: After surgical debulking, a MD catheter is placed in peritumoral brain tissue. Artificial cerebrospinal fluid (CSF) is continuously perfused at a rate of 1 μl/min. Fused CT/MRI scans confirm correct placement of the catheter in non-enhancing brain. Starting 24 hrs after surgery, patients are given a dose of TMZ (150 mg/m2), and serial ECF and plasma samples are collected over 24 hrs. TMZ concentrations are determined by LC/MS/MS. In vitro recovery of TMZ via the MD catheter has been determined to be 87±5.5% at a flow rate of 1 μl/min. Prior to and 24 hrs post TMZ, additional ECF samples are collected for analysis of glucose, glutamate, lactate, and pyruvate, which are measured using a CMA 600 Analyzer®. Results: Four patients have been enrolled. There have been no grade 3 or 4 catheter-related adverse events. Mean peak TMZ concentrations in brain ECF and plasma are 0.4±0.2 and 5.5±1.4 μg/ml, respectively. Mean TMZ AUC in brain ECF and plasma are 3.2±1.6 and 18.2±4.6 μg/mLxhr, with an average ECF/plasma AUC ratio of 18±4%. Mean basal levels of glucose, glutamate, lactate, and pyruvate in ECF are 0.4±0.3, 34±66, 3±4, 69±62 mM, respectively. No consistent changes were seen in these nPD markers 24 hrs after TMZ. Conclusions: Concentrations of TMZ in brain ECF obtained by MD are similar to published data of TMZ concentrations in the CSF (Clin Cancer Res 2004;10:3728–36). Baseline values of markers of brain tissue metabolism are consistent with previous data in patients with brain tumors (J Neuro-Oncol 2003; 61:151–60). Intracerebral MD is an important tool that can be applied to nPK/nPD studies of new and targeted agents for the treatment of brain tumors. (Supported by CA01727) No significant financial relationships to disclose.
Detection of R337H, a germline mutation predisposing to multiple cancers, in asymptomatic women participating in a breast cancer screening programme in southern Brazil
Authors: Palmero E. I. , Caleffi M. , Waddington Achatz M. I. , Martel-Planche G. , Marcel V. , Petroni Ewald I. , Giugliani R. , Schüler-Faccini L. , Hainaut P. , Ashton-Prolla P. 
Published: March 2020

21029 Background: A specific germline mutation at codon 337 in TP53 (R337H) has been detected in a number of unrelated subjects with familial cancer risk in South Brazil, suggesting that this mutation may be relatively common in this population. Methods: To assess the TP53 R337H prevalence in a group of asymptomatic individuals unselected for family history of cancer, we studied 750 women aged 40–69 ys participating in a mammographic screening programme in Porto Alegre, Brazil`s southernmost capital. DNA was extracted from peripheral blood using standard procedures and PCR-amplified to generate a 238-base product encompassing TP53 exon 10, which was analyzed by RFLP using the restriction enzyme HhaI. The mutant, uncleaved allele was identified in agarose gels and positive RFLP findings were further confirmed by an independent PCR amplification and bi-directional, automated sequencing. Results and Discussion: The R337H mutant was detected in two of the 750 participants (0.15%), suggesting a much higher prevalence for this than for other TP53 germline mutations causing the LFS/LFL syndromes in the general population. Interestingly, these two subjects reported a familial history of cancer, and were found to be 2nd degree relatives. Three additional family members were also positive: one woman affected with breast cancer at the age of 36 years and two asymptomatic 62- and 80-year-old women. The presence of four R337H-positive cancer- unaffected individuals in this family, two of them well above the age of 50, indicates that this is a low-penetrance allele. In addition, the pedigree does not fulfill any of the currently recognized clinical criteria for the diagnosis of LFS/LFLS syndrome. This is the first study to report detection of a germline TP53 mutation in a population-based screening programme. Conclusions: The TP53 R337H mutant appears to be relatively common and may occur in families that do not fulfill the known clinical criteria for LFS/LFLS, the family described here contains asymptomatic carriers suggesting partial penetrance. No significant financial relationships to disclose.
Tumor response rate as a function of number of prior therapies in phase II and III trials of topotecan (T) and eniluracil/5FU (EU)
Authors: Ho P. T. , Fleming R. A. , Pandite L. , Lampkin T. A. , Flynn A. A. 
Published: March 2020

2501 Background: Patients with 2 or more prior cytotoxic treatment regimens are often excluded from clinical trials because of expectations for greater tumor resistance to treatment. This retrospective cross-study analysis evaluated the relationship between tumor response rate (RR) and the number of prior therapies received. Methods: Phase II and III studies in the GSK database of topotecan (T, n=18) in patients with ovarian or small cell lung carcinoma (SCLC) and of eniluracil/5FU (EU, n=5) in patients with colorectal (CRC) or breast cancer were analyzed. This provided a total 4,220 patients consisting of 1,898 receiving T, 465 receiving various T comparator chemotherapy (paclitaxel, cyclophosphamide, doxorubicin or vincristine), 1,036 receiving EU, and 821 receiving EU comparator (5FU + leucovorin). Number of prior treatments was defined as the sum of all cytotoxic treatment regimens received. Best response was defined according to standard tumor response criteria with missing data or inevaluable assessments considered as progressive disease. Experimental (T or EU) vs. respective comparator arms were combined and an overall RR (CR + PR) in the analysis populations was assessed as a function of the number of prior treatments. Results: The overall RR for ovarian and SCLC patients receiving first-line treatment was 47%. RR declined to 17% for second-line therapy but was unchanged at 18% for those receiving third-line treatment. For all (CRC + breast cancer) patients in EU studies, there were no significant differences between first-, second-, or third-line treatment (RR=12%, 10% and 10% respectively). However, within the limited subset of breast cancer patients (n=145) in EU studies, RR was 54%, 14%, and 11% for first-, second-, and third-line treatments, respectively, suggesting no difference in RR once second-line treatment was administered. Conclusions: The presumption that a higher number of prior regimens always equates with greater treatment resistance may be incorrect. Patients in this analysis with 1 vs. 2 prior therapies exhibit equivalent RR to a broad range of cytotoxic therapies. Exclusion from clinical trials of patients with >1 prior treatment regimen who otherwise meet study eligibility criteria may not be warranted. No significant financial relationships to disclose.
Immunization of indolent non-Hodgkin’s lymphoma patients with autologous monocyte-derived dendritic cells loaded with heat shocked and killed autologous tumor cells: A phase I study
Authors: Di Nicola M. A. , Carlo-Stella C. , Zappasodi R. , Passoni L. , Liliana D. , Magni M. , Matteucci P. , Mortarini R. , Anichini A. , Gianni A. M. 
Published: March 2020

3006 Background: To evaluate the safety and tolerability of vaccination with DCs loaded with killed tumor cells, 18 patients with measurable relapse/refractory follicular (12) and lymphoplasmocytoid (6) lymphoma have been enrolled in a phase I study. Methods: Each patient received at 2-weekly intervals 4 SC injections of 50x10e6 tumor-loaded DCs. Immature DCs were generated by 5-days culture of autologous monocytes in the presence of IL-4 and GM-CSF. Autologous CD19+ tumor cells, harvested from lymph nodes (12) and/or peripheral blood (6), were heat shocked and then irradiated by UVC. DCs were loaded for 48 hrs with killed tumor cells and then were cultured for 12 hrs in the presence of TNF-a. Median prior number of treatment regimens was 2 (range 1–5) comprising 4 patients treated with high-dose chemotherapy. The vaccination was started at least 6-months after the last chemotherapy treatment. Results: All patients were evaluable for toxicity and for efficacy with a median follow-up of 30.5 months (range 18–45 months). Overall, vaccinations were well tolerated and no autoimmune reactions were observed. Mild erythema in the site of injection developed in the majority of patients (12/18), but only in 2 cases induration and extended erythema was observed. Six of 18 patients had objective responses. Three patients had partial responses (PR). One is still in PR and the others have a PR lasting 7 and 15 months, respectively. Three patients had complete remission (CR) and are are still in CR with a mean CR duration of 17 months. The remaining 12 patients had stable disease (8) or progressive disease (4). In the patients in PR, a significant increase of anti autologous tumor-specific T cells, evaluated by ELISPOT assay for IFN-γ, was observed in the post-vaccination lymph nodes, compared to the tissue sample taken before vaccination. In addition, in the responding patients a significant reduction in peripheral blood of FoxP3+ regulatory T cells was observed. Conclusion: The injection of DCs loaded with killed tumor cells is a well-tolerated procedure achieving clinical and immunological responses also in the presence of significant tumor burden. No significant financial relationships to disclose.
Antigen presenting cell (APC)-targeted hCGβ vaccine for cancer therapy
Authors: Morse M. , Chapman R. , Clay T. , Osada T. , Hobeika A. , Green J. , Davis T. , Keler T. 
Published: March 2020

3013 Background: CDX-1307 is a novel vaccine approach designed to target antigens directly into the endocytic compartments of dendritic cells (DCs) and other professional APCs. The β subunit of human chorionic gonadotropin (hCGβ) is selectively over-expressed by a number of epithelial tumors and has been reported to correlate with stage of disease and prognosis. We have coupled this tumor-associated antigen to a human monoclonal antibody (B11) that targets mannose receptors on human dendritic cells and macrophages, and have demonstrated the efficacy of this approach in preclinical models using hCGβ-expressing tumors and cell lines. Methods: In this phase I, dose-escalating study, sequential cohorts of 6 patients with relapsed epithelial tumors receive 4 biweekly intradermal injections of CDX-1307 at either 0.3, 1.0 or 2.5 mg, or 2.5 mg concurrent with GM-CSF. Objectives: safety and tolerability; DLT, humoral and cellular immune response, and clinical activity. Results: Enrollment in the first three cohorts (n=18) is complete with no DLTs. Common potential treatment-related toxicities were injection site reaction (n=5) and fatigue/malaise (n=4), and were generally mild to moderate in severity. One transient Grade 3 generalized allergic reaction in the 1.0 mg cohort was suspected possibly related to either a nut allergy or CDX-1307. One mixed response was seen, with variable effects on circulating hCGβ. CDX-1307 localized to dermal macrophages and DCs in post-treatment biopsies. Conclusions: Administration of CDX-1307 is well tolerated and results in antigen localization in APCs of the skin. Immune Response and tumor impact are under evaluation. Further development includes systemic delivery that may provide antigen targeting to a broad APC population, and combination with immunostimulants to generate optimal immune responses. No significant financial relationships to disclose.
A phase II clinical study of dendritoma vaccination combined with low dose interleukin-2 in advanced melanoma patients
Authors: Wei Y. C. , Stephenson J. J. , Li J. , Burgin K. E. , Bouton-Verville H. , Jakubchak S. , Holmes L. M. , Meyer K. , Martin J. , Trocha S. D. , Wagner T. E. 
Published: March 2020

3051 Background: The use of the fusion product of dendritic cells (DC) and tumor cells as a tumor vaccine represents one of the most promising approaches for cancer immunotherapy. We have developed a novel technology that instantly isolates the hybrids (Dendritomas) from the fusion mixture of DCs and tumor cells and thereby maintains tumor cellular diversity. Animal studies demonstrated that Dendritomas are superior activators of tumor cell specific antitumor immunity compared to fusion mixtures; and phase I clinical studies in advanced melanoma and renal cell carcinoma patients demonstrated that Dendritomas can be safely administered to cancer patients and are able to stimulate immunological and clinical responses in some of the patients. Methods: In order to determine the efficacy of Dendritoma vaccines, we designed a small phase II clinical trial in which individualized Dendritomas are manufactured from and injected into 15 stage IV melanoma patients. In order to boost the antitumor immune responses, a low dose interleukin-2 regime was followed only after the first Dendritoma vaccine. The patients received various numbers of vaccines (1 to 6) at six-week intervals. Clinical responses defined as complete response (CR), partial response (PR), stable disease (SD), mixed response (MR), progressive disease (PD), and no evidence of disease (NED) are monitored. The survival of the patients are monitored as well. Results: Twelve weeks after the first vaccine, three patients were NED; four patients were SD; two patients were PD/MR; and six patients were PD. At the time of the submission of this abstract, two patients were still NED and the median survival was 684 days with twelve of the fifteen patients (80%) surviving more than 431 days and eleven of fifteen patients (73%) surviving more than 519 days. Seven out of fifteen patients (47%) are still alive. Conclusions: The data from this small phase II study demonstrated that Dendritoma therapy combined with low dose IL-2 or other adjuvants may represent an effective therapy for melanoma patients and/or other cancer patients. No significant financial relationships to disclose.